A programmable gate array (FPGA) comprises a CPU coupled to a configuration memory array. Bitstream data used for configuring the configuration memory array is encoded to combine programming instructions and configuration data. The CPU receives and decodes the encoded bitstream data, and executes the programming instructions to efficiently load configuration data into the configuration memory array. For instance, configuration data can be temporarily stored in the CPU and reused where data patterns in the configuration memory array repeat. Use of the programmable CPU for loading the configuration memory array reduces the amount of data transmitted to the FPGA during array configuration.

1. Field of the Invention
This invention relates to gate arrays, and more particularly to a field programmable gate array in which programming instructions are carried by the configuration bitstream and executed by a CPU in the logic cell array.
2. Description of the Background Art
Digital logic can be implemented using several options: discrete logic devices, often called small-scale integrated circuits or SSI, programmable devices such as programmable logic arrays (PLAs) or programmable logic devices (PLDs), masked-programmed gate arrays or cell-based application specific integrated circuits (ASICs), and field programmable gate arrays (FPGAs).
FPGAs are general purpose programmable devices that are customized by the end users. FPGAs are composed of an array of configurable logic blocks that are programmably interconnected. The basic device architecture of an FPGA consists of an array of configurable logic blocks (CLBs) embedded in a configurable interconnect structure and surrounded by configurable I/O blocks (IOBs). An IOB allows signals to be driven off-chip or optionally brought into the FPGA. The IOB can typically perform other functions, such as tri-stating outputs and registering incoming or out-going signals. The configurable interconnect structure allows users to implement multi-level logic designs (multi-level refers to logic in which the output signal of one logic unit provides input to another logic unit and the output of that provides input to another, etc.). An FPGA can support tens of thousands of gates of logic operating at system speeds of tens of megahertz. The FPGA is programmed by loading programming data into the memory cells controlling the configurable logic blocks, I/O blocks, and interconnect structure. Further information about FPGAs appears in "The Programmable Logic Data Book", copyright 1994 by Xilinx, Inc. and available from Xilinx, Inc. at 2100 Logic Drive, San Jose, Calif. 95124, which is incorporated herein by reference.
Each configurable logic block in the FPGA can include configuration memory cells for controlling the function performed by that logic block. These configuration memory cells can implement a lookup table, control multiplexers, and control other logic elements such as XOR gates and AND gates. A lookup table stores a truth table which implements that combinational logic function corresponding to the truth table. Each configurable logic block may also be defined to include an adjacent portion of the interconnect structure. The interconnect structure includes programmable interconnect points which control the connection of wiring segments in the programmable interconnect network of the FPGA. Each programmable interconnect point may be a pass transistor controlled by a configuration memory cell. Wire segments on each side of the pass transistor are either connected or not connected depending on whether the transistor is turned on by the corresponding configuration memory cell. The multiplexer is a special-case one-directional routing structure that is controlled by a configuration memory cell. Although the multiplexer can be any width, controlling multiplexers with many inputs will require additional configuration memory cells. Switches that are built using multiplexers require fewer configuration memory cells than the number of multiplexer inputs.
Configuration is the process of loading a bitstream containing the program data into the configuration memory cells which control the configurable logic blocks and I/O blocks of the FPGA. The bitstream is loaded into the FPGA serially to minimize the number of pins required for configuration and to reduce the complexity of the interface to external memory. The bitstream is broken into packets of data called frames. As each frame is received, it is shifted through a frame register until the frame register is filled. The data in the frame register of the FPGA are then loaded in parallel into one row of configuration memory cells forming the memory array. (The configuration memory cells which control a configurable logic block typically occupy a two dimensional section of the array.) The configuration memory cells make up the lookup tables and control the programmable interconnect points, multiplexers, and other programmable elements of a configurable logic block or I/O block. Following the loading of the first frame, subsequent frames of bitstream data are shifted into the FPGA, and another row of configuration memory cells in the array of CLBs is designated to be loaded with a frame of bitstream data.
A limitation on the speed at which configuration of the FPGA occurs is the serial loading of the bitstream into the FPGA. This configuration bitstream bottleneck has become increasingly apparent as the number of configuration bits has increased from thousands to tens and hundreds of thousands of bits over the past several years. This dramatic increase in FPGA size has resulted in a corresponding increase in the time required for configuration and reconfiguration. As the bitstream length increases in the future to millions of bits and beyond, an alternative method of loading bitstream data must be developed. What is needed is a method and system for efficiently loading bitstream data into an FPGA for rapid configuration and reconfiguration of the memory cell array.

Field programmable gate array having programming instructions in the configuration bitstream


The present invention relates to benzoxazepinones of formula I:

This invention relates generally to 5,5-disubstituted-1,5-dihydro-4,1-benzoxazepin-2(3H)-ones which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as assay standards or reagents.
Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.
The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion""s protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell""s genes and those genes are used for virus reproduction.
At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle""s maturing into a virus that is capable of full infectivity.
The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system""s T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system""s effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body""s immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.
There are at least three critical points in the virus""s life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.
Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treading AIDS. This transcription must occur for the virion to reproduce because the virion""s genes are encoded in RNA and the host cell reads only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.
A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT), 2xe2x80x2,3xe2x80x2-dideoxycytidine (ddC), 2xe2x80x2,3xe2x80x2-dideoxythymidinene (d4T), 2xe2x80x2,3xe2x80x2-dideoxyinosine (ddI), and 2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-thia-cytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.
Non-nucleoside HIV reverse transcriptase inhibitors have also been discovered. As an example, it has been found that certain benzoxazinones are useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS. U.S. Pat. No. 5,519,021, the contents of which are hereby incorporated herein by reference, describes reverse transcriptase inhibitors which are benzoxazinones of the formula:
wherein X is a halogen, Z may be O. However, benzoxazinones are not part of the present invention.
U.S. Pat. No. 4,476,133 depicts CNS active 4,1-benzoxazepines of the formula:
wherein A-B can be NHxe2x80x94C(O), R is H or C1-5 alkyl, X is H, halo, or NO2, and Y is phenyl or pyridyl. No mention is made of 5,5-disubstituted-1,5-dihydro-4,1-benzoxazepin-2(3H)-ones which are the subject of the present invention.
EP 0,142,361 illustrates phospholipase A2 inhibitors of the formula:
wherein R1 can be a variety of cyclic and acyclic groups, but not hydrogen, R2 is H, alkyl, or phenyl, and Y1 is H, halo, NO2 or CF3. Compounds of the present invention have a hydrogen at the 1-position and do not have a phenyl group directly attached to the 5-position.
EP 0,567,026 and JP 08/259,447, which have similar disclosures, describe 4,1-benzoxazepinone derivatives of the formula:
wherein ring A may be optionally substituted phenyl (also optionally substituted heteroaryl in JP ""447), R1, R2, and R3 can be a variety of groups including H and optionally substituted hydrocarbon, X is a bond or spacer and Y (B in JP ""447) is optionally substituted carboxyl, hydroxyl, amino, phenyl, carbamoyl, or a nitrogen-containing heterocycle. In JP ""447, B is only optionally substituted phenyl or nitrogen-containing heterocycle. Compounds of this sort are not within the presently claimed invention.
Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a single inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.
Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.
It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I):
wherein A, W, X, Y, Z, Ra, Rb, R1 and R2 are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.
[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I:
xe2x80x83or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A is O or S;
W is N or CR3;
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
provided that if two of W, X, Y, and Z are N, then the remaining are other than N;
Ra is selected from H, CF3, CF2H, cycPr, C1-4 alkyl, C3-5 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, and phenyl substituted with 0-2 R10;
Rb is selected from H, CF3, CF2H, cycPr, C1-4 alkyl, C3-5 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, and phenyl substituted with 0-2 R10;
alternatively, Ra and Rb together form xe2x80x94(CH2)nxe2x80x94;
R1 is selected from CF3, CF2H, C1-4 alkyl, C3-5 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl;
R2 is selected from xe2x80x94Cxe2x89xa1Cxe2x80x94R8, xe2x80x94CHxe2x95x90CR7R8, xe2x80x94(CH2)pCHR7R8, xe2x80x94CHR7Cxe2x89xa1Cxe2x80x94R8, xe2x80x94CHR7CHxe2x95x90CHR8, and CHxe2x95x90CHCHR7R8;
provided that when either of Ra or Rb is phenyl, then R1 is other than C1-4 alkyl and C3-5 cycloalkyl and R2 is other than xe2x80x94(CH2)pCHR7R8;
R3 is selected from H, F, Cl, Br, I, C1-3 alkoxy, and C1-3 alkyl;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7b, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94;
R5 is selected from H, F, Cl, Br, and I;
alternatively, R4 and R5 together form xe2x80x94OCH2Oxe2x80x94 or a fused benzo ring;
R6 is selected from H, OH, C1-3 alkoxy, xe2x80x94CN, F, Cl, Br, I, NO2, CF3, CHO, C1-3 alkyl, and C(O)NH2;
R7, at each occurrence, is selected from H and C1-3 alkyl;
R7a, at each occurrence, is selected from H and C1-3 alkyl;
R7b, at each occurrence, is C1-3 alkyl;
R8, at each occurrence, is selected from H, C1-6 alkyl substituted with 0-3 R11, CH(xe2x80x94OCH2CH2Oxe2x80x94), C2-6 alkenyl, C3-7 cycloalkyl substituted with 0-2 R9, phenyl substituted with 0-2 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R10;
R9, at each occurrence, is selected from D, OH, C1-3 alkoxy, C1-3 alkyl, and F;
R10, at each occurrence, is selected from OH, C1-3 alkyl, C1-3 alkoxy, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3;
R11, at each occurrence, is selected from OR7, CN, F, Cl, Br, I, NO2, NR7R7a, CHO, C(O)CH3, C(O)NH2;
n, at each occurrence, is selected from 1, 2, 3, 4, and 5; and,
p, at each occurrence, is selected from 0, 1, and 2.
[2] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein:
Ra is H;
Rb is selected from H, CF3, CF2H, cyclopropyl, CHxe2x95x90CH2, and C1-4 alkyl;
R1 is selected from CF3, CF2H, C1-3 alkyl, and C3-5 cycloalkyl; and,
R8 is selected from H, C1-6 alkyl substituted with 0-3 R11, CH(xe2x80x94OCH2CH2Oxe2x80x94), C2-6 alkenyl, C3-5 cycloalkyl substituted with 0-1 R9, phenyl substituted with 0-1 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R10.
[3] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:
A is O;
R1 is selected from CF3, CF2H, C2H5, isopropyl, and cyclopropyl;
R3 is selected from H, F, Cl, Br, I, OCH3, and CH3;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, NR7C(O)OR7b, C(O)OR7, S(O)pR7, SO2NHR7, NR7SO2R7b, phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94;
R5 is selected from H and F;
R6 is selected from H, OH, OCH3, xe2x80x94CN, F, CF3, CH3, and C(O)NH2;
R7 is selected from H and CH3;
R7a is selected from H and CH3;
R7b is CH3;
R8 is selected from H, C1-4 alkyl substituted with 0-3 R11, CH(xe2x80x94OCH2CH2Oxe2x80x94), C2-4 alkenyl, C3-5 cycloalkyl substituted with 0-1 R9, phenyl substituted with 0-1 R10, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R10;
R9 is selected from D, OH, OCH3, CH3, and F;
R10 is selected from OH, CH3, OCH3, F, Cl, Br, I, CN, NR7R7a, and C(O)CH3; and,
p is selected from 1 and 2.
[4] In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:
Rb is selected from H, CF3, CF2H, cyclopropyl, CHxe2x95x90CH2, CH3, and CH2CH3;
R1 is selected from CF3, CF2H, and cyclopropyl;
R2 is selected from xe2x80x94Cxe2x89xa1Cxe2x80x94R8 and trans-CHxe2x95x90CR7R8;
R3 is selected from H, F, Cl, Br, and I;
R4 is selected from H, F, Cl, Br, I, C1-3 alkyl substituted with 0-3 R11, CHxe2x95x90CH2, Cxe2x89xa1CH, OCH3, OCF3, xe2x80x94CN, NO2, CHO, C(O)CH3, C(O)CF3, C(O)NH2, C(O)NHCH3, NR7R7a, C(O)OR7, NR7SO2R7b, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, R3 and R4 together form xe2x80x94OCH2Oxe2x80x94; and,
R11 is selected from OH, OCH3, CN, F, Cl, NR7R7a, C(O)CH3, and C(O)NH2.
[5] In a further preferred embodiment, the compound of the present invention is selected from:
5-(1-Butynyl)-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-5-(1-Butynyl)-7-chloro-1,5-dihydro-3-phenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
(+)-(5S)-7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
1,5-Dihydro-7-fluoro-5-isopropylethynyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
1,5-Dihydro-7-fluoro-5-(3-methylbutyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-trans-7-Chloro-1,5-dihydro-5-(2-furan-2-ylethenyl)-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
trans-7-Chloro-1,5-dihydro-5-(2-furan-2-yl)ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-7-Chloro-1,5-dihydro-5-(2-furanyl)ethynyl-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
5-Butyl-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one.;
rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-isopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
7-Chloro-5-phenylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-7-Chloro-5-isopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
7-Chloro-5-isopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
trans-7-Chloro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
7-Methoxy-5-(3-methylbutyl)-1,5-dihydro-S-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
7-Chloro-5-(3-pyridylethynyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
trans-7-Chloro-5-(3-pyrid-3-ylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
trans-7-Fluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
trans-6,7-Difluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-trans-6,7-Difluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
(+)-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
(3S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
(+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
(+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-6,7-Methylenedioxy-5-(2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-6,7-Methylenedioxy-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; and,
rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;
xe2x80x83or a pharmaceutically acceptable salt form thereof.
[6] In another preferred embodiment, the present invention provides a compound of formula II:
xe2x80x83or a stereoisomer or pharmaceutically acceptable salt form thereof.
[7] In another more preferred embodiment, the present invention provides a compound of formula IIa:
xe2x80x83or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein R1 is CF3.
In a second embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.
In a third embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.
In a fourth embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:
(a) a compound of formula I; and,
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
In another preferred embodiment, the reverse transcriptase inhibitor is a nucleoside reverse transcriptase inhibitor.
In another more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, 3TC, rescriptor, ddI, ddC, efavirenz, and d4T and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, and U-103017.
In an even more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, efavirenz, rescriptor, and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, and nelfinavir.
In a still further preferred embodiment, the nucleoside reverse transcriptase inhibitor is AZT.
In another still further preferred embodiment, the protease inhibitor is indinavir.
In a fifth embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:
(a) a compound of formula I; and,
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.
In a sixth embodiment, the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I.
In a seventh embodiment, the present invention to provides a novel a kit or container comprising a compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.
As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9dis intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9carylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 6-membered monocyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be guaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 6-membered monocyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 3 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, xe2x80x9cHIV reverse transcriptase inhibitorxe2x80x9d is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are not limited to, efavirenz (DuPont), rescriptor (delavirdine, Pharmacia and Upjohn), viviradine (Pharmacia and Upjohn U90152S), TIBO derivatives, BI-RG-587, nevirapine, L-697, 661, LY 73497, and Ro 18,893 (Roche).
As used herein, xe2x80x9cHIV protease inhibitorxe2x80x9d is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX-478 (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), DMP450 (DuPont), DMP850 (DuPont), DMP851 (DuPont) and U-103017 (Pharmacia and Upjohn). Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO94/19329, WO94/22840, and PCT Application Number US96/03426 and the protease inhibitors disclosed in WO94/04993,WO95/33464, WO96/28,418, and WO96/28,464.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the present invention, for example formula (I), are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contempleted by the present invention.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Each of the references cited below are hereby incorporated herein by reference.
Scheme 1 illustrates a method of making the oxazepinones of the present invention starting from an appropriately substituted aminoalcohol. The amine is acylated by an xcex1-halo acid halide (preferably an xcex1-bromoacyl bromide) in the presence of a weak base such as pyridine. After acylation, cyclization is effected by further treatment with base. A tertiary amine base such as diisopropylethylamine, sodium hydride, potassium hydride, lithium hydride, sodium carbonate, potassium carbonate or cesium carbonate, sodium or potassium alkoxides or similar bases may be used with cesium carbonate and sodium hydride being preferred. Any non-protic organic solvent may be used for the cyclization reaction with DMF being preferred. In cases where R1 and R2 are different and Ra and Rb are also different, two diastereomers are formed which may be separated by selective crystallization or chromatography. In the case where R1 and R2 are different and either Ra or Rb is H, cyclization with cesium carbonate in the presence of lithium bromide or lithium iodide will often afford a diastereomeric mixture in which one diastereomer greatly predominates. Thus, in some cases these cyclization conditions are greatly preferred. In cases where both Ra and Rb are H, either sodium hydride or cesium carbonate are preferred bases. When an appropriately strong base is used, both acylation and cyclization reactions illustrated in Scheme 1 may be effected in a single step.
Scheme 2 illustrates a second method of making the oxazepinones of the present invention starting from an appropriately substituted N-tritylaminoalcohol. The hydroxy group is alkylated with an xcex1-haloester in the presence of base, and then after removal of the trityl protecting group, treatment with base and/or heat effects cyclization to the oxazepinone. In some cases it may be preferable to use an unprotected amino group. Also, other protecting groups known to those of skill in the art can be used in place of the shown trityl group.
Scheme 3 illustrates a method of making 5,5-disubstituted-benzoxazepin-2-ones starting from an appropriately substituted 2-aminobenzoic acid. In Scheme 3, G can be R3, R4, R5 or R6 or a combination of two or more of these groups. The acid is converted to its N-methoxy-N-methyl amide derivative which can then be displaced to obtain the R1-substituted ketone. Subsequent addition of another metallic species provides the alcohol which is readily cyclized by the 2-step procedure described in Scheme 1.
Scheme 4 describes a means of obtaining 5-trifluoromethyl-benzoxazepin-2-ones starting from an appropriately substituted aniline. After iodination, the trifluoromethyl group can be introduced using a strong base and ethyl trifluoroacetate. The second 5-substituent can then be added through anion attack on the ketone or using other means well known to those of skill in the art. Cyclization can be then be completed as in Scheme 1.
Because certain benzo-substituents are incompatible with the methods of the previous schemes, it may be necessary to protect these groups before forming the benzoxazepinone. In Scheme 5 there is shown a means of obtaining carbonyl-substituted 5,5-disubstituted-benzoxazepin-2-ones. After iodination of an acetyl-aniline, the acetyl group is protected by means well known to those of skill in the art, such as using 1,3-propanedithiol. The same procedures as in Scheme 4 are used to arrive at the cyclized product. Deprotection of the ketone can then be achieved using HgCl2 and HgO or other means well known to those of skill in the art.
A method for forming 5,5-disubstituted-benzoxazepin-2-ones, wherein R2 is a vinyl or alkynyl group, is described in Scheme 6. Starting from an appropriately substituted ketone which can be obtained using the procedure of Scheme 3 or 4, an acetylide is added. The product can be deprotected and cyclized in two steps (Scheme 1) to obtain the alkynyl-substituted material. Alternatively, the vinyl compounds can be obtained by reduction of the alkyne with a reducing agent, such as LiAlH4, deprotection by standard means, and 2-step cyclization.
The acetylide which is required for the reactions illustrated in Scheme 6 may be generated directly from a terminal acetylene by treatment with a strong base such as n-butyllithium. An alternate method for generating an acetylide, illustrated in Scheme 6A, is by converting an aldehyde to a 1,1-dibromoolefin which is then reacted with 2 equivalents of n-butyllithium.
Scheme 7 describes an alternate route to 5,5-disubstituted-benzoxazepin-2-ones from anilines, wherein the aniline is protected, ester addition is accomplished using a strong base and the amine protecting group is removed. The R2 group can then be added, e.g. via an acetylide, followed by cyclization as in Scheme 1.
An intermediate useful in the preparation of the presently claimed compounds is 2-trifluoroacetylaniline. The starting 4-chloro-2-trifluoroacetylaniline can be made as shown in Scheme 4. Reduction and reoxidation removes the chloro group leaving the desired intermediate.
Scheme 9 describes a novel method of making 2-trifluoroacetylanilines as well as how these compounds can be further modified to make the presently claimed compounds. The protected aldehyde can be made from the N-methoxy-N-methyl amide of Scheme 3, by addition of a protecting group, preferably trityl, and reduction of the amide to the aldehyde. Other protecting groups known to those of skill in the art can be used in place of the shown trityl group.
Scheme 10 illustrates specific steps of Scheme 9. Intermediate IIIb (R1a is selected from CF3, CF3CF2, and CF3CF2CF2) is useful for making some of the presently claimed compounds. Pg is an amine protecting group as defined previously, preferably trityl (triphenylmethyl). The protected or unprotected aminobenzaldehyde, preferably protected, is treated with a perfluoralkyl trimethylsilane, preferably trifluoromethyl trimethylsilane, followed by fluoride anion, preferably tetrabutylammonium fluoride. In the same fashion, CF3CF2TMS, CF3CF2CF2TMS can also be used to prepare the appropriately substituted ketones. Other sources of fluoride anion such as sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride as well as oxyanionic species such as potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate can also be used. Aprotic solvents such as DMF and THF can be used, preferably THF. The amount of perfluoralkyl trimethylsilane used can be from about 1 to about 3 equivalents with an equivalent amount of fluoride anion or oxyanionic species. The reaction can be typically carried out at temperatures between about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably about xe2x88x9210 to about 10xc2x0 C., more preferably about 0xc2x0 C.
Conversion of IIIb to IIIc can be achieved by using an oxidizing agent well known to one of skill in the art such as MnO2, PDC, PCC, K2Cr2O7, CrO3, KMnO4, BaMnO4, Pb(OAc)4, and RuO4. A preferred oxidant is MnO2. Such conversion can be performed in an aprotic solvent like THF, DMF, dichloromethane, dichloroethane, or tetrachloroethane, preferably dichloromethane.
An additional means of making 5-alkynyl-benzoxazepin-2-ones is shown in Scheme 11. The alkyne group is added to the keto-aniline via a Grignard type addition, followed by cyclization. The alkyne group of the product can then be modified to obtain the desired compound.
In addition to the methods of obtaining keto-anilines described in Schemes 3 and 4, nucleophilic opening of isatoic anhydrides can also be used as shown in Scheme 12. This reaction is accomplished by using an anionic nucleophile of the group R1a. See Mack et al, J. Heterocyclic Chem. 1987, 24, 1733-1739; Coppola et al, J. Org. Chem. 1976, 41(6), 825-831; Takimoto et al, Fukuoka Univ. Sci. Reports 1985, 15(1), 37-38; Kadin et al, Synthesis 1977, 500-501; Staiger et al, J. Org. Chem. 1959, 24, 1214-1219.
It is preferred that the stoichiometry of the isatoic anhydride reagent to nucleophile is about 1.0 to 2.1 molar equivalents. The use of 1.0 eq. or more (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0) of anion (or anion precursor) is preferred to force the conversion and improve the isolated yield. Preferably, the temperature used is from xe2x88x9220 to +35xc2x0 C., with temperatures below 0xc2x0 C. being more preferred and xe2x88x9220xc2x0 C. being even more preferred. Reactions are run to about completion with time dependent upon inter alia nucleophile, solvent, and temperature. Preferably this nucleophilic addition is run in THF, but any aprotic solvent would be suitable. Reaction with the active nucleophilic anion is the only criterion for exclusion of a solvent.
Scheme 13 illustrates the synthesis of a 3,3-disubstituted oxazepinone from a monosubstituted oxazepinone. After first protecting the ring nitrogen with one of several amide protecting groups known to those skilled in the art, treatment with a strong base followed by an alkyl iodide gives after protecting group removal, a 3,3-disubstituted oxazepinone. Using the same sequence of reactions, a 3-monosubstituted oxazepinone (Ra above is H) can also be synthesized from a 3-unsubstituted oxazepinone.
Compounds of the present invention that are thioamides can be prepared as illustrated in Scheme 14 by treating the corresponding amides with either Lawesson""s reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] or phosphorous pentasulfide.
Compounds of the present invention in which Ra or Rb are vinyl or cyclopropyl can be prepared as illustrated in Scheme 15. 2-Aminoarylketones protected, for example, with an N-p-methoxybenzyl (PMB) group can be treated with an acetylide to give the corresponding acetylenic alcohol. Cyclization can be effected by 2,4-dibromobutyryl chloride and the PMB group can then be removed, for example, by treatment with ceric am monium nitrate. Displacement of the bromide with an arylselenide followed by oxidative elimination by treatment with hydrogen peroxide affords the 5-alkynyl-3-vinylbenzoxazepinone. The vinyl group can be converted to a cyclopropane ring by Pd(II) catalyzed reaction with diazomethane. If the acetylenic alcohol is reduced to the olefin with lithium aluminum hydride (LAH), the same reaction sequence can be used to prepare the trans-5-alkenyl-3-vinylbenzoxazepinone and the corresponding trans-5-alkenyl-3-cyclopropylbenzoxazepinone.
One isomer of a compound of Formula I may display superior activity compared with the other. Thus, all four of the following stereochemistries are considered to be a part of the present invention.
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tet. Lett. 1995, 36, 8937-8940. In addition, separation may be achieved by selective cystallization, optionally in the presence of a chiral acid or base thereby forming a chiral salt. other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

5, 5-disubstituted-1, 5-dihydro-4, 1-benzoxazepin-2 (3H)-ones useful as HIV reverse transcriptase inhibitors

Abstract: or stereoisomeric forms or mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same and methods of using the same for treating viral infection or as an assay standard or reagent.


The invention is characterized in: forming a magnetic field inside a flow channel tube, the tube wall of which is formed from a material that is nonmagnetic and which, when the pressure outside the flow channel tube is lower than the pressure inside the flow channel tube, passes a portion of the air flowing inside the tube through the tube wall and discharges same to the outside thereof; supplying air to the flow channel tube so that at least a region of laminar flow is formed inside the flow channel tube; and reducing the pressure outside the flow channel tube to a prescribed pressure.

To realize a low carbon society and to secure energy, efficient use of fossil fuels such as coal and oil is effective. For example, when burning coal in an iron-making blast furnace and a coal-fired power generation, which are comparatively large emission sources of CO2, oxygen (pure oxygen) or air (oxygen-enriched air), the oxygen concentration of which is increased compared to that of the atmosphere (air) as is, is blown instead of the atmosphere. This allows coal to be subjected to high-calorie burning and, as a result, thermal efficiency is increased.
Patent Literature 1 describes a cryogenic separation method as a method of producing pure, oxygen used for high-calorie burning of fossil fuel as described above. In this method, after air has been cooled and liquefied, oxygen is fractionated from the air by utilizing the difference in boiling point between oxygen and nitrogen.
Among practically used methods of producing oxygen or oxygen-enriched air, the above-described cryogenic separation method can produce oxygen or the like at a lowest cost. However, nowadays, there is a demand for further reducing the cost of oxygen or oxygen-enriched air.
However, with the above-described cryogenic separation method, since air is cooled to a cryogenic temperature and liquefied, a theoretical limit of Carnot refrigerator efficiency cannot be exceeded in principle. Specifically, the theoretical value of energy efficiency in the cryogenic separation method is low: equal to or less than 34%. With the cryogenic separation method, energy efficiency equal to or higher than the above-described value cannot be obtained.
Thus, it is very difficult to produce oxygen or oxygen-enriched air so as to further reduce the unit cost of production.
Patent Literature 2 describes a device that produces oxygen-enriched air from room-temperature air (about 300 K).
This device removes part of nitrogen from air so as to produce oxygen-enriched air by utilizing the fact that, among the components of air, only oxygen is paramagnetic and other components are non-magnetic.
Specifically, as illustrated in FIG. 14, this device includes a cylindrical container 102 and a pair of magnets 104. Air flows in the container 102, which is formed of a non-magnetic material. The pair of magnets 104 form a magnetic field in the container 102 in a direction perpendicular to the air flow direction. The air flowing in the container 102 is supplied from one end portion 102a of the container 102. Two separator plates 106 are disposed at another end portion 102b of the container 102. These two separator plates 106 have leading ends in the magnetic field formed by the pair of magnets 104 and are disposed in a position perpendicular to the magnetic field and parallel to each other. Thus, two separator plates 106 divide a region on the other end side in the container 102 into three sections in a direction perpendicular to the magnetic field. A first passage tube 110 is connected to an outlet 108b. In the container 102, the outlet 108b is open at the end of a central channel 108 interposed between two separator plates 106. Second passage tubes 114 are connected to respective outlets 112b. In the container 102, the outlets 112b are open at the ends of respective side channels 112 positioned on both sides of the central channel 108 with the central channel 108 interposed therebetween.
In a device 100 having the above-described structure, air supplied from the one end portion 102a flows toward the other end portion 102b in the container 102. When the air enters the magnetic field formed by the pair of magnets 104, only oxygen in the air is magnetized. Thus, components of the air other than oxygen straightly advances toward the other end portion 102b in the container 102 without being affected by the magnetic field. In contrast, the magnetized oxygen advances in a path bent by the magnetic field formed by the pair of magnets 104. Referring to FIG. 14, the magnetized oxygen is bent rightward or leftward and enters the side channels 112. Thus, air containing an increased amount of oxygen (oxygen-enriched air) is exhausted to the second passage tubes 114. By collecting the exhausted air, a specified amount of oxygen-enriched air is obtained.
Production of oxygen-enriched air from room-temperature air (300 K) is simulated by using the above-described device 100 that utilizes the magnetic field. The difference in oxygen concentration between room-temperature air and the oxygen-enriched air produced from this room-temperature air is about 0.1%. Furthermore, in the above-described device 100, a very high magnetic field gradient of, for example, 100 T/m, needs to be formed in the air flow direction in the container 102. Thus, producing this device for actual and practical use is very difficult.

Oxygen-enriched air producing device and oxygen-enriched air producing method


The present invention provides a dual frequency addressable smectic A liquid crystal composition having a crossover frequency, wherein the smectic A phase is induced by mixing of at least a first nematic liquid crystal compound or composition and a second nematic liquid crystal compound or composition.

1. Technical Field
The present invention relates to a liquid crystal composition, a liquid crystal element, a reflective display material, and a light-controlling material, and in particular, to a liquid crystal composition, a liquid crystal element, a reflective display material, and a light-controlling material that are favorably used in guest-host systems.
2. Related Art
Properties demanded for display include high visibility and low power consumption. Display devices in a guest-host system have been known as liquid crystal elements (liquid crystal display elements) satisfying these requirements and are highly anticipated as display devices that allow bright display and are suitable for reflective display. For example, liquid crystal compositions containing a dichroic dye having a particular substituent and a host liquid crystal and display devices in the guest-host system have been disclosed (see, for example, Japanese Patent Application Laid-Open (JP-A) No. 2004-75,821).
However, nematic liquid crystals, which have no memory property, require application of voltage for continuous display. In contrast, a method of using a nonvolatile smectic A liquid crystal having a memory property has been proposed, but this liquid crystal also has a problem in that a large amount of energy, such as heat, is needed for changing a displayed image.
Alternatively, "dual-frequency-addressing methods" are known, in which the orientation of liquid crystal is reversibly changed by an applied electric field by using a dual-frequency-addressable liquid crystal that has a dielectric anisotropy Δ∈ changing from positive to negative when the frequency of the applied voltage is increased (see, for example, Applied Physics Letters, Vol. 25, No. 4, pp. 186 to 188 (1974) and Applied Physics Letters, Vol. 41, No. 8, pp. 697 to 699 (1982)). Some smectic A liquid crystals which enable switching of the orientation of liquid crystal actively and exhibit dual frequency addressing have been reported (see, for example, Mol. Cryst. Liq. Cryst., 49, pp. 83-87 (1978)). However, such a system still has problems of very large voltage being required and slow response time. Accordingly, there exists a demand for a nonvolatile liquid crystal element that responds at low voltage in a short period of time.
Along with increased concern about the environment, materials allowing regulation of light quantity electrically, so-called electrical light-controlling materials, are increasing in importance. For example, electrochromic methods of using an oxidation-reduction reaction and polymer-dispersion liquid crystal (PDLC) methods of using a composite of a liquid crystal and a polymer have been proposed as such electrical light-controlling materials. However, the electrochromic systems have problems concerning the difficulty in increasing the area these of due to addressing with electrical current and remaining issues regarding the durability of the electrochromic colorant, while the PDLC systems are limited in application due to only being able to switch between a scattered white state and a transparent state and at times have a high voltage, and thus both systems still have problems to be overcome.
Light-controlling materials utilizing the guest-host system allow regulation of bright light and are thus attracting attention as a system suited for light-controlling applications. However, since the materials proposed so far (see, for example, JP-A No. 2000-347,224) required high voltage for addressing and do not have a memory property, they consume a large amount of power and still do not have a light-controlling property of a satisfactory level in some cases, and thus further improvement is demanded.

This patent is subject to a terminal disclaimer.

Liquid crystal composition, liquid crystal element, reflective display material, and light-controlling material


An electrical quick-thawing apparatus for quickly thawing frozen liquids includes a transmission plate and a clamping and heating device for receiving a container containing a frozen liquid. The clamping and heating device has a heating unit with at least one heating surface and at least one temperature sensor sensing a temperature at the outer wall of the container. An electrical control device including a temperature governor with a control circuit, a set point adjuster, and a switching device controlling heating unit is provided. The output terminal of the temperature sensor is connected to an input terminal of the control circuit. The output terminal of the set point adjuster is connected to an input terminal of the control circuit. The output terminal of the control circuit is connected to the switching device. The switching device controls the heating unit according to signals received from the temperature sensor and the set point adjuster. A highly dynamic linear drive is coupled to the transmission plate and moves transmission plate in a plane. The heating unit is coupled to the transmission plate. The linear drive is embodied as an electromagnetic transducer transforming electrical oscillations into mechanical oscillations at a frequency of 20 to 300 Hz. The electromagnetic transducer has diaphragm moveable in a plane. An oscillation transmission device couples the diaphragm to the transmission plate by a force-locking connection and/or a positive-locking connection.

The invention relates to an electrical quick-thawing apparatus for quickly thawing frozen liquids, for example injection or infusion solutions, comprising a transmission plate and a clamping and heating device for receiving a container containing the frozen liquid, especially a syringe or ampule, which clamping and heating device includes an electrical heating unit with at least one heating surface and at least one temperature sensor measuring the temperature at the outer wall of the container. Also included is an electrical control device with a temperature governor whereby the temperature sensor with its output terminal is connected to the temperature governor and with a control circuit which is connected with an outlet terminal to a switching device for controlling the heating unit and controls it depending on signals of the temperature sensor connected to the input terminal of the control circuit and the signals of a set point adjuster.
In clinical practice it is common to administer pharmaceutical products which are supplied by the pharmaceutical industry in standard concentrations and standard volumes and are diluted with carrier solutions to a patient-specific concentration for administration. Since these individually prepared preparations are often used in long-term therapies, the patient-specific active mixture is produced in a respectively large total volume. The individual portions that are to be administered in each session therefore must be filled into syringes or other containers and subsequently frozen.
Only in this manner is it possible to preserve the generally thermally instable active substances over the required time period.
One problem of this accepted and widely used conventional preservation method is that the individual samples require a relatively long thawing time. This is very cumbersome especially when the exact point of time of administration of the ampule volume cannot be exactly predetermined. Even though for the individual patient a time schedule for administering the substance volume is available conventional to first take a blood sample of the patient in order to determine according to the analysis results whether and when the next substance volume is to be administered. This approach thus often results in schedule changes and also in the loss of the already thawed active substance.
In order to avoid this time and cost problem, there is the urgent need to provide a quick-thawing apparatus and a method which allows to thaw the active substance volume quickly.
The prior art discloses microwave thawing devices for frozen liquids which are heated by microwaves of frequencies between 2,425 and 2,475 GHZ. However, these devices have the disadvantage that certain areas of the frozen liquid, due to focusing of the radiation, are overheated so that a uniform heating of the frozen liquid does not take place. The heating of the frozen liquid only in certain areas can result in damage to the ingredients or active substances of the liquid so that chemical modification of the ingredients or the active substances must be assumed. It is apparent that the thawing of infusion solutions or injection solutions in syringes or ampules with conventional microwave thawing devices must be avoided because a chemical modification of the medication as well as denaturation of vaccinations, proteins or serum within the infusion or injection solutions cannot be reliably prevented.
Furthermore, it should be noted that because of the damage of the medically active ingredients of the injection and infusion solutions their medical and therapeutic activity decreases with increasing thawing time. Furthermore, it has been shown that the resulting decrease of medical activity requires a higher dosage and thus a higher concentration of the medically active ingredients in the infusion and injection solutions so that more material must be used, thereby increasing substance use and costs.
Furthermore, the health-detrimental effect of the prior art methods for quickly thawing, such as methods employing microwaves, resulting in hot spot formation, or the use of hot flowing water etc., which may cause modified active substances or contamination with illness-causing microorganisms must be mentioned, whereby their disadvantageous long term effects have been elucidated only partially, but certainly considerable stress on the organism during the decay phase within the patient's body will result.
Also, it has been shown that the use of turntables in microwave thawing devices cannot ensure uniform heating of the frozen injection solutions especially in elongate containers, such as syringes or ampules used widely in the medical field, because, despite the rotation of the turntable causing the container to leave the focusing area, a local overheating of the frozen liquid can be so great that the aforementioned damages of the medication contained in the infusion and injection solutions will occur, i.e., no low-impact thawing will be performed.
Furthermore, the conventional thawing of frozen injection solutions contained in syringes by holding the syringes under hot flowing water, may result in contamination of the liquid by microorganisms which may be forced or introduced by the water jet from the exterior into the gap between the syringe plunger and the syringe body.
The prior art methods for thawing, for example, by heating the active substance volume by using microwave devices, subjecting the syringes to flowing hot water, should therefore be avoided for reasons of thermal instability of the active substances to be administered as well as the lack of required sterile handling of the medium. For these reasons, it is advisable to thaw the ampule at room temperature until thawed resulting however in the great disadvantage of a long thawing time and a need for greater concentration of the active material in the medium because of the expected decomposition of the heat-sensitive active substance.
Moreover, the degree of decomposition of the heat-sensitive active substance can only be estimated and is not exact because the thawing time depends on the actual room temperature which subject to fluctuations so that higher or lower active substance amounts than expected may be administered, a situation which can result in stress to the patient.
Another possibility, e.g., manually heating syringes by one's palm cannot prevent contamination by microorganisms. Furthermore, thawing by hand takes a long time whereby only injection solutions of a volume of 1 ml to 2 ml can be thawed within 5 minutes. However, in hospitals during daily routine work, in emergency rooms or at accidents on site, it is urgently needed and life saving to be able to quickly thaw infusion and injection solutions which are supplied, ready to be administered, in freezers.
Especially manual thawing by the user, which is suitable for only minimal liquid volumes, results in greater time expenditure because the user cannot perform at the same time other activities in hospitals, intensive care units, emergency situations etc., and this results in higher personnel costs.
Since manual thawing of larger amounts of injection solutions to be administered regularly hospitals is very time consuming, especially since the heat capacity of the palm of the user is minimal and the exchange or mixing of cold and warm liquids is time consuming, the conventional methods for thawing as used in hospitals, intensive care units, and emergency rooms are unsuitable and should not be used especially in view of the lack of sterile handling.
It is an object of the present invention to eliminate the aforementioned disadvantages of the prior art. Furthermore, it is desirable to provide a quick thawing apparatus which shortens the thawing time by a multiple and at the same time ensures a careful and sterile treatment of the active substances. Furthermore, it should be possible to provide the quick-thawing apparatus with a simple mechanicdevice in ordertoensure high transportation safety and also minimal maintenance. Also, the quick-thawing apparatus should be embodied such that a quick and sufficient cleaning and sterilization of its components is possible in order to avoid spreading of infection diseases in hospitals.


An apparatus and method for utilizing NIR spectrography for measuring major constituents of substances in real time includes a monochromator or other sensor having no moving optical parts. At least one of the monochromator and the substance are moving relative to one another. An NIR radiation source irradiates a substance and the reflected or passed-through radiation is transmitted to the monochromator, which isolates and detects narrow portions of the received spectrum. By analyzing the intensities and wavelengths of the received radiation, the presence and amount of major constituents of the substance can be determined.

1. Field of the Invention
The present invention relates to methods and apparatus for measuring constituents of substances and products. More particularly, though not exclusively, the present invention relates to a method and apparatus using near infrared spectrometry for real time product analysis.
2. Problems in the Art
In the field of agriculture, it is important to analyze agricultural products such as grain or forage to determine the amount of major constituents in the products. This is particularly important in breeding programs.
One prior art method of analyzing grain and other agricultural products is using near infrared spectroscopy (NIR). NIR is a well-established technique for detecting both chemical and physical properties of various materials. NIR provides an accurate and inexpensive method to analyze agricultural materials such as grain or forage. Major constituents that can be detected by using NIR include moisture, protein, oil, starch, amino acids, extractable starch, density, test weight, digestibility, cell wall content, and any other constituents or properties that are of commercial value.
There are various types of devices used for NIR. In general, these devices include light sensors in conjunction with light sources, which are used with any number of measuring devices. In optical spectrometers, the incident light from a light source is passed through a monochromator, which can be a filter or set of filters, a diffraction grating, or a prism whose angular displacement relative to the incoming light can be closely correlated with the single wavelength, or narrow band of wavelengths (which it sends on to the light sensor). The light sensor is selected so that its spectral responses match the wavelength of interest. The angular motion of the prism or diffraction grating can be mechanized so that a given spectrum is scanned at a known rate over a known time interval. Such a device is referred to as a scanning spectrometer. The wavelength of an observed peak can then be determined from the time counted from the start of a scan. Spectrometers may also be referred to as spectrophotometers when their spectral range extends between ultraviolet to infrared.
The constituent content of a grain sample, for example, is measured most accurately by prior art systems by drying and grinding the sample of the grain to particulate form. The ground sample is then irradiated with near infrared light. The reflected radiation is detected at narrow band wavelengths in the NIR spectrum to obtain raw reflectance data of the sample. The data can be used to provide accurate measurements of the content of constituents of the grain samples. In many prior art systems, it is difficult to obtain accurate measurements of the grain constituents without first drying and grinding the grain into particulate form.
Other prior art systems use scanning or oscillating spectrophotometric instruments. In such an instrument, a photo detector detects light energy, which is scanned through a spectrum at a rapid rate. Such an instrument employs an optical grating, which receives light through an entrance slit and disperses the light into a spectrum directed toward an exit slit. The optical grating is oscillated in order to rapidly scan the light transmitted through the exist slit through the spectrum dispersed by the grating. Another prior art instrument uses filters, which are tilted as they pass through a light beam to scan the transmitted light through a spectrum. Either type of instrument, the oscillating optical grating or the tilt filter type can be operated over a spectrum covering near infrared to analyze agricultural products such as grain. Using an oscillating grating or tilting filter type of instrument, the user can measure the reflectivity of the sample at narrow wavelength increments to determine the constituent contents of a grain sample. To use an oscillating grating or tilting filter instrument, the narrow bandwidth light is transmitted through the exit slit used to illuminate the grain sample. The light reflected from the sample is detected by photo detectors and the resulting photo detector signal is used to determine the constituent contents of the sample. As the grating oscillates, the center frequency of the light that irradiates the sample is swept through the NIR spectrum. Light from the diffraction grating that is reflected by the sample is detected by the photo detector. As an alternative to detecting the energy reflected from the sample, the energy may be transmitted through the sample and detected after being transmitted through the sample. In addition, instead of irradiating the sample with the output from the spectrophotometer, the sample can be irradiated with constant wide-band light and a reflected light being applied to the spectrophotometer.
If a grain sample is not ground, the light absorbency and reflectance varies considerably from sample to sample. This variation is caused by light scatter from the whole grain kernels and by the nonlinear surface reflectance effects. This variation makes it difficult to obtain accurate measurements from whole grain samples. Similar problems are encountered with forage samples, especially corn forage, but even more pronounced.
The spectrometers discussed require frequent calibration in order to generate accurate results. The calibrations must be performed frequently due to various dynamic factors including the change in light from a light source due to temperature sources. A typical method of calibrating (to correct for instrument response variation by baseline correction) a spectrometer is to replace the sample with a standard sample, for example, a white ceramic tile having high reflectance. The spectrometer scans the standard sample to provide standard values, which are used to calibrate the spectrometer. While this calibration method works fine in a lab environment, it could be impossible, or at least impractical in the environment of an agricultural implement such as a combine or a chopper.
The spectrometers discussed above have several disadvantages. The spectrometers discussed are only suitable for use in a laboratory. Prior art methods of grain analysis have a major disadvantage resulting from the large amount of sample handling. The samples must be harvested, collected, bagged, labeled, dried, and finally sent to the NIR lab, ground and analyzed for constituent analysis. This excessive sample handling adds both cost and time to the analysis. A need can therefore be seen for an NIR instrument combined with an implement such as a combine or chopper to automate the process of collecting an analyzing grain and forage samples. Such a system would reduce the cost and time of the analysis. Such a system could provide plant breeders and grain farmers with real time information and also enhance product development through high plot screening numbers, which would help develop products more rapidly.
The main problem with an NIR instrument combined with a machine such as a combine or chopper is that prior art grain or forage analysis instrumentation is very sensitive to mechanical vibrations. Scanning and oscillating spectrometers require very precise mechanical movements in order to obtain accurate results. The extreme vibrations found in the environment of a combine or chopper would result in damaged and inaccurate instrumentation equipment. In addition to the vibration, the combine or chopper environment is very dirty. The amount of dust and plant debris would severely effect the effectiveness of a conventional spectrometer.
Another problem with combining NIR instrumentation with an implement is that current NIR equipment requires a long time period for analysis. In the field of crop breeding programs, a large number of test plots are used to test products. A typical test plot of hybrid corn, for example, is comprised of two rows of corn with a length of 17 ft. A research combine used to harvest the test plots goes through each test plot in approximately 15 seconds. A typical spectrometer used in a lab to analyze grain requires more time than 30-90 seconds to analyze the grain or forage sample. Therefore, even if conventional NIR instrumentation is installed on an implement, the speed of harvesting test plots would be slowed down considerably by the slow speed of the NIR instrumentation.
A need can therefore be seen for NIR equipment in combination with an implement such as a combine or chopper which could operate effectively in the environment of a combine or chopper which also is capable of analyzing product samples in a short period of time.
Similar problems exist for other applications and functions where it would be beneficial to be able to analyze constituents of substances in non-laboratory settings. For example, it would be beneficial to be able to non-destructively, in essentially real time, determine constituents of substances when either the measurement equipment or the substance are moving relative to one another, or even when both are moving. An example is pre-harvested agricultural products. The sugar content of grapes growing on the grape vine could be measured by moving equipment by the vines on a vehicle. Another example is nutraceuticals. Nutraceuticals are plants that internally induce the production of pharmaceutically active components. It would valuable to be able to quickly and non-destructively evaluate such production by moving measurement equipment past the growing plants.
Another example relates to harvested agricultural products. Non-destructive, real time measurement of constituents during harvesting, during movement through a harvester machine, during handling such as unloading to a transport vehicle, during storage, during transport to another location, or even during further processing would advantageous.
Whether measurement occurs pre-harvest or post-harvest, benefits could be obtained for such things as hybrid development or breeding programs. Results could be stored and analyzed and compared.
In most of the above examples, the measurements would be taken in environments that would include physical forces such as vibration or potentially damaging or disruptive materials such as dust and debris. Such non-laboratory conditions are particularly problematic because environmental conditions can change quickly and repeatedly.
Other examples exist. Soil analysis in real time without taking soil samples would be beneficial. Therefore, there is room for improvement in the art.
A general feature of the present invention is the provision of a method and apparatus for measuring constituents of products in real time, which overcomes problems, found in the prior art.
A further feature of the present invention is the provision of a method and apparatus for measuring constituents of products which uses a monochromator which is robust, an example being a stationary grating with a photodiode array with a detector which has no moving optical parts and thus is more resilient to mechanical vibrations.
A further feature of the present invention is the provision of a method and apparatus for measuring constituents of products, which is capable of measuring the constituents in a short time period or is essentially real time.
Further features and advantages of the present invention include:
An apparatus and method of measuring the constituents of products which analyzes the products while the products are flowing or moving or while the measuring apparatus or steps are moving relative to the products, or both are moving.
An apparatus and method of measuring the constituents of products in which the monochromator is optically communicated to the product by a fiber optic connection.
An apparatus and method of measuring the constituents of products using the reflectance of radiation from the agricultural product or radiation after passing through the product.
An apparatus and method of measuring the constituents of products which measures the constituents in real time and stores the measurements for later use.
An apparatus and method of measuring the constituents of products which can be automatically calibrated.
An apparatus and method of measuring the constituents of products which senses the reflectance of the sample in more than one position in order to obtain higher accuracy.
An apparatus and method of measuring the constituents of products which can be used in non-laboratory settings including where environmental conditions can result in the measuring experiencing physical forces or dust and debris.
An apparatus and method of measuring the constituents of products which can be used in non-laboratory settings including where environmental conditions can change over time.
An apparatus and method of measuring the constituents of products which is highly flexible and applicable to a variety of substances and uses.
An apparatus and method of measuring the constituents of products which is durable.
An apparatus and method of measuring the constituents of products which is non-destructive of the substance to be measured. These as well as other features and advantages of the present invention will become apparent from the following specification and claims.
The present invention relates to a method and apparatus for measuring constituents of substances or products. The invention uses near infrared spectroscopy. A radiation source is used to irradiate a product while reflected or passed-through radiation is collected and measured with a sensor located within, near, or adjacent to the substance. A spectral separator or a monochromator, for example a diffraction grating or its equivalent which spreads the infrared light over a desired wavelength band, isolates narrow portions of the spectrum of received radiation. A detector analyzes the intensities of the radiation at various isolated portions of the spectrum. From this information, the major constituents of the substance or product can be determined. The measurement apparatus or steps can be in motion relative to the substance being measured or vice versa, or both can be moving.

Near infrared spectrometry for real time analysis of substances