An inverter circuit includes plural pairs of third coils, in which adjacent third coils are serially connected to each other so as to offset AC voltage generated from the paired third coils, one end of the paired third coils being connected to ground. Input terminals of plural diodes are connected to one end of the paired third coils so as to generate the voltage detection value by detecting voltage generated from the paired third coils. A fault detector compares the voltage detection value generated from the diodes with a predetermined threshold value to detect a fault and generates the comparison result.

1. Field of Invention
The present invention relates to liquid crystal displays and, more particularly, to a backlight assembly having an inverter for powering a plurality of discharge tubes, such as cold cathode fluorescent lamps, as a light source for the display.
2. Description of the Related Art
Conventional liquid crystal displays (LCDs) are made to be light-weight, compact and have low power consumption. Since the LCD is a non-emissive device, a light source such as cold cathode fluorescent lamp is used. The cold cathode fluorescent lamp is a kind of a fluorescent lamp that operates in the regular glow discharge region using an applied AC voltage. Since the cold cathode fluorescent lamp is not preheated by a filament, it is relatively more vibration resistant, has a thinner diameter and a longer life span compared to a hot cathode fluorescent lamp but requires a higher voltage to be applied, for which an inverter circuit is used.
As shown in FIG. 18, the conventional inverter circuit includes first and second inverters 11 and 12, a plurality of balance transformers 13, and a plurality of diodes 14.
Primary coils 13a of the balance transformers 13 are connected to output terminals of the first and second inverters 11 and 12. The first and second inverters 11 and 12 convert DC voltage into AC voltage and supply the AC voltage to two pairs of cold cathode fluorescent lamps 20 through the primary coils 13a of the balance transformers 13.
Among the secondary coils 13b of the balance transformers 13, adjacent secondary coils 13b are serially connected to each other to form a secondary coil serial loop, one end of the secondary coil serial loop being connected to the ground GND.
First ends of third coils 13c of the balance transformers 13 are connected to the ground GND through the secondary coil serial loop and second ends of the third coils 13c of the balance transformers 13 are connected to input terminals of the diodes 14.
Input terminals of the diodes 14 are connected to the first ends of the third coils 13c. The diodes 14 detect voltage generated from the third coils 13c and then generate voltage detection values.
Japanese Patent Unexamined Publication No. 2005-267923 discloses an error detection circuit employed in a discharge tube control circuit that controls the turn on/off of the first and second discharge tubes. An error signal generating device generates an error signal when the current balance of the first and second discharge tubes is different from the reference current balance.
However, as shown in FIG. 19, since the cold cathode fluorescent lamps are aligned between a diffusion plate and a reflective plate, when the cold cathode fluorescent lamps are turned on, heat is transferred upward by convection along the cold cathode fluorescent lamps causing the internal temperature of the backlight assembly to rise and lowering the lamps' impedance. FIG. 20 shows that, as the cold cathode fluorescent lamps generate heat, an impedance gradient occurs in the backlight assembly caused by the temperature gradient.
The conventional inverter circuit includes a circuit that detects voltage at the diodes connected to the third coils when the impedance changes due to the temperature gradient. The voltage value due to the impedance change must be taken into consideration when setting the threshold value used to detect the normal operation and abnormal operation. As a result, the conventional inverter circuit has a higher threshold value because of the increase of the voltage value caused by the impedance change according to the temperature gradient. For this reason, when the voltage is slightly increased due to arc discharge caused by an opening fault, the voltage level may not reach the threshold value, so that the voltage variation with temperature cannot be precisely detected.

Inverter circuit and backlight assembly having the same


Discussed is an apparatus for transmitting an encoded video stream, comprising: a slice generating unit that divides a frame, comprised in a video stream, into at least one or more slice; and a transmitting unit transmitting the slice in units of a packet within a slice deadline, which is a time limit required for transmission of the slice, the transmitting unit that preferentially transmits a header packet that contain a slice header information over other packets, and the slice header that comprises of information necessary for reconstructing the slice, wherein the transmitting unit comprises: a packet transmitter that retransmits the packet when the packet fails to be transmitted within the predetermined retry limit; and a header protector performing control for the header packet to be repeatedly transmitted within the slice deadline even when number of retransmissions of the header packet exceeds the predetermined retry limit.

1. Field of the Invention
The present invention relates to an apparatus for transmitting encoded video stream and a method for transmitting the same.
2. Discussion of the Related Art
Playback of digital video is realized by displaying a sequence of still images or frames at a constant rate, which is in units of frames per second (fps). For smooth video playback, frames must satisfy strict playout deadlines. Therefore, all network and playback delays must remain under the time constraint permitted between successive frames.
The H.264 codec is a highly efficient coding standard. Like traditional video compression techniques, H.264 uses predictive methods to reconstruct video sequences. This concept is derived from the fact that digital video typically exhibits spatial redundancy, which denotes similarities between pixels within a frame, and temporal redundancy, which are similarities between pixels in adjacent frames. Frames are divided into units of macroblocks (MBs), which are 16×16-pixel regions, and each MB is either intra-coded or inter-coded. An intra-coded MB is reconstructed using information from the current frame. Inter-coded MBs are reconstructed using information only from the previous frame (predicted), or from both previous and future frames (bi-predicted).
Frames can contain a mixture of different MB types and are labeled according to the types of references made for prediction. For example, a B-frame holds MBs that are bi-predicted; however, it may also contain intra-predicted MBs. A P-frame will contain MBs that are predicted from past frames and may also contain intra-predicted MBs. I-frames contain only intra-predicted MBs and do not reference other frames.
An encoded video consists of a sequence of Group of Pictures (GOP), which is a set of coded pictures that specifies the order of I-, P-, and B-frames.
FIG. 1 shows the frame ordering of a GOP in related art. The arrows indicate sources of predicted MBs from adjacent frames.
As shown in FIG. 1, only I-frames and P-frames serve as reference frames. Due to this interdependency between frames, errors can propagate through frames in a GOP when packet losses occur.
An HD video frame encoded using the H.264 standard is typically subdivided into multiple slices. Slices are classified by the types of MBs they contain.
FIG. 2 shows the hierarchical syntax of the H.264 bitstream in related art.
As shown in FIG. 2, the syntax is abstracted in two layers: the Video Coding Layer (VCL) that holds the actual compressed video data and the Network Abstraction Layer (NAL) that encapsulates the compressed data and additional information in a form suitable for packet-based networks.
The Network Abstraction Layer consists of a series of NAL units, which are the minimum units of data decodable by H.264. Three common NAL units are Sequence Parameter Set (SPS), Picture Parameter Sets (PPSs), and slices.
The SPS contains parameters common to an entire video, such as the profile and level the coded video conforms to. Therefore, if a packet containing SPS information is lost, the entire video cannot be decoded. The PPS contains common parameters that are applied to a sequence of frames, such as the entropy coding mode. If the PPS for a sequence of frames is lost, then these frames cannot be decoded. As mentioned before, a slice is the main unit for constructing a frame, and a frame can have either a single slice or multiple slices.
Each slice contains a slice header followed by video data containing MBs. A slice header contains information common to all the MBs within a slice. If a slice header is lost, then the entire slice cannot be decoded even if the slice data is properly received.
FIG. 3A and FIG. 3B show the effect of packet loss on a frame in related art. FIG. 3A shows the original transmitted frame, while FIG. 3B shows the received frame with some information missing due to packet loss.
As shown in FIG. 3B, the slice header for Slice 4 is lost, rendering the entire slice undecodable. In contrast, the slice header for Slice 5 is received but the last two Real Time Protocol (RTP) packets are lost, which allows most of the slice to be decoded.

Apparatus for transmitting encoded video stream and method for transmitting the same


Novel combinations of inhibitors of protein farnesyltransferase enzymes and HMG CoA reductases enzymes are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in preventing or treating cancer, restenosis, psoriasis, endometriosis, atherosclerosis, or viral infections.

The present invention relates to combinations of compounds that can be used in the medicinal field to treat, prophylactically or otherwise, uncontrolled or abnormal proliferation of human tissues. Specifically, the present invention relates to the combination of (I) compounds that inhibit protein farnesyltransferase (PFT), which has been determined to activate ras proteins that in turn activate cellular division and are implicated in cancer and restenosis; and (2) compounds that inhibit HMG CoA reductase, a necessary component in the biosynthesis of farnesylpyrophosphate (FPP), which is essential in the activation of ras proteins by PFT.
Ras protein (or p21) has been examined extensively because mutant forms are found in 20% of most types of human cancer and greater than 50% of colon and pancreatic carcinomas (Gibbs J. B., Cells 1991;65: 1, Cartwright T., et al., Chimica Oggi., 1992; 10:26). These mutant ras proteins are deficient in the capability for feedback regulation that is present in native ras, and this deficiency is associated with their oncogenic action since the ability to stimulate normal cell division cannot be controlled by the normal endogenous regulatory cofactors. The recent discovery that the transforming activity of mutant ras is critically dependent on post-translational modifications (Gibbs J., et al., Microbiol. Rev., 1989;53:171) has unveiled an important aspect of ras function and identified novel prospects for cancer therapy.
In addition to cancer, there are other conditions of uncontrolled cellular proliferation that may be related to excessive expression and/or function of native ras proteins. Post-surgical vascular restenosis is such a condition. The use of various surgical revascularization techniques such as saphenous vein bypass grafting, endarterectomy, and transluminal coronary angioplasty are often accompanied by complications due to uncontrolled growth of neointimal tissue, known as restenosis. The biochemical causes of restenosis are poorly understood and numerous growth factors and protooncogenes have been implicated (Naftilan A. J., et al., Hypertension, 1989; 13:706 and J. Clin. Invest., 83:1419; Gibbons G. H., et al., Hypertension, 1989;14:358; Satoh T., et al., Molec. Cell. Biol., 1993;13:3706). The fact that ras proteins are known to be involved in cell division processes makes them a candidate for intervention in many situations where cells are dividing uncontrollably. In direct analogy to the inhibition of mutant ras related cancer, blockade of ras dependant processes has the potential to reduce or eliminate the inappropriate tissue proliferation associated with restenosis, particularly in those instances where normal ras expression and/or function is exaggerated by growth stimulatory factors.
Ras functioning is dependent upon the modification of the proteins in order to associate with the inner face of plasma membranes. Unlike other membrane-associated proteins, ras proteins lack conventional transmembrane or hydrophobic sequences and are initially synthesized in a cytosol soluble form. Ras protein membrane association is triggered by a series of post-translational processing steps that are signaled by a carboxyl terminal amino acid consensus sequence that is recognized by protein farnesyltransferase (PFT). This consensus sequence consists of a cysteine residue located four amino acids from the carboxyl terminus, followed by two lipophilic amino acids, and the C-terminal residue. The sulfhydryl group of the cysteine residue is alkylated by farnesylpyrophasphate (FPP) in a reaction that is catalyzed by PFT. Following prenylation, the C-terminal three amino acids are cleaved by an endoprotease and the newly exposed alpha-carboxyl group of the prenylated cysteine is methylated by a methyl transferase. The enzymatic processing of ras proteins that begins with farnesylation enables the protein to associate with the cell membrane. Mutational analysis of oncogenic ras proteins indicate that these post-translational modifications are essential for transforming activity. Replacement of the consensus sequence cysteine residue with other amino acids gives a ras protein that is no longer farnesylated, fails to migrate to the cell membrane and lacks the ability to stimulate cell proliferation (Hancock J. F., et al., Cell, 1989;57:1617, Schafer W. R., et al., Science, 1989;245:379, Casey P. J., Proc. Natl. Acad. Sci. USA, 1989;86:8323).
Recently, PFTs have been identified and a specific PFT from rat brain was purified to homogeneity (Reiss Y., et al., Bioch. Soc. Trans., 1992;20:487-88). The enzyme was characterized as a heterodimer composed of one alpha-subunit (49 kDa) and one beta-subunit (46 kDa), both of which are required for catalytic activity. High level expression of mammalian PFT in a baculovirus system and purification of the recombinant enzyme in active form has also been accomplished (Chen W.-J., et al., J. Biol. Chem., 1993;268:9675).
In light of the foregoing, the discovery that the function of oncogenic ras proteins is critically dependent on their post-translational processing provides a means of cancer chemotherapy through inhibition of the processing enzymes. The identification and isolation of a PFT that catalyzes the addition of a farnesyl group to ras proteins provides a promising target for such intervention. Ras farnesyltransferase inhibitors have been shown to have anticancer activity in several recent articles.
Ras inhibitor agents act by inhibiting farnesyltransferase, the enzyme that anchors the protein product of the ras gene to the cell membrane. The role of the ras mutation in transducing growth signals within cancer cells relies on the protein being in the cell membrane so with farnesyltransferase inhibited, the ras protein will stay in the cytosol and be unable to transmit growth signals: these facts are well-known in the literature.
A peptidomimetic inhibitor of farnesyltransferase B956 and its methyl ester B 1086 at 100 mg/kg have been shown to inhibit tumor growth by EJ-1 human bladder carcinoma, HT1080 human fibrosarcoma and human colon carcinoma xenografts in nude mice (Nagasu, T., et al., Cancer Res., 1995;55:5310-5314). Furthermore, inhibition of tumor growth by B956 has been shown to correlate with inhibition of ras post-translational processing in the tumor. Other ras farnesyltransferase inhibitors have been shown to specifically prevent ras processing and membrane localization and are effective in reversing the transformed phenotype of mutant ras containing cells (Sepp-Lorenzino L., et al., Cancer Res., 1995;55:5302-5309).
In another report (Sun J., et al., Cancer Res., 1995;55:4243-4247), a ras farnesyltransferase inhibitor FT1276 has been shown to selectively block tumor growth in nude mice of a human lung carcinoma with K-ras mutation and p53 deletion. In yet another report, daily administration of a ras farnesyltransferase inhibitor L-744,832 caused tumor regression of mammary and salivary carcinomas in ras transgenic mice (Kohl, et al., Nature Med., 1995;1(8):792-748). Thus, ras farnesyltransferase inhibitors have benefit in certain forms of cancer, including those dependent on oncogenic ras for their growth. However, it is well-known that human cancer is often manifested when several mutations in important genes occurs, one or more of which may be responsible for controlling growth and metastases. A single mutation may not be enough to sustain growth and only after two of three mutations occur, tumors can develop and grow. It is therefore difficult to determine which of these mutations may be primarily driving the growth in a particular type of cancer. Thus, ras farnesyltransferase inhibitors can have therapeutic utility in tumors not solely dependent on oncogenic forms of ras for their growth. For example, it has been shown that various ras farnesyltransferase inhibitors have antiproliferative effects in vivo against tumor lines with either wild-type or mutant ras (Sepp-Lorenzino, supra, 1995). In addition, there are several ras-related proteins that are prenylated. Proteins such as R-Ras2/TC21 are ras-related proteins that are prenylated in vivo by both farnesyltransferase and geranylgeranyl transferase I (Carboni, et al., Oncogene, 1995;10:1905-1913). Therefore, ras farnesyltransferase inhibitors could also block the prenylation of the above proteins and therefore would then be useful in inhibiting the growth of tumors driven by other oncogenes.
With regard to the restenosis and vascular proliferative diseases, it has been shown that inhibition of cellular ras prevents smooth muscle proliferation after vascular injury in vivo (Indolfi C, et al., Nature Med., 1995; 1 (6):541-545). This report definitively supports a role for farnesyltransferase inhibitors in this disease, showing inhibition of accumulation and proliferation of vascular smooth muscle.
Inhibitors of the enzyme 3-hydroxy-3methylglutaryl-coenzyme A reductase or HMG CoA reductase (the major regulatory enzyme of the mevalonate pathway of cholesterol synthesis) have also been shown to display anticancer activity in experimental models. In one study, it was shown that inhibition of HMG CoA reductase by lovastatin selectively inhibited tumor growth in vitro and in animal models of hepatocellular, pancreatic, and central nervous system tumors (Maltese, et al., J. Clin. Invest., 1985;76:1748-1754). It has been observed that neoplastic cells synthesize large quantities of cholesterol from precursors such as mevalonate, which is also the precursor of isoprenoid moieties that are incorporated into or linked to several molecules essential for cell growth and replication. More specifically, these drugs inhibit HMG CoA reductase, the rate limiting enzyme for the production of polyisoprenoids and the farnesyl pyrophosphate precursor.
In light of the foregoing, the discovery that HMG CoA reductase inhibitors are important factors in cell growth and replication provides a means of cancer chemotherapy through inhibition of this enzyme. The identification and isolation of an HMG CoA reductase inhibitor that promotes uncontrolled cell growth and replication provides a promising target for such intervention.
The present invention provides novel combinations of (1) compounds that inhibit protein farnesyltransferase (PFT); and (2) compounds that inhibit HMG CoA reductase. In yet another aspect of the present invention, are disclosed pharmaceutical compositions which comprise therapeutically effective amounts of the novel combinations and a pharmaceutically acceptable carrier. In yet a further aspect of the present invention, are disclosed methods of using the pharmaceutical compositions to treat cancer, restenosis, psoriasis, proliferative cardiovascular disorders and the like.
In one embodiment, the compounds that inhibit PFT are preferably those that have an inhibitory action on PFT in an FPP-competitive nature and/or are cell permeable.
In another embodiment, the compounds that have an inhibitory action on PFT are those compounds having the Formula I
wherein
R21 is hydrogen or C1-C6 alkyl;
RQ is
n is 0 or 1;
Ra, Raxe2x80x2, and Raxe2x80x3 are independently C1-C6 alkyl, xe2x80x94(CH2)m-cycloalkyl, xe2x80x94(CH2)m-aryl, or xe2x80x94(CH2)m-heteroaryl;
each m is independently 0 to 3;
R1, R2, and R4 are independently hydrogen or C1-C6 alkyl;
xe2x80x83xe2x80x94(CH2)m-(heteroaryl substituted with Rb), or C1-C6 alkyl;
t is 2 to 6;
Rb is xe2x80x94O-phenyl, xe2x80x94O-benzyl, halogen, C1-C6 alkyl, hydrogen, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH2, xe2x80x94NHRa, NRaRaxe2x80x2,
xe2x80x83xe2x80x94(CH2)m-cycloalkyl, xe2x80x94Oxe2x80x94(CH2)m-aryl, xe2x80x94(CH2)m-aryl, or xe2x80x94(CH2)m-heteroaryl;
y is 2 or 3;
R5 is
Ri, Rg, and Rh are independently hydrogen, halogen, xe2x80x94OC1-C6 alkyl, C1-C6 alkyl,
xe2x80x83xe2x80x94SO2NRaRaxe2x80x2, xe2x80x94CHO, or xe2x80x94OCOCH3; and
Rc, Rd, Re, and Rf are independently C1-C6 alkyl, xe2x80x94(CH2)m-phenyl, hydrogen, xe2x80x94(CH2)mxe2x80x94OH, xe2x80x94(CH2)mNH2, xe2x80x94(CH2)m-cycloalkyl, or xe2x80x94CN, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of the compounds of Formula I
R1 is hydrogen, R2 is hydrogen, R4 is hydrogen, R21 is hydrogen or CH3; and
A is
In another preferred embodiment of the compound of Formula I
R3 is
xe2x80x83or xe2x80x94CH2xe2x80x94CH(CH3)2.
R1 is hydrogen, R2 is hydrogen, R4 is hydrogen, and R21 is hydrogen or CH3.
In another preferred embodiment of the compounds of Formula I R5 is
where Ri is hydrogen, Cl, Br, F, or NH2.
Also provided are compounds having the Formula II
wherein
R6 is xe2x80x94O-benzyl, xe2x80x94NH-benzyl, or
R21 is hydrogen or methyl;
R7 is hydrogen or methyl;
R8 is hydrogen, halogen, C1-C6 alkyl, xe2x80x94O-benzyl, xe2x80x94OC1-C6 alkyl, xe2x80x94CF3, xe2x80x94OH, xe2x80x94Oxe2x80x94(CH2)m-pyridyl, or phenyl;
R10, R11, R13, and R14 are independently hydrogen, C1-C6 alkyl, or xe2x80x94(CH2)m-phenyl;
each m is independently 0 to 3;
R12 is
Rj, Rk, and Rl are independently hydrogen, halogen, xe2x80x94OC1-C6 alkyl, xe2x80x94C1-C6 alkyl, xe2x80x94NHRa, or NH2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of the compounds of Formula II, R11 and R14 are methyl.
In another preferred embodiment of the compounds of Formula II, R8 is methyl or methoxy.
Also provided are compounds having the Formula III
wherein
X is NH, O or xe2x80x94N(CH3);
R15 is xe2x80x94O-benzyl, xe2x80x94CF3, hydrogen, halogen, xe2x80x94OC1-C6 alkyl, phenyl, xe2x80x94Oxe2x80x94(CH2)m-pyridyl, or xe2x80x94C1-C6 alkyl;
m is 0 to 3; and
R16 is a phenyl, hydrogen, or C1-C6 alkyl, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
Also provided are compounds having the Formula IV
wherein
X is NH, O or N(CH3);
R15 is xe2x80x94O-benzyl, xe2x80x94CF3, hydrogen, halogen, C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, phenyl, or xe2x80x94Oxe2x80x94(CH2)m-pyridyl;
R16 and R16xe2x80x2 are C1-C6 alkyl;
m is 0 to 3; and
R21 is hydrogen or methyl, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In another embodiment, the compounds that have an inhibitory action on PFT are those compounds having the Formula V
wherein
RQ is
X is 0 or 1;
R14 is hydrogen or C1-C6 alkyl;
A is xe2x80x94CORa, xe2x80x94CO2Raxe2x80x2, xe2x80x94CONHRaxe2x80x2, xe2x80x94CSRa,
Ra, Raxe2x80x2, and Raxe2x80x3 are independently C1-C6 alkyl, xe2x80x94(CH2)m-cycloalkyl, xe2x80x94(CH2)m-aryl, or xe2x80x94(CH2)m-heteroaryl;
each m is independently 0 to 3;
R1, R2, and R4 are independently hydrogen or C1-C6 alkyl;
xe2x80x83xe2x80x94(CH2)m-heteroaryl, xe2x80x94(CH2)m-naphthyl, xe2x80x94(CH2)m-(phenyl substituted with Rb), or xe2x80x94(CH2)m-(heteroaryl substituted with Rb);
t is 2 to 6;
Rb is xe2x80x94O-phenyl, xe2x80x94O-benzyl, halogen, C1-C6 alkyl, hydrogen, xe2x80x94OC1-C6 alkyl,
xe2x80x83xe2x80x94SO2Ra, xe2x80x94SO2NRaRaxe2x80x2, xe2x80x94CHO, xe2x80x94OCOCH3, xe2x80x94O(CH2)m-heteroaryl, xe2x80x94O(CH2)m-aryl, xe2x80x94O(CH2)m-cycloalkyl, xe2x80x94(CH2)m-aryl, xe2x80x94(CH2)m-cycloalkyl, xe2x80x94(CH2)m-heteroaryl, or xe2x80x94CHxe2x95x90CHC6H5;
y is 2 or 3;
R5 is
or
each n is independently 2, 3, or 4;
Ri, Rg, and Rh are independently hydrogen, halogen, xe2x80x94OC1-C6 alkyl, C1-C6 alkyl, xe2x80x94CN, xe2x80x94OPO3H2, xe2x80x94CH2PO3H2, xe2x80x94O-phenyl, xe2x80x94O-benzyl, xe2x80x94NH2,
xe2x80x83or xe2x80x94OCOCH3; and
Rc and Rd are independently C1-C6 alkyl, xe2x80x94(CH2)m-cycloalkyl or hydrogen, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In another preferred embodiment of the compounds of Formula V
R1 is hydrogen, R2 is hydrogen, R4 is hydrogen, R14 is hydrogen or methyl, and
A is
In another preferred embodiment of the compounds of Formula V
(phenyl substituted with Rb), or xe2x80x94(CH2)m-(heteroaryl substituted with Rb).
R1 is hydrogen, R2 is hydrogen, R4 is hydrogen, and R14 is hydrogen or methyl.
In another preferred embodiment of the compounds of Formula V
R5 is
In another embodiment, the compounds that have an inhibitory action on PFT are those compounds having the Formula VI
wherein
R6 is xe2x80x94O-benzyl, xe2x80x94NH-benzyl, xe2x80x94N(C1-C6 alkyl)-benzyl, or xe2x80x94SCH2-phenyl;
R8 is hydrogen, halogen, C1-C6 alkyl, xe2x80x94O-benzyl, xe2x80x94OCH2-pyridyl, xe2x80x94OC1-C6 alkyl, xe2x80x94CF3, xe2x80x94OH, or xe2x80x94phenyl;
R10 and R13 are independently hydrogen or C1-C6 alkyl;
each n is independently 2, 3, or 4;
R14 is hydrogen or methyl;
Rj, Rk, and Rl are independently hydrogen, halogen, xe2x80x94NH2, xe2x80x94NHRa, xe2x80x94OC1-C6 alkyl, or xe2x80x94C1-C6 alkyl, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In another embodiment, the compounds that have an inhibitory action on PFT are those compounds having the Formula VII
wherein
each n is 2, 3, or 4;
X is NH, O or xe2x80x94NCH3;
R15 is xe2x80x94O-benzyl, xe2x80x94CF3, hydrogen, halogen, xe2x80x94OH, -phenyl, xe2x80x94C1-C6 alkyl, xe2x80x94OCH2-pyridyl, or xe2x80x94OC1-C6 alkyl, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In another embodiment, the compounds that have an inhibitory action on PFT are those compounds having the Formula VIII
wherein:
n is 1 or 2;
A is COR2, CO2R2, CONHR2, CSR2, C(S)OR2, C(S)NHR2, or SO2R2 with R2 as defined below;
R is independently H or Me;
R2 is alkyl, (CH2)m-cycloalkyl, (CH2)m-aryl, (CH2)m-heteroaryl with m is 0, 1, 2, or 3;
R3 and R4 are independently
xe2x80x83or (CH2)nCONHxe2x80x94R6 with y is 1-5 and n as defined above and with R5 and R6 as defined below, or R3 and R4 are connected together to form a ring of the following type:
xe2x80x83with R5 and R6 as defined below, or (CH2)xxe2x80x94R7, with x is 2-5, and R7 as defined below;
R5 is R2, OR2, or SR2 with R2 as defined above;
R6 is (CH2)nR5, (CH2)nCO2R2, (CH2)nCONHR2, CH2)nCONH(CH2)n+1R5, CH(COR8)(CH2)nR5, with n, R2, and R5 as defined above and R8 as defined below;
R7 is (CH2)m-cycloalkyl, (CH2)m-aryl, (CH2)m-heteroaryl, O(CH2)m-cycloalkyl, O(CH2)m-aryl, O(CH2)m-heteroaryl with m is 0, 1, 2, or 3;
R8 is OH, O-alkyl, NH2, or NH-alkyl; and
X is H, Me, (CH2)nCO2R9, or (CH2)nP(O)(OR9)2, with R9 is H or alkyl;
and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In another embodiment, the compounds that have an inhibitory action on PFT are those compounds having the Formulas IX and X.
wherein:
A is limited to CO2R2, CONHR2, C(S)OR2, or C(S)NHR2 with R2 as defined below;
R is H or Me;
R2 is limited to alkyl, (CH2)m-cycloalkyl, (CH2)m-aryl, (CH2)m-heteroaryl, with m is 0, 1, 2, or 3;
R5 is limited to (CH2)m-aryl, Oxe2x80x94(CH2)m-aryl, or Oxe2x80x94(CH2)m-heteroaryl with m as defined above;
R6 is limited to CH2xe2x80x94R5, CH2CO2R2, CH2CONHR2, with n is 1 or 2, and with R5 and R2 as defined above; and
X is limited to H or Me;
and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of the compounds of Formulas IX and X,
A is further limited to CO2R2 or CONHR2, with R2 as defined below;
R is limited to H;
R2 is further limited to alkyl, or (CH2)m-aryl with m is 0, 1, 2, or 3;
R5 is further limited to (CH2)m-aryl or Oxe2x80x94(CH2)m-aryl with m as defined above;
R6 is limited to CH2xe2x80x94R5 or CH2CONHR2, with n is 1 or 2, and with R5 and R2 as defined above; and
X is limited to H or Me.
The compounds of the present invention that are PTE inhibitors, and their method of preparation are disclosed in copending U.S. Ser. Nos. 60/033,662 and 60/056,831, filed Dec. 17, 1996, and Aug. 22, 1997, respectively, and U.S. Pat. No. 5,571,792 issued Nov. 5, 1996. The information contained in these copending cases and patent are incorporated herein by reference.
Compounds that inhibit HMG CoA reductase are known to those of skill in the art. HMG CoA reductase inhibitors of the present invention include, but are not limited to the following compounds: lovastatin, provastatin, atorvastatin, velostatin, simvastatin and the like.
In another aspect, the present invention provides a pharmaceutically acceptable composition that comprises a combination of the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, and/or X and an HMG CoA reductase inhibitor.
Also provided is a method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or a risk of having restenosis a therapeutically effective amount of a combination of the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, and/or X and a compound that is an HMG CoA reductase inhibitor.
Also provided is a method of treating cancer, the method comprising administering to a patient having cancer a therapeutically effective amount of a combination of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, and/or X and a compound that is an HMG CoA reductase inhibitor.
Also provided is a method of treating psoriasis, the method comprising administering to a patient having psoriasis a therapeutically effective amount of a combination of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, and/or X and a compound that is an HMG CoA reductase inhibitor.
Also provided is a method of treating viral infection, the method of comprising administering to a patient having a viral infection a therapeutically effective amount of a combination of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, and/or X and a compound which is an HMG CoA reductase inhibitor.
In a more preferred embodiment, the cancer is lung cancer, colon cancer, breast cancer, pancreatic cancer, thyroid cancer, or bladder cancer.
In a most preferred embodiment, the compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, and X are
(S)-[1-[(4-Benzyloxy-benzyl)-(phenethyl-carbamoyl-methyl)-carbamoyl]-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-[[2-Benzyloxy-ethylcarbamoyl]-methyl]-[4-chlorobenzyl]-carbamoyl]-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-[(4-Benzyloxy-benzyl)-[(2-phenyl-propyl-carbamoyl)-methyl]-carbamoyl]-2-(1H-imidazole-4-yl)-ethyl]carbamic acid benzyl ester;
(S)-[1-[(4-Benzyloxy-benzyl)-[(2,2-diphenyl-ethylcarbamoyl)-methyl]-carbamoyl]-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-N-(4-Benzyloxy-benzyl)-2-(3-benzyl-ureido)-3-(1H-imidazole4yl)-N-[(2-phenyl-propylcarbamoyl)-methyl]-propionamide;
(S)-[1-{Biphenyl-4-ylmethyl-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{Biphenyl-4-ylmethyl-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-((4-Benzyloxy-benzyl)-{[2-(2-fluoro-phenyl)-ethylcarbamoyl]-methyl}-carbamoyl)-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(4-Benzyloxy-benzyl)-[(2-pyridin-2-yl-ethylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-((4-Benzyloxy-benzyl)-{[2-(2-bromo-phenyl)-ethylcarbamoyl]-methyl}-carbamoyl)-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(4-Benzyloxy-benzyl)-[(1-methyl-2-phenyl-ethylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(4-Benzyloxy-benzyl)-[(2-phenyl-2-pyridin-2-yl-ethylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(4-Chloro-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(4-Benzyloxy-benzyl)-[(2-phenyl-butylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-N-(4-Benzyloxy-benzyl)-3-(1H-imidazole-4-yl)-2-(3-phenyl-propionylamino)-N-[(2-phenyl-propylcarbamoyl)-methyl]-propionamide;
(S)-[1-{(4-Fluoro-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{(4-methyl-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{(4-methoxy-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-[1-[{[2-(2-Amino-phenyl)-propylcarbamoyl]-methyl}-(4-benzyloxy-benzyl)-carbamoyl]-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(4-Fluoro-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{Benzyl-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-((4-Benzyloxy-benzyl)-{[2-(2-chloro-phenyl)-2-phenyl-ethylcarbamoyl]-methyl}-carbamoyl)-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(4-Benzyloxy-benzyl)-[(2-ethyl-2-phenyl-butylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-N-(4-Benzyloxy-benzyl)-2-(3-benzyl-ureido)-3-(1H-imidazole-4-yl)-N-[(2-phenyl-propylcarbamoyl)-methyl]-propionamide;
(S)-N-(4-Benzyloxy-benzyl)-2-(3-benzyl-ureido)-3-(1H-imidazole4-yl)-N-[(2-phenyl-butylcarbamoyl)-methyl]-propionamide;
(S)-1-{(2-Chloro-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(4-Bromo-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(3-Chloro-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl)]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(4-Chloro-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl-}-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-((4-Benzyloxy-benzyl)-{[2-(2-chloro-phenyl)-propylcarbamoyl]-methyl}-carbamoyl)-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{(2-methoxy-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{[(2-phenyl-propylcarbamoyl)-methyl]-[4-(pyridin-4-ylmethoxy)-benzyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{(3-methoxy-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{[(2-phenyl-propylcarbamoyl)-methyl]-[4-(pyridin-3-ylmethoxy)-benzyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{naphthalen-1-ylmethyl-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-{2-(1H-Imidazole-4-yl)-1-[[(2-phenyl-propylcarbamoyl)-methyl]-(4-trifluoromethyl-benzyl)-carbamoyl]-ethyl}-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-pyridin-3-ylmethyl-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-[4-(pyridin-2-ylmethoxy)-benzyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-[1-{Benzyl-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{(2-methyl-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{(4-methoxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-[-{(4-Benzyloxy-benzyl)-[(2-cyano-2-phenyl-ethylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-pyridin-2-ylmethyl-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{(3-methyl-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-[1-{(4-Dimethylamino-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-[4-(pyridin-4-ylmethoxy)-benzyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-[4-(pyridin-3-ylmethoxy)-benzyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(2-(1-H-imidazole-4-yl)-1-{isobutyl-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-[1-{(4-Benzyloxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-2-(3-Benzyl-3-methyl-ureido)-N-(4-benzyloxy-benzyl)-3-(1H-imidazole-4-yl)-N-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-propionamide;
(S)-[1-{(4-Benzyloxy-benzyl)-[(2-hydroxy-2-phenyl-ethylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{(4-methoxy-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-[1-((4-Benzyloxy-benzyl)-{[2-(2-chloro-phenyl)-ethylcarbamoyl]-methyl}-carbamoyl)-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(4-Benzyloxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid thiophen-3-ylmethyl ester;
(S)-[1-{(4-Chloro-benzyl)-[1-(2-methyl-2-phenyl-propylcarbamoyl)-ethyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{(4-methyl-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{(2-methoxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-2-(3-Benzyl-3-methyl-ureido)-N-(4-chloro-benzyl)-3-(1H-imidazole-4-yl)-N-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-propionamide;
(S)-(2-(1H-Imidazole-4-yl)-1-{(3-methoxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-(2-(1H-Imidazole-4-yl)-1-{[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-[2-(pyridin-4-ylmethoxy)-benzyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-[1-{Cyclohexylmethyl-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(4-Benzyloxy-benzyl)-[(2-phenyl-pentylcarbamoyl)-methyl]-carbamoyl}-2-(3H-Imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{[2-(4-Benzyloxy-phenyl)-ethyl]-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-(2-(3H-imidazole-4-yl)-1-{[2-(4-methoxy-phenyl)-ethyl]-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-[1-[{[2-(2-Amino-phenyl)-ethylcarbamoyl]-methyl}-(4-benzyloxy-benzyl)-carbamoyl]-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(2-(1H-imidazol-4-yl)-1-{isobutyl-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-[1-{(4-Benzyloxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-methyl-carbamic acid benzyl ester;
(S)-[1-{(4-Benzyloxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3-methyl-3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-{(4-Benzyloxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1-methyl-1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-1-{(4-Benzyloxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid furan-2-ylmethyl ester;
(S)-[1-{(4-Benzyloxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid thiophen-2-ylmethyl ester;
(S)-1-{(4-Benzyloxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid pyridin-3-ylmethyl ester;
(S)-1-{(4-Benzyloxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid1H-imidazole-4-ylmethyl ester;
(S)-2-(3-Benzyl-ureido)-N-(4-chloro-benzyl)-3-(3H-imidazole-4-yl)-N-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-propionamide;
(S)-[1- ((4-Benzyloxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid4-methoxy-benzyl ester;
(S)-2-(3-Benzyl-thioureido)-3-(3H-imidazole-4-yl)-N-(4-methyl-benzyl)-N-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-propionamide;
(S)-2-Acetylamino-N-(4-benzyloxy-benzyl)-3-(3H-imidazole-4-yl)-N-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-propionamide;
(S)-(2-(3H-imidazole-4-yl)1-{[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-pyridin-4-ylmethyl-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-{2-(3H-Imidazole-4-yl)1-[(4-iodo-benzyl)-(phenethylcarbamoyl-methyl)-carbamoyl]-ethyl}-carbamic acid benzyl ester;
(S)-1-{(4-Amino-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-1-{(4-Ethoxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-1-{[4-(2-Dimethylamino-ethoxy)-benzyl]-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester;
(2-(1H-Imidazol-4-yl)1-{isobutyl-[(2-methyl-2-phenyl-propyl carbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-[1-((4-Benzyloxy-benzyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-1-((4-Benzyloxy-benzyl)-{[(1-phenyl-cyclopropylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-[1-((4-Benzyloxy-benzyl)-{[(1-phenyl-cyclopentylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-1-((4-Phenyl-benzyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-1-((4-Methoxy-benzyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-1-((4-Methyl-benzyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-N-(4-Benzyloxy-benzyl)-2-(3-benzyl-ureido)-3-(1H-imidazol-4-yl)-N-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-propionamide;
(S)-2-(3-Benzyl-3-methyl-ureido)-N-(4-benzyloxy-benzyl)-3-(1H-imidazol-4-yl)-N-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-propionamide;
(S)-1-((4-Benzyloxy-benzyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-thiocarbamic acid S-benzyl ester;
(S)-(2-(1H-Imidazol-4-yl)-1-{{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-[4-(pyridin-2-yl-methoxy)-benzyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester;
(S)-(1-((Cyclohexyl-methyl)-{[(-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
(S)-(1-((Isobutyl)-{[(1-phenyl-cyclobutylmethyl)-carbamoyl]-methyl}-carbamoyl)-2-(1H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester;
N-[(Phenylmethoxy)carbonyl]-L-histidyl-N-[2-(phenylmethoxy)ethyl]-N2-[[4-(phenylmethoxy)phenyl]methyl]glycinamide;
N-[(Phenylmethoxy)carbonyl]-L-histidyl-N2-[(1,1xe2x80x2-biphenyl)-4-ylmethyl]-N-[2-(phenylmethoxy)ethyl]glycinamide;
N-[N-[N-[(Phenylmethoxy)carbonyl]-L-histidyl]-N-[[4-(phenylmethoxy)phenyl]methyl]glycyl]glycine phenylmethyl ester;
N-[(Phenylmethoxy)carbonyl]-L-histidyl-N-(4-phenylbutyl)-N2-[[4-(phenylmethoxy)phenyl]methyl]glycinamide;
N-[(Phenylmethoxy)carbonyl]-L-histidyl-N-(3-phenoxypropyl)-N2-[[4-(phenylmethoxy)phenyl]methyl]glycinamide;
(S)-[1-(1H-Imidazol-3-ylmethyl)-2-oxo-2-[[2-(phenylmethoxy)ethyl][4-(phenylmethoxy)phenyl]methyl]amino]ethyl]carbamic acid, phenylmethyl ester; and
[1-(1H-Imidazol-4-ylmethyl)-2-oxo-2-[1,2,3 ,4-tetrahydro-7-(phenylmethoxy)-3-[[2-(phenylmethoxy)ethyl]amino]carbonyl]-2-isoquinolinyl]ethyl]carbamic acid, phenylmethyl ester.
The present invention provides a combination of (1) compounds that inhibit protein farnesyltransferase (PFT); and (2) compounds that inhibit HMG CoA reductase.
While not intending to be limited by theory, it is believed by the inventors that a therapeutic synergy results from the administration of a combination of the compounds of Formulas I, II, III, IV, V, VI, VII, VIII, IX, and/or X which have an inhibitory action on PFT and compounds that have an inhibitory action on HMG CoA reductase. As discussed above, farneslyation of activated ras oncogene product by PFT is a critical step for its oncogenic function. It has been discovered that certain PFT inhibitors inhibit PFT in an FPP-competitive manner. Because HMG CoA reductase inhibitors, like lovastatin, reduce the cellular FPP pool, the HMG CoA reductase inhibitors have been found to ameliorate the activity of these FPP-competitive inhibitors.
Synthesis of FPP is dependent upon the enzymatic activity of HMG CoA reductase. It is believed that an inhibitor of HMG CoA reductase will decrease the availability of FPP, a necessary substrate for PFT leading to uncontrolled cell growth and reproduction. The combination of FPP-competitive PFT and HMG CoA reductase inhibitors, therefore, is believed to have an effect on diseases characterized by uncontrolled cell growth and reproduction, like cancer, restenosis and proliferative vascular disorders.
Compounds that inhibit HMG CoA reductase are known to those of skill in the art. HMG CoA reductase inhibitors of the present invention include, but are not limited to the following compounds: lovastatin, pravastatin, velostatin, atorvastatin, cerivastatin, simvastatin and the like.
In one embodiment, the compounds that inhibit PFT are those compounds that inhibit PFT in an FPP-dependent manner and/or are cell permeable. In preferred embodiments, the compounds that inhibit PFT are those compounds set forth in the summary of the invention.
The term xe2x80x9calkylxe2x80x9d means a straight or branched hydrocarbon having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated hydrocarbon ring which contains from 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
The term xe2x80x9carylxe2x80x9d means an aromatic ring which is a phenyl, 5-fluorenyl, 1-naphthyl, or 2-naphthyl group, unsubstituted or substituted by 1 to 3 substituents selected from alkyl, O-alkyl and S-alkyl, OH, SH, F, Cl, Br, I, CF3, NO2, NH2, NHCH3, N(CH3)2, NHCO-alkyl, (CH2)mCO2H, (CH2)mCO2-alkyl, (CH2)mSO3H, (CH2)mPO3H2, (CH2)mPO3(alkyl)2, (CH2)mSO2NH2, and (CH2)mSO2NH-alkyl wherein alkyl is defined as above and m is 0, 1, 2, or 3.
The term xe2x80x9cheteroarylxe2x80x9d means a heteroaromatic ring which is a 2- or 3-thienyl, 2- or 3-furanyl, 2-or 3-pyrrolyl, 2-, 3-, or 4-pyridyl, imidazolyl, 2-, 3-, 4-, 5-, 6-, or 7-indoxyl group, unsubstituted or substituted by 1 or 2 substituents from the group of substituents described above for aryl.
The symbol xe2x80x9c-xe2x80x9d means a bond.
The term xe2x80x9cpatientxe2x80x9d means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.
A xe2x80x9ctherapeutically effective amountxe2x80x9d is an amount of any of the combinations set forth in the present invention that when administered to a patient ameliorates a symptom of a viral infection, restenosis, cancer, atherosclerosis, psoriasis, endometriosis, or prevents restenosis or atherosclerosis. A therapeutically effective amount of the combinations of PFT and HMG CoA reductase inhibitor of the present invention can be easily determined by one skilled in the art by administering a quantity of a compound to a patient and observing the result. In addition, those skilled in the art are familiar with identifying patients having cancer, viral infections, restenosis, atherosclerosis, psoriasis, or endometriosis or who are at risk of having restenosis or atherosclerosis.
The term xe2x80x9ccancerxe2x80x9d includes, but is not limited to, the following cancers:
breast;
ovary;
cervix;
prostate;
testis;
esophagus;
glioblastoma;
neuroblastoma;
stomach;
skin, keratoacanthoma;
lung, epidermoid carcinoma, large cell carcinoma, adenocarcinoma;
bone;
colon, adenocarcinoma, adenoma;
pancreas, adenocarcinoma;
thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma;
seminoma;
melanoma;
sarcoma;
bladder carcinoma;
liver carcinoma and biliary passages;
kidney carcinoma;
myeloid disorders;
lymphoid disorders, Hodgkins, hairy cells;
buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx;
small intestine;
colon-rectum, large intestine, rectum;
brain and central nervous system; and
leukemia.
The term xe2x80x9cpharmaceutically acceptable salts, esters, amides, and prodrugsxe2x80x9d as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9csaltsxe2x80x9d refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laureate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphtholate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci, 1977;66:1-19 which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C1-C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkyl amines and secondary C1-C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems,xe2x80x9d Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.
The combinations of compounds of the present invention can be administered to a patient alone or as part of a composition that contains other components such as excipients, diluents, and carriers, all of which are well-known in the art. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), Cremophor EL (a derivative of castor oil and ethylene oxide; purchased from Sigma Chemical Co., St. Louis, Mo.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agarxe2x80x94agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, Cremophor EL (a derivative of castor oil and ethylene oxide; purchased from Sigma Chemical Co., St. Louis, Mo.), polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The above farnesyl protein transferase compounds to be employed in combination with the HMG CoA reductase inhibitors set forth above will be used in therapeutic amounts as indicated in the Physicians"" Desk Reference (PDR) 47th Edition (1993), which is incorporated herein by reference, or such therapeutically useful amounts as would be known to one of ordinary skill in the art.
The combinations can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. The determination of optimum dosages for a particular patient is well known to those skilled in the art. The combination can be administered as separate compositions or as a single dosage form containing both agents.
The combinations of compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.01 to about 2000 mg per day of PFT inhibitor and about 0.1 to about 500 mg per day of HMG CoA reductase inhibitor. The specific dosage used, however, can vary.
The compounds comprising the combinations of the present invention can exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.
In addition, the compounds of the combinations of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The examples presented below are intended to illustrate particular embodiments of the invention, and are not intended to limit the scope of the specification or the claims in any way.

Combinations of protein farnesyltransferase and HMG CoA reductase inhibitors and their use to treat cancer


In an optical wavelength converting apparatus, a fundamental wave impinges upon a crystal of a nonlinear optical material, the type II of phase matching between the fundamental wave and its second harmonic is effected, and the second harmonic of the fundamental wave is thereby radiated out of the optical wavelength converting apparatus. Two crystals constituted of the same material are employed as the crystal. The two crystals have equal lengths and are located in orientations such that corresponding optic axes may be shifted 90.degree. from each other. The optical wavelength converting apparatus yields the second harmonic having the maximum possible output power and yet can be kept small in size and low in cost.

1. Field of the Invention
This invention relates to an optical wavelength converting apparatus for converting a fundamental wave into its second harmonic. This invention particularly relates to an optical wavelength converting apparatus, wherein a crystal of a nonlinear optical material, with which the type II of phase matching between a fundamental wave and its second harmonic is effected, is utilized.
2. Description of the Prior Art
Various attempts have heretofore been made to convert the fundamental wave of a laser beam into its second harmonic, e.g. to shorten the wavelength of a laser beam, by using a nonlinear optical material. As an optical wavelength converting apparatus for carrying out such wavelength conversion, there has heretofore been known a bulk crystal type of optical wavelength converting apparatus as described in, for example, "Hikari Electronics No Kiso" (Fundamentals of Optoelectronics) by A. Yariv, translated by Kunio Tada and Takeshi Kamiya, Maruzen K. K., pp. 200-204.
Also, laser diode pumped solid lasers have been proposed in, for example, Japanese Unexamined Patent Publication No. 62(1987)-189783. The proposed laser diode pumped solid lasers comprise a solid laser rod, which has been doped with a rare earth metal, such as neodymium (Nd). The solid laser rod is pumped by a semiconductor laser (a laser diode). In the laser diode pumped solid laser of this type, in order for a laser beam having as short a wavelength as possible to be obtained, a bulk single crystal of a nonlinear optical material for converting the wavelength of a laser beam, which has been produced by solid laser oscillation, is located in a resonator of the solid laser. The laser beam, which has been produced by the solid laser oscillation, is thereby converted into its second harmonic, or the like.
As the crystal of the nonlinear optical material, a biaxial crystal, such as a KTP crystal, is often employed. How to effect the phase matching with a KTP biaxial crystal is described in detail by Yao, et al. in J. Appl. Phys., Vol. 55, p. 65, 1984. The method for effecting the phase matching with a biaxial crystal will be described hereinbelow.
With reference to FIG. 4, the direction, along which a fundamental wave travels, and the optic axis Z of the crystal make an angle .theta.. The projection of the direction, along which the fundamental wave travels onto the plane in which the optic axes X and Y lie, and the optic axis X make an angle .phi.. The refractive index of the crystal with respect to the fundamental wave, which impinges upon the crystal at an arbitrary angle of incidence, and the refractive index of the crystal with respect to the second harmonic of the fundamental wave are represented respectively by EQU n.sup..omega., n.sup.2.omega. ( 1)
The refractive indexes of the crystal with respect to the light components of the fundamental wave, which have been polarized respectively in the X, Y, and Z optic axis directions, and the refractive indexes of the crystal with respect to the light components of the second harmonic, which have been polarized respectively in the X, Y, and Z optic axis directions, are represented by EQU n.sub.X.sup..omega., n.sub.Y.sup..omega., n.sub.Z.sup..omega., n.sub.X.sup.2.omega., n.sub.Y.sup.2.omega., n.sub.Z.sup.2.omega.( 2)
When k.sub.X, k.sub.Y, and k.sub.Z, are defined as follows: EQU k.sub.X =sin.theta..multidot.cos.phi. EQU k.sub.Y =sin.theta..multidot.cos.phi. EQU k.sub.Z =cos.theta.
the following formulas obtain: ##EQU1##
Solutions of Formulas (3) and (4) represent the conditions under which the phase matching can be effected.
When B1, C1, B2, and C2 are defined as follows: ##EQU2## the solutions of Formulas (3) and (4) are represented by the formulas ##EQU3## When the condition EQU n.sup..omega.,.sub.2 =n.sup.2.omega.,.sub.1 ( 8)
is satisfied, the phase matching between the fundamental wave and its second harmonic is effected. Such phase matching is referred to as the type I of phase matching.
Also, when the condition EQU 1/2(n.sup.107,.sub.1 +n.sup..omega.,.sub.2)=n.sup.2.omega.,.sub.1( 9)
is satisfied, the phase matching between the fundamental wave and its second harmonic is effected. Such phase matching is referred to as the type II of phase matching
In cases where the type II of phase matching is effected with a biaxial crystal, the fundamental wave impinging upon the crystal is subjected to two refractive indexes of the crystal. By way of example, the nonlinear optical constant d24 of the crystal may be utilized. Specifically, as illustrated in FIG. 5, a fundamental wave 11, which has been polarized linearly in the direction indicated by the double headed arrow P, may be introduced into a crystal 10. The direction indicated by the double headed arrow P inclines at an angle of 45.degree. from the Y optic axis of the crystal 10 towards the Z axis of the crystal 10. (The fundamental wave 11 comprises the linearly polarized light component in the Y axis direction and the linearly polarized light component in the Z axis direction.) In this manner, a second harmonic 12, which has been polarized linearly in the Y axis direction, may be obtained from the crystal 10. In such cases, the linearly polarized light component of the fundamental wave 11 in the Z axis direction is subjected to a refractive index EQU n.sup.107,.sub.1 ( 10)
Also, the linearly polarized light component of the fundamental wave 11 in the Y' direction, which direction is normal to the direction of travel of the fundamental wave 11 and to the Z axis, is subjected to a refractive index EQU n.sup..omega.,.sub.2 ( 11)
Thus the fundamental wave 11 is subjected to the two refractive indexes.
Strictly speaking, in cases where the crystal 10 has been cut into the shape shown in FIG. 5, the fundamental wave 11 impinges upon the crystal 10 such that it has been polarized linearly in the Y' direction (which inclines from the Y axis towards the X axis) and in the Z axis direction. The second harmonic 12 is obtained as light which has been polarized in the Y' direction. However, practically, no problem occurs when consideration is made in the manner described above.
As described above, in cases where the type II of phase matching is to be effected with a biaxial crystal, a fundamental wave, which has been polarized linearly in one direction, has heretofore impinged upon a nonlinear optical material such that polarized light components may occur in directions along which the two crystallographic axes of the nonlinear optical material extend. Therefore, the fundamental wave has heretofore been subjected to two refractive indexes. If the fundamental wave is subjected to two refractive indexes, a phase difference .DELTA. will occur between the polarized light components, which are subjected to different refractive indexes. The phase difference .DELTA. is represented by the formula EQU .DELTA.=(n.sup..omega.,.sub.2 -n.sup..omega.,.sub.1)L.multidot.2.pi./.lambda. (12)
where .lambda. represents the wavelength of the fundamental wave, and L represents the length of the crystal. The length, L, of the crystal is the effective length, i.e., the length of the optical path of the fundamental wave in the crystal.
If the phase difference .DELTA. occurs, the direction of linear polarization of the fundamental wave will change in accordance with the value of the phase difference .DELTA.. If the direction of linear polarization of the fundamental wave thus changes, the angles of the direction of linear polarization of the fundamental wave, with respect to the optic axes of the crystal of the nonlinear optical material, will shift from the predetermined values of the angles, at which the maximum possible efficiency of wavelength conversion can be achieved. As a result, the output power of the second harmonic becomes low. Such fluctuations in the output power of the second harmonic occur periodically. The fluctuations in the output power of the second harmonic are classified into those which are dependent on the temperature and which occur in the pattern shown in FIG. 6, in accordance with the dependency of the parameters in Formula (12) upon the temperature, and those which are dependent on the length of the crystal and which occur in the pattern shown in FIG. 7.
Therefore, in order for the second harmonic having the maximum possible output power to be obtained, it is necessary that the temperature of the crystal or the length of the crystal be set to appropriate values. An example of an optical wavelength converting apparatus, in which the temperature of a crystal is adjusted, is disclosed in, for example, U.S. Pat. No. 4,913,533. Also, examples of optical wavelength converting apparatuses, in which the length of a crystal is adjusted, are disclosed in, for example, Japanese Unexamined Patent Publication Nos. 1(1989)-152781 and 1(1989)-152782.
Also, in Japanese Unexamined Patent Publication No. 1(1989)-152781, an optical wavelength converting apparatus is disclosed in which a crystal of a nonlinear optical material having a trapezoidal cross-sectional shape is located in a resonator. The crystal is moved up and down with respect to the trapezoid, and the length of the optical path of the fundamental wave in the crystal is thereby changed. In this manner, the phase difference .DELTA. is adjusted.
However, in cases where the length of the crystal is kept the same, and the temperature of the crystal is adjusted such that the second harmonic having the maximum possible output power may be obtained, a large electric power source for the adjustment of the temperature and a large heat sink must be employed such that the temperature of the crystal may be adjusted to a value falling within a wide range. Therefore, the size of the optical wavelength converting apparatus cannot be kept small in size, and the cost of the optical wavelength converting apparatus cannot be kept low.
Also, ordinarily, in cases where the temperature of the crystal is adjusted to a predetermined appropriate value, it inevitably occurs that the position, at which the temperature of the crystal is monitored, (or the position at which the temperature in the resonator is monitored) and the part of the crystal, through which the fundamental wave actually passes, are spaced apart from each other. Therefore, if the temperature in the optical wavelength converting apparatus is changed by a change in the ambient temperature, or the like, the detected temperature will not coincide with the temperature of the part of the crystal, through which the fundamental wave passes. As a result, the temperature of the part of the crystal through which the fundamental wave passes will be adjusted to a value different from the desired value. Accordingly, the second harmonic having the maximum possible output power cannot be obtained.
In cases where the temperature of the crystal is kept the same, and the length of the crystal is adjusted to a value appropriate for the temperature of the crystal, the length of the crystal must be adjusted very strictly. Therefore, it is difficult for the second harmonic having the maximum possible output power to be obtained. Even if it is possible for the second harmonic having the maximum possible output power to be obtained, because the length of the crystal must be measured and adjusted strictly, the cost of the optical wavelength converting apparatus cannot be kept low.
With the optical wavelength converting apparatus disclosed in Japanese Unexamined Patent Publication No. 1(1989)-152781, it is necessary for the crystal of the nonlinear optical material to be moved a comparatively large distance. Therefore, if the direction of linear polarization of the fundamental wave is adjusted, the position of the resonator mode will shift from the correct position. Also, with the optical wavelength converting apparatus disclosed in Japanese Unexamined Patent Publication No. 1(1989)-152781, the fundamental wave easily undergoes the longitudinal multimode. As a result, the problem occurs in that mode competition noise occurs easily.


A device is described. The device includes a suture guide and a tissue retracting surface to enable accurate and safe delivery of sutures through tissue.

There are difficulties sometimes associated with the closure of wound sites for example, where the defect is greater than two centimetres in length. There are difficulties in particular in finding the fascia layer through which a suture must be passed to ensure good and adequate fascial recruitment and there is also the risk of damaging internal structures when deploying a suture passer. When suturing abdominal wounds a retractor is often used to open the defect and present the abdominal layers to the user making it easier to place the suture through the relevant layers. The device disclosed here provides for retractor functionality while enabling accurate and protected suture deployment.
The consequences of inadequate closure may be serious. For example, the patient may be subject to an early or late onset hernia, wound dehiscence, bowel stricture, infection, or bleeding from the defect.


A recording apparatus, which records on a recording medium by using a plurality of recording heads, includes: a carriage for moving the plurality of recording heads in a direction crossing the direction in which the recording medium is fed; and a control section which, when at least two of the plurality of recording heads are of the same recording color, performs recording by alternately using such recording heads for a predetermined number of lines, whereby the amounts of ink consumed by the plurality of recording heads are equalized to make the ink service lives of the recording heads substantially the same.

1. Field of the Invention
The present invention relates to a recording apparatus which records on a recording medium by moving a plurality of heads in predetermined directions.
2. Description of the Related Art
Disposable-type recording heads have been widely used in recording apparatuses like word processors and electronic calculators having printers. For example, in many serial-type recording apparatuses for color recording, a plurality of recording heads are integrally attached to a carriage of the apparatus and arranged side by side thereon.
In such a color recording apparatus, the arrangement of the recording heads for different colors is determined beforehand, and the recording heads are operated in accordance with the order of their arrangement to selectively use them for recording.
However, when two-color printing, for example, in red and black, is to be performed, red and black recording heads, which are arranged at predetermined positions on the carriage, are selectively operated, line by line, by a CPU provided inside the recording apparatus body, in accordance with the data input from the outside.
For example, in the case of an electronic calculator having a printer, a plus data output is usually recorded in black, and a minus data output is recorded in red. However, there may also be a case where the two recording heads mounted in such a calculator are of the same color.
In this case, there is no need to select between recording colors in accordance with the input data, as either of the two heads is usable for recording. However, this leads to the following problem: in the above-described system in which the CPU controls recording, it is previously determined which of the two heads is to be used for recording according to the kind of data to be recorded. That is, each time recording is performed, the CPU determines the recording head to be used in accordance with the kind of data input from the outside, with the result that although the two heads are of the same color, they are not equally used, as the head to be used depends on the kind of data input from the outside. Thus, there is the possibility that the amount of ink used by one head will be different from that used by the other. This is undesirable from the viewpoint of efficient use of ink.

Recording method and apparatus in which use of recording heads is equalized


An apparatus for separating magnetic particles from a fluid, the apparatus comprising a tubular housing comprising an interior surface, an exterior surface, a first inlet port, a first outlet port, a second outlet port, and a channel; a tubular filter medium disposed within the tubular housing and comprising an inner surface and an outer surface, the filter medium partitioning the channel into a first passageway between the first inlet port of the tubular housing and the second outlet port of the tubular housing, and a second passageway in communication with the first outlet port of the tubular housing; and a wire coil wound around the exterior surface of the tubular housing, the wire coil comprising a first lead and a second lead. In operation, the wire coil is connected to a direct current power supply to effect enhanced separation of magnetic particles from a flowing fluid stream.

This invention relates in one embodiment to a fluid processing apparatus, and more particularly to an apparatus that can separate or concentrate magnetic particles in a flowing fluid.
1. Field of the Invention
A fluid separation and delivery apparatus for separating and/or concentrating magnetic particles in a flowing fluid, by the use of a filtration device.
2. Description of Related Art
There is a need in many industries for a simple apparatus and process to separate or concentrate a first phase relative to a second phase in a two phase flowing fluid. Such commercial and industrial applications for the present invention occur in the fields of medicine, food manufacturing, energy, electronics, imaging devices, chemicals, ceramics, and many others.
In one embodiment, for example, this invention relates to a liquid dispersion filtration and delivery processes in the manufacturing or fabrication of products in which effective filtration is required in order to ensure the quality of end products, for example, the manufacturing or fabrication and coating of thin films such as photoconductors, photographic film, and magnetic films. In particular, one embodiment of the invention relates to a high precision, high purity micro-filtered coating dispersion filtration and delivery apparatus including a crossflow filtration device in close proximity to a coating operation.
Photoconductive members or photoreceptors, that are for example organic, and which are used in electrophotographic machines, are well known. In the manufacture or fabrication of organic photoreceptors or the like, an organic solvent, a binder resin, and a pigment can be combined and milled for use in a charge generation layer thereof. The pigment and binder resin are chosen to optimize their photoconductive properties, but it is not always possible to optimize the dispersion quality of the resulting coating fluid. Charge generating dispersions that become unstable over time are a common problem in the fabrication of certain organic photoreceptors. Unstable dispersions and particulate impurities result in coating defects in the charge generating layer that lower coating yield during the fabrication process.
Current known photoreceptor coating dispersions containing pigments such as, e.g. benzimidazole perylene and hydroxygallium phthalocyanine, flocculate extensively when quiescent or when handled at low shear flow conditions. Reference may had to U.S. Pat. No. 6,195,443 of Hammond, the disclosure of which is incorporated herein by reference. Further reference may be had to the paper, "A Novel Technique for Investigation of Flow Behavior of Flocculating Dispersions," J. Hammond et al, presented at the International Coating Science and Technology Symposium, Wilmington, Del., May 1998, the disclosure of which is incorporated herein by reference.
Conventional filters in which all of the coating fluid entering the filter housing passes through the filter element typically operate at low shear near the surface of the filter medium. Thus, when a highly flocculating dispersion is delivered into a conventional filter device by a conventional delivery system, flocs of pigment ordinarily tend to form near the surface of the filter medium. The flow field moves the flocs onto the surface and into the bulk of the filter medium, ultimately resulting in plugging of the filter. In photoreceptor manufacturing or similar film or web coating operations, a plugged filter may cause a significant amount of downtime for a filter change, including restart and stabilization of the coating process (for example, for the purging of air bubbles from the filter device). This is obviously a costly interruption of such manufacturing process.
In one coating process embodiment, an initial countermeasure to such a filter problem was simply to use a filter element with a 40 micron pore size. Such a pore size was large enough that the pigment flocs, which form near the filter medium, did not plug the filter. Attempts to filter the dispersion using filter elements rated to retain particles small than 40 microns resulted in plugging of the filters with pigment flocs.
However, in embodiments of organic photoreceptor manufacturing, and other thin film device manufacturing, it is undesirable to use a filter that will allow the passage of particles in the 1 micron to 40 micron size range. Such particles and/or flocs may disrupt flow out of the extrusion die or other coating applicator, causing streaks. Also, the presence of particles of this large a size in the wet coated generator layer is known to result in defects in the dried generator layer. Both particles and streaks will show as defects in the final printed output to the end customer; therefore, any photoreceptor having such defects will not be acceptable.
The suggested use of a crossflow filter is an improvement over prior art filters. However, conventional coating fluid delivery systems in which such a filter is installed are ordinarily not optimum. They are often complex and do not locate the filter in close proximity to the coating die or other coating applicator. Therefore, such a conventional delivery system does not minimize the incidence of particulate defects and pigment flocs, which may be present in the coating fluid that is delivered into the die, and subsequently onto the coated film or photoreceptor. As such, the problem of filtering the coating dispersion at a process location immediately before and in close proximity to the coating application has not been addressed. Such a location of the filter significantly reduces the opportunity for the filtrate to be re-contaminated with undesired particles as it flows from the filter to the coating applicator. The use of a filter in very close proximity to the end use of the filtrate is known as "point-of-use" filtration in the semiconductor industry, and is a highly desired apparatus and process attribute.
There are numerous other applications for the apparatus and processes of the present invention. The present invention is not limited in any way solely to the production of a filtrate. Rather, the present invention is an apparatus and a process to separate or concentrate a first phase relative to a second phase in a multi-phase flowing fluid; or to separate or concentrate a first particle size population relative to a second particle size population in a multi-phase flowing fluid.
For example, in the manufacturing of a foodstuff such as a soup, the present invention may be used to perform a separation thereby providing a first highly viscous, stew-like product stream to a first destination, and a second less viscous broth-like product stream to a second destination. The present invention is further advantageous because it provides a filtration process wherein a high fluid shear rate exists at the surface of the filter medium. Such a process is useful in the preparation of shear-thinning foodstuffs, such as peanut butter. In one embodiment of the apparatus and process of the present invention, the present invention may be used to perform a separation of flowing peanut butter, wherein a first product stream comprises a "crunchy" peanut butter product comprising solid peanut chunks dispersed in liquid peanut butter flowing to a first destination, and a second product stream comprises a "creamy" liquid peanut butter flowing to a second destination. Many other similar uses of the present invention will be apparent to those skilled in the art.
In the preparation of abrasive particulate slurries used in e.g., surface cleaning, roughening, smoothing, and/or polishing, the present invention may be used to provide a first product stream comprising a population of large particles, and a second product stream comprising a population of small particles. Such a process may be used in the preparation of e.g., high precision optics. In the field of energy, such a use of the present invention has similar applicability in the preparation of coal-water slurries. In the field of mining, such a use of the present invention has similar applicability in the preparation of mineral or ore slurries prior to extraction or smelting.
In the semiconductor electronics industry, the present invention may be used to prepare a substantially particulate-free filtrate to be delivered to a filtrate-using destination, such as e.g., a wafer, magnetic storage disc, or compact disc spin-coating process. Such spin-coating operations are well known in the art of data disc manufacturing and semiconductor manufacturing.
The present invention is also widely applicability in biomedical devices, to separate or concentrate a first phase relative to a second phase in a flowing metabolic fluid; or to separate or concentrate a first particle size population relative to a second particle size population in a flowing metabolic fluid. In one embodiment, the apparatus of the present invention is miniaturized and integrated into a small implantable device, which may be used as e.g. an artificial organ performing a separation process. In another embodiment, the apparatus of the present invention is miniaturized and integrated into a small implantable device, which may be used as e.g. an device to deliver a drug comprising a material phase which would otherwise flocculate or congeal if not maintained in a flowing state at high shear.
Accordingly, embodiments of the present invention are provided that meet at least one or more of the following objects of the present invention:
It is an object of this invention to provide an apparatus and a method for producing a filtrate comprising fine particles in a liquid, in close proximity to a filtrate-using destination.
It is an object of this invention to provide an apparatus and a method for producing a filtrate comprising fine particles wherein the filter medium does not plug and become blocked by such particles.
It is an object of this invention to provide an apparatus and a method for producing a filtrate comprising fine particles, which is simple to construct.
It is an object of this invention to provide a method for producing a filtrate and a decantate, which is simple to operate and control.
It is an object of this invention to provide an apparatus and a method for producing a first fluid stream comprising large particles and a second fluid stream comprising small particles, wherein the filter medium does not plug and become blocked by such particles.
It is an object of this invention to provide an apparatus and a method for producing a filtrate comprising fine particles wherein the filter medium does not plug and become blocked by such particles, and wherein such apparatus is made sufficiently small as to be implantable within a human body.
It is an object of this invention to provide an apparatus and method for filtering and/or classifying a fluid containing magnetic particles.

This patent is subject to a terminal disclaimer.


A door assembly for a home appliance includes a door that opens and closes a heating chamber. The door may include a first plate and a second plate, the first and second plates forming a first air gap in the door for insulating heat in the heating chamber. Additionally, a valve may be provided in the door, the valve may selectively allow air outside the first air gap to communicate with the first air gap.

1. Field of the Invention
The present invention relates to a door assembly which opens and closes a heating chamber of home appliance, to an electric oven employing the door assembly, and to method for operating the electric oven.
2. Discussion of the Related Art
Electric oven is an apparatus which heats food deposited in a heating chamber thereof using heaters operable by electricity, such as, a ceramic heater, a sheath grill heater, and/or a halogen heater.
Electric oven can cook food quickly and has a high thermal efficiency. In addition, electric oven is relatively safe from a fire started by a flame compared to gas oven. Therefore, electric oven gets more popular nowadays.
Meanwhile, dirt including ingredient of food and oil sticks to inner walls of the heating chamber of the electric oven while cooking. It is hard for the user to clean the dirt stuck to the inner walls of the heating chamber. Therefore, some electric ovens provide a special function which automatically cleans the inner walls of the heating chamber.
During the operation of the electric oven in an automatic cleaning mode, heaters of the electric oven heats up the heating chamber to a very high temperature, for example, over 450 degree Celsius higher than a temperature from 100 to 300 degree Celsius at which food is cooked. Therefore, the dirt stuck to the inner walls of the heating chamber is pyrolyzed and carbonized during the automatic cleaning mode. After the electric oven finishes the automatic cleaning mode, the user can easily remove carbonized dirt from the inner walls of the heating chamber by sweeping it with a brush.
Heat in the heating chamber is transferred to a door which opens and closes the heating chamber when the heaters heat up the heating chamber to cook food or to clean the inner walls of the heating chamber. Because the door is also heated by the heaters during the operation of the electric oven, the user may get a burn in case he/she accidentally touches the door during the operation of the electric oven, especially in the automatic cleaning mode.
In order to solve this problem, some electric ovens automatically cool down the door during the operation of the electric oven. These electric ovens include a fan that forms air flows running through an inner space of the door during the operation of the electric oven. The air flow generated by the fan usually cools down an inner surface of the door as well as an outer surface of the door while running through the inner space of the door. Therefore, the heating chamber as well as the door is cooled down by the air flow running through the door.
Accordingly, thermal efficiency of electric oven decreases when the fan cools the door during the operation of the electric oven. In addition, food deposited in the heating chamber is not evenly cooked because an area in the heating chamber adjacent to the door is so cooled compared to another area in the heating chamber opposite to the side adjacent to the door. Further, cooking time of electric oven increases.

Door assembly for home appliance, electric oven using the same, and method for operating electric oven


Extended wavelength tunability is achieved in a saturable absorber for applications such as modelocking lasers by realizing a semiconductor structure having a tapered energy bandgap profile in a portion of the saturable absorber wherein the profile is given as a function of the distance along the propagation axis of the saturable absorber. For certain applications, at least one mirror is monolithically integrated with the saturable absorber.

Extremely short duration optical pulses are important for high speed signal processing and communications. Optical pulses in this category are commonly called ultrashort optical pulses and have durations in the picosecond and sub-picosecond range. Ultrashort optical pulses have been obtained by techniques such as passive modelocking wherein a nonlinear element is placed either within the lasing cavity or within a cavity external to the lasing cavity. One such nonlinear element is a saturable absorber.
Saturable absorbers are materials which display a change in opacity related to the incident radiation intensity at a particular wavelength. Solids, liquids, and gasses may be used as saturable absorbers based upon the chosen wavelength of operation. The saturable absorber acts as a shutter. It absorbs all weak radiation incident upon it. As the intensity of the incident radiation reaches a sufficiently high level called the saturation intensity of the saturable absorber, the incident radiation is permitted to pass through the absorber. In general, the attenuation of the incident radiation caused by the saturable absorber is relatively low because the absorber is saturated into a transparent state at the wavelength for the incident radiation.
Organic materials such as dyes exhibit a broadband absorption response of several hundred nanometers. But, dyes require the use of mechanical elements such as nozzles and the like which are relatively large, subject to mechanical malfunction, and not easily integrable with solid state lasers. When used as saturable absorption elements, semiconductors form compact, reliable elements suitable for integration with solid state lasers. In contrast to organic materials, semiconductor materials are inherently narrowband saturable absorption elements having an absorption response of several tens of nanometers. Generally, semiconductor materials have a significantly narrower operating range than the tuning bandwidth of the laser system in which the semiconductor materials act as saturable absorbers. In order to modelock the laser for pulsed operation at a particular wavelength in the tuning range of a laser, it would be necessary to have a plurality of different replaceable narrowband saturable absorbers to cover the entire tuning range of wavelengths for the laser. Thus, there is no single solid state saturable absorber available having a sufficiently broadband absorption response which is substantially coextensive with the tuning range of available lasers.

Broadband semiconductor saturable absorber


An oral cannabis composition comprising molecularly separated cannabinoids, MCT oil and a terpene blend. A method of producing the oral cannabis composition comprising the steps of a) producing cannabis extract by supercritical carbon dioxide extraction; b) after step a), winterizing the cannabis extract; c) after step b), distilling the winterized cannabis extract to produce molecularly separated cannabinoids; d) after step c), mixing the molecularly separated cannabinoids with MCT oil; and e) after step d), mixing the mixture of MCT oil and molecularly separated cannabinoids with a terpene blend. A second method comprises the steps of a) selecting a desired mixture of molecularly separate cannabinoids; b) after step a), mixing the molecularly separated cannabinoids with MCT oil; and c) after step b), mixing the mixture of MCT oil and molecularly separated cannabinoids with a terpene blend.

Many users have the desire for cannabis compositions with consistent and targeted effects. However, this is difficult to achieve because there are over 800 known cultivars, each comprising unique plant molecule assortments. Even within the same cultivar, the chemical composition will vary each time it is grown due to environmental factors and mutation. The chemical composition of the plant has a profound effect on the user's experience as it relates to flavor and scent, as well as induced therapeutic benefit (examples: mood, energy level, mental acuity, pain relief, etc.). Due to the plant's inconsistent chemical composition, it is difficult to achieve cannabis compositions that have consistent effects from batch to batch.
As such, there is a need for improved cannabis compositions that produce targeted and consistent effects.
The present invention overcomes several of the deficiencies, disadvantages and undesired parameters associated with known cannabis compositions and methods of producing same.

Compositions comprising molecularly separated cannabinoids and terpene blends and methods of producing