Various conveyors and/or other components of one or more machines for the production and/or processing of cigarettes or other smokers' products are indirectly monitored to allow for automatic pinpointing of that component which affects the quality of products. The products are tested to generate test signals, and such signals are thereupon evaluated to ascertain the presence or absence of various constituents each of which is characteristic of the influence of a different component upon the quality of products. Once the presence or absence of a constituent is ascertained, the corresponding component is automatically pinpointed in response to a signal from the evaluating device. In the case of conveyors, the prime mover of the respective machine is driven at a reduced speed until that portion of the pinpointed conveyor which actually affects the quality of products assumes a predetermined position of ready accessibility to an attendant or to equipment which automatically eliminates the cause for the presence or absence of the respective constituents in the test signals.

The present invention relates to a method and apparatus for pinpointing the causes of malfunction of machines for the manufacture and/or processing of cigarettes and/or other commodities which constitute or form part of smokers' products. More particularly, the invention relates to a method and apparatus for ascertaining those conveyors, guides, tubes and/or other components of machines for the manufacture and/or processing of smokers' products which influence or can influence the quality of such products. Still more particularly, the invention relates to a method and apparatus for ascertaining (and preferably pinpointing) those changes in the characteristics and/or condition of certain components of one or more machines for the manufacture and/or processing of smokers' products which are likely to or invariably exert an adverse influence upon the quality of smokers' products, especially rod-shaped articles including plain or filter tipped cigarettes, cigars or cigarillos, filter rod sections or the like.
Many types of machines for the production and/or processing of smokers' products are prone to malfunction. This is due to the extremely high output of such machines (recent types of cigarette makers can turn out in excess of 100 cigarettes per second), to unpredictable changes in the characteristics (moisture content, particle size, specific weight, etc.) of natural, reconstituted or substitute tobacco, to complexity of machines, to inept and/or careless handling of machines, and/or other factors. For example, particles of tobacco are likely to clog the suction ports of rotary conveyors which are used in many types of cigarette makers and filter tipping machines so that the ports cannot properly attract tobacco shreds, unwrapped tobacco fillers, wrapped fillers, filter plugs, plain cigarettes or filter cigarettes. Also, adhesive paste is likely to contaminate conveyors or other machine components which come into contact with cigarette paper webs, uniting bands, wrappers of plain or filter cigarettes or other adhesive-coated or adhesive-containing parts of smokers' products. Still further, filter rod sections or portions thereof (e.g., filter plugs of double unit length) are likely to be wedged in the guides, flutes or other portions of machine parts in a filter rod making, filter rod propelling or filter tipping machine. Finally, parts of such machines can become inoperative as a result of wear, as a result of improper maintenance and/or for other reasons to necessitate at least short-lasting stoppage or reduction in the speed of the respective machine until the damaged machine part is replaced or repaired. The aforediscussed defects of conveyors and/or other machine parts must be eliminated without delay because they are highly likely to and normally do affect the quality of smokers' products.
As a rule, at least certain types of smokers' products are tested prior to introduction into a packing machine or into storage. For example, plain or filter cigarettes are tested to ascertain the condition of their wrappers and/or tobacco-containing ends. Cigarettes wherein the permeability of wrappers and/or the density of tobacco-containing ends is excessive or too low are segregated from other (satisfactory) cigarettes. When the number of rejects reaches or exceeds a certain percentage of the total output of a cigarette maker or filter tipping machine, the machine or the testing device generates a signal to warn the attendants or automatically stops the main prime mover. By examining the defective cigarettes, an experienced attendant is likely to rapidly ascertain the cause of production of excessive numbers of rejects. In many instances, simple cleaning of a conveyor or the like to remove tobacco dust, larger fragments of tobacco leaves, squashed filter plugs, dried adhesive paste or the like suffices to restore the respective components to their operative condition.
However, in many instances, the search for the cause of malfunction of a machine for the making and/or processing of smokers' products (hereinafter called cigarettes) is a tedious and time-consuming task, even if such task is performed by a highly skilled and careful attendant. Losses in output are extremely high, i.e., losses in the output of a cigarette maker often amount to tens and hundreds of thousands of articles.
In accordance with a presently known proposal, those components of a machine for the manufacture and/or processing of cigarettes which are most likely or more likely to become partly or fully inoperative are equipped with mechanical, electronic or other types of sensors (as a rule, the sensors monitor the products or parts of products in or on the selected components) which generate signals in response to detection of malfunction or inferior products. For example, a sensor can generate a visible or audible signal when the filter plug of a filter cigarette is missing, when the quantity of adhesive in the seam of the wrapper of a cigarette is too low or excessive, when the wrapper exhibits a large hole, when a web of cigarette paper is defective or for other reasons. The attendant notes the signal (e.g., a lighted lamp) at a point which is remote from the defective component and proceeds to rapidly eliminate the cause of defects.
The installation of numerous sensors in a cigarette making or processing machine could greatly reduce the downtimes by enabling the attendants to pinpoint the causes of malfunction with a minimum of delay. However, the number of sensors which can be installed at a reasonable cost and without interfering with normal operation of the machine is evidently limited. Furthermore, the installation of lamps or other signal generating devices next to the respective sensors or machine components would result in further crowding of the machine and would contribute significantly to sensitivity and maintenance cost of such machine. Therefore, the just discussed proposal failed to gain widespread acceptance in the industry, mainly because its remedial action is not all-embracing.
U.S. Pat. No. 3,242,321 granted Mar. 22, 1966, to Henry R. Chope proposes to combine a testing device with several detectors which monitor vibrations of selected conveyors or other components of a machine in such a way that, when the quality of tested products is less than satisfactory, the detectors are addressed in a given sequence to ascertain whether or not the vibratory movements of corresponding components are normal. If the vibrations of a component are different from normal, the detector-addressing circuit causes one of several lamps to transmit a visible signal and to thus pinpoint the presumably defective component. The patent mentions that the just discussed system can be installed in a cigarette maker. However, applicants and their assignee are not aware of any cigarette makers or other machines for the manufacture or processing of smokers' products which incorporate such system or a similar arrangement for rapid detection of components which cause a lowering of the quality of the ultimate product or products.
A highly likely reason for the absence of a system of vibration detectors in a cigarette maker or a similar or related machine is that a filter plug which is wedged in a stationary guide or the adhesive-contaminated tubular guide of a cutoff for plain or filter cigarettes or filter plugs is quite unlikely to cause detectable changes in vibration of the respective machine components. First of all, the machines for mass-production of smokers' products are sturdy, so that the presence of dried adhesive or of a jammed filter plug is not supposed to change the frequency and/or amplitude of vibrations of affected components. Secondly, detection of minute changes of vibrations would necessitate resort to highly sensitive detectors which would contribute excessively to the initial and/or maintenance cost of the machine.

Method and apparatus for pinpointing the causes of malfunction of machines for the manufacture and/or processing of cigarettes or the like


A helmet system comprising a helmet (11), a vizor (13) pivotally mounted on the helmet, and mounted on the vizor (13), an electro-optical system, e.g. a night vision goggle, including an eyepiece (33) positioned between a transparent part (19) of the vizor and the user's eye so as to provide the user with a view of a scene forward of the user through the eyepiece, the eyepiece also serving as a combiner to provide the user with a virtual image of a display produced by the electro-optical system superimposed on his view of the forward scene through the eyepiece.

This invention relates to helmet systems.
More particularly the invention relates to helmet systems of the kind comprising a helmet and a vizor which is angularly displaceable with respect to the helmet about a transverse axis fixed with respect to the helmet.
Such helmet systems, especially when for use in combat aircraft, frequently also include an electro-optical system including a combiner eyepiece through which a user of the helmet system is able to view a scene forward of the user and which serves to reflect light rays derived from a display surface of the electro-optical system to provide the user with a virtual image of the display surface superimposed on his view of the forward scene through the eyepiece.
The electro-optical system typically comprises a night vision system providing an intensified image of the forward scene. However the electro-system may additionally or alternatively display other data, for example flight data in the case of a helmet system for use in an aircraft.
It is sometimes desirable for the helmet system user to be able to use the vizor and the electro-optical system simultaneously, and this can present considerable difficulty in respect of mounting the vizor and the electro-optical system on the helmet.


An imaging device for imaging an eye includes an eyepiece, an illumination system, an imaging system, and a controller. The illumination system includes a light source that emits illumination light along an illumination path through the eyepiece to the eye to produce a retinal diffuse reflection and a corneal specular reflection. The imaging system includes a first camera that captures a retinal image based on the retinal diffuse reflection and a first set of optical elements, a second camera that captures a corneal specular reflection image based on the corneal specular reflection and a second set of optical elements. The first camera captures at least some residual corneal specular reflection in the retinal image. The controller subtracts the residual corneal specular reflection from the retinal image based on the corneal specular reflection image.

Reflections and ghost images in many eye imaging applications affect the contrast and inhibit proper evaluation and diagnosis of different eye conditions by health care professionals. When imaging the eye, more than 2% of the illumination light is reflected by the cornea thereby generating a corneal reflection. Such reflection can happen even after careful choice of the illumination pattern and light angle. This corneal reflection can easily overwhelm the desired retinal image. Some imaging systems (e.g., fundus cameras) can be constructed and optimized so that the majority of the corneal reflection is outside of its field of view. However, these imaging systems are large, complex, and expensive. Furthermore, these systems have other disadvantages, including for example, being very sensitive to eye position and pupil diameter, having limited feedback loop speed, and having limited field of view. Accordingly, there is much room for significant advancement in eye imaging technology in order to reduce the size, complexity, and cost of such devices, such that they are affordable, reliable, and simpler to use by health care professionals.

Eye imaging methods and devices with reflection reduction


A nut plate assembly includes a plate member comprising an aperture defined therethrough. The nut plate assembly also includes a shell member having a first end joined to the plate member and a second end opposite the first end. The nut plate assembly further includes a bias member disposed within the shell member and a nut comprising a shoulder portion configured to receive a portion of the bias member. The nut is disposed within the shell member and moveable between a first position proximate the shell member first end and a second position proximate the shell member second end. The bias member is configured to bias the nut toward one of the first position and the second position. The nut plate assembly also includes a retention member configured to retain the nut within the shell member.

The field of the disclosure relates generally to nut plates, and more specifically to nut plates including a spring-loaded nut.
At least some known floating nut plates include a base or bottom plate with an opening and support a nut or similar fastener element that is captured on the base by a retainer or cage component. Such nut plates facilitate holding components, for example panels, together when a fastener is threadably engaged with the nut plate and tightened, while still enabling some movement between the components. In such known nut plates, the nut receives a fastener, such as a bolt, screw, or other threaded component element passed through an opening in the components and threaded into the nut. The opening in the component may be sized to enable the nut and fastener to move laterally to accommodate some movement between the fastened components.
At least some known floating nut plates may be used in the aerospace industry. In aerospace applications, the types and numbers of fasteners for a panel assembly can be significant. Some panel fasteners for a particular panel assembly may have different lengths, while otherwise looking similar to other panel fasteners. When the panel assembly is removed, a user may typically place all the panel fasteners in a separate location to keep from misplacing the fasteners. However, when replacing the panel assembly, the user may inadvertently use an incorrect length fastener for a particular panel fastener location. This can lead to an improperly attached panel assembly.


A heat resistant work shoe including a heat ventilating support for the shoe, the shoe having a plurality of holes for the ventilation of hot air, a reflective means provided at its lower part and the reflective means having concave surface coinciding with the curvature of the shoe upper in which it is located.

The present invention relates to a heat resistant work shoe, enabling the wearer to tolerate working on hot asphalt and other heated working surfaces.
For work shoes to correctly isolate the user's foot from intense heat of hot asphalt, the work shoe must necessarily capture some of the conducted heat through the sole and out of the work shoe itself.
Prior art work shoes present a disadvantage since the said soles become hot on hot surfaces and they may even be unbearable to wear, especially in the case of working on hot asphalt materials which may reach 350 degrees F., with the consequent inconvenience and even a risk of burn blisters if the work shoes are exposed to hot asphalt for any considerable period of time.
Shoes incorporating simple or safe ventilating features are already known. Nevertheless, all those devices are based on the elimination of built-up body heat and perspiration. In addition, various shoes have built-in air chambers for the additional purpose of providing resilient air cushions within a shoe.
However, for various reasons the manufacture of high heat resistant work shoes is still necessary. Thus, shoes including parts which ventilate body heat air by means of outlet conduits and the like are known.
U.S. Pat. No. 4,438,573 to McBarron, U.S. Pat. No. 4,888,887 to Solow, and U.S. Pat. No. 4,999,932 to Grim describe air cushioned shoes with pumping members. The ventilating features of these shoes are to regulate the air pressure within the air cushioned reservoirs of the shoes.
U.S. Pat. No. 3,284,930 to Baldwin, U.S. Pat. No. 4,654,982 to Lee, and U.S. Pat. No. 4,941,271 to Lakie, describe boots, such as ski boots, with air and moisture ventilation chambers with outlet ventilation ports on the upper part of the boots.
U.S. Pat. No. 4,224,746 to Kim, U.S. Pat. No. 4,417,407 to Fukuoka, U.S. Pat. No. 4,602,441 of El Sakkaf, U.S. Pat. No. 4,760,651 to Pon-Tzu, U.S. Pat. No. 4,813,160 to Kurnetz, U.S. Pat. No. 4,993,173 to Gardiner, U.S. Pat. No. 4,835,883 to Tetrault, U.S. Pat. No. 5,010,661 to Chu and U.S. Pat. No. 5,025,575 to Lakie also disclose shoes or boots with air ventilation chambers wherein cool air is directed into the shoe or boot and warm moist body heat generated air is directed out of the shoe or boot.
U.S. Pat. No. 4,546,555 to Spaderman, U.S. Pat. No. 4,813,159 to Weiss, U.S. Pat. No. 4,813,161 to Lesley, U.S. Pat. No. 4,813,162 to Harris and U.S. Pat. No. 4,888,888 to Ashton disclose several cushioning features for footwear.
With respect to temperature control footwear, U.S. Pat. No. 4,249,319 to Yoshida, U.S. Pat. No. 4,658,515 to Oatman and U.S. Pat. No. 4,777,740 top Akagi describe shoes or boots designed to insulate and retain heat within the shoe or boot during cold environmental conditions.
Specifically, Yoshida '319 employs the introduction of exothermic heat inserts, Oatman '515 uses a chamber with insulated particles and heat reflective foil to reflect heat back to the foot of the wearer, and Akagi '740 uses closely stitched foam layers to retain heat in cold weather conditions.
These prior art patents have various ventilating features for shoes or boots, some with venting outlet ports located on various areas of the footwear, and some with air ventilating tubes or conduits to increase cushioned comfort and to reduce perspiration for the wearer.
However, none of the devices disclosed in these prior art patents utilize a reflective material specifically combined with a venting system to reduce inside intense shoe temperature build-up for the wearer of work shoes in high heat work environments, such as on hot asphalt road work.
The present invention includes a sole structure with a light upper inner sole separated from a heavier, lower inner sole by a heat collecting chamber, wherein the space between two soles includes a squeezable, bendable insert of numerous, preferably cylindrical, resilient supporting bodies to facilitate air circulation therebetween.
According to the preferred embodiment, an additional heat reflective means is constituted by a layer of cork material capable of dissipating some of the heat reflected away from the shoe by the reflective foil.
An advantageous characteristic, according to the invention, is that the thin reflective layer parts of the work shoe have a concavity, wherein they adapt themselves to the curvature of the upper part of the shoe upper in which they are placed.


An online system optimizes for longer attribution window conversions with an additive decomposition model by predicting the probability that a predefined action happens given an impression/click. The online system receives a content item from a content provider for display to a target user, and predicts a probability that a target user will convert given an interaction with the content item by the target user. The online system computes, by a first trained model, a short-term conversion probability of a conversion event happening within a first conversion window after the interaction. The online system computes, by a second trained model, a long-term conversion probability of the a conversion event happening within a second conversion window after the interaction, the second conversion window being longer than the first conversion window. The online system computes the conversion probability given the interaction based on the short-term conversion probability and the long-term conversion probability.

This disclosure generally relates to content distribution of online systems, and in particular to optimizing for long attribution window (e.g., 14 days) conversion with an additive decomposition model.
Content providers produce content to target their content towards certain audiences within online systems. With the advent of online systems such as social networking systems, content providers have increasingly relied on the online systems to create effective sponsored content within the online system to greatly increase engagement among users of the online systems. There is a cost associated with sending content to a user, and the content provider would like to optimize how content is created and delivered to the user. If a content provider sends the content to a user that is not interested in the content, the content provider wastes resources. If the content provider does not send the content to a user when the user is receptive to the content, the content provider does not take advantage of the user's interest.
To enhance content delivery within an online system, the online system for a content provider may predict the probability of a predefined action happening after a campaign is launched from the content provider. However, the online system may have to wait until enough data is collected to improve delivery of content to users. For example, the online system can predict the probability of a predefined action happening given an impression/click, or can predict the conversion rate. However, conversion events can span over a wide range of content delivery spectrum, e.g., from clicking a link, viewing a home page of a content item, to adding to a shopping cart and purchasing. Existing solutions for modeling clicks and conversions predict the conversion rate for conversion events that happen within 1-day post click, i.e., a 1-day attribution window. Although a 1-day attribution window may be reasonable for conversion events such as viewing a product home page right after a click, other conversion events such as adding to a shopping cart or purchasing may happen days or even weeks after a click. For example, for content providers in the travel business, it usually takes a much longer time for a user to decide whether to buy airline tickets after the user clicks an online offering from a content provider. The gap between what existing solutions offer and what content providers really care about can have a negative impact on the content providers' experience with the online system.

Conversion optimization with long attribution window


To provide a method for producing a magnetic disk, whereby a magnetic recording layer is formed at a high temperature. A method for producing a magnetic disk, which comprises a step of forming a magnetic recording layer on a glass substrate having a temperature of at least 550° C., wherein the glass substrate comprises, as represented by mol percentage, from 62 to 74% of SiO2, from 6 to 18% of Al2O3, from 2 to 15% of B2O3 and from 8 to 21%, in total, of at least one component selected from MgO, CaO, SrO and BaO, provided that the total content of the above seven components is at least 95%, and further contains less than 1%, in total, of at least one component selected from Li2O, Na2O and K2O, or contains none of these three components.

In recent years, along with an increase in the recording capacity of a hard disk drive, densification for a high recording density has been in progress at a high pace. However, along with the densification for a high recording density, microfabrication of magnetic particles is likely to impair thermal stability, thus leading to a problem of cross talk or a decrease in the S/N ratio of a playback signal. Under the circumstance, attention has been drawn to a thermal assist magnetic recording technique as a combined technique of optics and magnetism. This is a technique wherein a magnetic recording layer is irradiated with a laser beam or near field light to lower the coercive force locally at the heated portion, and in such a state, an external magnetic field is applied for recording, and the recorded magnetization is retrieved by e.g. GMR element, whereby recording can be made on a high coercive force medium, and it becomes possible to microfabricate magnetic particles while maintaining the thermal stability. However, in order to form a high coercive force medium in the form of a multi-layered film, it is required to sufficiently heat the substrate, and a highly heat resistant substrate is desired.
Further, also for a perpendicular magnetic recording system, a magnetic recording layer different from a conventional one has been proposed in order to meet the requirement for densification for a high recording density, but for the formation of such a magnetic recording layer, the substrate is required to be heated at a high temperature, in many cases.
Whereas, a silicon substrate has been proposed as a substrate which is useful for the above mentioned thermal assist magnetic recording technique (Patent Document 1).

Method for producing magnetic disk, and glass substrate for information recording medium


A circuit design process for the reduction of routing congestion is described. This process includes a block placement operation, an initial pin optimization for the block placement, and global routing based upon the initial pin optimization. Congestion data is generated from the global routing and, in an automated process, the pins are re-optimized, based upon the congestion data. This process can be used as part of a custom layout design process, for example.

1. Field of Invention
The present invention generally relates to integrated circuit ("IC") and electronics design processes and electronic design automation tools. More specifically, the present invention relates to automated IC design data and, more specifically, to routing congestion removal during pin optimization, particularly for custom IC design.
2. Description of Related Art
A typical custom design flow 100 is shown in FIG. 1. After design entry 101, layout generation 103 and initial design 105 follow floorplanning. As shown in FIG. 1, the floorplanning stage 107 includes block placement 109 and pin optimization 111. During pin optimization 111, pins of blocks and top level design blocks are placed based on connectivity to minimize the overall wire length. Even though the wire length is minimized in this process, many times the pin optimization results in hot spots (highly congested areas) in order to minimize wire-length. Global routing 113 provides the congestion data in the design. If there are high congestion areas in the design 115, then the designer will either manually re-position the pins 117 or, alternately, restart pin optimization on selected pins with a new set of constraints until the level of congestion is acceptable and continuing on 119.
There does not currently exist any solution in the custom IC design domain to consider congestion during pin optimization. Hence it is a repetitive task to run the global router and re-position pins manually to minimize congestion in the design in order to get the desired results.


This invention relates generally to compounds and processes for synthesizing derivatives of 2-3-O-isopropylidene-xcex1-L-xylo-2-hexulofuranosonic acid. The compounds of this invention are useful, inter-alia, for the inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies, including inflammatory and autoimmune diseases, such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection and psoriasis. This invention also relates to pharmacological compositions containing derivatives of 2-3-O-isopropylidene-xcex1-L-xylo-2-hexulofuranosonic acid and the methods of treating such pathologies as listed above.

This invention relates generally to compounds and processes for synthesizing derivatives of 2-3-O-isopropylidene-xcex1-L-xylo-2-hexulofuranosonic acid. The compounds of this invention are useful, inter-alia, for the inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies, including inflammatory and autoimmune diseases, such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection and psoriasis. This invention also relates to pharmacological compositions containing derivatives of 2-3-O-isopropylidene-xcex1-L-xylo-2-hexulofuranosonic acid and the methods of treating such pathologies as listed above.
Cell adhesion is a process by which cells associate with each other and migrate towards a specific target localized within the extracellular matrix. Specialized molecules, called cell adhesion molecules (CAMs), mediate these reactions. CAMs have been demonstrated to participate in various cell-cell, cell-extracellular matrix, and platelet-platelet interactions. CAMs influence the leukocytes"" adhesion to the vascular endothelium, their transendothelial migration, retention at extravascular sites, and activation of T cells and eosinophils. These processes are central to the pathogenesis of inflammatory and autoimmune diseases. Therefore, CAMs are considered potential targets for treating such disorders.
CAMs can be classified into three groups: integrins, selectins, and the immunoglobulin superfamily. Of these, integrins are the key mediators in the adhesive interactions between hemopoietic cells and their microenvironment. They are comprised of alpha-beta heterodimers and integrate signals from the outside to the inside of cells, and vice versa. Integrins can be classified on the basis of the beta subunits they contain. For example, the beta-1 subfamily contains beta-1 subunit noncovalently linked to one of the 10 different alpha subunits.
The alpha-4 beta-1 integrin, also known as VLA4 (very late activation antigen 4), is a member of the beta-1 integrin family and comprises alpha-4 and beta-1 subunits. VLA4 interacts with two specific ligandsxe2x80x94the vascular cell adhesion molecule (VCAM-1) and the CS1 region of the protein fibronectin. Adhesion mediated by VLA4 is central to the process of transendothelial migration of leukocytes. Ligation of VLA4 is followed by gross rearrangement of the cytoskeleton, leading to flattening of cells along the blood vessel wall, followed by expression of specific molecules that digest the endothelial cell wall and diapedesis. Once in the extraluminal region, the interactions of VLA4 with extracellular fibronectin play a crucial role in the migration of leukocytes to the site of inflammation, T cell proliferation, expression of cytokines and inflammatory mediators. Additionally, VLA4 ligation provides co-stimulatory signals to the leukocytes, resulting in enhanced immunoreactivity. Thus, appropriate VLA4 antagonists would, in theory, ameliorate the immune response through a twofold action-inhibition of T cell recruitment at the site of inflammation and inhibition of co-stimulatory activation of immune cells.
In this respect, inhibitors of VLA4 interactions have been demonstrated to exhibit beneficial therapeutic effects in several animal models of inflammatory and allergic diseases, including sheep allergic asthma (Abraham et al, J. Clin. Invest. 1994;93:776); arthritis (Wahl et al, J. Clin. Invest. 1994;94:655); experimental allergic encephalomyelitis (Yednock et al, Nature (Lond), 1992;356:63 and Baron et al, J. Exp. Med. 1993;177:57); contact hypersensitivity (Chisolm et al, Eur J. Immunol. 1993;23:682); type I diabetes (Yang et al, Proc. Natl. Acad. Sci. (USA) 1993;90:10494); and inflammatory bowel disease (Podolsky et al, J. Clin. Invest. 1993;92:372).
The CS1 moiety region of fibronectin involved in the interaction with VLA4 was identified as the tripeptide Leu-Asp-Val (LDV) (Komoriya et al, J. Biol. Chem. 1991;266:15075). Several peptides containing the LDV sequence were synthesized and shown to inhibit the in vivo interaction of VLA4 to its ligands (Ferguson et al, Proc. Natl. Acad. Sci. (USA) 1991;88:8072; Wahl et al, J. Clin. Invest. 1994;94:655; Nowlin et al, J. Biol. Chem. 1993;268(27):20352; and PCT publication WO91/4862).
Despite these advances a need for small and specific inhibitors of VLA4-dependent cell adhesion molecules remains. Ideally, such inhibitors are water soluble with oral efficacy. Such compounds would provide useful agents for the treatment, prevention or suppression of various inflammatory pathologies mediated by VLA4 binding.
It is generally known that isopropylidene and benzylidene groups are the most commonly used protective groups in carbohydrate chemistry. Although both groups are introduced into a molecule under similar conditions, the location of the protection can be quite different, and this difference is directly related to the stability of each protected molecule. Since protection normally occurs under conditions that allow reversibility, the reaction proceeds until equilibrium is reached. The distribution of products at equilibrium is determined by their relative thermodynamic stabilities. In other words, these reactions are thermodynamically controlled. Benzylidene groups prefer to be part of 6-membered ring acetals, while the ketals resulting from acetonation generally are 5-membered rings. The difference is attributed to the effect of the methyl and phenyl substituents on the stability of the particular ring systems. These blocking methods are described in the U.S. Pat. Nos. 2,715,121, 4,056,322, 4,735,934, 4,996,195 and 5,010,058, the disclosures of which are incorporated herein by reference. Other blocking methods are also described in J. Carbohydr. Chem. 1985;4:227 and 1984;3:331; Methods in Carbohydr. Chem. 1962;1:107 and 1962;1:191; Can J. Chem. 1984;62:2728, 1969;47:1195, 1455, and 1970;48:1754, all incorporated herein by reference. The prior art reveals that D-glucose is blocked at the 1,2;5,6-positions with either the isopropylidene or cyclohexylidene blocking group, leaving the 3-position open to undergo derivatization. The therapeutic activity of hexoses and their derivatives are also disclosed in some of the above-cited prior art.
The compounds of the present invention were screened for inhibitory activity in VLA4-mediated cell adhesion assay and the classical murine hypersensitivity assay in mice. Several compounds exhibited significant inhibitory activity in both tests. The salts of these compounds could be easily solubilized in water and used in the treatment of chronic, cell adhesion-mediated, allergic, autoimmune and inflammatory disorders, such as bronchial asthma and rheumatoid arthritis. Some of the prior art describes development of peptide derivatives as cell adhesion antagonists for treatment of these diseases. However, because treatment of chronic diseases requires prolonged (mid-term to long-term) administration of drugs, the development of specific, orally available cell adhesion inhibitors would be very beneficial.
There is no example available in the prior art wherein the compounds, containing a sugar nucleus coupled with carbamate moiety, of the present invention are used as therapy for the inhibition, prevention and suppression of VLA4-mediated cell adhesion and pathologies associated with that adhesion.
An object of the present invention is to provide a process for synthesizing a new class of compounds that exhibit significant activity as VLA4 antagonists.
Most of the compounds described in U.S. Pat. No. 5,637,570 have shown significant anti-cancer activities and were devoid of any anti-cell adhesion activities. Therefore, the compounds of the present invention were designed and synthesized so as to enhance their anti-cell adhesion properties. It was discovered that, for a compound to be active as a cell adhesion inhibitor, it is best if the sugar has a carbamate moiety along with other functionalities.
It is a further object of this invention to provide a process for the preparation of novel carbohydrate-based water-soluble compounds that exhibit significant activity to be used as cell adhesion antagonists.
Other objects and advantages of the present invention will be set forth in the description that follows, will be in part apparent from the description, or may be learned by the practice of the invention. The objects and advantages of this invention may be realized and obtained by means of the mechanisms and combinations pointed out in the appended claims.
In order to achieve the above-mentioned objects and in accordance with one aspect of the present invention, there is provided a process for the synthesis of monosaccharide derivatives and the derivatives themselves, having the structure of Formula I:
wherein R is C1 to C15 alkyl, alkene, alkyne (straight chain or branched), aryl, substituted aryl or alkylaryl, R, is phenyl, o-, m- or p-chlorophenyl, tolyl, methoxyphenyl or nitrophenyl and R2 is H, pyrrolidinyl, piperidinyl, morphilinyl or hexamethyleneimino or a radical of the formula xe2x80x94NHR3 wherein R3 is C1 to C15 alkyl, alkene or alkyne (straight chain or branched) or a radical of Formula III:
wherein n is a whole number up to 5 and
is a five-, six- or seven-membered heterocyclic ring containing one or more heteroatoms, and wherein preferably
is pyrrolidinyl, piperidinyl, morpholinyl or hexamethyleneimino moieties.
Preferred compounds are those wherein R1 and R2 are not H at the same time. Acid addition salts of the above compounds are also included in the invention.
In accordance with another aspect of the present invention there is provided a list of compounds as shown below in the description of the invention section.
In accordance with another aspect of the present invention there are provided methods of preventing, inhibiting or suppressing cell adhesion in an animal (the term animal as used herein includes humans or mammals), comprising administering to said animal, the compounds described above.
In accordance with another aspect of the present invention there is provided a method for treating an animal suffering from bronchial asthma, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriasis, allograft rejection, and other inflammatory and/or autoimmune disorders, comprising administering to said animal, the compounds described above.
In accordance with yet another aspect of the present invention there is provided a method for preventing, inhibiting or suppressing cell adhesion-associated inflammation with compounds described above.
In accordance with a further aspect of the present invention there is provided a method for preventing, inhibiting or suppressing a cell adhesion-associated immune or autoimmune response with the compounds described above.
In accordance with another aspect of the present invention there is provided a method for treating or preventing a disease selected from the group consisting of asthma, arthritis, psoriasis, allograft rejection, multiple sclerosis, diabetes and inflammatory bowel disease, with the compounds as described above.
The compounds of the present invention are novel and exhibit significant potency in terms of their activity, which was determined by in vitro VLA4-mediated cell adhesion assay and in vivo mouse ear swelling test. The compounds that were found active in in vitro assay were tested in vivo. Some of the compounds of the present invention were found to be potent VLA4 antagonists. Therefore, the present invention provides the pharmaceutical compositions for the possible treatment of bronchial asthma and other inflammatory and autoimmune disorders. In addition, the compounds of the above invention can be administered orally or parenterally.
The compounds of the present invention may be prepared by techniques well-known in the art and familiar to the average synthetic organic chemist. In addition, the compounds of the present invention may be prepared by the following novel and inventive reaction sequence, which also show preferred R, R1 and R2 groups.
2,3-0-Isopropyl-1-0-alkyl or arylalkyl-6-deoxy-6-aminosubstituted-L-xylo-2-hexulofuranose compounds of Formula II, as shown in Scheme I, are prepared according to the method described in U.S. Pat. No. 5,637,570 and are the intermediates for the synthesis of the compounds of Formula I of the present invention. Thus, the following intermediates were prepared following the process as described in U.S. Pat. No. 5,637,570:
2,3-O-isopropylidene-6-deoxy-6-hexamethyleneimino-1-O-dodecyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-hexamethyleneimino-1-O-decyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-hexamethyleneimino-1-O-heptyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-pyrrolidinyl-1-O-dodecyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-pyrrolidinyl-1-O-decyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-pyrrolidinyl-1-O-heptyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-morphilinyl-1-O-dodecyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-morphilinyl-1-O-decyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-morphilinyl-1-O-heptyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-piperidinyl-1-O-dodecyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-piperidinyl-1-O-decyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-piperidinyl-1-O-heptyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-ethylpyrrolidinyl-1-O-dodecyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-ethylpyrrolidinyl-1-O-decyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-ethylpyrrolidinyl-1-O-heptyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-ethylmorpholinyl-1-O-dodecyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-ethylmorpholinyl-1-O-decyl-xcex1-L-xylo-2-hexulofuranose
2,3-O-isopropylidene-6-deoxy-6-ethylmorpholinyl-1-O-heptyl-xcex1-L-xylo-2-hexulofuranose.
Thus, the compound of Formula II is treated with an appropriate isocyanate in a suitable solvent at low temperature, preferably at 0-10xc2x0 C. to afford the compounds of Formula I of the present invention. An illustrative list of particular compounds according to the invention and capable of being produced by Scheme I include:
Compound No. Chemical Name
01. 2,3-O-Isopropylidene-1-O-decyl-4-(methylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
02. 2,3-O-Isopropylidene-1-O-dodecyl-4-(methylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
03. 2,3-O-Isopropylidene-1-O-dodecyl-4-(phenylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
04. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
05. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-tolylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
06. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
07. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
08. 2,3-O-Isopropylidene-1-O-decyl-4-(phenylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
09. 2,3-O-Isopropylidene-1-O-decyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
10. 2,3-O-Isopropylidene-1-O-decyl-4-(p-tolylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
11. 2,3-O-Isopropylidene-1-O-decyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
12. 2,3-O-Isopropylidene-1-O-decyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
13. 2,3-O-Isopropylidene-1-O-heptyl-4-(phenylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
14. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
15. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-tolylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
16. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
17. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
18. 2,3-O-Isopropylidene-1-O-dodecyl-4-(phenylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
19. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
20. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-tolylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
21. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
22. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
23. 2,3-O-Isopropylidene-1-O-decyl-4-(phenylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
24. 2,3-O-Isopropylidene-1-O-decyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
25. 2,3-O-Isopropylidene-1-O-decyl-4-(p-tolylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
26. 2,3-O-Isopropylidene-1-O-decyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
27. 2,3-O-Isopropylidene-1-O-decyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
28. 2,3-O-Isopropylidene-1-O-heptyl-4-(phenylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
29. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
30. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-tolylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
31. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
32. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
33. 2,3-O-Isopropylidene-1-O-dodecyl-4-(phenylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
34. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
35. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-tolylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
36. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
37. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
38. 2,3-O-Isopropylidene-1-O-decyl-4-(phenylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
39. 2,3-O-Isopropylidene-1-O-decyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
40. 2,3-O-Isopropylidene-1-O-decyl-4-(p-tolylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
41. 2,3-O-Isopropylidene-1-O-decyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
42. 2,3-O-Isopropylidene-1-O-decyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
43. 2,3-O-Isopropylidene-1-O-heptyl-4-(phenylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
44. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
45. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-tolylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
46. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
47. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
48. 2,3-O-Isopropylidene-1-O-dodecyl-4-(phenylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
49. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
50. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-tolylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
51. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
52. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
53. 2,3-O-Isopropylidene-1-O-decyl-4-(phenylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
54. 2,3-O-Isopropylidene-1-O-decyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
55. 2,3-O-Isopropylidene-1-O-decyl-4-(p-tolylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
56. 2,3-O-Isopropylidene-1-O-decyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
57. 2,3-O-Isopropylidene-1-O-decyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
58. 2,3-O-Isopropylidene-1-O-heptyl-4-(phenylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
59. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
60. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-tolylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
61. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
62. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
63. 2,3-O-Isopropylidene-1-O-dodecyl-4-(phenylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
64. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
65. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-tolylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
66. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
67. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
68. 2,3-O-Isopropylidene-1-O-decyl-4-(phenylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
69. 2,3-O-Isopropylidene-1-O-decyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
70. 2,3-O-Isopropylidene-1-O-decyl-4-(p-tolylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
71. 2,3-O-Isopropylidene-1-O-decyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
72. 2,3-O-Isopropylidene-1-O-decyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
73. 2,3-O-Isopropylidene-1-O-heptyl-4-(phenylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
74. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
75. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-tolylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
76. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
77. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
78. 2,3-O-Isopropylidene-1-O-dodecyl-4-(phenylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
79. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
80. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-tolylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
81. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
82. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
83. 2,3-O-Isopropylidene-1-O-decyl-4-(phenylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
84. 2,3-O-Isopropylidene-1-O-decyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
85. 2,3-O-Isopropylidene-1-O-decyl-4-(p-tolylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
86. 2,3-O-Isopropylidene-1-O-decyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
87. 2,3-O-Isopropylidene-1-O-decyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
88. 2,3-O-Isopropylidene-1-O-heptyl-4-(phenylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
89. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
90. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-tolylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
91. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
92. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-(2-ethylpiperidinyl)-xcex1-L-xylo-2-hexulofuranose
93. 2,3-O-Isopropylidene-1-O-dodecyl-4-(phenylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
94. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
95. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-tolylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
96. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
97. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
98. 2,3-O-Isopropylidene-1-O-decyl-4-(phenylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
99. 2,3-O-Isopropylidene-1-O-decyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
100. 2,3-O-Isopropylidene-1-O-decyl-4-(p-tolylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
101. 2,3-O-Isopropylidene-1-O-decyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
102. 2,3-O-Isopropylidene-1-O-dodecyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
103. 2,3-O-Isopropylidene-1-O-heptyl-4-(phenylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
104. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-chlorophenylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
105. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-tolylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
106. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-methoxyphenylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
107. 2,3-O-Isopropylidene-1-O-heptyl-4-(p-nitrophenylcarbamate)-6-deoxy-6-(2-ethylmorphilinyl)-xcex1-L-xylo-2-hexulofuranose
108. 2,3-O-Isopropylidene-1-O-dodecyl-4-(methylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
109. 2,3-O-Isopropylidene-1-O-dodecyl-4-(methylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
110. 2,3-O-Isopropylidene-1-O-dodecyl-4-(methylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
111. 2,3-O-Isopropylidene-1-O-dodecyl-4-(methylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
112. 2,3-O-Isopropylidene-1-O-dodecyl-4-(methylcarbamate)-6-deoxy-6-(2-ethylmorpholinyl)-xcex1-L-xylo-2-hexulofuranose
113. 2,3-O-Isopropylidene-1-O-decyl-4-(methylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
114. 2,3-O-Isopropylidene-1-O-decyl-4-(methylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
115. 2,3-O-Isopropylidene-1-O-decyl-4-(methylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
116. 2,3-O-Isopropylidene-1-O-decyl-4-(methylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
117. 2,3-O-Isopropylidene-1-O-decyl-4-(methylcarbamate)-6-deoxy-6-(2-ethylmorpholinyl)-xcex1-L-xylo-2-hexulofuranose
118. 2,3-O-Isopropylidene-1-O-heptyl-4-(methylcarbamate)-6-deoxy-6-pyrrolidinyl-xcex1-L-xylo-2-hexulofuranose
119. 2,3-O-Isopropylidene-1-O-heptyl-4-(methylcarbamate)-6-deoxy-6-morpholinyl-xcex1-L-xylo-2-hexulofuranose
120. 2,3-O-Isopropylidene-1-O-heptyl-4-(methylcarbamate)-6-deoxy-6-hexamethyleneimino-xcex1-L-xylo-2-hexulofuranose
121. 2,3-O-Isopropylidene-1-O-heptyl-4-(methylcarbamate)-6-deoxy-6-piperidinyl-xcex1-L-xylo-2-hexulofuranose
122. 2,3-O-Isopropylidene-1-O-heptyl-4-(methylcarbamate)-6-deoxy-6-(2-ethylpyrrolidinyl)-xcex1-L-xylo-2-hexulofuranose
123. 2,3-O-Isopropylidene-1-O-heptyl-4-(methylcarbamate)-6-deoxy-6-(2-ethylmorpholinyl)-xcex1-L-xylo-2-hexulofuranose.
The sugar derivatives of the present invention exhibit various pharmacological properties and are useful for treating animals, the term animal as defined herein includes human or mammal, with various inflammatory and autoimmune disorders, such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection and psoriasis.
The free amino compounds of the present invention are basic and form organic and inorganic acid salts. The resulting salts are useful by themselves and in the therapeutic composition and method of use. These salts may be prepared by the usual prior art techniques, such as suspending the compound in water and then adding one equivalent of the desired organic or mineral acid. Examples of preferred acids include hydrochloric, sulphuric, nitric, maleic, benzoic, tartaric, acetic, p-aminobenzoic, oxalic, succinic and glucoronic acid.
The neutral solution of the resulting salt is subjected to rotary evaporation under diminished pressure to the volume necessary to ensure precipitation of the salt upon cooling, which is then filtered and dried. The salts of the present invention may also be prepared strictly under non-aqueous conditions. For example, dissolving the free amine in a suitable organic solvent, adding exactly one equivalent of the desired acid to the same solvent and stirring the solution at 0-5xc2x0 C. causes precipitation of the amine salt, which is then filtered, washed with solvent and dried. The amine salts are often preferred for use in formulating the therapeutic compositions as they are crystalline and relatively more stable and non-hydroscopic. The amine salts are also better adapted for intramuscular injection than are the free amines.
Because of their valuable pharmacological properties, the compounds of the present invention may be administered to an animal for treatment orally, topically, rectally, internasally or by parenteral route. When the therapeutic composition is to be administered orally, it is preferred that the compounds of the present invention are admixed with a filler and/or binder, such as starch and a disintegrator. The admixture may be pressed into a tablet conveniently sized for oral administration. Capsules may also be filled with the powdered therapeutic composition for oral administration. Alternatively, a water solution of the amine salt or suspension of the therapeutic composition may be admixed with a flavored syrup and administered orally. A salt of the free acid is usually preferred when the compound is administered by parenteral route.
The pharmaceutical compositions of the present invention are preferably produced and administered in dosage units, with each unit containing a certain amount of at least one compound of the invention and/or at least one physiologically acceptable base salt addition thereof. The dosage may be varied over extremely wide limits, as the compounds are effective at low dosage levels and relatively free of toxicity. The compounds may be administered in the low micromolar concentration, which is therapeutically effective, and the dosage may be increased as desired up to the maximum dosage tolerated by the patient.
The present invention also includes within its scope prodrugs of the compounds of Formula I. In general, such prodrugs will be functional derivatives of these compounds which are readily converted in vivo into the defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known.
The present invention also includes the enantiomers, diastereomers, N-oxides, polymorphs and pharmaceutically acceptable salts of these compounds as well as metabolites having the same type of activity. This invention further includes pharmaceutical compositions comprising the molecules of Formula I or prodrugs, metabolite enantiomers, diastereomers, N-oxides, polymorphs or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carriers and optionally included excipients.

Derivatives of monosaccharides as cell adhesion inhibitors


A semiconductor device includes a SiGe base bipolar transistor. The SiGe base bipolar transistor includes an emitter layer, a collector layer and a SiGe base layer formed of silicon containing germanium. A Ge concentration of the SiGe base layer is increased from 0% to 10% from a side of the emitter layer towards a side of the collector layer.

1. Field of the Invention
The present invention relates to a semiconductor device and a semiconductor manufacturing method. More particularly, the present invention relates to a semiconductor device and a semiconductor manufacturing method, which can minimize a drop in a current gain at a time of an increase in a collector current density and also improve a variation in a collector current.
2. Description of the Related Art
As a conventional technique, for example, there is a technique disclosed in Japanese Laid Open Patent Application (JP-A-Heisei, 7-147287). That is, this is a SiGe base bipolar transistor, in which each of a base layer and a collector layer are constituted by a single crystal silicon layer containing germanium (Element Symbol: Ge), and an occurrence of a parasitic energy barrier is protected in a base-collector junction region, and a drop in a cut-off frequency is suppressed.
FIG. 1 is a device section view describing a conventional SiGe base bipolar transistor. In FIG. 1, a symbol 201 denotes a P-type silicon substrate. A symbol 202 denotes an N+-type buried layer. A symbol 203A denotes a first collector layer. A symbol 203B denotes a second collector layer. A symbol 205 denotes an insulation separation oxide film. A symbol 206 denotes a diffusion layer to pull out a collector. A symbol 207 denotes an oxide film. A symbol 208 denotes a P-type poly-crystal silicon layer to pull out an outer base. A symbol 209 denotes a silicon nitride film. A symbol 210 denotes a P-type SiGe base layer (silicon germanium base layer). A symbol 211 denotes a silicon nitride film. A symbol 212 denotes a poly-crystal silicon film to pull out an emitter. And, a symbol 213 denotes an emitter layer.
In the conventional SiGe base bipolar transistor, the N+-type buried layer 202 having a high concentration and the first collector layer 203A having a first Ge concentration distribution and the second collector layer 203B having a second Ge concentration distribution are formed on the P-type silicon substrate 201, as shown in FIG. 1. The P-type SiGe base layer 210 resulting from a selectively epitaxial growth and the emitter layer 213 constituted by an N-type diffusion layer are formed on the first collector layer 203A.
FIG. 2 is a graph showing the profile of a Ge percentage content (germanium percent content) and an impurity concentration with respect to a depth of the conventional SiGe base bipolar transistor. In the conventional SiGe base bipolar transistor, the first collector layer 203A having the first Ge concentration distribution and the second collector layer 203B having the second Ge concentration distribution (germanium concentration distribution) are formed in the N+-type buried layer 202 having the high concentration in which N-type impurity is doped at about 1020 cmxe2x88x923, as shown in FIG. 2. Then, the P-type SiGe base layer 210 in which P-type impurity is doped at about 5xc3x971018 cmxe2x88x923 and the poly-crystal silicon film 212 to pull out an emitter in which the N-type impurity is doped at about 2xc3x971020 cmxe2x88x923 are formed on the first collector layer 203A. The emitter layer 213 is formed by using the impurity thermal diffusion from the poly-crystal silicon film 212 to pull out an emitter in which the N-type impurity is doped.
With regard to the Ge concentration distribution of the P-type SiGe base layer 210, in the P-type SiGe base layer 210, an emitter region side has a low distribution, and a collector region side has a high distribution. That is, the emitter region side has a Ge percentage content of 0%, and the collector region side has a slant concentration distribution having a percentage content of 10%. FIG. 3 shows an energy band structure at this time.
FIG. 3 is a graph showing an energy band at the slant Ge profile (slant germanium profile). As shown in FIG. 3, in the case of the conventional SiGe base bipolar transistor, in the P-type crystal SiGe base layer 210, an inclination can be set for a conductive band side of an energy band, correspondingly to a Ge composition ratio (germanium composition ratio). Thus, an electron implanted from an emitter is accelerated in the P-type SiGe base layer 210 by an electrical field caused by the slant energy band structure. Hence, it is possible to reduce a base transit time of the electron and accordingly improve a cut-off frequency fT.
However, in the case of the conventional SiGe base bipolar transistor, in order to make the cut-off frequency fT higher by using the slant Ge profile, it is necessary to reduce a thickness of the P-type SiGe base layer 210. For example, it is noted that the thickness of the P-type SiGe base layer 210 is about 90 nm and the cut-off frequency fT=20 GHz. In order to set the cut-off frequency fT to 60 GHz, the thickness of the P-type SiGe base layer 210 must be reduced to about 30 nm. This brings about the following problems.
As the first problem, a constant region is narrow because of a drop in a current gain hFE in a high current region when the slant Ge profile is used, although an analog circuit especially requires that a current gain hFE (=collector current/base current) is constant in a wide current region of a collector current.
The reason is as follows. In the profile that the impurity concentration in the base is constant and the Ge concentration is slant such as the slant Ge profile, a collector current density Jc is represented by the following equation (1):                     Jc        =                                            qDn                                            xe2x80x83                                                          ni                2                                                    NA                                            xe2x80x83                                          Wb                                                                    Δ                                            xe2x80x83                                                          EgGe                                                  (                  grade                  )                                                      kT                                          exp                                      xe2x80x83                        [                                          Δ                                                  xe2x80x83                                                                  EgGe                                                        (                    0                    )                                                              kT                        ]                                              equation  (1)
xcex94EgGe(0): Contraction Amount of Band Gap by Ge at Tip of Depletion Layer between Emitter And Base
xcex94EgGe(grade): Ge Slant Amount in Neutral Base
Dn: Diffusion Constant of Electron in Base
NA: Base Impurity Concentration
Wb: Base Width
ni: Intrinsic Carrier Density
q: Charge
In the case of the slant Ge profile of the conventional SiGe base bipolar transistor, when the thickness of the P-type SiGe base layer 210 is reduced, this reduction causes the Ge inclinations (germanium inclinations) to be sharp at the positions of the formations of the emitter-base junction and the depletion layer between the emitter and the base. This results in a large reduction in a contraction amount xcex94Eg,Ge(0) of a band gap when the depletion layer between the emitter and the base is contracted as a voltage between the emitter and the base is made higher. Thus, the collector current is dropped in accordance with the equation (1), and the current gain hFE is largely dropped.
The second problem is the occurrence of a large variation in a collector current flowing when a certain voltage is applied between the base and the emitter. The variation in the collector current has great influence on a circuit operation when a transistor is used as a constant current source, for example, such as a case of an ECL circuit.
The reason of the variation in this collector current is as follows. The emitter layer 213 is formed by using the impurity thermal diffusion from the poly-crystal silicon film 212 to pull out an emitter in which the N-type impurity is doped. The reduction in the thickness of the P-type SiGe base layer 210 causes the Ge inclination (germanium inclination) to be sharp at the position where the emitter-base junction is formed. As a result, the slight variation at the junction position leads to the difference of the contraction amount xcex94Eg,Ge(0) in the band gap. That is, the collector current is proportional to the contraction amount xcex94Eg,Ge(0) in the band gap as an exponential function, which brings about the large variation in the collector current.
Japanese Laid Open Patent Application (JP-A-2000-31162) discloses the following hetero junction bipolar transistor. The hetero junction bipolar transistor is provided with: a collector layer constituted by a semiconductor containing a first conductive type impurity; a base layer that is provided adjacently to the collector layer and constituted by a compound crystal semiconductor containing a second conductive type impurity; and an emitter layer that is provided opposite to the collector layer with the base layer between and constituted by the semiconductor containing the first conductive type impurity. The base layer is provided such that a band gap of the compound semiconductor is gradually reduced from the emitter side towards the collector side and a concentration of the second conductive type impurity is gradually reduced from the emitter side towards the collector side.
Japanese Laid Open Patent Application (JP-A-Heisei, 11-214399) discloses the following bipolar semiconductor device. The bipolar semiconductor device is provided with: a semiconductor layer having a first conductive type of a buried layer so as to form a collector region, on a substrate; a first insulation film formed on the semiconductor layer; a second conductive type of a first conductive film similarly formed on the semiconductor layer so as to form a base region, a second conductive type of a second conductive film which is formed on the first insulation film and connected to the first conductive film so as to form a base pull-out electrode; and a first conductive type of a third conductive film which is separated through a second insulation film from the second conductive film and formed on the first conductive film so as to form an emitter region, wherein the first insulation film and the second conductive film are coated with glass material insulation film, and the surface of the glass material insulation film is flat.
Japanese Laid Open Patent Application (JP-A-Heisei, 10-79394) discloses the following bipolar transistor. The bipolar transistor at least contains: a first conductive type of a single crystal silicon layer; a many-layer film composed of a first insulation film having an opening provided on a surface of the first conductive type of the single crystal silicon layer, a second conductive type of a poly-crystal layer of a conductive type opposite to the first conductive type, and a second insulation film; a first conductive type of a single crystal silicon germanium layer provided in the opening; a second conductive type of a single crystal silicon germanium layer provided on the first conductive type of the single crystal silicon germanium layer; and a second conductive type of a poly-crystal silicon germanium layer placed in contact with both the second conductive type of the single crystal silicon germanium layer and the second conductive type of the poly-crystal layer.
Moreover, Japanese Publication Patent Application (JP-B2-Heisei, 07-44185) discloses the following semiconductor device. The semiconductor device is a bipolar transistor, in which on a silicon substrate or a silicon epitaxial layer having a first conductive type, has a compound crystal layer composed of silicon and germanium, and has a second conductive type impurity layer in the compound crystal, and has a silicon layer having a first conductive type impurity on the compound crystal layer of the silicon and the germanium, and has a hetero junction in a manner of forming a p-n junction on a boundary between the compound crystal layer of the silicon and the germanium and the silicon layer, wherein it is formed on the silicon substrate or the silicon epitaxial layer so that a germanium concentration included in the compound crystal composed of the silicon and the germanium is gradually higher towards the boundary between an outer compound crystal layer and the silicon layer thereon.
The present invention is accomplished in view of the above mentioned problems. Therefore, an object of the present invention is to provide a semiconductor device and a semiconductor manufacturing method, which can minimize a drop in a current gain at a time of an increase in a collector current density and also improve a variation in a collector current.
In order to achieve an aspect of the present invention, a semiconductor device, includes: a SiGe base bipolar transistor; and wherein the SiGe base bipolar transistor includes: an emitter layer; a collector layer; and a SiGe base layer formed of silicon containing germanium, and wherein a Ge concentration of the SiGe base layer is increased from 0% to 10% from a side of the emitter layer towards a side of the collector layer.
In this case, the SiGe base bipolar transistor includes: a P-type silicon substrate; and an N+-type buried layer having a high concentration formed in the P-type silicon substrate, and wherein the collector layer is formed of an N-type having a low concentration and is formed on the N+-type buried layer, and wherein the SiGe base bipolar transistor further including: an undoped SiGe layer in which an impurity is not doped, the undoped SiGe layer being formed on the N-type collector layer; a first SiGe base layer as a part of the SiGe base layer having a first Ge concentration distribution formed on the undoped SiGe layer; and a second SiGe base layer as another part of the SiGe base layer having a second Ge concentration distribution formed on the first SiGe base layer, and wherein the emitter layer is formed of an N-type diffusion layer formed in the second SiGe base layer.
In this case, an N-type impurity is doped at about 1016 cmxe2x88x923 as the low concentration of the N-type collector layer, and the N-type impurity is doped at about 1020 cmxe2x88x923 as the high concentration of the N+-type buried layer.
Also in this case, the undoped SiGe layer has a Ge concentration of about 10% and a thickness of about 30 nm.
Further in this case, a P-type impurity is doped at about 1xc3x971019 cmxe2x88x923 in the first SiGe base layer and the second SiGe base layer.
Further in this case, the semiconductor device further includes: a poly-crystal silicon film to pull out an emitter in which an N-type impurity is doped at about 2xc3x971020 cmxe2x88x923, the poly-crystal silicon film being formed on the second SiGe base layer.
In this case, the emitter layer is formed as a result that an impurity thermal diffusion is performed on the poly-crystal silicon film.
Also in this case, the SiGe base layer includes a first SiGe base layer and a second SiGe base layer, and wherein a thickness of the second SiGe base layer is about 20 nm, and a Ge concentration in the second SiGe base layer is increased from about 0% to about 2% from the side of the emitter layer towards the side of the collector layer, and wherein a thickness of the first SiGe base layer is about 10 nm, and a Ge concentration in the first SiGe base layer is increased from about 2% to about 10% from the side of the emitter layer towards the side of the collector layer.
Further in this case, the SiGe base bipolar transistor including: a P-type silicon substrate; and an N+-type buried layer having a high concentration in which an N-type impurity is doped at about 1020 cmxe2x88x923 formed in the P-type silicon substrate, and wherein the collector layer is formed of an N-type having a low concentration in which the N-type impurity is doped at about 1016 cmxe2x88x923 and is formed on the N+-type buried layer, and wherein the SiGe base bipolar transistor further including: an undoped SiGe layer in which an impurity is not doped, wherein the undoped SiGe layer is formed on the N-type collector layer and has a Ge concentration of about 10% and a thickness of about 30 nm; a third SiGe base layer as a part of the SiGe base layer having a third Ge concentration distribution formed on the undoped SiGe layer; a fourth SiGe base layer as another part of the SiGe base layer having a fourth Ge concentration distribution formed on the third SiGe base layer; and a Si base layer as other part of the SiGe base layer.
In this case, a P-type impurity is doped at about 1xc3x971019 cmxe2x88x923 in the third SiGe base layer, the fourth SiGe base layer and the Si base layer.
Also in this case, the semiconductor device further includes: a poly-crystal silicon film to pull out an emitter in which an N-type impurity is doped at about 2xc3x971020 cmxe2x88x923, the poly-crystal silicon film being formed on the Si base layer.
Further in this case, the emitter layer is formed as a result that an impurity thermal diffusion is performed on the poly-crystal silicon film.
In this case, the SiGe base layer includes a third SiGe base layer and a fourth SiGe base layer, and a Si base layer, and wherein a thickness of the Si base layer is about 20 nm, and wherein a thickness of the fourth SiGe base layer is about 5 nm, and a Ge concentration in the fourth SiGe base layer is increased from about 0% to about 2% from the side of the emitter layer towards the side of the collector layer, and wherein a thickness of the third SiGe base layer is about 5 nm, and a Ge concentration in the third SiGe base layer is increased from about 2% to about 10% from the side of the emitter layer towards the side of the collector layer.
In order to achieve another aspect of the present invention, a semiconductor with a SiGe base bipolar transistor manufacturing method, includes: (a) providing an emitter layer; (b) providing a collector layer; and (c) providing a SiGe base layer formed of silicon containing germanium, and wherein a Ge concentration of the SiGe base layer is increased from 0% to 10% from a side of the emitter layer towards a side of the collector layer.
Also in this case, the semiconductor with a SiGe base bipolar transistor manufacturing method further includes: (d) providing a P-type silicon substrate; and (e) forming an N+-type buried layer having a high concentration in the P-type silicon substrate, and wherein the collector layer is formed of an N-type having a low concentration and is formed on the N+-type buried layer, and wherein the semiconductor with the SiGe base bipolar transistor manufacturing method further including: (f) forming an undoped SiGe layer in which an impurity is not doped on the N-type collector layer; (g) forming a first SiGe base layer as a part of the SiGe base layer having a first Ge concentration distribution on the undoped SiGe layer; and (h) forming a second SiGe base layer as another part of the SiGe base layer having a second Ge concentration distribution on the first SiGe base layer, and wherein the emitter layer is formed of an N-type diffusion layer formed in the second SiGe base layer.
In this case, an N-type impurity is doped at about 1016 cmxe2x88x923 as the low concentration of the N-type collector layer, and the N-type impurity is doped at about 1020 cmxe2x88x923 as the high concentration of the N+-type buried layer.
Also in this case, the undoped SiGe layer has a Ge concentration of about 10% and a thickness of about 30 nm.
Further in this case, a P-type impurity is doped at about 1xc3x971019 cmxe2x88x923 in the first SiGe base layer and the second SiGe base layer.
In this case, the semiconductor with a SiGe base bipolar transistor manufacturing method further includes: (i) forming a poly-crystal silicon film to pull out an emitter in which an N-type impurity is doped at about 2xc3x971020 cmxe2x88x923 on the second SiGe base layer.
Also in this case, the emitter layer is formed as a result that an impurity thermal diffusion is performed on the poly-crystal silicon film.
Further in this case, the SiGe base layer includes a first SiGe base layer and a second SiGe base layer, and wherein a thickness of the second SiGe base layer is about 20 nm, and a Ge concentration in the second SiGe base layer is increased from about 0% to about 2% from the side of the emitter layer towards the side of the collector layer, and wherein a thickness of the first SiGe base layer is about 10 nm, and a Ge concentration in the first SiGe base layer is increased from about 2% to about 10% from the side of the emitter layer towards the side of the collector layer.
In this case, the semiconductor with a SiGe base bipolar transistor manufacturing method further includes: (j) providing a P-type silicon substrate; and (k) forming an N+-type buried layer having a high concentration in which an N-type impurity is doped at about 1020 cmxe2x88x923 in the P-type silicon substrate, and wherein the collector layer is formed of an N-type having a low concentration in which the N-type impurity is doped at about 1016 cmxe2x88x923 and is formed on the N+-type buried layer, and wherein the semiconductor with the SiGe base bipolar transistor manufacturing method further including: (l) forming an undoped SiGe layer in which an impurity is not doped on the N-type collector layer, the undoped SiGe layer having a Ge concentration of about 10% and a thickness of about 30 nm; (m) forming a third SiGe base layer as a part of the SiGe base layer having a third Ge concentration distribution on the undoped SiGe layer; (n) forming a fourth SiGe base layer as another part of the SiGe base layer having a fourth Ge concentration distribution on the third SiGe base layer; and (o) forming a Si base layer as other part of the SiGe base layer.
Also in this case, a P-type impurity is doped at about 1xc3x971019 cmxe2x88x923 in the third SiGe base layer, the fourth SiGe base layer and the Si base layer.
Further in this case, the semiconductor with a SiGe base bipolar transistor manufacturing method, further includes: (p) forming a poly-crystal silicon film to pull out an emitter in which an N-type impurity is doped at about 2xc3x971020 cmxe2x88x923 on the Si base layer.
In this case, the emitter layer is formed as a result that an impurity thermal diffusion is performed on the poly-crystal silicon film.
Also in this case, the SiGe base layer includes a third SiGe base layer and a fourth SiGe base layer, and a Si base layer, and wherein a thickness of the Si base layer is about 20 nm, and wherein a thickness of the fourth SiGe base layer is about 5 nm, and a Ge concentration in the fourth SiGe base layer is increased from about 0% to about 2% from the side of the emitter layer towards the side of the collector layer, and wherein a thickness of the third SiGe base layer is about 5 nm, and a Ge concentration in the third SiGe base layer is increased from about 2% to about 10% from the side of the emitter layer towards the side of the collector layer.
The purpose of the present invention characteristically lies in a semiconductor device containing a SiGe base bipolar transistor having a slant Ge profile in which a Ge concentration of a SiGe base layer is increased from 0% to 10% from an emitter region side towards a collector region side.
In this case, an N+-type buried layer having a high concentration and an N-type collector layer having a low concentration are formed on a P-type silicon substrate of the SiGe base bipolar transistor, and an undoped SiGe layer in which an impurity is not doped, a first SiGe base layer having a first Ge concentration distribution and a second SiGe base layer having a second Ge concentration distribution are formed on the N-type collector layer having the low concentration, and an emitter layer made of an N-type diffusion layer is formed on the second SiGe base layer.
Also in this case, the SiGe base bipolar transistor is formed such that the N-type collector layer having the low concentration in which an N-type impurity is doped at about 1016 cmxe2x88x923 is formed on the N+-type buried layer having the high concentration in which the N-type impurity is doped at about 1020 cmxe2x88x923.
Further in this case, the SiGe base bipolar transistor is formed such that the undoped SiGe layer having a Ge concentration of about 10% and a thickness of about 30 nm, the first SiGe base layer having a first Ge concentration distribution and the second SiGe base layer having a second Ge concentration distribution are formed on the N-type collector layer having the low concentration.
In this case, the SiGe base bipolar transistor is formed such that the P-type impurity is doped at about 1xc3x971019 cmxe2x88x923 in the first SiGe base layer and the second SiGe base layer.
Also in this case, the SiGe base bipolar transistor is formed such that a poly-crystal silicon film to pull out an emitter in which the N-type impurity is doped at about 2xc3x971020 cmxe2x88x923 is formed on the second SiGe base layer.
Further in this case, the emitter layer of the SiGe base bipolar transistor is formed by using the impurity thermal diffusion from the poly-crystal silicon film to pull out the emitter in which the N-type impurity is doped.
In this case, the SiGe base bipolar transistor is designed such that a thickness of the second SiGe base layer is about 20 nm, a Ge concentration is increased from about 0% to about 2% from the emitter region side towards the collector region side in the second SiGe base layer, a thickness of the first SiGe base layer is about 10 nm, and a Ge concentration in the first SiGe base layer is increased from about 2% to about 10%.
Also in this case, the SiGe base bipolar transistor is formed such that the N-type collector layer of the low concentration in which the N-type impurity is doped at about 1016 cmxe2x88x923 on the N+-type buried layer having the high concentration in which the N-type impurity is doped at about 1020 cmxe2x88x923, and the undoped SiGe layer having a Ge concentration of about 10% and a thickness of about 30 nm, a third SiGe base layer having a third Ge concentration distribution, a fourth SiGe base layer having a fourth Ge concentration distribution, and a Si base layer are formed on the N-type collector layer having the low concentration.
Further in this case, the SiGe base bipolar transistor is formed by the formation of a poly-crystal silicon film to pull out an emitter, in which the P-type impurity is doped at about 1xc3x971019 cmxe2x88x923 on the third SiGe base layer, the fourth SiGe base layer and the Si base layer, and the N-type impurity is doped at about 2xc3x971020 cmxe2x88x923 on the Si base layer.
In this case, the emitter layer of the SiGe base bipolar transistor is formed by using the impurity thermal diffusion from the poly-crystal silicon film to pull out the emitter in which the N-type impurity is doped.
Also in this case, the SiGe base bipolar transistor is designed such that a thickness of the Si base layer is about 20 nm, a thickness of the fourth SiGe base layer is about 5 nm, a Ge concentration is increased from about 0% to about 2% from the emitter region side in the fourth SiGe base layer, a thickness of the third SiGe base layer is about 5 nm, and a Ge concentration in the third SiGe base layer is increased from about 2% to about 10%.
The semiconductor manufacturing method has a step of forming a SiGe base bipolar transistor having a slant Ge profile in which a Ge concentration of a SiGe base layer is increased from 0% to 10% from an emitter region side towards a collector region side.
In this case, the present invention further includes the steps of: forming the N-type collector layer having the low concentration in which the N-type impurity is doped at about 1016 cmxe2x88x923, on the N+-type buried layer having the high concentration in which the N-type impurity is doped at about 1020 cmxe2x88x923; forming the undoped SiGe layer having a Ge concentration of about 10% and a thickness of about 30 nm, the first SiGe base layer having a first Ge concentration distribution, and the second SiGe base layer having a second Ge concentration distribution, on the N-type collector layer having the low concentration; doping the P-type impurity at about 1xc3x971019 cmxe2x88x923 on the first SiGe base layer and the second SiGe base layer; forming a poly-crystal silicon film to pull out an emitter in which the N-type impurity is doped at 2xc3x971020 cmxe2x88x923, on the second SiGe base layer; and setting a thickness of the second SiGe base layer to about 20 nm, increasing the Ge concentration from about 0% to about 2% from an emitter region side towards a collector region side in the second SiGe base layer, setting a thickness of the first SiGe base layer to about 10 nm, and increasing the Ge concentration in the first SiGe base layer from about 2% to about 10%.
The semiconductor manufacturing method further includes the steps of: forming the N-type collector layer having the low concentration in which the N-type impurity is doped at about 1016 cmxe2x88x923, on the N+-type buried layer having the high concentration in which the N-type impurity is doped at about 1020 cmxe2x88x923; forming the undoped SiGe layer having a Ge concentration of about 10% and a thickness of about 30 nm, a third SiGe base layer having a third Ge concentration distribution, a fourth SiGe base layer having a fourth Ge concentration distribution and a Si base layer, on the N-type collector layer having the low concentration; doping the P-type impurity at about 1xc3x971019 cmxe2x88x923 on the third SiGe base layer, the fourth SiGe base layer and the Si base layer; forming a poly-crystal silicon film to pull out an emitter in which the N-type impurity is doped at 2xc3x971020 cmxe2x88x923, on the Si base layer; forming an emitter layer by using the impurity thermal diffusion from the poly-crystal silicon film to pull out the emitter in which the N-type impurity is doped; and setting a thickness of the Si base layer to about 20 nm, setting a thickness of the fourth SiGe base layer to about 5 nm, increasing the Ge concentration from about 0% to about 2% from an emitter region side in the fourth SiGe base layer, and also setting a thickness of the third SiGe base layer to about 5 nm, and then increasing the Ge concentration in the third SiGe base layer from about 2% to about 10%.

Semiconductor device having the effect that the drop in the current gain is kept to the minimum, when the substrate density is amplified and that the variation in the collector current is improved


A backside illuminated image sensor includes a photodiode arranged in a substrate, a first insulating layer arranged on a front surface of the substrate, a bonding pad arranged on the first insulating layer, and a second insulating layer arranged on the first insulating layer and the bonding pad. The bonding pad is partially exposed by an opening passing through the substrate and the first insulating layer, and an edge portion of the bonding pad is supported by the first and second insulating layers.

The present disclosure relates to a backside illuminated image sensor and a method of manufacturing the same.
An image sensor is a semiconductor device that converts an optical image into electrical signals. Image sensors known in the art include charge coupled devices (CCDs) and CMOS image sensors.
CMOS image sensors include unit pixels, each including a photodiode and metal-oxide-semiconductor (MOS) transistors. CMOS image sensors can sequentially detect the electrical signals of the unit pixels using a switching method in order to form an image. CMOS image sensors can be front side illuminated image sensors or backside illuminated image sensors.
A front side illuminated (or front-illuminated) image sensor may include photodiodes formed in a substrate, transistors formed on a front surface of the substrate, wiring layers formed on the front surface of the substrate, and a color filter layer and micro lens array formed on the wiring layers.
In contrast, a backside illuminated (or back-illuminated) sensor can arrange the wiring behind the photodiode layer. Backside illuminated image sensor therefore have an improved light-receiving efficiency in comparison with front side illuminated image sensors. Backside illuminated image sensors can, however, be more difficult to manufacture, resulting in lower yields and higher prices.
One manufacturing difficulty can result from a bonding pad formed on an insulating layer. The bonding pad may be connected with the wiring layers on the front surface of the substrate by a contact passing through the substrate and the insulating layer. However, when the bonding pad has a relatively thin thickness, the bonding pad may be damaged or peeled away from the substrate during the wire bonding process.

Backside illuminated image sensor and method of manufacturing the same