Field-effect transistors include source, drain and gate structures. A biasing voltage applied across gate and source terminals allows the flow of charge carriers, namely electrons or holes, between source and drain. High electron mobility transistors (HEMTs) are characterized by heterojunctions having different materials on either side of the junctions. Electrons remain close to the heterojunction and form two dimensional electron gas (2DEG). A bias applied to the gate modulates the number of electrons and controls the conductivity of the transistor.
Active matrix devices such as displays (e.g. televisions, laptop monitors), imagers (e.g. x-ray imagers) and sensors typically use hydrogenated amorphous silicon (α-Si:H) and, in some applications, low-temperature poly-silicon (LTPS) thin-film transistor (TFT) backplanes on glass or, for flexible devices, clear plastic. However, for very high resolution applications (>1000 pixels per inch (ppi)), such as micro-displays or pico-projectors, the carrier mobility of a-Si:H (electron mobility of about 1 cm2/Vs) is too low to provide sufficient drive current at short TFT channel widths. For applications requiring high drive current, such as active matrix organic light emitting diode (AMOLED) displays, it is necessary to shrink the gate length and/or increase the gate width of a-Si:H transistors. This leads to increasing the processing cost of a-Si:H active matrix circuits due to the relatively small gate lengths as well as a significant trade-off in display resolution due to larger gate widths. LTPS is more expensive than a-Si:H, but capable of providing higher drive currents. The device-to-device variation of threshold voltage and mobility in LTPS transistors requires compensation circuitry that limits the resolution of the active matrix. Single crystalline silicon (c-Si) has been used as an alternative for very high resolution backplanes, but processing c-Si can require high temperatures not compatible with glass substrates currently used in manufacturing a-Si:H or LTPS devices or clear plastic substrates that may be used.
Some existing displays have pixel densities of about 100 PPI (pixels per inch), each pixel including three RGB sub-pixels. Pixel dimensions of such devices may be about one hundred microns (100 μm). Such displays further include organic light emitting diodes (OLEDs) requiring a drive current of about 300 nA for a 100 μm pixel. Amorphous hydrogenated silicon thin film transistors (TFTs) having standard SiNx gate dielectrics are employed in conjunction with the OLEDs. Using such TFTs, resolutions greater than 150 PPI are difficult.


Array antennas are used for example in satellites of a satellite system for worldwide navigation (GNSS; GNSS=Global Navigation Satellite System), such as the currently constructed European satellite navigation system, better known under the name “Galileo”, in satellite-based imaging radar systems employing Synthetic-Aperture-Radar (SAR) sensors or in Telecommunication satellites. In order to control the antenna excitation, the characteristics of each branch of the distribution network and array radiator elements of the array antenna must be known. Typical parameters describing the characteristics are the propagation time, the phase and the magnitude of a signal propagating through each branch of the array. The characteristics may be used to calibrate the different paths or branches of an array antenna, thus enabling an improved control of the excitation. Usually, an estimation or determination of the characteristics and a calibration cannot be performed during normal operation of an antenna, since this requires emitting special test or calibration signals, which would interrupt the normal operation. This aspect is particular important in case of a GNSS, where the system requirements of operational continuity are usually mandatory.


This invention relates to a device for providing traction to the powered wheels of a vehicle. The device is useful for extricating a vehicle which has become stuck on a slippery surface, such as ice, snow, or mud, as well as for assisting a vehicle which is to be driven on such surfaces.
Previously, there have been many devices which were adapted to be attached to the powered wheels of a vehicle to increase its traction. Such devices included conventional chains and many cleated devices. One of the problems with such past devices was that they usually included means for pulling the cleats tightly against the tire. This tight arrangement caused the cleats to constantly rub against and to ultimately destroy the tire.
Another of the problems with such past devices was that the cleats were often fixed to or urged against the cleat holder. This tight arrangement also caused the cleats to constantly rub against and to ultimately destroy the tire.
Another of the problems with such past devices was that the devices were difficult or impossible to mount onto the tires unless the tires were lifted above the driving surface. Obviously, such lifting is not possible when the vehicle is stuck in a rut.
Another of the problems with many such past devices was they they required two cleat holders, one on the outside and one on the inside of the tire. This caused the person installing the device to have to reach around to the inner side of the tire (under the vehicle) and to have to work on apparatus elements that he could not see.
The object of this invention is to overcome all of the foregoing problems by providing a tire traction device that is maintained loose on the tire and loose on the cleat holder; that does not destroy the tire; that does not require the tire to be lifted off the ground; and that does not require a second cleat holder to be used on the inner side of the tire. It is another object of this device to achieve the foregoing object while simultaneously providing the vehicle with greatly increased traction at an inexpensive price.


The present invention relates to an X-ray CT (Computed Tomography) imaging method, subject center position detection method and X-ray CT apparatus, and more particularly to an X-ray CT imaging method, subject center position detection method and X-ray CT apparatus which can detect whether the center position of a subject is significantly offset from a scan center.
In X-ray CT imaging, a human operator adjusts the height of a top plate for laying a subject by visual measurement so that the center position of the subject coincides with a scan center (a center of rotation of an X-ray tube) with minimum offset.
However, the adjustment by the operator""s visual measurement sometimes makes the center position of the subject significantly offset from the scan center, which results in poor homogeneity in the CT value of a subject""s image. Moreover, overrange may occur near the scan center, when the scan center falls outside the subject.
It is therefore an object of the present invention to provide an X-ray CT imaging method, subject center position detection method and X-ray CT apparatus which can detect whether the center position of a subject is significantly offset from a scan center.
In accordance with a first aspect of the present invention, there is provided an X-ray CT imaging method for performing a scan by an X-ray tube rotating around a subject, comprising the steps of: detecting a subject center position based on a projection profile acquired by imaging the subject; and giving a warning when a calculated distance between the subject center position and a scan center exceeds a predefined range.
The X-ray CT imaging method of the first aspect displays a warning on a display screen or gives a vocal prompt to a human operator to adjust the position when the subject center position is offset from the scan center by an amount exceeding a predefined range (e.g., 50 cm). Thus, the method can detect whether the center position of a subject is significantly offset from a scan center.
In accordance with a second aspect, there is provided a subject center position detection method comprising the steps of: acquiring a projection profile by imaging a subject from a direction orthogonal to a plane containing a body axis of the subject by an X-ray CT apparatus for performing a scan by an X-ray tube rotating around the subject; defining an X-ray detector channel index corresponding to a calculated centroid of the projection profile as a centroid channel index; examining a projection value in the projection profile toward a direction along a first direction of the subject from the centroid channel index; defining a channel index having a projection value no more than a predetermined projection value threshold Pth as a first threshold channel index; examining on the other hand a projection value in the projection profile toward a direction along a second direction of the subject opposite to the first direction from the centroid channel index; defining a channel index having a projection value no more than the predetermined projection value threshold Pth as a second threshold channel index; defining an intermediate value between the first and second threshold channel indices as a subject position channel index; and obtaining a subject center position from the subject position channel index.
A projection profile acquired by imaging a subject lying on a top plate from a direction orthogonal to a plane containing the subject""s body axis contains a projection of the top plate as well as a projection of the subject. Thus, the centroid of the projection profile is shifted toward the top plate relative to a subject center position. Therefore, the subject center position should be determined on a side opposite to the top plate with respect to the centroid of the projection profile.
The subject center position detection method of the second aspect introduces xe2x80x9cprojection value threshold Pthxe2x80x9d as a parameter, searches channels having respective values no more than the projection value threshold Pth in two directions, calculates an intermediate of the retrieved two channels, and determines the subject center position on a side opposite to the top plate with respect to the centroid of the projection profile based on the intermediate. Thus, the subject center position can be accurately determined with the effect of the top plate eliminated.
In the subject center position detection method of the above configuration, the projection value threshold Pth may be selected empirically as, for example, xc2xd of a projection value corresponding to the centroid channel index.
Moreover, in the subject center position detection method of the above configuration, the subject center position can be determined more accurately by first removing profiles other than the subject""s profile from the projection profile, and then calculating the centroid.
In accordance with a fifth aspect, there is provided an X-ray CT apparatus for performing a scan by an X-ray tube rotating around a subject, comprising: projection profile acquisition means for acquiring a projection profile by imaging the subject; subject position detection means for detecting a subject center position based on the acquired projection profile; and warning displaying means for displaying a warning when the distance between the subject center position and a scan center exceeds a predefined range.
The X-ray CT apparatus of the fifth aspect can suitably implement the X-ray CT imaging method as described regarding the first aspect.
In accordance with a sixth aspect, there is provided an X-ray CT apparatus for performing a scan by an X-ray tube rotating around a subject, comprising subject center position detection means configured to: define an X-ray detector channel index corresponding to a calculated centroid of a projection profile acquired by imaging a subject from a direction orthogonal to a plane containing a body axis of the subject as a centroid channel index; examine a projection value in the projection profile toward a direction along a first direction of the subject from the centroid channel index; define a channel index having a projection value no more than a predetermined projection value threshold Pth as a first threshold channel index; examine on the other hand a projection value in the projection profile toward a direction along a second direction of the subject opposite to the first direction from the centroid channel index; define a channel index having a projection value no more than the predetermined projection value threshold Pth as a second threshold channel index; define an intermediate value between the first and second threshold channel indices as a subject position channel index; and obtain a subject center position from the subject position channel index.
The X-ray CT apparatus of the sixth aspect can suitably implement the subject center position detection method as described regarding the second aspect.
In the X-ray CT apparatus of the above configuration, the projection value threshold Pth may be selected empirically as, for example, xc2xd of a projection value corresponding to the centroid channel index.
Moreover, in the X-ray CT apparatus of the above configuration, the subject center position can be determined more accurately by first removing profiles other than the subject""s profile from the projection profile, and then calculating the centroid.
To remove profiles other than the subject""s profile from the projection profile, a one-dimensional minimum value filter, followed by a one-dimensional maximum value filter, for example, may be applied to the projection file.
The X-ray CT imaging method, subject center position detection method and X-ray CT apparatus of the present invention can detect whether the center position of a subject is offset from a scan center, and can notify an operator of the result of the detection. Thus, even when the subject center position is significantly offset from the scan center, the position of the subject is adjusted and imaging is repeated, whereby an X-ray image with good quality can be obtained.
Further objects and advantages of the present invention will be apparent from the following description of the preferred embodiments of the invention as illustrated in the accompanying drawings.


Spray dryers basically have three essential functions of (1) spraying feed liquid, (2) drying resulting microdrops and (3) separating and recovering a resulting fine powder product, and ordinarily have an atomizer, a drying chamber and a fine powder recovering unit, respectively, corresponding to the above functions.
As examples of these spray dryers, there have hitherto been known those shown in FIGS. 9 and 10 (see Japanese Patent Publication No. 32601/1983 and Japanese Utility Model Laid-Open No. 26950/1983).
In the spray dryer of FIG. 9, a feed liquid is sprayed into a drying chamber 1 from a nozzle 5 and is momentarily heated by hot air from an inlet 2, whereby the liquid component of the feed liquid is evaporated and the solid component is made into a fine powder. The majority of the fine powder is taken out as a product via a rotary valve 6. Part of the fine powder accompanies hot air, passes a waste gas outlet 3 and enters a cyclone 7, and is recovered from a rotary valve 8.
The spray dryer of FIG. 10 is a type using, as an atomizer, a rotary spraying disc (a rotary disc) 10 in place of the nozzle 5.
In the spray dryers as shown in FIGS. 9 and 10, a fine powder product is recovered separately in the main section of the dryer and in the cyclone. In this case, a powder of lighter particles having smaller particle diameters is recovered in the cyclone and a powder of heavier particles having larger particle diameters is taken out from the main section; accordingly, slight compositional variations in the product occurs.
In the past, this compositional variation posed little problem depending upon the type of product.
It has been required recently that spray dryers can perform, instead of conventional few grade, large quantity type production, many grade, small quantity type production especially for medicines, fine ceramics, etc.
Also, it is increasingly required that spray dryers produce a product of higher purity.
Under these new situations requiring a spray dryer capable of providing many grade, small quantity type production and a powder of the higher purity, the abovementioned compositional variation of product which posed little problem in the past has entered a new phase. Moreover a new problem has arisen.
That is, with the increase in the frequency of product switch-over, the rapid and complete washing of the deposit adhering to the inner wall of the drying chamber has become necessary. It is necessary because if washing takes a long time it is detrimental to the efficient execution of many grade, small quantity type production and also because the complete washing of the deposit adhering to the inner wall of the drying chamber, which is required in the product switchover when a product of higher purity and higher quality is needed, is very difficult. Moreover, when a product harmful to humans is produced, washing is extremely difficult because the operator is prohibited from making direct contact with the product.
Further, the requirement for a product of higher purity has turned the above-mentioned slight compositional variation among products into a problem.


1. Field of the Invention
The present invention relates to a computer terminal apparatus used for voting at an election, and an electronic system for voting at an election and totaling the votes cast.
2. Description of the Related Art
Conventionally, at presidential elections, elections of Diet members, and the like, voters go to polling stations, where the voters write candidate names on ballot papers and cast the ballot papers into ballot boxes. Thereafter, vote counting and totaling of election returns are manually performed.
As described above, in the conventional voting at elections, voting operations, totaling operations, and the like are not automated much. Therefore, it takes much time to perform voting and totaling operations. In addition, vote totaling errors often occur.


1. Field of the Invention
This invention relates in general to an article of furniture, and, more particularly, to that class known as wardrobes.
2. Description of the Related Art
Wardrobes must act as repositories for a large number of small and large wardrobe articles such as shirts, belts and jewelry. The problem is then to store these variously sized items in a compact, yet readily accessible manner for presentation and use that does not wrinkle or mess the items for wear.


1. Field of Invention
The present invention is directed to a novel bar-code symbol driven Internet Access Terminal, and method of accessing Internet-based information resources by scanning bar code symbols encoded with Uniform Resource Locators (URLs) or Domain Name/Path Name (DN/PN) portions thereof indicating the location of such information resources on the Internet.
2. Background of the Invention
Presently, several techniques have been developed for connecting to or accessing (i.e., xe2x80x9csurfingxe2x80x9d among) Internet-based information resources on the World Wide Web (WWW) using a conventional graphical user interface (GUI) based Internet browser programs, such as the Navigator(copyright) from Netscape Communications, Inc. or the Internet Explorer(copyright) from Microsoft, Inc. The availability of any particular Web-site surfing technique depends on where the Internet user finds him or her self in the Internet browser program at any particular instant of time.
For example, if one is currently at a Web-site (i.e., in a particular HyperText Markup Language (HTML) document), at which there is a highlighted or embedded xe2x80x9clinkxe2x80x9d specifying the Internet address of another Web-site (i.e., another HTML document), then the user can access (i.e., xe2x80x9csurf toxe2x80x9d) this other Web-site by simply xe2x80x9cclicking onxe2x80x9d or selecting the highlighted URL with his or her pointing device (i.e., xe2x80x9cmousexe2x80x9d) in a conventional manner. The ability to connect to other Web-sites by simply pointing and clicking on a highlighted URLs embedded in an HTML document has contributed enormously to the growth and popularity of the Internet in the last few years.
If the user desires to connect to a Web-site that is not referenced in a HTML document viewed through a browser program, then the user oftentimes finds it necessary to manually enter the URL of the Web-site (e.g., xe2x80x9chttp://www.metrologic.comxe2x80x9d) into the browser program. This requires manually pressing a sequence of keys on a keyboard or remote control device, corresponding to the characters of the URL being selected. In addition to being time consuming, this Web-site surfing technique is prone to errors, causing the browser program to connect to the wrong Web-site or return a message stating that the Domain Name of the Web-site sought after cannot be found. From a practical point of view, this is quite frustrating to the Internet user.
More recently, with the growth and ever increasing complexity of the WWW, it is becoming popular to use printed publications (e.g., magazines, catalogues, directories, etc.) which list Web-sites, corresponding URLs and content descriptions, as navigational aids, much in same way that the TV GUIDE(copyright) magazine is used to help viewers select programs during television viewing. Again, however, each time a listed Web-site is to be viewed, the user is forced to manually enter into the Internet browser program, the lengthy character string associated with the URL of the Web-site being selected. Only thereafter, does the browser program automatically connect the user""s client system (i.e., Internet Terminal) to the Internet Server computer supporting the selected Web-site.
While the development of HTML and GUI-based Web browser programs have made accessing Web-sites relatively simple, the above shortcomings and drawbacks of prior art Internet technology clearly indicate a great need in the art for an improved system and method of accessing information resources on the Internet.
Accordingly, it is a primary object of the present invention to provide an improved method and apparatus for accessing and navigating among information resources on the Internet, while avoiding the shortcomings and drawbacks of prior art systems and methodologies.
A further object of the present invention is to provide an Internet Access System which includes a bar code symbol reader for reading DN/PN-encoded (Domain Name and Path Name encoded) or URL-encoded (Uniform Resource Location encoded) bar code symbols printed on various types of objects, including print media, which, when read thereby, automatically connects the Internet Access System to the Internet Server that contains the information resource specified by the scanned DN/PN-encoded or URL-encoded bar code symbol.
A further object of the present invention is to provide such Internet Access System, wherein the bar code symbol reader may be a laser scanning bar code symbol reader, a CCD-type bar code symbol, or a Wand-type bar code symbol reader.
A further object of the present invention is to provide such an Internet Access System, wherein the DN-encoded bar code symbol printed on various types of print media is a DN/PN-encoded truncated-type bar code symbol, having a very low height to length ratio, thereby allowing many URL-encoded bar code symbols to be printed on a single sheet or page of a Web-site guide, along with their corresponding human-readable URLs and content descriptions.
A further object of the present invention is to provide such an Internet Access System, wherein the URL-encoded bar code symbol printed on various types of print media is a URL-encoded truncated-type bar code symbol, having a very low height to length ratio, thereby allowing many URL-encoded bar code symbols to be printed on a single sheet or page of a Web-site guide, along with their corresponding human-readable URLs and content descriptions.
Another object of the present invention is to provide such an Internet Access System in the form of a desktop, laptop or palmtop computer system that is connected to the Internet by way of an Internet Service Provider (ISP), wherein the computer system has a GUI-based web browser program and a programmed bar code symbol scanner interfaced therewith for automatically surfing to information resources (e.g., Web-sites) listed in a Web-site guide by simply scanning corresponding URL-encoded bar code symbols printed on the pages thereof.
A further object of the present invention is to provide an Internet Access System in the form of an interactive web-based television system, wherein the web-based television system comprises an Internet terminal unit connected to the Internet by way of an ISP, an audio-visual display monitor for displaying graphical and audio information content of Web-sites, and a portable Internet surfing device having a wireless IR-based communication link to the Internet terminal unit and an integrated bar code symbol scanner for automatically surfing to (or among) Web-sites listed in a Web-site guide by simply scanning corresponding URL-encoded bar code symbols printed on the pages thereof.
A further object of the present invention is to provide such an Internet Access System in the form of a Scanner Integrated Terminal, wherein the Scanner Integrated Terminal is connectable to the Internet by way of a wireless (RF) link to an ISP, and has an integrated GUI-based web browser program, display panel, keypad, and programmed bar code symbol scanner for automatically surfing to Web-sites listed in a Web-site guide by simply scanning corresponding DN-encoded (or URL-encoded) bar code symbols printed on the pages thereof.
Another object of the present invention is to provide a novel method of surfing to Web-sites on the Internet by scanning URL-encoded bar code symbols into GUI-based web browser programs, without the need of manual data entry operations or the like.
A further object of the present invention is to provide an Internet Access System, which includes an optical character reader programmed to read the character strings of URLs printed on various types of print media which, when read thereby, automatically connects the Internet Client System to the Internet Server that supports the Web-site specified by the read URL.
Another object of the present invention is to provide such an Internet Access System in the form of a desktop, laptop or palmtop computer system that is connected to the Internet by way of an Internet Service Provider (ISP), wherein the computer system has a GUI-based web browser program and a programmed optical character reader interfaced therewith for automatically surfing to Web-sites listed in a Web-site guide by simply reading corresponding URLs printed on the pages thereof.
A further object of the present invention is to provide an Internet Access System in the form of an interactive web-based television system, wherein the web-based television system comprises an Internet terminal unit connected to the Internet by way of an ISP, an audio-visual (AV) display monitor for displaying graphical and audio information content of Web-sites, and a portable Internet surfing device having a wireless IR-based communication link to the Internet Terminal unit and an integrated optical character reader for automatically surfing to Web-sites listed in a Web-site guide by simply scanning corresponding URLs printed on the pages thereof.
A further object of the present invention is to provide such an Internet Access System in the form of a Scanner Integrated Terminal, wherein the Scanner Integrated Terminal is connectable to the Internet by way of a wireless (RF) link to an ISP, and has an integrated GUI-based web browser program, display panel, keypad, and programmed optical character reader for automatically surfing to Web-sites listed in a Web-site guide by simply scanning corresponding URLs printed on the pages thereof.
Another object of the present invention is to provide a novel method of surfing to Web-sites on the Internet by optically scanning the character strings of URLs into GUI-based web browser programs, without the need of manual data entry operations and the like.
Another object of the present invention is to provide a novel system and method for printing URL-encoded bar code symbols on various types of print media which, when read thereby, automatically connects the Internet Client System to the Internet Server that supports the Web-site specified by the scanned URL-encoded bar code symbol.
Another object of the present invention is to provide such a system in the form of suitably programmed desktop Web-linked computer workstation or laptop computer system having a graphical user interface and an Internet browser program having a plug-in type URL-Menu Composition/Printing Module that supports the bar code menu composition, transmission and printing processes of the present invention.
A further object of the present invention is to provide such a system, in which the Internet browser program and plug-in URL-Menu Composition/Printing Module allow the user to easily compile the following information structure during operation of the Internet browser program: a list of human-readable URLs corresponding to a set or course of information serving Web-sites, a set of URL-encoded bar code symbol data structures corresponding thereto, a set of titles assigned to the URLs, a set of brief descriptions of content served at the Web-sites, and date or dates the set of Web-sites were last visited by the compiler for subsequent printing in the form of a menu.
A further object of the present invention is to provide such a system, in which the compiled information structure can be electronically transmitted to a remote site, by e-mail, facsimile transmission, or other protocol available over the Internet, and thereafter printed out using appropriate print-driver software, so that the Web-sites listed in the compiled information structure can be easily visited by reading the corresponding URL-encoded bar code symbol into the Internet browser program using a bar code scanner.
Another object of the present invention is to provide a novel Web-site guide or directory comprising one or more sheets having a plurality of URL-encoded bar code symbols, corresponding human-readable URLs and Web-site content descriptions printed thereon.
Another object of the present invention is to provide a novel Web-based document tracking and management system, in which each printed document (e.g., brochure, drawing, 3-D objects or specimens, photograph, specification, blue-print, and the like) to be tracked and managed within the system is uniquely assigned and affixed with a printed URL-encoded bar code symbol that specifies (i.e.,points to) a particular information storage location within an HTML-encoded relational database management system (RDBMS), realized on an Web-based information server located on the Internet or behind the corporate firewall of an HTTP-supporting Intranet.
Another object of the present invention is to provide such a Web-based document tracking and management system, in which information relating to a document registered within the system can be easily accessed therefrom by simply scanning the printed URL-encoded bar code symbol on the document using the bar code symbol reader associated with an Internet Access Terminal (i.e., client computer system) of the present invention.
Another object of the present invention is to provide such a Web-based document tracking and management system, in which the Internet Access Terminal of each user can be used to: (1) assign a URL-encoded bar code symbol to any document to be registered with the system; (2) enter document-related information into the information storage location assigned to the document within the Web-based RDBMS; (3) print out URL-encoded bar code symbols for attachment to corresponding documents registered within the system; (4) modify at any time the document-related information currently stored in the information storage location assigned to the document within the Web-based RDBMS; and (5) access such document related information from the system by simply reading its corresponding URL-encoded bar code symbol.
Another object of the present invention to provide a Web-based package routing, tracking and delivering system and method that uses URL-encoded bar code symbols on parcels and packages.
A further object of the present invention is to provide such a Web-based package routing, tracking and delivery system and method, wherein one or more Routing, Tracking and Delivery (RTD) Internet Server Subsystems are connected to the Internet and updated at any instant of time with package related information produced by either (i) a Package Log-In/Shipping Subsystem that is located at a product shipping location (e.g., warehouse) and connected to the RTD Internet Server by a first data communication link, (ii) a Package Routing Subsystem that is located at a hub station and connected to the RTD Internet Server by a second data communication link, or (iii) a Portable Package Delivery Subsystem that is carried by the package delivery person and connected to the RTD Internet Server by a wireless data communication link.
A further object of the present invention is to provide such a Web-based package routing, tracking and delivery system and method, wherein at each remote hub station within the system: the URL/ZIP-CODE encoded bar code symbol is automatically scanned; the encoded destination Zip Code is locally recovered and used to route the package at the hub station; and the locally recovered URL is used to access the RTD Internet Server and update the location of the package within the system.
Another object of the present invention is to provide such a Web-based package routing, tracking and delivery system and method, wherein when the URL/ZIP-CODE Encoded bar code symbol is read by the deliveryman or courier using a portable (wireless) Internet Access Terminal, the recovered URL is used to automatically access the RTD Internet Server and display on the Internet Access Terminal, precise up-to-date parcel delivery information, payment-method terms, handling instructions and the like.
These and other Objects of the Present Invention will become apparent hereinafter.


The present invention relates to the field of macrolide compounds having antibacterial activity, pharmaceutical compositions containing the compounds, and methods of treating bacterial infections with the compounds.
Erythromycins are well-known antibacterial agents widely used to treat and prevent bacterial infection caused by Gram-positive and Gram-negative bacteria. However, due to their low stability in acidic environment, they often carry side effects such as poor and erratic oral absorption. As with other antibacterial agents, bacterial strains having resistance or insufficient susceptibility to erythromycin have developed over time and are identified in patients suffering from such ailments as community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections. Particularly problematic pathogens include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin- and macrolide-resistant Streptococcus pneumoniae. Therefore, continuing efforts are called for to identify new erythromycin derivative compounds with improved antibacterial activity, and/or unanticipated selectivity against various target microorganisms, particularly erythromycin-resistant strains.
The following references relate to various erythromycin derivatives disclosed as having antibacterial activity:
EP 216,169 and U.S. Pat. No. 4,826,820 to Brain et al. disclose antibacterially active 6-carbamate erythromycin derivatives stated to xe2x80x9chave antibacterial properties, in particular against Gram-positive bacteria but also against some Gram-negative bacteria.xe2x80x9d
U.S. Pat. No. 5,444,051, No. 5,561,118, and No. 5,770,579, all to Agouridas et al., disclose erythromycin compounds such as those of the formulae
wherein substituents are as described in the respective references, which are all stated to be useful as antibiotics.
U.S. Pat. No. 5,866,549 to Or et al. and WO 98/09978 (Or et al.) disclose 6-O-substituted ketolides stated to have increased acid stability relative to erythromycin A and 6-O-methyl erythromycin A and enhanced activity toward gram negative bacteria and macrolide resistant gram positive bacteria.
WO 97/17356 (Or et al.) discloses tricyclic erythromycin derivatives stated to be useful in the treatment and prevention of bacterial infections.
WO 99/21871 (Phan et al.) discloses 2-halo-6-O-substituted ketolide derivatives of the formula
wherein substituents are as described in the respective reference, which are stated to possess antibacterial activity.
WO 99/21864 (Or et al.) discloses 6,11-bridged erythromycin derivatives having antibacterial activity.
EP1146051 to Kaneko et al. discloses macrolide compounds of the following formula that are useful as antibacterial and antiprotozoal agents in mammals,
wherein substituents are as described in the reference.
WO 00/75156 (Phan et al.) discloses 6-O-carbamate ketolide derivatives that are useful as antibacterials for the treatment and prevention of infections in a mammal.
The invention provides compounds of Formula 1:
Wherein
R1 and R2 are independently selected from hydrogen, optionally substituted xe2x80x94CRfRg(C1-C8)alkyl, optionally substituted xe2x80x94CRfRg(C2-C8)alkenyl, optionally substituted xe2x80x94CRfRg(C2-C8)alkynyl, optionally substituted cycloalkyl, and optionally substituted (C5-C7)-cycloalkenyl, provided that R1 and R2 are not both hydrogen, wherein the substituents are selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, xe2x80x94COORa, xe2x80x94OCORa, xe2x80x94ORa, xe2x80x94SRa, xe2x88x92SORa, xe2x80x94SO2Ra, xe2x80x94NRaRb, xe2x80x94CONRaRb, xe2x80x94OCONRaRb, xe2x80x94NHCORa, xe2x80x94NHCOORa, and xe2x80x94NHCONRaRb, wherein
Ra and Rb are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; and
Rf and Rg are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, COORa, and CONRaRb;
or R1 and R2, together with the nitrogen atom to which they are attached, form an optionally substituted nitrogen-containing heterocycle, wherein the substituents are selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, xe2x80x94COORa, xe2x80x94OCORa, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94NRaRb, xe2x80x94CONRaRb, xe2x80x94OCONRaRb, xe2x80x94NHCORa, xe2x80x94NHCOORa, and xe2x80x94NHCONRaRb;
R3 is hydrogen or xe2x80x94Wxe2x80x94V, wherein
W is selected from the group consisting of (a) xe2x80x94NHxe2x80x94(CH2)pxe2x80x94, (b) xe2x80x94(CH2)qxe2x80x94, (c) xe2x80x94Oxe2x80x94(CH2)rxe2x80x94, (d) xe2x80x94NHxe2x80x94C1-C6alkenyl-, (e) xe2x80x94C1-C6alkenyl-, (f) xe2x80x94Oxe2x80x94C1-C6alkenyl-, (g) xe2x80x94NHxe2x80x94C1-C6alkynyl-, (h) xe2x80x94C1-C6alkynyl-, and (i) xe2x80x94Oxe2x80x94C1-C6alkynyl-;
p is 0 to 5;
q is 0 to 5; and
r is 0 to 5;
and
V is selected from the group consisting of (a) hydrogen, (b) aryl, (c) substituted aryl, (d) heteroaryl, (e) substituted heteroaryl, and (f) Ar1xe2x80x94Ar2, wherein Ar1 and Ar2 are independently selected from the group consisting of (i) aryl, (ii) substituted aryl, (iii) heteroaryl, and (iv) substituted heteroaryl;
R4 is selected from hydrogen, halogen, and hydroxy;
R5 is hydrogen or a hydroxy protecting group;
R6 is selected from hydrogen, alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C1-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl, C3-C6-cycloalkyl, C5-C8-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group;
X and Xxe2x80x2, together with the carbon atom to which they are attached, form Cxe2x95x90O, Cxe2x95x90NRc, or Cxe2x95x90NORc, wherein Rc is independently selected from hydrogen, alkyl, alkenyl and alkynyl; and
Y and Yxe2x80x2, together with the carbon atom to which they are attached, form Cxe2x95x90O, xe2x80x94CHOH, Cxe2x95x90NRc, or Cxe2x95x90NORc, wherein Rc is independently selected from hydrogen, alkyl, alkenyl and alkynyl;
or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt, esters or pro-drugs thereof.
Compounds of the above formula are useful as antibacterial agents for the treatment of bacterial infections in a subject such as human and animal.
The present invention is also directed to a method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said subject a therapeutically effective amount of the compound of Formula 1.
The present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by bacterial infection, which comprises administering to the subject a prophylactically effective amount of the compound of Formula 1.
Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing specification.
Relative to the above description, certain definitions apply as follows.
Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
Unless specified otherwise, the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, and xe2x80x9calkynyl,xe2x80x9d whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, or any number within this range. The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain hydrocarbons. xe2x80x9cAlkenylxe2x80x9d refers to a straight or branched chain hydrocarbon with at least one carbonxe2x80x94carbon double bond. xe2x80x9cAlkynylxe2x80x9d refers to a straight or branched chain hydrocarbon with at least one carbonxe2x80x94carbon triple bound. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. xe2x80x9cAlkoxyxe2x80x9d radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. xe2x80x9cCycloalkylxe2x80x9d groups contain 3 to 8 ring carbons and preferably 5 to 7 ring carbons. xe2x80x9cCycloalkenylxe2x80x9d groups contain 5 to 8 ring carbons and at least one carbonxe2x80x94carbon double bond. The alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and alkoxy group may be independently substituted with one or more members of the group including, but not limited to, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, xe2x80x94OCORa, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94COORa, xe2x80x94NRaRb, xe2x80x94CONaRb, xe2x80x94OCONRaRb, xe2x80x94NHCORa, xe2x80x94NHCOORa, and xe2x80x94NHCONRaRb, wherein Ra and Rb are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl. xe2x80x9cAralkyl,xe2x80x9d xe2x80x9cheteroaralkyl,xe2x80x9d and xe2x80x9cheterocycloalkylxe2x80x9d are alkyl groups substituted with aryl, heteroaryl, and heterocyclo, respectively. xe2x80x9cArylalkenyl,xe2x80x9d xe2x80x9cheteroarylalkenyl,xe2x80x9d and xe2x80x9cheterocycloalkenylxe2x80x9d are alkenyl groups substituted with aryl, heteroaryl, and heterocyclo, respectively. xe2x80x9cArylalkynyl,xe2x80x9d xe2x80x9cheteroarylalkynyl,xe2x80x9d and xe2x80x9cheterocycloalkynylxe2x80x9d are alkynyl groups substituted with aryl, heteroaryl, and heterocyclo, respectively.
The term xe2x80x9cacylxe2x80x9d as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group. The term xe2x80x9cAcxe2x80x9d as used herein, whether used alone or as part of a substituent group, means acetyl.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo and iodo. (Mono-, di-, tri-, and per-)halo-alkyl is an alkyl radical substituted by independent replacement of the hydrogen atoms thereon with halogen.
xe2x80x9cArylxe2x80x9d or xe2x80x9cAr,xe2x80x9d whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, aryl, heteroaryl, heterocyclo, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-COxe2x80x94Oxe2x80x94, C1-C8-alkyl-COxe2x80x94NHxe2x80x94, or carboxamide. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. xe2x80x9cPhxe2x80x9d or xe2x80x9cPHxe2x80x9d denotes phenyl.
Whether used alone or as part of a substituent group, xe2x80x9cheteroarylxe2x80x9d refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-3 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical may be joined to the rest of the molecule via any of the ring atoms. Exemplary heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, N-oxo-pyridyl, 1,1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, indazolyl, indolizinyl, benzofuryl, cinnolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), imidazopyridinyl (such as imidazo[4,5-b]pyridinyl or imidazo[4,5-c]pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, and thienothienyl. The heteroaryl group may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, aryl, heteroaryl, heterocyclo, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-COxe2x80x94Oxe2x80x94, C1-C8-alkyl-COxe2x80x94NHxe2x80x94, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1 H-quinoline.
The terms xe2x80x9cheterocycle,xe2x80x9d xe2x80x9cheterocyclic,xe2x80x9d and xe2x80x9cheterocycloxe2x80x9d refer to an optionally substituted, fully saturated, partially saturated, or non-aromatic cyclic group which is, for example, a 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at (east one heteroatom in at least one carbon atom containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The nitrogen atoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolinyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; 2-oxazepinyl; azepinyl; and the like. Exemplary bicyclic heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; benzothiopyranyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone; benzopyranyl; dihydrobenzopyranyl; indolinyl; chromonyl; coumarinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and the like. The heterocyclic group may be substituted by independent replacement of 1 to 3 hydrogen atoms thereon with OH, CN, mercapto, nitro, amino, C1-C8-alkyl, aryl, heteroaryl, heterocyclo, C1-C8-alkoxyl, C1-C8-alkylthio, C,-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-COxe2x80x94Oxe2x80x94, C1-C8-alkyl-COxe2x80x94NHxe2x80x94, or carboxamide.
Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted-aryl, a second substituted-heteroaryl, or a second substituted-heterocycle to give, for example, a 4-pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl.
Designated numbers of carbon atoms (e.g., C1-8) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
The term xe2x80x9chydroxy protecting groupxe2x80x9d refers to groups known in the art for such purpose. Commonly used hydroxy protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), which is incorporated herein by reference. Illustrative hydroxyl protecting groups include but are not limited to tetrahydropyranyl; benzyl; methylthiomethyl; ethythiomethyl; phenylsulfonyl; triphenylmethyl; trisubstituted silyl such as trimethyl silyl, triethylsilyl, tributylsilyl, tri-isopropylsilyl, t-butyldimethylsilyl, tri-t-butylsilyl, methyidiphenylsilyl, ethyidiphenylsilyl, and t-butyidiphenylsilyl; acyl and aroyl such as acetyl, pivaloylbenzoyl, 4-methoxybenzoyl, and 4-nitrobenzoyl; and alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl.
Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
Some of the compounds of the present invention may have trans and cis isomers. In addition, where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers. The non-racemic forms may be obtained by either synthesis or resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.
The phrase xe2x80x9ca pharmaceutically acceptable saltxe2x80x9d denotes one or more salts of the free base which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable. These salts may be derived from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like. Suitable salts are furthermore those of inorganic or organic bases, such as KOH, NaOH, Ca(OH)2, Al(OH)3, piperidine, morpholine, ethylamine, triethylamine and the like.
Included within the scope of the invention are the hydrated forms of the compounds which contain various amounts of water, for instance, the hydrate, hemihydrate, and sesquihydrate forms. The present invention also includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
The term xe2x80x9csubjectxe2x80x9d includes, without limitation, any animal or artificially modified animal. As a particular embodiment, the subject is a human.
The term xe2x80x9cdrug-resistantxe2x80x9d or xe2x80x9cdrug-resistancexe2x80x9d refers to the characteristics of a microbe to survive in presence of a currently available antimicrobial agent such as an antibiotic at its routine, effective concentration.
The compounds described in the present invention possess antibacterial activity due to their novel structure, and are useful as antibacterial agents for the treatment of bacterial infections in humans and animals.
In particular, compounds of Formula 1 wherein R1 and R2 are independently selected from hydrogen, substituted C1-C8-alkyl, substituted xe2x80x94CH2C2-C8-alkenyl, and substituted xe2x80x94CH2C2-C8-alkynyl, wherein the substituents are selected from CN, nitro, xe2x80x94COORa, xe2x80x94OCORa, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94NRaRb, xe2x80x94CONaRb, xe2x80x94OCONRaRb, xe2x80x94NHCORa, xe2x80x94NHCOORa, and xe2x80x94NHCONRaRb, wherein Ra and Rb are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl; provided that R1 and R2 are not both hydrogen;
R3 is hydrogen;
R4 is selected from hydrogen, halogen, and hydroxy;
R5 is hydrogen or a hydroxy protecting group;
R6 is selected from hydrogen, alkyl, C2-C10-alkenyl, C2-C10-alkynyl, aryl, heteroaryl, heterocyclo, aryl(C,-C10)alkyl, aryl(C2-C10)alkenyl, aryl(C2-C10)alkynyl, heterocyclo(C1-C10)alkyl, heterocyclo(C2-C10)alkenyl, and heterocyclo(C2-C10)alkynyl, C3-C6-cycloalkyl, C5-C8-cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1-6 carbon atoms in each alkyl or thioalkyl group;
X and Xxe2x80x2, together with the carbon atom to which they are attached, form Cxe2x95x90O, Cxe2x95x90NRc, or Cxe2x95x90NORc, wherein Rc is independently selected from hydrogen, alkyl, alkenyl and alkynyl; and
Y and Yxe2x80x2, together with the carbon atom to which they are attached, form Cxe2x95x90O, xe2x80x94CHOH, Cxe2x95x90NRc, or Cxe2x95x90NORc, wherein Rc is independently selected from hydrogen, alkyl, alkenyl and alkynyl
are embodiments of the present invention for such purposes. More particularly, R2 is hydrogen, R4 is hydrogen or fluorine, X and Xxe2x80x2 form Cxe2x95x90O together with the carbon atom to which they are attached, and Y and Yxe2x80x2 form Cxe2x95x90O together with the carbon atom to which they are attached.
Compounds of Formula 1, which are represented by Formula 1xe2x80x2:
wherein R1, R2, R3, and R4 are as described above are also embodiments of this invention. More particularly, R2 and R3 are hydrogen and R4 is fluorine.
Compounds of Formula 1, which are represented by Formula 1xe2x80x3:
wherein R1, R2, R3, and R4 are as described above, are further embodiments of this invention. More particularly, R2 and R3 are hydrogen and R4 is fluorine.
Compounds of Formula 1 wherein R5 may be selected from acyl and aroyl are further embodiments of this invention.
This invention also provides processes for preparing the instant compounds.
The compounds of Formula I may be prepared from readily available starting materials such as erythromycin and erythromycin derivatives well known in the art. Outlined in Schemes 1 through 18 are representative procedures to prepare the compounds of the instant invention:
Scheme I illustrates the method of synthesis of the 2xe2x80x2,4xe2x80x3-diacetyl-6-carbamyl-11,12-dideoxy-11,12-iminocarbonyloxyerythromycin A (VI) and the 2xe2x80x2-acetyl-6-carbamyl-11,12-dideoxy-3-O-descladinosyl-11,12-iminocarbonyloxyerythromycin A (1a) precursors to the compounds of the invention.
Erythromycin A is treated with acetic anhydride in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, and an acylation catalyst, such as DMAP, in a suitable solvent such as methylene chloride, chloroform or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 2 to 48 hours to afford 2xe2x80x2,4xe2x80x3,11-triacetylerythromycin A (I). The 10,11-anhydro derivative (II) can be readily obtained by treatment of I with a base in an inert solvent such as THF, dioxane, DME, or DMF at a temperature ranging from xe2x88x9278xc2x0 C. to 80xc2x0 C. for 1-24 hours. Suitable bases to effect the elimination reaction include, but are not limited to, sodium hexamethyidisilazide, potassium hexamethyldisilazide, LDA, lithium tetramethylpiperidide, DBU, and tetramethylguanidine. It will be apparent to one skilled in the art that alternative methods for synthesis of 2xe2x80x2,4xe2x80x3-diacetyl-10,11-anhydroerythromycin A are available, including conversion of erythromycin A to the 11,12-cyclic carbonate derivative with ethylene carbonate, followed by elimination with tetramethylguanidine, as described in Hauske, J. R. and Kostek, G., J. Org. Chem. 1982, 47,1595. Selective protection of the 2xe2x80x2 and 4xe2x80x3-hydroxyl groups can then be readily accomplished with acetic anhydride in the presence of a tertiary amine base. Likewise, alternative protecting group strategies may be employed. For example, erythromycin A may be treated with benzoic anhydride, propionic anhydride, or formic acetic anhydride under similar conditions as described above to obtain the 2xe2x80x2,4xe2x80x3,11-triacylated erythromycin A derivative followed by elimination to afford the corresponding 10,11-anhydro compound.
Once the suitably protected 10,11-anhydro derivative is obtained, derivatization of both tertiary hydroxyl groups can be carried out by treatment with trichloroacetylisocyanate in an inert solvent, such as methylene chloride, chloroform, or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 1-24 hours to yield the di-(N-trichloroacetyl)carbamate derivative (III). The N-trichloroacetylcarbamate functionalities can be hydrolyzed to the corresponding primary carbamates by treatment with a suitable base, such as triethylamine, in an aqueous solvent mixture, such as methanol/water for 1-24 hours at a temperature ranging from 20xc2x0 C. to 80xc2x0 C. Alternative bases may likewise be used to effect this conversion, such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Under the reaction conditions, the primary carbamate formed at the 12-position undergoes spontaneous Michael addition to the electrophilic 11-position of the xcex1,xcex2-unsaturated ketone and the 2xe2x80x2-acetoxy group is hydrolyzed to the corresponding hydroxyl to afford the cyclic carbamate derivative (IV). Compound IV is generally isolated as a mixture of methyl epimers at the C10-position, which can be readily converted to the desired C10-xcex2-methyl epimer (V) by treatment with an equilibrating base, such as potassium t-butoxide, tetramethylguanidine, or DBU in a suitable solvent, such as THF, dioxane, DME, DMF or t-butanol at a temperature ranging from xe2x88x9278xc2x0 C. to 80xc2x0 C. for 1 to 24 hours. Reprotection of the 2xe2x80x2-hydroxyl group to give VI can be carried out by treatment with acetic anhydride in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, and optionally an acylation catalyst, such as DMAP, in a suitable solvent such as methylene chloride, chloroform or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 2 to 48 hours. It is understood that an orthogonal protection strategy of the sugar hydroxyls may also be employed by treatment of V with alternate reagents such as benzoic anhydride, benzyl chloroformate, hexamethyidisilazane, or a trialkylsilyl chloride. Finally, selective removal of the cladinose sugar can be accomplished by reaction of VI with an acid, such as hydrochloric, sulfuric, chloroacetic, and trifluoroacetic, in the presence of alcohol and water to afford 1a. Reaction time is typically 0.5-24 hours at a temperature ranging from xe2x88x9210xc2x0 C. to 37xc2x0 C.
Scheme 2 depicts synthesis of compounds of formulae 1b, 1c and 1d, wherein RCHO is an aldehyde (R may be a member of the group including, but not limited to, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkenyl, arylalkynyl, aralkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkyl, heterocycloalkenyl, heterocycloalkynyl, and heterocycloalkyl). Oxidation of the 3-hydroxy group of 1a to yield compound 1b can be effected with DMSO and a carbodiimide, such as EDCI, in the presence of pyridinium trifluoroacetate in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. Alternative methods of oxidation include N-chlorosuccinimide and dimethylsulfide complex followed by treatment with a tertiary amine base, Dess-Martin periodinane, or oxalyl chloride/DMSO followed by treatment with a tertiary amine base. Removal of the 2xe2x80x2-acetyl group of compound 1b is readily accomplished by transesterification with methanol for 2-48 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C. to yield compound 1c. Alternative methods for deprotection of the 2xe2x80x2-acetyl group include hydrolysis in the presence of an alkali metal hydroxide or alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. Compounds of formula 1d can be obtained by selective alkylation of the primary carbamate of 1c with a suitably substituted aldehyde in the presence of a reducing agent and acid. Alternatively, the corresponding acetal may be used in place of the suitably substituted aldehyde in this reaction. Preferred reagents for effecting this transformation are triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at xe2x88x9220xc2x0 C. to 100xc2x0 C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the aldehyde or acetal.
It will be clear to one skilled in the art that the order of the steps in the synthetic sequence leading to compounds of the invention can be altered, provided that the functionality present in the molecule is compatible with the desired selective transformations. This is illustrated in Scheme 3. For example, compound 1a can be treated under similar conditions as described above for the reductive alkylation of compound 1c (Scheme 2) to yield compounds of the formula 1e. Removal of the 2xe2x80x2-acetyl group of compound 1e as described for the conversion of compound 1b to compound 1c (Scheme 2) provides compounds of formula 1g. Alternatively, oxidation of the 3-hydroxyl of compound 1e to the ketone of compound 1f can be conducted as described for the analogous transformation of 1a to 1b in Scheme 2. Finally, deprotection of the 2xe2x80x2-acetyl group of 1f is readily effected as described for the conversion of compound 1b to compound 1c (Scheme 2) to provide the compounds of formula 1d, wherein R is as previously defined.
Scheme 4 illustrates an alternate route for the preparation of the compounds of the invention (1d). Reaction of compound VI with a suitably substituted aldehyde and a reducing agent, such as triethylsilane, in the presence of an acid, such as trifluoroacetic acid, in a suitable solvent, such as acetonitrile, methylene chloride, or toluene, at a temperature ranging from xe2x88x9220xc2x0 C. to 100xc2x0 C. for 2-96 hours leads to the simultaneous removal of the cladinose sugar and the selective alkylation of the primary carbamate to afford compound 1e. Alternatively, the corresponding acetal of the suitably substituted aldehyde may be used to effect this transformation. Conversion of compound 1e to compound 1f and compound 1f to compound 1d can be conducted as described above.
Scheme 5, wherein R4a is halogen and R is as described above, illustrates the procedures by which compounds of formula 1b can be converted to compounds of formula 1j.
Fluorination of compound 1b can be accomplished with any one of a number of fluorinating reagents, including N-fluorobenzenesulfonimide in the presence of base, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis[tetrafluoroborate] (SELECTFLUOR(trademark)) in the presence of base, 10% F2 in formic acid, 3,5-dichloro-1-fluoropyridinium tetrafluoroborate, 3,5-dichloro-1-fluoropyridinium triflate, (CF3SO2)2NF, N-fluoro-N-methyl-p-toluenesulfonamide in the presence of base, N-fluoropyridinium triflate, and N-fluoroperfluoropiperidine in the presence of base to give 1h wherein R4a is F. Chlorination of 1b can be effected with hexachloroethane in the presence of base, sulfuryl chloride, thionyl chloride, trifluoromethanesulfonyl chloride in the presence of base, chlorine, or sodium hypochlorite in the presence of acetic acid to give 1 h wherein R4a is Cl. Suitable brominating agents would include pyridinium hydrobromide perbromide, bromine in acetic acid, N-bromosuccinimide in the presence of base, 1,2-dibromoethane in the presence of base, or carbon tetrabromide in the presence of base to give 1h wherein R4a is Br. Suitable iodinating agents include N-iodosuccinimide in the presence of base or iodine to give 1h wherein R4a is I.
Transformation of the halogenated derivatives 1h to the corresponding compounds of formula 1j can be accomplished through analogous synthetic routes as above. Reaction of 1h with a suitably substituted aldehyde or acetal in the presence of a reducing agent and acid yields compounds 1i. Reagent combinations for effecting this transformation include triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at xe2x88x9220xc2x0 C. to 100xc2x0 C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the aldehyde or acetal. Compounds 1i are then converted to the corresponding compounds of formula 1j by reaction with methanol for 2-48 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C.
It will be understood by one skilled in the art of organic synthesis that the halogenation reaction can also be conducted at a later stage in the synthetic sequence. For example, halogenation of compound 1f (Scheme 3) affords the corresponding 2-halo derivative, which likewise can be converted to compounds of the invention by deprotection of the 2xe2x80x2-acetyl group under the previously described conditions.
Schemes 6A and 6B illustrate the procedures by which compounds of the formula 1b can be converted to 2xcex1- and 2xcex2-fluoro derivatives of formulae 1n and 1q. Fluorination of compound 1b can be accomplished as described herein above. Reagent combinations for the conversion of compound 1b to the 2xcex1-fluoro derivative 1 k include SELECTFLUOR and sodium hexamethyldisilazide in DMF and N-fluorobenzenesulfonimide and potassium t-butoxide in THF. Typically, the reaction is conducted at xe2x88x9278xc2x0 C. to xe2x88x9260xc2x0 C. for 5 minutes to 24 hours. Reagent combinations for the conversion of compound 1b to the 2xcex2-fluoro derivative 10 include N-fluorobenzenesulfonimide and sodium hydride in DMF. Typically, this reaction is conducted at 0xc2x0 C. to 20xc2x0 C. for 1 to 24 hours.
Transformation of the fluorinated derivatives 1k and 1o to the corresponding compounds of the invention 1n and 1q, respectively, can be accomplished through analogous synthetic routes as above. Reaction of 1k or 1o with a suitably substituted aldehyde or acetal in the presence of a reducing agent and acid yields compounds 1m and 1p, respectively. Reagent combinations for effecting this transformation include triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at xe2x88x9220xc2x0 C. to 100xc2x0 C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the aldehyde or acetal. Compounds 1m and 1p are then converted to the corresponding compounds of the invention 1n and 1q, respectively, by reaction with methanol for 2-48 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C.
It will be also understood by one skilled in the art of organic synthesis that the fluorination reaction can also be conducted at a later stage in the synthetic sequence. For example, fluorination of compound 1f (Scheme 3) affords the corresponding 2-fluoro derivative, which likewise can be converted to compounds of the invention by deprotection of the 2xe2x80x2-acetyl group under the previously described conditions.
Other compounds of the invention may also be suitable substrates for further transformation to yield other compounds of the present invention. Some of these transformations are illustrated in Schemes 7-11.
Scheme 7 illustrates the conversion of the 3-(4-nitrophenyl)-2-propenyl analog (1r) to the 3-[4-(4H-1,2,3-triazol-4-yl)phenyl]-2-propenyl analog (1t) via the intermediacy of the 3-(4-aminophenyl)-2-propenyl derivative (1s) wherein R4 is as described above. The selective reduction of the nitro group of 1r to the amine of 1s can be conducted with tin(II) chloride in ethanol at a temperature ranging from 20xc2x0 C. to 78xc2x0 C., typically for 1 to 24 hours. Alternative methods for reduction of the nitro group can also be employed, including iron/hydrochloric acid, iron/acetic acid, tin/hydrochloric acid, zinc/ammonium chloride, or sodium borohydride/nickel chloride. Conversion of the amino group of 1s to the 1,2,4-triazole of 1t is effected by condensation of the amine with N,N-dimethylformamide azine dihydrochloride in the presence of a base, such as pyridine. Reaction time is typically 2 to 72 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 115xc2x0 C.
Scheme 8 depicts the conversion of 3-(4-bromophenyl)-2-propenyl analog (1u) to the 3-(1,1xe2x80x2-biphen-4-yl)-2-propenyl analog (1v) wherein R4 is as described above. Reaction of the aryl bromide with an aryl boronic acid derivative to give the biaryl derivative is conducted under typical Suzuki coupling conditions, i.e., in the presence of a Pd0 catalyst, typically palladium tetrakistriphenylphosphine, and a base, typically sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, or triethylamine in a suitable solvent, such as toluene, ethanol, methanol, DME, or THF. Reaction time is typically 2 to 48 hours at a temperature ranging from 20xc2x0 C. to 110xc2x0 C. Aryl iodides and aryl triflates are also suitable substrates for this conversion.
Scheme 9 illustrates the conversion of a substituted N-propenylcarbamate derivative (1w) to the corresponding substituted N-propylcarbamate compound (1x), wherein Rxe2x80x2 may be a member of the R group except alkenyl and alkynyl, and R and R4 is as described above. Typically, this transformation is conducted via catalytic transfer hydrogenation, in which the olefin is reacted with ammonium formate in the presence of a suitable catalyst, such as palladium on carbon, in a suitable solvent, such as methanol or ethanol, at a temperature ranging from 20xc2x0 C. to 60xc2x0 C. for 15 minutes to 24 hours. Other methods for reduction of the double bond could also be applicable, for example treatment with hydrogen in the presence of a noble metal catalyst, such as palladium or platinum. It will be obvious to one skilled in the art that the analogous N-propynylcarbamate may likewise be reduced to the corresponding N-propylcarbamate under similar conditions.
Scheme 10 illustrates a method for conversion of a secondary carbamate derivative (1j) to a tertiary carbamate derivative (1y), wherein Rxe2x80x3 is an independent member of the R group, and R and R4 are as described above, by reaction with an aldehyde and a suitable reducing agent, typically triethylsilane, in the presence of an acid, typically trifluoroacetic acid, in an appropriate solvent, such as acetonitrile, methylene chloride, or toluene. Reaction times are typically 2 to 96 hours at a temperature ranging from 20xc2x0 C. to 110xc2x0 C. Alternative methods for effecting this conversion may also be contemplated, for example reaction of a suitably protected secondary carbamate precursor with an alkyl halide in the presence of a sufficiently strong base, such as sodium hydride, potassium hexamethyidisilazide, or LDA.
Scheme 11 illustrates the conversion of compounds 1d, wherein R is as previously defined, to compounds containing a 2-hydroxy substituent (1z). This transformation may be conducted by treatment of compound 1d with charcoal in the presence of air in a suitable solvent, such as methanol or ethanol. It will be apparent to one skilled in the art of organic synthesis that other methods may be employed to effect this conversion, including for example treatment of 1d with a base, such as potassium hexamethyldisilazide or LDA, and an oxidant, such as camphorsulfonyloxaziridine or MoOPh.
Scheme 12 illustrates the conversion of 1axe2x80x2 to compounds of the invention 1bxe2x80x2, 1cxe2x80x2, 1dxe2x80x2, 1exe2x80x2, 1fxe2x80x2, and 1gxe2x80x2 with a nitrogen-containing substituent on the carbamate in the 6-position, wherein R4 and Ra are as described above. Reaction of 1axe2x80x2 with a protected aminoaldehyde derivative, such as N-(benzyloxycarbonyl)glycinal, in the presence of a suitable reducing agent, such as triethylsilane, and a suitable acid, such as trifluoroacetic acid affords the protected amine derivative (1bxe2x80x2). Typically this reaction is conducted in an appropriate solvent, such as acetonitrile, methylene chloride, or toluene, for 2 to 96 hours at a temperature ranging from 20xc2x0 C. to 110xc2x0 C. Deprotection of 1bxe2x80x2 to afford the corresponding amine derivative (1cxe2x80x2) can be readily effected by procedures known in the art, such as catalytic hydrogenation in the presence of a noble metal catalyst or catalytic transfer hydrogenation with palladium on carbon in the presence of cyclohexadiene or ammonium formate at a temperature ranging from 20xc2x0 C. to 60xc2x0 C. Typically these reactions are conducted in an inert solvent such as methanol or ethanol. Conversion of 1cxe2x80x2 to several of the compounds of the invention (Scheme 12) can be conducted with techniques known in the art, such as reductive alkylation with formaldehyde in the presence of a suitable reducing agent, such as sodium cyanoborohydride, and an acid, such as acetic acid to afford the alkylated amine derivative (1dxe2x80x2). Alternatively, 1cxe2x80x2 may be converted to the amide derivative (1exe2x80x2) by acylation with a suitably substituted acid chloride or acid anhydride in the presence of a base, such as pyridine, optionally in the presence of an acylation catalyst, such as DMAP. Amine derivative (1cxe2x80x2) may also be converted to a carbamate (1fxe2x80x2) by treatment with a suitably substituted chloroformate or pyrocarbonate derivative in the presence of pyridine. Finally, reaction of 1cxe2x80x2 with a suitably substituted isocyanate in an inert solvent, such as tetrahydrofuran or methylene chloride, provides access to the correponding urea derivatives (1gxe2x80x2). Optional deprotection of the 2xe2x80x2-acetyl group of 1bxe2x80x2, 1cxe2x80x2, 1dxe2x80x2, 1exe2x80x2, 1fxe2x80x2, and 1gxe2x80x2 is readily effected as described for the conversion of compound 1b to compound 1c (Scheme 2).
Scheme 13 illustrates the analogous procedure whereby 1axe2x80x2 is converted to compounds of the invention 1hxe2x80x2, 1ixe2x80x2, 1jxe2x80x2, and 1kxe2x80x2 with a carbonyl-containing substituent on the carbamate in the 6-position, wherein R4 and Ra are as described above. Reaction of 1axe2x80x2 with, for example, benzyl 4-oxobutanoic acid (Cannon, J. G. and Garst, J. E., J. Org. Chem. 1975, 40, 182) in the presence of a suitable reducing agent, such as triethylsilane, and a suitable acid, such as trifluoroacetic acid affords the benzyl ester derivative (1hxe2x80x2). Typically this reaction is conducted in an appropriate solvent, such as acetonitrile, methylene chloride, or toluene, for 2 to 96 hours at a temperature ranging from 20xc2x0 C. to 110xc2x0 C. Deprotection of 1hxe2x80x2 to afford the corresponding acid derivative (1ixe2x80x2) can be readily effected by procedures known in the art, such as catalytic hydrogenation in the presence palladium on carbon in an inert solvent such as methanol or ethanol. Conversion of 1ixe2x80x2 to other compounds of the invention (Scheme 13) can be executed with techniques known in the art, such as reaction with a suitably substituted alcohol or amine in the presence of a coupling agent such as dicyclohexylcarbodiimide, BOP, or PyBOP, optionally in the presence of a base, such as diisopropylethylamine, and an acylation catalyst, such as DMAP or HOAt, to afford the corresponding ester derivative (1jxe2x80x2) or amide derivative (1kxe2x80x2). Optional deprotection of the 2xe2x80x2-acetyl group of 1hxe2x80x2, 1ixe2x80x2, 1jxe2x80x2, and 1kxe2x80x2 is readily effected as described for the conversion of compound 1b to compound 1c (Scheme 2).
A method of synthesis of 9-oxime compounds of formulae 1lxe2x80x2, 1mxe2x80x2, 1nxe2x80x2, 1oxe2x80x2, 1pxe2x80x2, 1qxe2x80x2, and 1rxe2x80x2 is illustrated in Scheme 14. Compound V is converted to compound 1lxe2x80x2 by a two-step process. Treatment of compound V with hydroxylamine in the presence of an acid such as acetic acid or formic acid in an alcoholic solvent such as methanol, ethanol, or 2-propanol at a temperature from 50xc2x0 C. to 100xc2x0 C. results in oxime formation and partial hydrolysis of the cladinose sugar. Complete hydrolysis of the cladinose to provide compound 1lxe2x80x2 is then effected by treatment with an acid, such as hydrochloric, sulfuric, chloroacetic, or trifluoroacetic, in the presence of alcohol and water. Preferred conditions for the oxime formation are the use of acetic acid in 2-propanol as solvent. Preferred conditions for cladinose removal are hydrochloric acid in aqueous ethanol. Protection of the 2xe2x80x2hydroxyl group and the oxime hydroxyl group followed by oxidation of the 3-hydroxyl provides compound 1mxe2x80x2. Protection of the 2xe2x80x2 and oxime hydroxyl groups as their acetates can be carried out by treatment of 1lxe2x80x2 with acetic anhydride in the presence of a tertiary amine base (such as triethylamine, diisopropylethylamine) or pyridine, and optionally an acylation catalyst, such as DMAP, in a suitable solvent such as methylene chloride, chloroform or THF at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. for 2 to 48 hours. Oxidation of the 3-hydroxy group can be effected with DMSO and a carbodiimide, such as EDCI, in the presence of pyridinium trifluoroacetate in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 37xc2x0 C. Alternative methods of oxidation include N-chlorosuccinimide and dimethylsulfide complex followed by treatment with a tertiary amine base, Dess-Martin periodinane, or oxalyl chloride/DMSO followed by treatment with a tertiary amine base. Fluorination of compound 1mxe2x80x2 with SELECTFLUOR and sodium hexamethyidisilazide in DMF provides compound 1nxe2x80x2. Compounds of formula 1oxe2x80x2 and 1pxe2x80x2 can be obtained by selective alkylation of the primary carbamate of 1mxe2x80x2 and 1nxe2x80x2, respectively, with a suitably substituted aldehyde in the presence of a reducing agent and acid. Alternatively, the corresponding acetal may be used in place of the suitably substituted aldehyde in this reaction. Preferred reagents for effecting this transformation are triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at xe2x88x9220xc2x0 C. to 100xc2x0 C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the aldehyde or acetal. Removal of the 2xe2x80x2-acetyl and oxime acetyl groups of compounds of formulae 1oxe2x80x2 and 1pxe2x80x2 is readily accomplished by transesterification with methanol for 2-48 hours at a temperature ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C. to yield compounds of formulae 1qxe2x80x2 and 1rxe2x80x2, respectively. Alternative methods for deprotection of the 2xe2x80x2-acetyl and oxime acetyl groups include hydrolysis in the presence of an alkali metal hydroxide or alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol.
Scheme 15 illustrates a method of synthesis of 3,9-dioxime compounds. Treatment of a 3,9-diketo compound such as a compound of formula 1d with hydroxylamine or an alkoxylamine in an alcoholic or aqueous alcoholic solvent at a temperature from 50xc2x0 C. to 120xc2x0 C. for 2 to 72 hours provides compounds of formula 1sxe2x80x2. The hydroxylamine or alkoxylamine may optionally be used in the form of an acid addition salt. The reaction may also be performed in the presence of an acid catalyst such as acetic acid, formic acid, propionic acid, or hydrochloric acid.
Scheme 16 illustrates an additional method for the preparation of compounds of the invention of Formula 1. The method is illustrated for the preparation of compounds of formula 1 uxe2x80x2 from the compound of formula 1c via the compounds of formula 1txe2x80x2 as intermediates. Compounds of formula 1txe2x80x2 (where Rd and Re are independently selected from the group consisting of hydrogen, CN, nitro, xe2x80x94C(O)Rh, xe2x80x94C(O)ORh, xe2x80x94C(O)NRhRi, xe2x80x94SO2Rh, optionally substituted C1-C8-alkyl, optionally substituted aryl, and optionally substituted heteroaryl, where Rh and Ri are independently selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl) can be obtained by reaction of 1c with a suitably substituted 1,4-dialdehyde or its equivalent in the presence of an acid. Equivalents of 1,4-dialdehydes include 2,5-dialkoxytetrahydrofurans, 1,4-dialdehyde monoacetals, and 1,4-dialdehyde diacetals. A preferred acid for effecting this transformation is trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at xe2x88x9220xc2x0 C. to 100xc2x0 C. Typically, the reaction is conducted for from 2-96 hours.
Preferred 1,4-dialdehydes or their equivalents include 2-formyl-4,4-dimethoxybutanenitrile, tetrahydro-2,5-dimethoxy-3-furancarboxaldehyde, tetrahydro-2,5-dimethoxy-3-furancarboxylic acid methyl ester, and tetrahydro-2,5-dimethoxy-3-furancarboxylic acid ethyl ester. Compounds of formula 1txe2x80x2 can be converted to compounds of formula 1uxe2x80x2 by displacement of the pyrrole with primary amines or cyclic secondary amines in a suitable solvent, such as acetonitrile, dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran, at a temperature ranging from xe2x88x9220xc2x0 C. to 120xc2x0 C. for 0.5 to 72 hours. Preferred substrates for this conversion are those in which the pyrrole is substituted with electron-withdrawing groups including, but not limited to, cyano, formyl, and alkoxycarbonyl. A particularly preferred substrate is compound 1txe2x80x2, where Rd=CN and Re=H.
It will be clear to one skilled in the art that the order of the steps in the synthetic sequence leading to compounds of the invention can be altered, provided that the functionality present in the molecule is compatible with the desired selective transformations. This is illustrated in Scheme 17. For example, compound 1a can be converted to compounds of formula 1vxe2x80x2 under similar conditions as described above for the conversion of compound 1c to compound 1txe2x80x2 (Scheme 16). Removal of the 2xe2x80x2-acetyl group of compounds of formula 1vxe2x80x2 as described for the conversion of compound 1b to compound 1c (Scheme 2) provides compounds of formula 1wxe2x80x2. Compounds of formula 1wxe2x80x2 may then be converted to compounds of formula 1xxe2x80x2 by treatment with primary amines or cyclic secondary amines as described for the conversion of compounds of formula 1txe2x80x2 to compounds of formula 1uxe2x80x2 (Scheme 16). Alternatively, oxidation of the 3-hydroxyl of compounds of formula 1vxe2x80x2 to the ketone of compounds of formula 1yxe2x80x2 can be conducted as described for the analogous transformation of 1a to 1b in Scheme 2. Deprotection of the 2xe2x80x2-acetyl group of compounds of formula 1yxe2x80x2 is readily effected as described for the conversion of compound 1b to compound 1c (Scheme 2) to provide the compounds of formula 1txe2x80x2. Compounds of formula 1txe2x80x2 may then be converted to compounds of formula 1uxe2x80x2 as described above in Scheme 16.
Scheme 18 illustrates a method for the synthesis of compounds of formula 1zxe2x80x2 in which Rj and Rk taken together with the atoms to which they are attached form a nitrogen-containing heterocycle. Treatment of 1c with a dialdehyde or dialdehyde equivalent in the presence of a reducing agent and acid provides compounds of formula 1zxe2x80x2. Dialdehyde equivalents include dialdehyde monoacetals, dialdehyde diacetals, 2,5-dialkoxytetrahydrofurans, 2,6-dialkoxytetrahydropyrans, and 2-alkoxy-3,4-dihydro-2H-pyrans. Preferred reagents for effecting this transformation are triethylsilane and trifluoroacetic acid in a suitable solvent, like acetonitrile, methylene chloride, or toluene at xe2x88x9220xc2x0 C. to 100xc2x0 C. Typically, the reaction is conducted for from 2-96 hours depending on the reactivity of the dialdehyde or dialdehyde equivalent. It will be clear to one skilled in the art that the reaction illustrated in Scheme 18 can also be conducted at different stages in the synthetic sequence to access compounds analogous to compounds of formula 1zxe2x80x2.
When the aldehydes or acetals used in the preparation of compounds 1d, 1e, 1i, 1m, 1p, and 1y are not commercially available, they can be obtained by conventional synthetic procedures, in accordance with literature precedent, from readily accessible starting materials using standard reagents and reaction conditions. Exemplary syntheses of several of the aldehydes used in the preparation of 1d, 1e, 1i, 1m, 1p, and 1y are presented hereinafter as reference examples.
When the dialdehydes or dialdehyde equivalents used in the preparation of compounds 1txe2x80x2, 1vxe2x80x2, and 1zxe2x80x2 are not commercially available, they can be obtained by conventional synthetic procedures, in accordance with literature precedent, from readily accessible starting materials using standard reagents and reaction conditions. Exemplary syntheses of several of the dialdehydes or dialdehyde equivalents used in the preparation of compounds 1txe2x80x2, 1vxe2x80x2, and 1zxe2x80x2 are presented hereinafter as reference examples.
When the amines used in the preparation of compounds 1uxe2x80x2 and 1xxe2x80x2 are not commercially available, they can be obtained by conventional synthetic procedures, in accordance with literature precedent, from readily accessible starting materials using standard reagents and reaction conditions. Exemplary syntheses of several of the amines used in the preparation of compounds 1uxe2x80x2 and 1xxe2x80x2 are presented hereinafter as reference examples.
Compounds of the invention wherein R3 is a group other than H may be prepared by methods described in WO00/75156, which is hereby incorporated by reference.
Compounds of the invention wherein R5 is a hydroxy protecting group other than acyl may be prepared by methods analogous to those shown in the above schemes with appropriate reagents that are either commercially available or may be made by known methods.
Compounds of the invention wherein R6 is a group other than ethyl may be prepared beginning with modified erythromycin derivatives as starting materials as described in various publications including, but not limited to, WO99/35157, WO00/62783, WO00/63224, and WO00/63225, which are all incorporated by reference herein.
These compounds have antimicrobial activity against susceptible and drug resistant Gram positive and Gram negative bacteria. In particular, they are useful as broad spectrum antibacterial agents for the treatment of bacterial infections in humans and animals. These compounds are particularly activity against S. aureus, S. epidermidis, S. pneumoniae, S. pyogenes, Enterococci, Moraxelia catarrhalis and H. influenzae. These compounds are particularly useful in the treatment of community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections.
Minimal inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art. The in vitro antimicrobial activity of the compounds was determined by the microdilution broth method following the test method from the National Committee for Clinical Laboratory Standards (NCCLS). This method is described in the NCCLS Document M7-A4, Vol. 17, No. 2, xe2x80x9cMethods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobicallyxe2x80x94Fourth Editionxe2x80x9d, which is incorporated herein by reference.
In this method two-fold serial dilutions of drug in cation adjusted Mueller-Hinton broth are added to wells in microdilution trays. The test organisms are prepared by adjusting the turbidity of actively growing broth cultures so that the final concentration of test organism after it is added to the wells is approximately 5xc3x97104 CFU/well.
Following inoculation of the microdilution trays, the trays are incubated at 35xc2x0 C. for 16-20 hours and then read. The MIC is the lowest concentration of test compound that completely inhibits growth of the test organism. The amount of growth in the wells containing the test compound is compared with the amount of growth in the growth-control wells (no test compound) used in each tray. As set forth in Table 1, compounds of the present invention were tested against a variety of Gram positive and Gram negative pathogenic bacteria resulting in a range of activities depending on the organism tested.
Table 1 below sets forth the biological activity (MIC, xcexcg/mL) of some compounds of the present invention.
This invention further provides a method of treating bacterial infections, or enhancing or potentiating the activity of other antibacterial agents, in warm-blooded animals, which comprises administering to the animals a compound of the invention alone or in admixture with another antibacterial agent in the form of a medicament according to the invention.
When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, diluents, and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing for example, from about 0.5% to 5% of suspending agent, syrups containing, for example, from about 10% to 50% of sugar, and elixirs containing, for example, from about 20% to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.5% to 5% suspending agent in an isotonic medium. These pharmaceutical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with the carrier, more usually between 5% and 60% by weight.
Compositions for topical application may take the form of liquids, creams or gels, containing a therapeutically effective concentration of a compound of the invention admixed with a dermatologically acceptable carrier.
In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred. These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacological acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.1 mg/kg to about 400 mg/kg of animal body weight, which may be given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 0.07 g to 7.0 g, preferably from about 100 mg to 2000 mg. Dosage forms suitable for internal use comprise from about 100 mg to 1200 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
The production of the above-mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredients(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).
The following examples describe in detail the chemical synthesis of representative compounds of the present invention. The procedures are illustrations, and the invention should not be construed as being limited by chemical reactions and conditions they express. No attempt has been made to optimize the yields obtained in these reactions, and it would be obvious to one skilled in the art that variations in reaction times, temperatures, solvents, and/or reagents could increase the yields.