An important intermediate for preparing cephalosporin antibiotics, 7-aminodesacetoxy cephalosporanic acid (7-ADCA), is prepared by a novel bioprocess in which a transformed Penicillium chrysogenum strain is cultured in the presence of an adipate feedstock to produce adipoyl-6-APA (6-amino penicillanic acid); and the in situ expression of an expandase gene, e.g., from Streptomyces clavuligerus, with which the P. chrysogenum has been transformed, converts the adipoly-6-APA by ring expansion to adipoyl-7-ADCA. The final product, 7-ADCA, is then prepared by cleavage of the adipoyl side chain using an adipoyl acylase. The entire synthesis, accordingly, is carried out using bioprocesses, and is efficient and economical.

1. Field of the Invention
The present invention is in the field of synthesis methods for the preparation of commercial cephalosporin antibiotics, of which there are presently a significant number, these therapeutic agents now being in their fourth generation. The large variety of side chains to be found in commercial cephalosporins and the significant economic importance of the cephalosporins has placed increased importance on achieving more economic and efficient methods of preparing key intermediates which permit ready synthesis of the various cephalosporins.
One of these key intermediates is 7-aminodesacetoxy cephalosporanic acid (7-ADCA), which may be represented by the following formula: ##STR1## Currently, 7-ADCA is produced from penicillin G and requires four or five chemical steps to expand the penicillin ring system from 5 members to the 6-membered ring which characterizes cephalosporins. As is typical of totally chemical synthesis, this process has serious disadvantages. Among these are the requirements of a multi-step and complex process, expensive reagents, significant quantities of process by-products resulting in effluent treatment problems, and purification of a highly impure starting material before chemical treatment begins. Consequently, there has been an ongoing search for a microbiological or fermentative process which would achieve enzymatic ring expansion and side chain cleavage to provide 7-ADCA on a more economic basis than the chemical process currently in use.
Accordingly, the present invention is particularly in the field of preparing the key cephalosporin intermediate 7-ADCA, and more particularly, in the field of bioprocesses for the preparation of 7-ADCA.
To date, the search for a successful bioprocess for making 7-ADCA has largely proved futile, certainly with respect to one of commercial scale. For example, while it has been possible to prepare 6-amino penicillanic acid (6-APA) by direct fermentation and/or by enzymatic treatment of penicillin G, leaving only ring expansion necessary to give 7-ADCA, it has been found that, unfortunately, the Cephalosporium or Streptomyces enzymes which carry out ring expansion in the normal metabolic pathways of these microorganisms do not accept 6-APA as a substrate. These enzymes, which are collectively referred to in the art as the DAOCS or expandase enzyme, are defined as enzymes which catalyze the expansion of penam ring structures found in penicillin-type molecules to ceph-3-em rings, as found in the cephalosporins. Hereafter, these enzymes will be referred to as "the expandase enzyme".
A substrate on which the expandase enzyme does operate is penicillin N, which upon ring expansion, gives deacetoxy cephalosporin C (DAOC). Here, it is only necessary to cleave the (D)-a-aminoadipoyl side chain to give 7-ADCA, but this side chain has proven stubbornly resistant to enzymatic cleavage, giving only unacceptably low yields.
In accordance with the present invention it has been possible to achieve an efficient bioprocess wherein a penicillin compound (having an adipoyl side chain) is produced by a novel fermentation process in high titers, said penicillin compound being an acceptable substrate for the expandase enzyme system which is produced in situ by the same microorganism which produces the penicillin compound, having been transformed to express said expandase enzyme system. The expandase enzyme then operates to ring expand the penicillin compound to a cephalosporin compound in high yields. And, importantly in the second critical step, the side chain of the penicillin compound, now a cephalosporin compound, is removable by another enzyme system in surprisingly high yields. The unexpected result of this unique bioprocess which comprises the present invention is the production of 7-ADCA in surprisingly high yields.
2. Brief Description of the Prior Art
Cantwell et al., in Curr Genet (1990) 17:213-221, have proposed a bioprocess for preparing 7-ADCA by ring expansion of penicillin V followed by enzymatic hydrolysis of the resulting deacetoxycephalosporin V to form 7-ADCA. This proposal is based on the availability of a cloned penicillin N expandase gene (cefE) from S. clavuligerus, Kovacevic et al., J. Bacteriol. (1989) 171:754-760 and U.S. Pat. No. 5,070,020. However, since the expandase operates on penicillin N, its natural substrate, but not on penicillin V, the proposal requires genetic engineering to produce a modified expandase gene which can ring-expand the penicillin V. The required modification was not achieved by Cantwell et al., however, and they only succeeded in transforming Penicillium chrysogenum with the cef E gene from Streptomyces clavuligerus and getting low-level expression of the DAOCS (expandase) enzyme.
The expandase enzyme has been well studied in the art, both with respect to its activity and its genetic sequence. For example, in Wolfe U.S. Pat. Nos. 4,510,246 and 4,536,476, cyclase, epimerase and ring expansion enzymes were isolated separately from a cell free extract of prokaryotic .beta.-lactam producing organisms, including Streptomyces clavuligerus, to provide stable enzyme reagents. EP-A-0 366 354 describes an isolated and purified expandase enzyme from S. clavuligerus which is characterized, including by a terminal residue and amino acid composition, and is said to have a molecular weight of about 34,600 Daltons. This is in contrast, however, to the molecular weight of 29,000 assigned to what would appear to be the same enzyme in U.S. Pat. No. 4,536,476. EP-A-0 233 715 discloses isolation and endonuclease restriction map characterization of the expandase enzyme obtained from S. clavuligerus, transformation and expression in a host of said enzyme, and demonstration of ring expansion of penicillin N substrate using said enzyme. U.S. Pat. No. 5,070,020 discloses the DNA sequence encoding the expandase enzyme obtained from S. clavuligerus and describes the transformation of a P. chrysogenum strain with an expression vector containing said DNA sequence, thereby obtaining expression of the expandase enzyme. While it is suggested that this enzyme is useful for the expansion of substrates other than penicillin N, there is no actual demonstration of such an expansion.
The work described above has focused on the expandase enzyme derived from prokaryotic S. clavuligerus. This same enzyme, or at least an enzyme apparently having the same ring expansion activity, is also expressed by strains of eukaryotic Cephalosporium acremonium (also referred to as Acremonium chrysogenum). However, in such strains expandase activity is expressed by a bifunctional gene (cefEF), which also expresses the DACS (hydroxylase) activity whose natural function is to convert the desacetoxycephalosporanic acid (DAOC) product of the expandase enzyme to deacetyl cephalosporin C (DAC). The result is a single, but bifunctional expandase/hydroxylase enzyme. While there have been efforts to separate the activities of these two gene products, none have yet been successful. For example, EP-A-0 281 391 discloses the isolation and DNA sequence identification of the DAOCS/DACS gene obtained from C. acremonium ATCC 11550 together with the corresponding amino acid sequences of the enzymes. A Penicillium is transformed and expresses the enzymes, however, the attempted conversion of penicillins G and V to the corresponding cephalosporins is never demonstrated. Further, despite a suggestion that genetic engineering techniques provide a ready means to separate the genetic information encoding DAOCS from DACS and separately express them, no actual demonstration of such separation is set forth.
The DAOCS/DACS (expandase/hydroxylase) enzyme of C. acremonium has also been well studied in the art, both with respect to its activity and its characteristics and genetic sequence. For example, in Demain U.S. Pat. No. 4,178,210; 4,248,966; and 4,307,192 various penicillin-type starting materials are treated with a cell-free extract of C. acremonium which epimerizes and expands the ring to give a cephalosporin antibiotic product. Wu-Kuang Yeh U.S. Pat. No. 4,753,881 describes the C. acremonium enzyme in terms of its isoelectric point, molecular weights, amino acid residues, ratio of hydroxylase to expandase activities and peptide fragments.
The prior art discussed above deals with only a single aspect of the present invention, i.e., the transformation of a P. chrysogenum strain with the gene expressing the expandase enzyme and obtaining expression of that enzyme. The art, however, has only used the expressed enzyme to ring-expand penicillin N, not penicillins G and V. Even in that case, penicillin N has a 7-position side chain which cannot be cleaved enzymatically to give 7-ADCA, as in the method of the present invention. The present invention relies on the surprising discovery that an adipoyl side chain can be efficiently added by a P. chrysogenum strain, that the expandase enzyme expressed in situ can use that compound efficiently as a substrate for ring expansion to adipoyl 7-ADCA, and that the adipoyl side chain can then be efficiently removed by yet another enzyme to give 7-ADCA. While various isolated fragments of the present invention may be found in the prior art, there has been no suggestion that they be combined to give the unexpected results obtained with the method of the present invention.
For example, production of 6-adipoyl penicillanic acid is known in the art; see Ballio, A. et al., Nature (1960) 185, 97-99. The enzymatic expansion of 6-adipoyl penicillanic acid on an in vitro basis is also known in the art. See Baldwin et al., Tetrahedron (1987) 43, 3009-3014; and EP-A-0 268 343. And, enzymatic cleavage of adipoyl side chains is also known in the art; see Matsuda et al., J. Bact. (1987) 169, 5815-5820.
The adipoyl side chain has the following structure: COOH--(CH.sub.2).sub.4 --CO--, while a side chain of closely related structure is that of glutaryl, having the following formula: COOH--(CH.sub.2).sub.3 --CO--. The enzymatic cleavage of glutaryl side chains is known in the art. See, e.g., Shibuya et al., Agric. Biol. Chem. (1981) 45, 1561-1567; Matsuda and Komatsu, J. Bact. (1985) 163, 1222-1228; Matsuda et al., J. Bact. (1987) 169, 5815-5820; Jap. 53-086084 (1978-Banyu Pharmaceutical Co. Ltd.); and Jap. 52-128293 (1977-Banyu Pharmaceutical Co. Ltd.).
Also, EPA-A-0 453 048 describes methods for improving the adipoyl-cleaving activity of the glutaryl acylase produced by Pseudomonas SY-77-1. By substituting different amino acids at certain locations within the alpha-subunit, a three to five times higher rate of adipoyl cleavage (from adipoyl-serine) was observed. It should be noted that although EP-A-0 453 048, apparently, demonstrates an acylase with improved activity towards adipoyl-side chains, it does not describe any ways (either chemical or through a bioprocess in any way analogous to that described in the instant specification) in which an adipoly-cephalosporin might be generated in the first place.
Where a (D)-a-aminoadipoyl side chain is present, it is known in the art to first enzymatically remove the amino group and shorten the side chain with a (D)-aminoacidoxidase, leaving a glutaryl (GL-7) side chain, with removal of the glutaryl side chain by a second enzyme (glutaryl acylase). Such a two-step cleavage is disclosed in Matsuda U.S. Pat. No. 3,960,662; EP-A-0 275 901; Jap. 61-218057 (1988-Komatsu, Asahi Chemical Industry Co.); WO 90/12110 (1990-Wong, Biopure Corp.); and Isogai et al., Bio/Technology (1991) 9, 188-191.

Recombinant expandase bioprocess for preparing 7-aminodesacetoxy cephalosporanic acid (7-ADCA)


A mold for a prototype metal casting or the like may advantageously be made by forming a casting pattern of adhesively bonded aggregate particles using a binder containing a principle constituent that is soluble in supercritical carbon dioxide; forming a rigid shell mold about the pattern of materials that are unaffected by supercritical carbon dioxide; thereafter exposing the pattern and mold combination to supercritical carbon dioxide to remove the pattern binder adhesive and leave unbonded aggregate particles in the mold and removing the aggregate particles from the mold to leave a mold cavity that faithfully defines the pattern shape.

There is a continuing need for a low cost method of forming a single casting or a relatively few castings such as may be required for prototype parts or for very low volume production. There have been developed a number of prototype-making processes that yield plastic parts or synthetic resin-coated aggregate parts that are built up, section by section, by a controlled scanning laser beam that polymerizes a layer of molten plastic or fuses a layer of polymeric film coated aggregate particles. However, there is no low cost method for making a single mold or relatively few molds for making a few cast metal parts.
As stated, it is known to coat ceramic particles or sand particles, glass beads or the like with a suitable fusible polymer film for the purpose of building a prototype part of such materials. In this practice, a flat surface is usually dusted or coated with a number of such particles, and a computer-controlled laser beam sweeps back and forth over the particles selectively heating those that are to be fused together to constitute a particular layer or planar section of the part to be fused together. The work surface or stage carrying the flat section is then lowered by the thickness of a particle layer, a new layer of particles applied, and the process of fusing the new layer of particles with the laser beam is repeated. In this way of forming successive layers of bonded particles or polymerized monomers, virtually any shape of a prototype part can be formed. However, the part is representative only of the shape of the adhesive bound particles and cannot represent all properties of a desired cast metal part. Furthermore, such prior art prototypes could not be used as casting patterns because they were not strong enough to form a two-part mold around them and they could not be easily removed from such a mold.
It is an object of this invention to provide a method of making a pattern and mold for the production of one or a few metal castings.

Method of making a mold for metal casting


An apparatus and method for reproducing pit information precisely from a magnetic optical disk without being adversely affected by heat accumulation. The signal reproducing apparatus reproduces signals using a neural network constituting a decoder that decodes pits on the disk. The signal reproducing method provides learning using a sigmoid function and carries out signal reproduction using a step function.

1. Field of the Invention
The present invention relates to an apparatus and method for reproducing signals from a magnetic optical disk.
2. Description of the Prior Art
Today, magnetic optical disks are coming into general use as a secondary mass storage for use with personal computers, workstations and the like. Signals are recorded on the magnetic optical disk as follows: In an appropriately biased magnetic field, a laser beam is applied to the magnetic optical film on the disk surface. The laser beam heats up the film where required to reverse polarity, forming pits that represent signals. The magnetic optical disk thus contains recordings at higher density than the conventional optical disk whose pits are physically formed depressions (or projections). In this respect, the magnetic optical disk is suitable for use as a mass storage.
FIG. 19 shows a typical relationship between pits recorded on the magnetic optical disk on the one hand, and a reproduced RF signal obtained by irradiating a laser beam to these pits on the other. As shown in FIG. 19, when the recording density is increased, one optical spot formed by the laser beam tends to irradiate two pits or more. As a result, higher recording densities leave the reproduced RF signal more likely to be affected by adjacent pits.
One solution to the above problem is to equalize the reproduced RF signal using a digital filter, as depicted in FIG. 20. In the example of FIG. 20, the input RF signal is delayed successively by "n" delay circuits 11 through 1n. The signals output by the delay circuits 11 through 1n enter "n" multipliers 21 through 2n which correspond to the respective delay circuits. After multiplication, the multipliers produce coefficients w1 through wn. The outputs of the multipliers 21 through 2n enter an adder 3 for addition. Coefficients w1 through wn from the multipliers 21 through 2n are then adjusted to a predetermined value. In this manner, the outputs of the RF signal from the adder 3 are equalized for a predetermined characteristic.
As signals are recorded over time on the magnetic optical disk, the pits recorded later tend to be larger than those recorded earlier due to such effects as heat response and accumulation, as illustrated in FIGS. 21 and 22. When the pits are read for reproduction, the larger pits proportionately raise the level of the RF signal. This means that the waveform of the reproduced RF signal no longer stays linear. In that case, equalizing the reproduced RF signal with the digital linear filter of FIG. 20 is not enough to obtain information accurately corresponding to the individual pits. Although it is conceivable to vary the coefficients "w" in accordance with the data (pit) pattern, this gives rise to a possibility of error propagation. Furthermore, attempts to vary the coefficients "s" in units of pits are unrealistic from a practical point of view.

Apparatus and method for signal reproduction


Disclosed is a modular spill containment rail system for containing a hazardous spilled substance from at least one battery. The system has a plurality of containment rails that are connectable to one another to define a perimeter around the battery. Each rail has at least one wall with a first end and a second end. At least one male connection device orthogonally protrudes from the first end and at least one female opening may be provided in the second end. A first end of a first rail may be removably received within a second end of second rail. Upon connecting the rails, at least a part of the first end of the first rail may be in an overlapping relationship with the second end of the second rail. A method for assembling a system and a containment system with a flexible liner and a neutralizing material are also disclosed herein.

In our industrial society, devices often contain substances that may leak or spill undesirably onto other devices, personally, or the environment. For example, batteries may be stored on battery racks or other structures where the batteries serve as a backup power supply for data communication centers and computers. These batteries may contain acidic or alkaline substances that may leak or spill onto other batteries, cables, equipment, and other devices as well as personnel, thereby posing a hazard to people and property. Sulfuric acid, commonly found in batteries, is an extremely hazardous material regulated by the federal, state and local governments. With respect to batteries, Article 64 of the Uniform Fire Code requires a four-inch high containment barrier with an acid neutralization capability to a pH of 7-9. Similarly, other devices that may use spill containment systems include, but are not limited to, air conditioning units that may drip water from condensation or leak Freon, or water heaters that may leak water.
Therefore, the inventor has found that it is desirable to contain leaks and spills from hazardous devices such as batteries. While spill containment systems exist, the existing systems need to be improved. For example, storage space for battery backup systems is precious and as companies become increasingly dependent on computers, their need for storing a greater number of batteries increases. Thus, companies utilizing battery backup systems would like to be able to store as many batteries as they can in their space, such as a warehouse or basement or other rooms. Some of the rooms may have structures that obstruct the floor space (such as columns); others may have non-rectangular areas. Battery spill containment systems preferably should be able to be installed in virtually any of these diverse rooms. The systems should also be able to be installed quickly and easily in a given space at a low cost, and with minimal effort and time. Additionally, the rails of the spill containment systems should provide a reinforced and secure environment around the perimeter of the batteries.
Therefore, the inventor has found that it is desirable to have improved designs of a battery spill containment system that permits a greater number of batteries to be stored in a given space, easy access to the batteries, increased safety, and modularity of designs.


A color inspection system capable of making a determination on pass or failure with accuracy equivalent to that for the case of a visual inspection even in the case of inspecting various textile products as measurement targets, such as raised cloth, cloth with printed patterns such as a marbled pattern, moire pattern and detailed pattern is provided. With the color inspection system, an illuminant is set to shine a light on the surface of a textile product placed on the top surface of a measuring platform to thereby make measurements from a direction at an angle of 45 degrees from the surface of a measuring region of the textile product by use of a spectroradiometer of a measuring unit. The spectroradiometer is provided with a wide range lens attached thereto to thereby expand a measuring region. The results of measurement by the spectroradiometer are inputted to an information processor of a determination unit. The information processor computes color values for the whole measuring region to be compared with standard color values stored in a memory to thereby make a determination on pass or fail.

In quality control of textile products, quality control of a surface color thereof is one of important items, and it is regarded that points of importance in controlling color are how close to a standard color the surface color is rendered, and how to decide color tolerance.
Such quality control of color has been conducted by skilled inspectors in accordance with JIS (Z 8723) in the past. However, a color inspection through visual inspection conducted by the inspector has problems such as a lack of unity between determinations made by a plurality of inspectors, and variation in determinations made by one inspector.
Accordingly, in order to cope with the problems, a proposal has been made to conduct a color inspection on textile products, using a color measuring instrument. For example, in Patent Document 1, there has been disclosed a method whereby color measuring is made of continuous lengths, such as a piece of cloth, film, sheet, and so forth, while transferring the same by use of a plurality of sensors.
In Patent Document 2, there has been disclosed a method whereby color measurement by the color element refers to a predetermined color system with reference to a plurality of images about an inspection region of an input image which is inputted by a CCD color camera, and so forth, to thereby find a frequency distribution showing a relationship between color measured values and pixel numbers, making a determination on whether or not a target for inspection is excellent in color shade by comparing the frequency distribution with a standard frequency distribution as a preset. In Patent Document 3, there has been disclosed a method whereby reflected light from a color measuring region of a predetermined area, including patterns, is received by a sectrophotometer to thereby compute the average surface color values of one kind or more, and a determination is made on whether or not a patterned fabric is acceptable on the basis of the color difference between the average surface color values and a standard value. Further, in Patent Document 4, there has been disclosed a method whereby a fabric of weaving or knitting is run, and upon detection of a mark thereof, running is stopped to press down the fabric of weaving or knitting, thereby measuring the color values by a calorimeter.                Patent Document 1 JP 08-15026 A        Patent Document 2 JP 09-203664 A        Patent Document 3 JP 60-33020 A        Patent Document 4 JP 5 1-99088 A


Interpretation of a shot gather and a stack of seismic data. In one implementation, the shot gather is sorted into a first component shot gather, a second component shot gather and a third component shot gather. The first component shot gather is represented as a first subimage, the second component shot gather is represented as a second subimage, and the third component is represented as a third subimage. The first subimage is then merged with the second subimage and the third subimage to create a false color image. The shot gather of seismic traces may then be interpreted based on the false color image. The first component may by an x component, the second component may be a y component and the third component may be a z component. The first subimage may be a red or cyan subimage, the second subimage may be a green or yellow subimage and the third subimage may be a blue or magenta subimage.

The following descriptions and examples are not admitted to be prior art by virtue of their inclusion within this section.
In a seismic survey, a source may be actuated to generate seismic energy, and the resultant seismic wavefield may be sampled by an array of seismic receivers disposed at a distance from the seismic source. Each receiver may be configured to acquire seismic data, which are normally in the form of a record or trace representing the value of some characteristic of the seismic wavefield against time. The acquired seismic data are a representation of the seismic wavefield at the receiver location. Information about the earth's sub-surface can be obtained from the acquired seismic data.
One well-known type of a seismic receiver is the seismic geophone. A geophone contains one or more sensors mounted in a casing. A geophone may be a single component geophone, which contains one sensor that records the component of the seismic wavefield parallel to a pre-determined direction. Information about the vertical component of the seismic wavefield may be obtained using a single component geophone oriented such that the sensing direction of the geophone is substantially vertical. Alternatively, a geophone may be a three-component geophone which includes three sensors oriented to record the components of the seismic wavefield in three orthogonal directions, which are typically denoted as x, y and z components.
Three-component seismic data are commonly displayed on three separate plots. Consequently, it is often difficult to jointly interpret all three components at the same time. However, joint interpretation of two components may be possible using hodogram displays, where the seismic data are windowed in time and offset, and both components are plotted in one display. The resulting ellipses may be analyzed for the length and orientation of their half axes to obtain information about the wave mode of the seismic data. This method, however, often results in substantial degradation of the temporal and spatial resolution of the result, due to its requirement of windowing the data.

Interpretation of shot gather and stack of seismic data


A face shield support includes an adjustable frame which fits over the head of a user during use and provides support for the face shield frame. In one embodiment, the frame includes a first, or frontal strap that extends from approximately above the ears of the user and across the forehead of the user, and a second or rear adjustable strap extending from approximately above the ears of the user and around the base of the user's head adjacent the occipital lobe. Connecting the rear and frontal straps are a pair of mounting members which secure the face shield frame to the support and which also pivotally connect the frontal and rear adjustable straps. An upper bridge may also be provided which extends over the top portion of a user's head and further secures the frontal and rear straps together. The frontal strap may optionally included an expanded frontal area for additional comfort.

The use of face shields to protect a user's eyes and face from various occupational hazards is well known in the art. Face shields are used in numerous professions as protective equipment including, for example, in the chemical, medical, construction, and manufacturing fields. Face shields are typically supported on a user's head by a headband, visor, or helmet, or other type of support system, with the face shield attached such that it is positioned in front of the user's face during operation. Many known supports allow the face shield to pivot from a lowered position (during use) to an upward position (when not in use) so that the face shield does not have to be entirely removed when not in use. It is also common for face shields to be worn for extended periods of time. As such, it is desirable that the face shield support be comfortable to wear. In addition, the face shield should be positioned to provide adequate protection while not obstructing visibility. In order to provide for the proper fit, the support should be adjustable in order to accommodate variations in the size and shape of different user's heads. As will be appreciated, proper fit of the face shield over the user's head is desirable because it aids in both the comfort and proper positioning of the face shield.
While a variety of face shield supports exist today, there is a continued need in the art for additional face shield supports that have lasting comfort, which provide the desired positioning of the face shield for a variety of users, and which are simple to use.

Bacou-Dalloz Eye & Face Protection, Inc.


An optical splitter includes a main waveguide, a tapered waveguide, and a split waveguide group having first and second split waveguides. The side portions of the tapered waveguide taper and expand from a first end portion toward second end portions. The widths of the split waveguides differ from each other. The whole width of the split waveguide group at connecting portions between the tapered waveguide and the split waveguides is smaller than the width of the tapered waveguide at the second end portions. Step portions are formed between the split waveguide group and the side portions.

1. Field of the Invention
This invention relates to an optical splitter that is applied to, for example, a device for splitting a signal light beam in optical communications and the like.
2. Description of the Related Art
For example, in a device for optical integrated circuits used for optical communications, a so-called Y-split waveguide is known as one means for splitting a signal light beam. A splitter capable of asymmetrically splitting optical power at a ratio of 60 to 40 or a ratio of 90 to 10 is also demanded.
For example, a prior art optical splitter as shown in FIG. 14 has a main waveguide 1, a tapered waveguide 2, and a pair of split waveguides 3 and 4. The widths W3 and W4 of the split waveguides 3 and 4 are caused to differ from each other to allow optical power to be split asymmetrically. The tapered waveguide 2 tapers and expands from the main waveguide 1 toward the split waveguides 3 and 4, i.e., from width W1 to width W2. A split portion end face 5 of width Wg is formed between the split waveguides 3 and 4.
In the prior art optical splitter shown in FIG. 14, the width W2 of the tapered waveguide 2 at the connecting portions of the tapered waveguide 2 and the split waveguides 3 and 4 is equal to the sum of the widths W3 and W4 of the split waveguides 3 and 4 and the width Wg of the split end face 5. In other words, the optical splitter is designed to have the following relationships: W2=(W3+W4+Wg) and W3≠W4.
FIG. 15 shows a relationship between a ratio between the widths W3 and W4 of the split waveguides 3 and 4 and each of a split ratio and a split excessive loss in the prior art optical splitter shown in FIG. 14. In FIG. 15, the horizontal axis represents a ratio between the widths W3 and W4 of the split waveguides 3 and 4 [W3/(W3+W4)]. The left vertical axis represents a split ratio between the split waveguides 3 and 4, and the right vertical axis represents a split excessive loss. The sum of the widths W3 and W4 of the split waveguides 3 and 4 is 10 μm, and the section of the main waveguide 1 is a 7 μm×7 μm square. The relative refractive index difference between a core and a clad layer is 0.45%, the width Wg of the split portion end face 5 is 3 μm, the length of the tapered waveguide 2 is 600 μm, and the wavelength of an optical signal is 1.55 μm.
On the other hand, Jpn. Pat. Appln. KOKAI Publication No. 9-80244 describes an optical splitter wherein the positions of a pair of split waveguides are displaced in a width direction of a tapered waveguide. This prior art is directed to an optical splitter as shown in FIG. 16. The optical splitter has a pair of split waveguides 3′ and 4′ whose widths W5 are equal to each other, and the central axes of the split waveguides 3′ and 4′ are displaced by ΔX in the width direction of a tapered waveguide 2 from the central axes of the main waveguide 1 and tapered waveguide 2.
FIG. 17 shows a relationship between the amount of axial displacement ΔX and each of a split ratio and a split excessive loss in the prior art optical splitter shown in FIG. 16. In FIG. 17, the horizontal axis represents the amount of axial displacement ΔX. The left vertical axis represents the split ratio between the split waveguides 3′ and 4′, and the right vertical axis represents the split excessive loss. The section of each of the main waveguide 1 and split waveguides 3′ and 4′ is a 7 μm×7 μm rectangle. The relative refractive index difference between a core and a clad layer is 0.45%, the width Wg of a split portion end face 5 is 3 μm, the length of the tapered waveguide 2 is 600 μm, and the wavelength of an optical signal is 1.55 μm.
The prior art optical splitter shown in FIG. 14 has the drawback that the split excessive loss is as high as about 0.2 dB over the full range of 50 percent to 80-odd percent of split ratio as shown in FIG. 15.
In contrast, the prior art optical splitter shown in FIG. 16 has the drawback that the split excessive loss becomes high as the split ratio increases as shown in FIG. 17. For this reason, there is a limit to the increase in the split ratio.


The invention relates to a combustion chamber, in particular of a gas turbine, comprising an external wall structure that surrounds an internal area and an internal wall, which is formed by the surface of a housing that is located in the internal area. Said combustion chamber can be cooled essentially by convection by an air stream that flows between the external wall structure and the internal wall, whereby the air stream is conducted in a closed cooling air canal. The housing can be mounted in the internal area of the combustion chamber by means of a suspension device, which comprises a large number of fixing elements that are arranged on the periphery of the housing and are braced against the wall structure.

Usually the surfaces of a combustion chamber exposed to the hot gas are cooled by means of impingement cooling, wherein the cooling medium used for cooling impinges practically vertically on a surface to be cooled. This type of cooling is very effective, but the cooling medium experiences a large pressure loss in the process as a result of the impingement on the surface to be cooled.
In a gas turbine, air taken from an air stream generated by a compressor is normally used as the cooling medium. If impingement cooling is the main cooling method employed here, then, owing to the large pressure loss occurring in the process, once cooling is complete, the air used in the process normally can no longer be used for the combustion because the mass flow rate of the cooling air is too low after the cooling. Thus once cooling is complete, the cooling air is no longer available for the combustion. This means there is no alternative but to accept a loss of air that typically ranges from 4 to 8% of the mass flow rate generated by a compressor. In addition, such a loss of air leads to a reduction in the efficiency of the turbine.
DE 197 51 299 C2 discloses a combustion chamber that has a wall structure surrounding an internal area and an inner wall offset from this wall structure.
An intermediate wall having orifices through which cooling steam passes for impingement cooling of the inner wall is also arranged in the intermediate area formed by the wall structure and the inner wall.
The combustion chamber is steam cooled, wherein the cooling steam enters an outer cooling area, passes from here through the orifices into an inner cooling area and there cools by impingement cooling the side of the inner wall not facing the hot gas.
The disadvantage here is that the cooling medium—cooling steam in this case—suffers a large loss in pressure as a result of the impingement cooling. If cooling air were to be used instead of cooling steam in the combustion chamber described, then the cooling air flow would no longer be usable for the combustion because of the large pressure loss.

Combustion chamber, in particular of a gas turbine


The cable tie strap, having elongate strap body and a locking head provides for receipt of the cable tie strap in the head in either direction. The cable tie strap includes a hollow locking head and an elongate strap having toothing on each side of the strap. A locking bar is positioned within the hollow head. The strap body may be inserted into the hollow head in either direction. The locking bar is lockingly engagable with the toothing on either side of the strap upon insertion of the strap into the head in either direction.

In the state of the art are well-known self-locking cable tie straps for binding together in a bundle wires or cables for the realization of harnesses of any kind.
The cable tie straps according to the known art comprise a head part provided with a retaining tooth or pawl, sometimes realized with a metallic insert, arranged to cooperate with a flexible member integral with the head and provided with a toothing on one side arranged for engaging in an irreversible way the retaining tooth or pawl at the moment of the fastening of the bundle of cables and wires. These tie straps according to the prior art have the tooth or pawl in the head that operate in a unidirectional way and are arranged to cooperate with the toothing on the flexible member or tail that is provided with the toothing on one side only.
This known construction of the self-locking tie straps with an irreversible locking entails that owing to the asymmetrical structure of the same, at the moment of their application for the binding of cables or wires it is necessary to pay attention to the direction of insertion of the flexible member or tail to ensure correct engagement and locking with the head.
There are also known members for the temporary locking of electrical wires with a releasable locking with a symmetrical structure used for the temporary locking of electrical cords of electrical or electronic apparatus during the packaging, having a symmetrical structure that is however not suitable for assemblies of the industrial type and that do not show the capabilities of locking and safety of locking of the cable tie straps for industrial use mentioned above.
It is also to be remarked that in the cable tie straps for industrial use to which the present invention is mainly referred, the known asymmetrical structure does not shown inconveniences when these straps are applied by hand; a minimum amount of attention on the part of the operator is sufficient.
However, in the case of binding machines of the industrial type, the asymmetry of the known cable tie straps entails several serious inconveniences. The cable tie straps according to the prior art owing to the asymmetry cause a partially free binding at the base of connection of the flexible part or tail with the head part. This free part at the base of the head assumes a more or less acute angle in relation to the pull exerted at the binding and related to the diameter of the cables, straining the material of the strap at the connection part with the head possible development of nicks or breakage at the connection base.
The straps according to the prior art are provided as tapes to allow the feeding of the tapes to an automatic binding tool.
The asymmetrical shape of the straps according to the prior art fed from an auxiliary distributor is the main origin of jamming of the mechanism of the auxiliary distributor as well as of the binding tool and the feeding conduit, since the feeding method is based on a transfer of the strap along a closed path by fluid propulsion (compressed air). The orientation of the strap is consequently extremely important to ensure the receiving of the strap within the binding tool into a correct position.
In order to ensure the correct orientation, systems according to the prior art use a flexible tube having a square or rectangular cross section that reproduces the outline of the head of the strap and consequently the strap inserted into an auxiliary device of the distributor is "shot" along the piping by means of a jet of air, maintaining its orientation.
This method that seems correct became critical and causes inconvenience when there is impressed a torsion to the square section piping or when the piping itself is bent with a radius shorter than a given limit.

Self-locking cable tie strap with a symmetrical structure


Devices and methods for therapy control based on electromechanical timing involve detecting electrical activation of a patient's heart, and detecting mechanical cardiac activity resulting from the electrical activation. A timing relationship is determined between the electrical activation and the mechanical activity. A therapy is controlled based on the timing relationship. The therapy may improve intraventricular dyssynchrony of the patient's heart, or treat at least one of diastolic and systolic dysfunction and/or dyssynchrony of the patient's heart, for example. Electrical activation may be detected by sensing delivery of an electrical stimulation pulse to the heart or sensing intrinsic depolarization of the patient's heart. Mechanical activity may be detected by sensing heart sounds, a change in one or more of left ventricular impedance, ventricular pressure, right ventricular pressure, left atrial pressure, right atrial pressure, systemic arterial pressure and pulmonary artery pressure.

Heart disease (cardiomyopathy) can cause a patient to exhibit symptoms of congestive heart failure (CHF). CHF is a result of the weakening of the heart's cardiac function characterized by reduced pumping capacity and efficiency. Chronic cardiac rhythm problems can also be the result of cardiomyopathy. The modification of the heart's structure that causes the reduction in pumping capacity also causes modification of the heart's electrical characteristics. The heart's electrical pathways can become stretched out of shape and chemically damaged. This makes arrhythmias much more likely to occur in CHF patients.
Implantation of a pacemaker is a preferred method of treatment for arrhythmias in CHF patients. Although many types of heart problems may require a pacemaker, one method of treatment suited for CHF patients is known as cardiac resynchronization therapy (CRT). CRT uses a pacemaker with multiple pacing leads to coordinate the heart's chambers to act together in a sequence that will pump blood more efficiently.
It is likely that CRT candidates will have various forms of cardiomyopathy, and these patients may exhibit other measurable symptoms of reduced cardiac function besides arrhythmia. The reduced cardiac function of the heart is taken into account when applying CRT in order to tailor the treatment based on the needs of a particular patient. Various external factors must also be taken into account by the pacing system, one of those factors being the current state of activity of the patient.
Rate adaptive pacemakers are currently used that can estimate body activity by detecting body activity or breathing rate and depth, and therefore modify the pacing rate applied to the heart. These indicators can give a rough estimate of metabolic demand for a given patient. It would be beneficial to have more accurate measures of metabolic demand, especially measures that can determine the pumping capacity and pumping efficiency of a heart in order to measure and improve the efficacy of the therapy for the CHF patient.

Method and apparatus for controlling cardiac therapy based on electromechanical timing


Compounds of the formula

The present invention relates to heterocyclic-cyclic amine derivatives of the formula I below, and pharmaceutically acceptable salts of such compounds. The compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from dementia and Alzheimer""s disease.
Alzheimer""s disease is associated with degeneration of a cholinergic neurons in the basal forebrain that play a fundamental role in cognitive functions, including memory. Becker et al., Drug Development Research, 12, 163-195 (1988). As a result of such degeneration, patients suffering from the disease exhibit a marked reduction in acetylcholine synthesis, choline acetyltransferase activity, acetylcholinesterase activity and choline uptake.
It is known that acetylcholinesterase inhibitors are effective in enhancing cholinergic activity and useful in improving the memory of Alzheimer""s patients. By inhibiting acetylcholinesterase enzyme, these compounds increase the level of the neurotransmitter acetylcholine, in the brain and thus enhance memory. Becker et al., supra, report that behavioral changes following cholinesterase inhibition appear to coincide with predicted peak levels of acetylcholine in the brain. They also discuss the efficacy of the three known acetylcholinesterase inhibitors physostigmine, metrifonate, and tetrahydroaminoacridine.
European Patent Application EP A 0 229 391 relates to piperidine derivatives of the formula: R1xe2x80x94Xxe2x80x94Axe2x80x94R2. European Patent Application EP A 296 560 relates to a cyclic amine compound of the formula
All documents cited herein, including the foregoing, are incorporated herein in their entireties.
The present invention relates to compounds of the formula
wherein R1 and R2 are independently selected from hydrogen, (C1-C6)alkoxy, benzyloxy, phenoxy, hydroxy, phenyl, benzyl, halo, nitro, cyano, COR5, xe2x80x94COOR5, xe2x80x94CONHR5, xe2x80x94NR5R6, xe2x80x94NR5COR6, xe2x80x94OCONR5R6, xe2x80x94NHCOOR5, (C1-C6)alkyl optionally substituted with from 1 to 3 fluorine atoms; SOpCH2-phenyl or SOp(C1-C6)alkyl, wherein p is 0, 1 or 2; pyridylmethyloxy or thienylmethyloxy; 2-oxazolyl, 2-thiazolyl and benzenesulfonamide; wherein the phenyl moieties of said phenoxy, benzyloxy, phenyl, benzyl and benzenesulfonamide groups, the pyridyl and thienyl moieties of said pyridylmethyloxy or thienylmethyloxy and the oxazolyl and thiazolyl moieties of said 2-oxaxolyl and 2-thiazolyl may optionally be substituted with 1 or 2 substituents independently selected from halo, (C1-C4)alkyl, trifluoromethyl, (C1-C4)alkoxy, cyano, nitro and hydroxy.
or R1 and R2, when attached to adjacent carbon atoms and when X is oxygen, sulfur or NR4 wherein R4 is hydrogen or (C1-C4 alkyl) may form, together with the carbon atoms to which they are attached, a group of the formula
xe2x80x83wherein J is oxygen, sulfur or NR4, xe2x80x9caxe2x80x9d is 1 or 2, R3 is hydrogen or (C1-C6)alkyl and Q is oxygen, sulfur, NH, CHCH3, C(CH3)2, xe2x80x94CHxe2x95x90CHxe2x80x94, or (CH2)l wherein l is an integer from 1 to 3;
X is oxygen, sulfur, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, or NR4 wherein R4is hydrogen or (C1-C4)alkyl;
Y is xe2x80x94(CH2)mxe2x80x94, xe2x80x94CHxe2x95x90CH(CH2)nxe2x80x94, xe2x80x94NR4(CH2)mxe2x80x94, or xe2x80x94O(CH2)mxe2x80x94 wherein R4 is defined as above, n is an integer from 0 to 3 and m is an integer from 1 to 3;
R5 and R6 are each independently selected from hydrogen, (C1-C6)alkyl, phenyl or benzyl, wherein the phenyl moieties of said phenyl and benzyl may optionally be substituted with 1 or 2 substituents independently selected from fluoro, chloro, bromo, iodo, (C1-C4)alkyl, trifluoromethyl, (C1-C4)alkoxy, cyano, nitro and hydroxy, or NR5R6 together form a 4 to 8 membered ring wherein one atom of the ring is nitrogen and the others are carbon, oxygen or nitrogen (e.g. pyrrolidinyl, piperidinyl, morpholino, piperazinyl or N-methylpiperazinyl), or NR5COR6 together form a 4 to 8 membered cyclic lactam ring;
M is xe2x80x94CHxe2x80x94 or nitrogen;
L is phenyl, phenyl-(C1-C6)alkyl, cinnamyl or pyridylmethyl, wherein the phenyl moieties of said phenyl and phenyl-(C1-C6)alkyl may optionally be substituted with 1 to 3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C6)alkylcarbonyl, xe2x80x94OCONR5R6, xe2x80x94NHCOOR5 or halo; or L is a group of the formula
xe2x80x83wherein b is an integer from 1 to 4, R13 and R14 are independently selected from hydrogen, (C1-C4)alkyl, halo and phenyl, E and F are independently selected from xe2x80x94CHxe2x80x94 and nitrogen, and G is oxygen, sulfur or NR4 wherein R4 is defined as above, with the proviso that when E and F are both nitrogen, one of R13 and R14 is absent; and
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl and (C1-C6)alkoxy, with the proviso that said (C1-C6)alkoxy is not attached to a carbon that is adjacent to a nitrogen.
This invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. Examples of such pharmaceutically acceptable acid addition salts are the salts of hydrochloric acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, di-p-toluoyl tartaric acid, and mandelic acid.
This invention also relates to a pharmaceutical composition for inhibiting cholinesterase comprising a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
This invention also relates to a method for inhibiting cholinesterase in a mammal comprising administering to a mammal an amount of a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof effective in inhibiting cholinesterase.
This invention also relates to a method for enhancing memory or treating or preventing Alzheimer""s disease in a mammal comprising administering to a mammal an amount of a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof effective in enhancing memory or treating or preventing Alzheimer""s disease.
This invention also relates to compounds of the formula
wherein W is a leaving group; j is an integer from 0 to 2; R10 is a nitrogen protecting group; and R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl and (C1-C6)alkoxy, with the proviso that said (C1-C6)alkoxy is not attached to a carbon that is adjacent to a carbon that is adjacent to a nitrogen. These compounds are useful as intermediates in the synthesis of compounds of the formula I.
This invention also relates to compounds of the formula
wherein
R1, R2,
R7, R8,
X, Y and M are as defined above and R11 is hydrogen or a nitrogen protecting group. These compounds are useful as intermediates in the synthesis of compounds of the formula I.
This invention also relates to compounds of the formula:
wherein R1, R2, R7, R8 and L are as defined above and Yxe2x80x2 is xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)mxe2x80x94. These compounds are useful as intermediates in the synthesis of compounds of the formula I.
The term xe2x80x9cmammalxe2x80x9d, as used herein, includes humans.
The term xe2x80x9chaloxe2x80x9d, as used herein, includes chloro, bromo, iodo or fluoro.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched, or cyclic moieties or combinations thereof.
The term xe2x80x9c(C1-C4)alkylcarbonylxe2x80x9d, as used herein, refers to a substituent of the formula
wherein R15 is alkyl.
The term xe2x80x9c(C1-C4)alkoxycarbonylxe2x80x9d, as used herein, refers to a substituent of the formula V above, wherein R15 is (C1-C4)alkoxy.
The term xe2x80x9c(C1-C6)alkoxycarbonylxe2x80x9d, as used herein, refers to a substituent of the formula V above, wherein R15 is (C1-C6)alkoxy.
The term xe2x80x9c(C1-C6)alkylcarbonylxe2x80x9d, as used herein, refers to a substituent of the formula V above, wherein R15 is (C1-C6)alkyl.
Preferred compounds of this invention are compounds of the formula I wherein X is oxygen or sulfur, Y is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, M is xe2x80x94CHxe2x80x94 and L is benzyl, R1 and R2 are (C1-C6)alkyl, (C1-C6)alkoxy, NR5R6, or NR5COR6, R3 is hydrogen or (C1-C6)alkyl, J is oxygen or sulfur and Q is CH(CH3), CH(CH3)2, xe2x80x94CHxe2x95x90CH or (CH2)l and the pharmaceutically acceptable salts of such compounds.
3-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
5-Methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
5,6-Dimethyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
5-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
7-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-Acetamido-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-Amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-Benzamide-3-[2-[1-(phenylmethyl)-4-piperidinyl]-ethyl]-1,2-benzisoxazole;
6-Benzenesulfonamide-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-(4-Morpholinyl)-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]-ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
1-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-isoquinoline;
3-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisothiazole;
4-[2-[-(Phenylmethyl)-4-piperidnyl]ethyl]-1,3-quinazoline;
6-Hydroxy-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2-benzisoxazole;
6-Bromo-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2-benzisoxazole;
6-Cyano-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2-benzisoxazole;
6-Carboxamide-3-[2-[1-(phenylmethyl)-4-piperidyl]-ethyl]-1,2-benzisoxazole;
3-[(1-Phenylmethyl-4-piperidyl)methoxy]-1,2-benzisoxazole;
3-[(1-Phenylmethyl-4-piperidyl)methylamino]-1,2-benzisoxazole;
3-[2-(1-Phenylmethyl)-4-piperidyl)ethylamino]-1,2-benzisoxazole;
3-[3-[1-(Phenylmethyl)-4-piperidyl]propyl]-1,2-benzisoxazole;
trans-3-[2-[1-(Phenylmethyl)-4-piperidyl]ethenyl]-1,2-benzisoxazole;
3-[2-[1-(Phenylmethyl)-4-piperazinyl]ethyl]-1,2-benzisoxazole;
5,7-Dihydro-7-methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-7-ethyl-3-[2[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-3-[2-[1-(2-chloro-5-thiophenemethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-3-[2-[1-(2-methyl-4-thiazolemethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
3-[2-[1-(3-Bromophenylmethyl)-4-piperidinyl]-5,7-dihydro-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
3-[2-[1-(4-Bromophenylmethyl)-4-piperidinyl]ethyl]-5,7-dihydro-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-3-[3-[1-(phenylmethyl)-4-piperidinyl]propyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
3-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-5,6,8-trihydro-7H-isoxazolo[4,5-g]quinolin-7-one;
6,8-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]-ethyl]-7H-pyrrolo[5,4-g]-1,2-benzisoxazol-7-one;
5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[5,4-f]-1,2-benzisoxazol-6-one;
3-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-1H-indazole;
and the pharmaceutically acceptable salts of such compounds.
Examples of other compounds of the formula I are:
6-Phenylamino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-(2-Thiazolyl)-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-(2-Oxazolyl)-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-Pyrrolidinyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-Piperidinyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
5,7-Dihydro-5,5-dimethyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]-ethyl]-7-n-propyl-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-7-i-propyl-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
3[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-6-phenylmethylsulfone-1,2-benzisoxazole;
1-Methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1H-indazole; and
3-[1-Phenylmethyl-4-piperidinyl)methyl]-1,2-benzisoxazole.
The compounds of formula I may have optical centers and may therefore occur in different isomeric forms. The invention includes all stereoisomers of such compounds of formula I, including mixtures thereof.
The preparation of compounds having the formula I and certain of the starting materials used in their synthesis is illustrated in the following reaction schemes. Except where otherwise stated, in the reaction schemes and discussion that follow, R1, R2, R3, R4, R5, R6, R7, R8, R13, R14, E, G, X, Y, M, L, a, b, l, m, n, p, and structures I, A, B, and K are defined as above.
All articles, books, patents and patent applications cited in the following discussion are incorporated herein by reference.
The preparation of compounds of the formula I wherein Y is xe2x80x94(CH2)m and M is xe2x80x94CHxe2x80x94 is illustrated in scheme 1. These compounds are designated in scheme 1 and hereinafter referred to as compounds of the formula I-A (those wherein L is phenyl-(C1-C6)alkyl, pyridylmethyl or a group of the formula K) and compounds of the formula I-B (those wherein L is phenyl or cinnamyl).
Referring to scheme 1, compounds of the formula I-A may be prepared by deprotonating a compound of the formula II with a base in the presence of, or followed by the addition of an alkylating agent of the formula III wherein R10 is a nitrogen protecting group and W is a leaving group. When R10 is a nitrogen protecting group, this reaction produces an intermediate of the formula IV. This intermediate is then deprotected to yield a secondary piperidine of the formula VI as a free base or a salt of the free base, after which such free base or salt is alkylated with a compound of the formula WL, wherein W is defined as above and L is phenyl-(C1-C6)alkyl, pyridylmethyl or a group of the formula K.
Examples of suitable leaving groups (W) are mesylate, tosylate, chloride, iodide and bromide. Examples of suitable nitrogen protecting groups (R10) are amides such as N-formyl and N-acetyl and carbamates such as t-butoxycarbamate (BOC). The preferred nitrogen protecting group is BOC. Appropriate bases for use in the preparation of compounds of the formula IV include strong bases such as lithium diisopropylamide (LDA), n-butyllithium, s-butyllithium, and lithium (or sodium or potassium) hexamethyldisilazide (LiHMDS, NaHMDS, or KHMDS). LDA and s-butyllithium are preferred.
The reaction of a compound of formula II with a compound of formula III is generally carried out in a polar, aprotic solvent such as diethyl ether, 1,2-dimethoxyethane, or tetrahydrofuran (THF). Temperatures may range from about xe2x88x9278xc2x0 C. to about 30xc2x0 C. This reaction is preferably conducted in THF at about xe2x88x9278xc2x0 C.
Usually, compounds of the formula II are deprotonated in the presence of a compound of formula III. However, in cases where the compound of formula II has more than one acidic proton, it is preferable to carry out the deprotonation step first followed by the immediate and rapid addition of the alkylating agent of formula II.
The protecting group (R10) can be removed from compounds of the formula IV to form the corresponding compounds of formula VI by methods known to those skilled in the art. For example, when R10 is BOC or another carbamate, it can be removed with an acid such as hydrogen bromide (gas or aqueous), hydrogen chloride (gas or aqueous) or trifluoroacetic acid. In the case of trifluoroacetic acid, a t-butyl cation scavenger such as thioanisole may be added. When an acid is used as the deprotecting agent, an acid addition salt of the compound of formula VI is produced rather than the free base of such compound. Appropriate solvents include non-polar solvents such as methylene chloride, as well as polar solvents such as diethyl ether, ethyl acetate, dioxane, alcohols (e.g. methanol or ethanol) and water. Temperatures may range from about xe2x88x9220xc2x0 C. to about the reflux temperature of the solvent. It is preferable to use trifluoroacetic acid in methylene chloride with or without thioanisole at about 0xc2x0 C.
Alternatively, when R10 is BOC, it can be removed with a trialkylsilyltrifluoromethanesulfonate derivative such as trimethylsilyl-, triethylsilyl-, or t-butyldimethylsilyltrifluoromethanesulfonate in the presence of an aromatic or tertiary amine base such as 2,6-lutidine or triethylamine. Appropriate solvents for this reaction include norpolar solvents such as methylene chloride and polar aprotic solvents such as THF, diethyl ether or DMF. Temperatures may range from about xe2x88x9220xc2x0 C. to room temperature. It is preferable to use trimethylsilyltrifluoromethane-sulfonate and 2,6-lutidine in methylene chloride at a temperature from about 0xc2x0 C. to about room temperature.
The intermediate secondary piperidine of the formula VI, obtained as the free base or salt as described above, is reacted with 2-10 equivalents of a base and then with an alkylating agent of the formula WL, wherein W is defined as above and L is phenyl-(C1-C6)alkyl, pyridylmethyl or a group of the formula K. Suitable bases include tertiary amines such as triethylamine and diisopropylethyl-amine, aromatic amines such as pyridine and dimethylaminopyridine, and metal carbonates such as sodium bicarbonate or sodium or potassium or cesium carbonate. When W is chloride, catalytic iodide (potassium iodide or tetra-n-butylammonium iodide) may be added. Appropriate solvents include non-polar solvents such as methylene chloride and polar solvents such as dimethylformamide, THF, acetontrile, acetone, dioxane, and alcohols such as methanol or ethanol. It is preferable to carry out the alkylation in the presence of triethylamine in methylene chloride at room temperature or in the presence of sodium carbonate in dimethylformamide at room temperature.
Alternatively, the intermediate secondary piperidine of formula VI, when obtained as a salt after removal of the protecting group, can be deprotonated to the free amine by dissolving or suspending it in an appropriate solvent (e.g., methylene chloride or ethyl acetate), mixing it with aqueous sodium bicarbonate or aqueous sodium or potassium hydroxide and recovering the free amine from the organic layer by conventional extraction techniques. The free amine can then be subjected to alkylation with the appropriate alkylating agent of the formula WL under the conditions described above using 1-2 equivalents of an appropriate base.
The starting materials of formula II can be prepared according to methods known in the art. When X is oxygen, the starting 3-methyl-1,2-benzisoxazoles can be prepared by procedures similar to those described by Wunsch et al., Adv. Heterocycl. Chem., 1967, 8, 277; Smalley, R. K., Adv. Heterocycl. Chem. 1981, 29, 2; and Thakar et al., Indian J. Chem. 1977, 15B, 1058. The appropriate o-hydroxy acetophenones are converted to the corresponding oximes by reaction with hydroxylamine hydrochloride in the presence of an appropriate base such as potassium or sodium hydroxide, sodium acetate or pyridine, preferably aqueous potassium hydroxide or aqueous sodium acetate, in a polar solvent such as methanol, ethanol, or water, preferably ethanol, at a temperature from about room temperature to about 120xc2x0 C. The oxime is then converted to the corresponding oxime acetate by acetylation with an appropriate acylating agent such as acetic anhydride. Temperatures for this reaction may range from about room temperature to the reflux temperature of the solvent. Temperatures between 80xc2x0 C. and 130xc2x0 C. are preferred.
Ring closure to form the benzisoxazole ring may be carried out by heating the neat oxime acetate at a temperature from about 125xc2x0 C. to about 200xc2x0 C. under atmospheric pressure or reduced pressure (e.g., from about 0.01 mm Hg (1.33xc3x9710xe2x88x925 bars) to about 760 mm Hg (1.01 bars)). Ring closure is preferably accomplished by heating the oxime acetate at reflux in an appropriate base such as pyridine, or by heating the oxime acetate at a temperature of about 130xc2x0 C. in a polar solvent such as DMF or DMSO (dimethylsulfoxide) in the presence of several equivalents of an appropriate base such as pyridine or 2,6-lutidine.
Alternatively, ring closure can be carried out directly from the oxime by reaction with an acyl or sulfonyl chloride such as oxalyl or thionyl chloride in the presence of an aromatic amine such as pyridine (See Kalkote et al., Aust. J. Chem. 1977, 30, 1847). Suitable solvents include polar solvents such as diethyl ether or THF. Temperatures can range from about 0xc2x0 C. to about room temperature. Another method of closure involves treatment of the oxime with one or less equivalents of a base such as potassium hydroxide in a polar solvent such as methanol at temperatures ranging from about room temperature to about 100xc2x0 C. (Crabbe et al., J. Chem. Soc. Perkin Trans. I, 1973, 2220).
When X is sulfur, the starting 3-methyl-1,2-benzisothiazoles can be prepared from o-methylthio acetophenones following procedures similar to those described above for the benzisoxazoles (See McKinnon et al., Can. J. Chem., 1988, 66, 1405 and references cited therein) The o-methylthio acetophenones are converted into the corresponding oximes and ring closure is carried out directly by reaction with an appropriate acylating agent such as acetic anhydride in a base such as pyridine. The reaction temperature may range from about room temperature to about 130xc2x0 C., and is preferably about 120xc2x0 C.
When X is NR4 wherein R4 is hydrogen the starting 3-methyl-1H-indazoles can be prepared according to methods described by Behr et al., xe2x80x9cPyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings,xe2x80x9d Heterocyclic Compounds, R. H. Wiley, Ed., 1967, 289; Bartsch et al., J. Heterocycl. Chem., 1984, 21, 1063; Hannig et al., Pharmazie 1976, 31, 534; Barton et al., J. Chem. Soc. Chem. Comm., 1982, 450; Ruechardt et al., Liebigs Ann. Chem., 1980, 908; and Rees et al., J. Chem. Soc. D, 1971, 827. N-Alkylation of 3-methyl-1H-indazoles (X is NR4 wherein R4 is (C1-C4)alkyl) can be carried out as described by Behr et al., xe2x80x9cPyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings,xe2x80x9d Heterocyclic Compounds, R. H. Wiley, Ed., 1967, 309; Palmer et al., J. Chem. Soc., Perkin Trans. II, 1975, 1695; and Claramunt et al., Heterocycles 1985, 23, 2895.
When X is xe2x80x94CHxe2x95x90CHxe2x80x94, the starting 1-methylisoquinolines can be prepared according to the Bischler-Napieralksi or Pictet-Spengler methods (See Organic Reactions, Vol. VI, chapters 2 and 3, pp. 74-190, John Wiley and Sons, New York, 1951).
When X is xe2x80x94Nxe2x95x90CHxe2x80x94, the starting 4-methylquinazolines can be prepared according to methods described by Byford et al., Indian J. Chem., 1988, 27B, 396; Higashino, T., Chem. Pharm. Bull., 1962, 10, 1043; and Uff et al., J. Chem. Soc., Perkin Trans. I, 1986, 2295.
When X is xe2x80x94CHxe2x95x90Nxe2x80x94 the starting 1-methylphthalazines can be prepared according to methods described by Kant et al., J. Heterocycl. Chem., 1985, 22, 1065 and references cited therein; Acheson et al., J. Chem. Soc. C, 1966, 2218; and Gabriel et al., Chem. Ber. 1897, 30, 3022.
When X is xe2x80x94Nxe2x95x90Nxe2x80x94, the starting 4-methyl-1,2,3-benzotriazines can be prepared according to methods described by Adger et al., J. Chem. Soc., Perkin Trans. I, 1975, 31; Boulton et al., Ibid., 1988, 1509; and Rees et al., J. Chem. Soc. D, 1971, 828.
When one or both of R1 and R2 are NH2, the starting material of formula II may be prepared from the corresponding NHAc precursor (Ac=acetyl) by acid hydrolysis. The acid hydrolysis can be carried out with aqueous hydrochoric acid at temperatures ranging from about 50xc2x0 C. to about 120xc2x0 C. Heating to reflux (about 120xc2x0 C.) in 1N HCl is preferred. The corresponding NHBz (Bz=benzoyl) or NHSO2C6H5 compounds can be prepared from the corresponding amino derivative by reaction with the appropriate benzoyl or benzenesulfonyl chloride in the presence of a base such as triethylamine, pyridine, or dimethylaminopyridine. Suitable solvents include methylene chloride, THF, diethylether, or dimethylformamide. Temperatures may range from about xe2x88x9220xc2x0 to about 80xc2x0 C. When one or both of R1 and R2 is NHBz, it is preferable to use triethylamine/dimethylaminopyridine in methylene chloride at room temperature. When one or both of R1 and R2 is NHSO2Ph, it is preferable to use pyridine in methylene chloride at 0xc2x0 C.
Cyclic dialkylamino compounds of the formula II (i.e., those wherein one or both of R1 and R2 are NR5R6 wherein NR5R6 together form a ring) can also be prepared from the corresponding amino derivative by alkylation with the appropriate bis-halide reagent of the formula
wherein each A is independently bromide or chloride and B is oxygen or (CH2)q wherein q is 0 to 2, in the presence of an appropriate base such as triethylamine or diisopropylethylamine (Hunig""s base), in an appropriate nonpolar solvent such as toluene or xylene. The alkylation is typically carried out at a temperature from about room temperature to about 150xc2x0 C. It is preferably conducted in the presence of Hunig""s base in toluene at about 120xc2x0 C. (reflux). (See Verboom et al., J. Org. Chem. 1984, 49, 269).
Alternatively, these cyclic dialkylamino derivatives may be prepared by nucleophillic displacement of an aromatic fluoride with the appropriate cyclic amine. Suitable solvents for this reaction include polar aprotic solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, pyridine and hexamethylphosphoramide. Acetonitrile and pyridine are preferred. The reaction may be run in the presence of a base such as a tertiary or aromatic amines (e.g., triethylamine, diisopropylethylamine, pyridine or dimethylaminopyridine), preferably pyridine or triethylamine. The reaction temperature may range from about room temperature to about 160xc2x0 C., and is preferably from about 80xc2x0 C. to about 160xc2x0 C.
When R1 and R2, together with the carbons to which they are attached, form a group of the formula
and X is oxygen or sulfur, the starting material of formula II may be prepared by the following procedure which is illustrated only for cases wherein R1 and R2 form a group of formula A.
First, a compound of the formula VIII wherein Xxe2x80x2 is hydroxy, thiol or methyl sulfide is prepared by Friedel-Crafts acylation of the corresponding compound of the formula VII, wherein Xxe2x80x3 is methoxy or methyl sulfide with an acylating agent such as acetyl chloride or acetic anhydride, preferably acetyl chloride, in the presence of a Lewis acid such as aluminum chloride, titanium tetrachloride or boron triflouride etherate, preferably aluminum chloride. Appropriate solvents include carbon disulfide, 1,2-dichloroethane and nitrobenzene. Carbon disulfide and 1,2-dichloroethane are preferred. Generally, this reaction is conducted at a temperature from about room temperature to about 200xc2x0 C., preferably from about 50xc2x0 C. to about 100xc2x0 C.
Alternatively, a compound of formula VIII wherein Xxe2x80x2 is hydroxy, may also be obtained by Fries rearrangement of the corresponding compound of the formula VII wherein Xxe2x80x3 is acetyloxy. A mixture of VII and a Lewis acid such as aluminum chloride, boron trifluoride etherate or titanium tetrachloride is heated at temperatures from about 80xc2x0 C. to 200xc2x0 C. either neat or in the presence of a solvent such as nitrobenzene, or 1,2-dichloroethane. The Fries rearrangment is preferably conducted neat with aluminum chloride at 170-190xc2x0 C.
The compounds of formula VIII obtained by the foregoing process may be converted to the corresponding starting materials of formula II by the procedure described above for 1,2-benzisoxazoles and 1,2-benzisothiazoles.
Referring to scheme 1, compounds of the formula III may be prepared from the corresponding compounds wherein W is hydroxy by methods known in the art. For example, compounds of the formula III wherein W is iodide can be prepared by reacting the hydroxy counterpart with iodine and triphenylphosphine in the presence of a base such as pyridine or imidazole in a non-polar solvent such as benzene or toluene at a temperature from about room temperature to about 130xc2x0 C. Preferably, the reaction is carried out in benzene in the presence of pyridine at about 90xc2x0 C. (reflux).
Compounds of the formula I-B may be prepared by deprotonating a compound of the formula II with a base in the presence of, or followed by the addition of, an alkylating agent of the formula III wherein R10 is phenyl or cinnamyl and W is defined as above. Suitable and preferred bases, solvents and conditions are similar to those described above for the preparation of compounds of the formula IV.
Scheme 2 illustrates the preparation of compounds of the formula I wherein Y is xe2x80x94CHxe2x95x90CH(CH2)nxe2x80x94 via an aldol-type condensation. These compounds are designated in scheme 2 and hereinafter referred to as compounds of the formula I-C. Referring to scheme 2, a compound of the formula IX wherein R9 is hydrogen is deprotonated with a base followed by immediate and rapid addition of an aldehyde of the formula X. Suitable bases and solvents are the same as those described above for the first reaction in scheme 1. The reaction temperature may range from about xe2x88x9278xc2x0 C. to about room temperature. The reaction is preferably carried out using lithium diisopropylamide in THF at about xe2x88x9278xc2x0 C. and allowed to warm to room temperature.
If an intermediate alcohol is formed, it can be dehydrated to the olefin under standard acidic conditions, using an acid such as dilute hydrochloric acid, p-toluenesulfonic acid or pyridinium p-toluenesulfonate, preferably p-toluenesulfonic acid, in a solvent such as benzene, toluene, THF or methylene chloride, at a temperature from about 0xc2x0 C. to about 130xc2x0 C. Preferably, the dehydration is carried out in benzene at about 80xc2x0 C. (reflux) with azeotropic removal of water. Dehydration may also be accomplished by treatment with Burgess"" reagent (Et3+NSO2xe2x88x92NCO2Me) in methylene chloride or benzene at a temperature from about room temperature to about 80xc2x0 C.
Alternatively, the intermediate alcohol may be converted into a good leaving group such as mesylate or tosylate and then eliminated with an appropriate base. The mesylate or tosylate can be prepared under standard conditions by reacting the alcohol with methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine. Appropriate solvents include methylene chloride and THF, with methylene chloride being preferred. Temperatures may range from about 0xc2x0 C. to about 60xc2x0 C., and are preferably from about 0xc2x0 C. to about room temperature. Elimination to form the olefin can then be carried out with a base such as diazabicycloundecane or diazabicyclononane in a suitable solvent such as benzene, methylene chloride, or THF, with benzene or methylene chloride being preferred, at a temperature from about 0xc2x0 C. to about 100xc2x0 C., preferably from about room temperature to about 100xc2x0 C.
Compounds of the formula I-C may also be prepared by a Wittig reaction from compounds of the formula IX wherein R9 is bromine, chlorine or iodine. According to this procedure, a compound of formula IX is converted into its phosphonium salt by treatment with triphenylphosphine in a nonpolar solvent such as benzene, toluene or xylene, preferably toluene, at a temperature from about room temperature to about 150xc2x0, preferably from about 80xc2x0 C. to about 120xc2x0 C. The phosphonium salt may then be deprotonated with a strong base such as sodium hydride, potassium t-butoxide, potassium hydride or n-butyllithium in a suitable solvent such as diethylether or THF, at a temperature from about 0xc2x0 C. to about 80xc2x0 C. The deprotonation is preferably carried out with sodium hydride in THF at about room temperature.
Scheme 2xe2x80x2 illustrates an alternative preparation of compounds of the formula I wherein X is oxygen or NR4, Y is (CH2)m or xe2x80x94CHxe2x95x90CH(CH2)n and M is carbon (i.e. xe2x80x94CHxe2x80x94). These compounds are designated in Scheme 2xe2x80x2, and hereinafter referred to as compounds of the formula I-F (those where Y is xe2x80x94CHxe2x95x90CH(CH2)nxe2x80x2 and nxe2x80x2 is an integer from 0 to 3) and I-G (those where Y is (CH2)m and nxe2x80x2 is an integer from 0 to 1). Referring to Scheme 2xe2x80x2, compounds of the formula I-F may be prepared by deprotonating a compound of the formula XV with a suitable base followed by addition of an aldehyde of formula XVI to give an intermediate of formula XVII. This intermediate is then transformed to compounds of the formula I-F by reaction with an appropriate amine.
Appropriate bases for use in the preparation of compounds of the formula XVII include lithium diisopropylamide, lithium or sodium or potassium hexamethyldisilazide, or n-butyllithium, preferably lithium diisopropylamide or lithium hexamethydisilazide. The reaction of a compound of formula XV with a compound of formula XVI is generally carried out in a polar aprotic solvent such as diethyl ether, 1,2-dimethoxyethane, or tetrahydrofuran. Temperatures may range from xe2x88x9278xc2x0 C. to 80xc2x0 C. This reaction is preferably conducted in THF at xe2x88x9278xc2x0 C. and allowed to warm to room temperature.
A compound of formula I-F is then obtained from an intermediate of formula XVII by reaction with an amine such as hydrazine or hydroxylamine in the presence of a base such as sodium or potassium hydroxide, sodium or potassium carbonate, or sodium or potassium alkoxide (methoxide or ethoxide), preferably sodium or potassium hydroxide. In some cases (when amine is hydrazine), addition of a base may not be necessary. Suitable solvents for this reaction include methanol, ethanol, i-propanol, water, or, when amine is hydrazine, hydrazine itself may be used as a solvent. Temperatures may range from 50xc2x0 C. to 120xc2x0 C. It is preferable to react XVII with hydrazine at 120xc2x0 C. (reflux), or with hydroxylamine and potassium hydroxide in EtOH/water at 100xc2x0 C. (reflux). Upon reaction with hydroxylamine, the intermediate oxime obtained may be isolated and then cylclized to compounds of the formula I-F following the suitable and preferred conditions described above for the preparation of starting materials 3-methyl-1,2-benzioxazoles.
Compounds of the formula I-G may be prepared by reducing an intermediate of formula XVII to give a compound of formula XVIII. The intermediate of formula XVII may then be reacted with an amine to give compounds of the formula I-G. An intermediate of formula XVII is reduced with hydrogen gas to an intermediate of formula XVIII in the presence of a catalyst such as palladium on carbon, platinum oxide, or rhodium on carbon, preferably platinum oxide in a polar solvents such as ethyl acetate, tetrahydrofuran, ethanol, or acetic acid, preferably EtOH. Pressure may range from atmospheric to 50 psi (3.45 bars), preferably 40-50 psi (2.76-3.45 bars) and temperature may range from room temperature to 80xc2x0 C., preferably room temperature.
A compound of formula I-G is then obtained from an intermediate of formula XVIII following the suitable and preferred conditions described above for the preparation a compound of formula I-F from an intermediate of formula XVII.
Scheme 3 illustrates the preparation of compounds of the formula I wherein Y is xe2x80x94O(CH2)mxe2x80x94 or xe2x80x94NR4(CH2)m. These compounds are designated in scheme 3 and hereinafter referred to as compounds of the formula I-D. Referring to scheme 3, compounds of the formula I-D may be prepared by reacting a compound of the formula XI wherein R12 is chloro or bromo, with a nucleophile of the formula XII, wherein Z is xe2x80x94NHR4 or xe2x80x94OH. When Y is NR4(CH2)m (i.e., Z is xe2x80x94NHR4), the amine of formula XII is generally reacted with the appropriate compound of formula XI either neat or in a polar solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), THF or pyridine. DMSO and DMF are preferred solvents. An acid acceptor such as diazabicycloundecane, pyridine, lutidine, triethylamine or metal carbonates such as potassium or sodium or cesium carbonate may be added. Metal carbonates such as potassium carbonate are preferred. The reaction temperature may range from about room temperature to about 160xc2x0 C. and is preferably from about 100xc2x0 C. to about 160xc2x0 C.
When Y is O(CH2)m (i.e., Z is xe2x80x94OH), the alkoxide anion is formed and this species is reacted with the compound of formula XI. According to this procedure, the alcohol (XII) is deprotonated with a suitable base, after which the appropriate compound of formula XI is added and the mixture is heated. Examples of suitable bases are sodium, sodium hydride and potassium hydride with sodium hydride being preferred. Suitable solvents include THF, DMF and DMSO, with THF and DMF being preferred. This reaction is generally conducted at a temperature from about 40xc2x0 C. to about 160xc2x0 C. Temperatures between about 60xc2x0 C. and about 160xc2x0 C. are preferred.
Alternatively, compounds of the formula I-D may be prepared by reacting a compound of formula XI with a nucleophile of the formula XIX wherein Z and R10 are defined as above. This reaction produces an intermediate of formula XX which is then deprotected to yield a secondary piperidine of formula XXI as a free base or a salt of the free base, after which such free base or salt is alkylated with a compound of the formula WL, wherein W is defined as above and L is phenyl(C1-C6)alkyl, pyridylmethyl, or a group of the formula K.
Suitable and preferred bases, solvents, and conditions for the reaction of a compound of formula XI with a nucleophile of the formula XIX are similar to those described for the reaction of a compound of the formula XI with a nucleophile of the formula XII for the preparation of compounds of the formula I-D. Suitable and preferred bases, solvents, and conditions for the transformations of compounds of the formulas XX and XXI to prepare compounds of the formula I-D are similar to those described in scheme 1 for compounds of the formulas IV and VI to prepare compounds of the formula I-A.
Scheme 4 illustrates the preparation of compounds of the formula I wherein Y is xe2x80x94(CH2)mxe2x80x94 and M is nitrogen. These compounds are designated in scheme 4 and hereinafter referred to as compounds of the formula I-E. Referring to scheme 4, a compound of the formula XIII wherein R12 is chloro, bromo or iodo is reacted with a compound of the formula XIV. This reaction may be carried out in the presence of an acid acceptor such as pyridine, 2,6-lutidine or a metal carbonate (e.g., sodium bicarbonate or sodium or potassium carbonate). When R12 is chloro or bromo, a catalytic amount of a displacement promoter may be added. Examples of suitable displacement promoters are sodium iodide, potassium iodide or tetra-n-butylammonium iodide. Generally, this reaction is conducted in a nonpolar solvent such as toluene or xylene, or in a polar solvent such as THF, DMF or DMSO, preferably xylene or DMF, at a temperature from about room temperature to about 160xc2x0 C., preferably from about 90xc2x0 C. to about 160xc2x0 C.
Scheme 5 illustrates the preparation of compounds of the formula I wherein X is xe2x80x94Nxe2x95x90CHxe2x80x94 and M is carbon (i.e. xe2x80x94CH). These compounds are designated in scheme 5 and hereinafter referred to as compounds of the formula I-H. Referring to scheme 5, a compound of the formula IIxe2x80x2 may be deprotonated with one equivalent of a base followed by addition of a silylating agent (trimethylsilyl chloride). Sequential deprotonation with a second equivalent of the same base followed by addition of an alkylating agent of the formula III and appropriate work-up produces an intermediate of the formula IVxe2x80x2. This intermediate is then deprotected as described in scheme I to yield a secondary piperidine of formula VIxe2x80x2 as a free base or a salt of the free base, after which such free base or salt is alkylated with a compound of the formula WL, wherein W is defined as above and L is phenyl(C1-C6)alkyl, pyridylmethyl, or a group of the formula K.
Suitable bases, solvents, and temperatures for deprotonation of a compound of the formula IIxe2x80x2 are the same as those described above for the first reaction in scheme I, preferably LDA in THF at 0xc2x0 to room temperature. After addition of the first equivalent of base, a silylating agent such as trimethylsilyl or triethylsilyl chloride is added, preferably trimethylsilyl chloride. A second equivalent of the same base is then added followed by an alkylating agent of the formula III. The trimethylsilyl group is then removed under acidic conditions by stirring the crude reaction mixture with dilute hydrochloric acid for 30-60 min at room temperature. Then, the crude reaction mixture is made basic with aqueous sodium carbonate, or aqueous sodium or potasium hydroxide, preferably aqueous sodium hydroxide, and the intermediate of formula IVxe2x80x2 is extracted with an organic solvent by conventional extraction techniques. Suitable and preferred conditions for the transformation of intermediates of the formula IVxe2x80x2 to compounds of the formula I-H are the same described in scheme I for the preparation of compounds of the formula I-A.
Scheme 6 illustrates the preparation of compounds of the formula I wherein Y is (CH2)m. M is carbon (i.e. xe2x80x94CHxe2x80x94), J is sulfur and Q is CHCH3, C(CH3)2, xe2x80x94CHxe2x95x90CH, or (CH2)l. These compounds are designated in scheme 6 and hereinafter referred to as compounds of the formula I-I. Referring to scheme 6, a compound of the formula I-I may be prepared from the corresponding compound of the formula IVxe2x80x3 where J is oxygen by reacting with a phosphorus sulfide to give an intermediate of the formula XXII. This intermediate is then deprotected as described in scheme I to yield a secondary piperidine of formula VIxe2x80x3 as a free base or a salt of the free base, after which such free base or salt is alkylated with a compound of the formula WL, wherein W is defined as above and L is phenyl(C1-C6)alkyl, pyridylmethy, or a group of the formula K.
The transformation of a compound of formula IVxe2x80x3 to an intermediate of formula XXII is carried out with a phosphorous sulfide such as phosphorous pentasulfide (P2S10) or Lawesson""s reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] in an non-polar solvent such as benzene, toluene, or xylene. Temperatures may range from 50xc2x0 C. to 160xc2x0 C. Lawesson""s reagent in toluene at 80xc2x0 C. is preferred. Suitable and preferred conditions for the transformation of intermediates of the formula XXII to compounds of the formula I-I are the same ones described in scheme 1 for the preparation of compounds of the formula I-A.
Scheme 7 illustrates the preparation of compounds of the formula I wherein Y is (CH2)m, M is carbon (i.e. xe2x80x94CHxe2x80x94), and R3 is (C1-C6)alkyl. These compounds are designated in scheme 7 and hereinafter referred to as compounds of the formula I-J. Referring to scheme 7, a compound of the formula I-J may be prepared from the corresponding compounds of the formula IVxe2x80x2xe2x80x3 where R3 is hydrogen by deprotonating with a base followed by addition of the appropriate alkylating agent (preferably the appropriate (C1-C6)alkyl chloride, bromide, or iodide) to give an intermediate of formula XXIII. This intermediate is then deprotected as described in scheme 1 to yield a secondary piperidine of formula VIxe2x80x2xe2x80x3 as a free base or a salt of the free base, after which such base or salt is alkylated with a compound of the formula WL, wherein W is defined as above and L is phenyl(C1-C6)alkyl, pyridylmethyl, or a group of the formula K.
Suitable bases for the transformation of a compound of the formula IVxe2x80x2xe2x80x3 to a compound of the formula XXIII include sodium hydride, potassium hydride, lithium diisopropylamide, or n-butyllithium, preferably sodium hydride. The reaction is generally carried out in a polar aprotic solvent such as tetrahydrofuran, dimethylformamide, or 1,2-dimethoxyethane and temperatures may range from xe2x88x9278xc2x0 C. to 80xc2x0 C. The reaction is preferably conducted in dimethylformamide at room temperature. Suitable and preferred conditions for the transformation of intermediates of the formula XXIII to compounds of the formula I-J are the same described in scheme 1 for the preparation of compounds of the formula I-A.
Alternatively, a compound of the formula I-J may be prepared directly from the corresponding compound of the formula I-Axe2x80x2 wherein L is phenyl-(C1-C6)alkyl, pyridylmethyl or a group of the formula K and R3 is hydrogen or I-Bxe2x80x2 wherein L is phenyl or cinnamyl and R3 is hydrogen. Compounds of the formula I-Axe2x80x2 and I-Bxe2x80x2 are prepared according to the methods described in scheme 1 for the preparation of compounds I-A and I-B. Suitable and preferred bases, solvents, and conditions for the transformation of compounds of the formula I-Axe2x80x2 and I-Bxe2x80x2 to compounds of the formula I-J are the same described above for the preparation of compounds of the formula XXIII.
When one or both of R1 and R2 are OH, compounds of the formula I may be prepared from the corresponding xe2x80x94OMe precursor by dealkylation with a Lewis acid such as aluminum trichloride, boron trichloride, boron tribromide, or a protic acid such as aqueous hydrochloric or hydrobromic acid. Suitable solvents for the reaction with Lewis acids include non-polar solvents such as benzene, toluene, dichloromethane, or 1,2-dichlorethane. Temperatures may range from xe2x88x9278xc2x0 C. to 120xc2x0 C. Aqueous hydrobromic acid (48%) at 100-120xc2x0 C. (reflux) is preferred.
When one or both of R1 and R2 are NH2, compounds of the formula I may be prepared from the corresponding NHAc precursor (Ac=acetyl) by acid hydrolysis under the suitable and preferred conditions described above for the formation of starting materials of formula II wherein one or both of R1 and R2 are NH2. The corresponding nitrile (xe2x80x94CN) compounds can be prepared from the corresponding amino compounds via a diazonium salt formation by reacting the amino compound with nitrous acid (made from aqueous hydrochloric acid and sodium nitrite) followed by neutralization and addition to CuCN. Suitable solvents include polar protic solvents such as water or biphasic mixtures with non-polar solvents such as benzene, toluene, or xylene. Neutralization may be carried out by adding a base such as sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide until pH 7. Temperatures may range from xe2x88x9220xc2x0 C. to 60xc2x0 C. It is preferable to carry out the diazonium salt formation in water at 0xc2x0 C., to neutralize with sodium carbonate, and to add the diazonium salt to a biphasic mixture of aqueous CuCN and toluene at 0xc2x0 C., followed by heating to 50xc2x0 C.
When one or both of R1 and R2 are carboxamide (xe2x80x94CONH2), compounds of the formula I may be prepared from the corresponding nitrile (xe2x80x94CN) precursor by reaction with a base such as sodium hydroxide, potassium hydroxide or tetramethylammonium hydroxide in a polar solvent such as water, methanol, ethanol, or t-butanol. Temperatures may range from room temperature to 120xc2x0 C. Potassium hydroxide in t-butanol at 85-100xc2x0 C. is preferred.
Compounds of the formula I other than those of formulae I-A-I-J may be prepared by methods that will be obvious to those skilled in the art from the procedures described above and other known methods.
In each of the above reactions, pressure is not critical. Pressures in the range of about 0.5-3 atm (0.5-3 bars) are suitable, and ambient pressure (generally, about one atmosphere) is preferred as a matter of convenience. Also, for those reactions where the preferred temperature varies with the particular compounds reacted, no preferred temperature is stated. For such reactions, preferred temperatures for particular reactants may be determined by monitoring the reaction using thin layer chromatography.
The compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to as the xe2x80x9cactive compounds of the inventionxe2x80x9d) may be administered to a patient by various methods, for example, orally as capsules or tablets, parentally as a sterile solution or suspension, and in some cases, intravenously in the form of a solution. The free base compounds of the invention may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts.
The daily dose of the active compounds of the invention is generally in the range of from about 0.005 to about 300 mg/day, optionally from about 1 to 300 mg/day, and preferably from about 0.01 to about 1 mg/day for the average adult human, and may be administered in single or divided doses.
When incorporated for parenteral administration into a solution or suspension, the active compounds of the invention are present in a concentration of a least 1 weight percent, and preferably between about 4 to 70 weight percent (based on the total weight of the unit). The parenteral dosage unit typically contains between about 5 to 100 mg of active compound(s).
The active compounds of the invention may be administered orally with an inert diluent or an edible carrier, or they may be enclosed in gelatin capsules or compressed into tablets. Such preparations should contain at least 0.5% of active compound(s), but the concentration may vary depending upon the particular form and may be from 4 to 70 weight percent (based on the total weight of the unit). The oral dosage unit typically contains between 1.0 mg to 300 mg of active compound.
The cholinesterase inhibiting activity of the active compounds of the invention may be determined by a number of standard biological or pharmacological tests. One such procedure for determining cholinesterase inhibition is described by Ellman et al. in xe2x80x9cA New and Rapid Colorimetric Determination of Acetylcholinesterase Activityxe2x80x9d, Biochem. Pharm. 1, 88, (1961).

Heterocyclic-cyclic amine derivatives as cholinesterase inhibitors

Abstract: Compounds of the formula

Abstract: wherein R1 R2, R7, R8, X, Y, M and L are defined as below. The compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from. dementia and Alzheimer""s disease.