The present invention relates to a furnace and a method for drawing an optical fiber from heated and molten preform.
Various techniques have been known relating to a furnace for drawing an optical fiber from heated preform formed with silica glass as a main component, and they are described in Japanese Patent No. 2,542,679, Japanese Patent Laid-Open No. 147969/1993 and Japanese Patent Laid-Open No. 2832/1997. Since the figures and terminology in these prior arts differ partially from those used in this invention, descriptions will be made below where they are interpreted according to the figures and terminology used in this invention in order to clarify the difference between the prior arts and this invention.
A main part of the furnace for drawing an optical fiber disclosed in Japanese Patent No. 2,542,679 is shown in FIG. 8, in which numeral 21 denotes a preform, 21a denotes an optical fiber, 22 denotes an inner tube, 22a denotes a gas blowing inlet, 23 denotes an outer tube, 24 denotes a gas supplying inlet, 24a denotes a gas passage, 25 denotes a dummy rod, 25a denotes a connecting part, 26 denotes a retainer, 27 denotes a seal piston, 28 denotes a muffle tube, and 29 denotes a heater.
In the furnace for drawing an optical fiber, the dummy rod 25 and the preform 21 are arranged inside the muffle tube 28 and the inner tube 22 arranged to be connected to an upper end of the muffle tube 28, while they are connected via the connecting part 25a and are descended together. The vicinity of a lower end of the preform 21 is melted through heating by the heater 29 arranged outside the muffle tube 28, and the optical fiber 21a is drawn downward from the lower end of the preform 21. The inner tube 22 arranged to be connected to the upper end of the muffle tube 28 is to contain the long preform 21 on starting the drawing.
The gas passage 24a is formed between the inner tube 22 and the outer tube 23 arranged outside the same, and an inert gas is supplied from the gas supplying inlet 24 to the gas passage 24a, so as to blow the inert gas into the inside of the inner tube 22 from the numerous gas blowing inlets 22a provided circumferentially and in the height direction on the wall surface of the inner tube 22. The inert gas is flowed inside the inner tube 22 and the muffle tube 28 to prevent oxidation deterioration of the muffle tube and the like, and when the temperature distribution of the inert gas by heating and the flow of the inert as are not uniform, the fluctuation of the diameter of the optical fiber drawn from the preform is liable to occur.
Therefore, in this example of the furnace for drawing an optical fiber, the seal piston 27 connected to the dummy rod 25 via the retainer 26 and moved with the dummy rod 25 is provided at the dummy rod 25 arranged on the upper part of the preform 21. In the beginning of drawing, the dummy rod 25 and the seal piston 27 are in the upper part because the preform is long. With proceeding the drawing, the preform 21 is shortened from the lower end, and is descended, and thus, the dummy rod 25 and the seal piston 27 are also descended.
In this case, if the seal piston 27 were not present, the space between the dummy rod 25 and the inner tube 22 would gradually increase, but because the seal piston 27 is present, the volume of space above the preform 21 is substantially constant. Therefore, it has been said that turbulence of the stream of the inert gas in the space between the preform 21 and the seal piston 27 occurs only scarcely due to the provision of the seal piston 27.
In the furnace using the seal piston for drawing an optical fiber, when the preform has a length of 1.5 m or more, the seal piston necessarily has an proportionate length, and the weight thereof becomes also heavy. Because a supporting member for supporting them at the upper part must withstand the weight of the preform and the seal piston, the supporting member becomes also necessarily large. Because the seal piston must resist to high temperature, a heat resistant material, such as carbon, quartz and the like, is necessarily used for the seal piston, and it becomes costly when it is of large scale.
Furthermore, because the seal piston moves as sliding on the inner wall surface of the inner tube, dust is liable to come from the sliding part, which may adversely affect the strength of the drawn optical fiber.
Furthermore, as the seal piston descents, the numerous gas blowing inlets provided in the wall surface of the inner tube are sealed one by one from the upper part with the seal piston, a precise controller for continuously controlling the gas flow rate is necessary to maintain the constant flow rate of the stream of the inert gas.
A furnace for drawing an optical fiber disclosed in Japanese Patent Laid-Open No. 147969/1993 will then be described. A main part of the furnace for drawing an optical fiber is shown in FIG. 9. In FIG. 9, the same references as in FIG. 8 show the same components. Numeral 30 denotes a separating plate, 30a denotes a gap, 30b denotes pores, 31a denotes an upper space, 31b denotes a lower space, and 32 denotes an upper lid. The furnace for drawing an optical fiber shown in FIG. 9 is different from that shown in FIG. 8 in the following points. There is no member corresponding to the seal piston in FIG. 8, and an upper end of an inner tube 22 is closed with the upper lid 32 except for the part through which a dummy rod 25 penetrates.
In the furnace for drawing an optical fiber, a preform 21 is arranged inside a muffle tube 28 and the inner tube 22 connected to an upper end thereof, and the preform 21 is supported by hanging by the dummy rod 25 through a connecting part 25a. The vicinity of the lower end of the preform 21 is heated and melted by a heater 29 arranged outside the muffle tube 28, and an optical fiber 21a is drawn downward.
An outer tube 23 is arranged concentrically outside the inner tube 22, and an inert gas is blown into the inside of the inner tube via a gas blowing inlet 22a through a gas passage 24a formed with the outer tube 23 and the inner tube 22. The inert gas is introduced to the gas passage 24a from a gas supplying inlet 24. The inert gas blown into the inner tube 22 descends through the space between (the inner tube 22 and the muffle tube 28) and (the preform 21 or the dummy rod 25), then it is exhausted through the vicinity of the optical fiber 21a.
The space inside the inner tube 22 is separated by the separating plate 30 comprising a quartz plate or the like into an upper part and a lower part, and the inert gas flows from the upper space 31a of the separating plate 30 to the lower space 31b through the gap 30a between the separating plate 30 and the inner tube 22 or the pores 30b provided in the separating plate 30. Because the lower space 31b is of a relatively high temperature and turbulence of the gas stream is decreased owing to the presence of the separating plate 30, it has been said that an optical fiber having a small fluctuation in diameter can be drawn even in the case of a large preform.
However, in the case of this furnace for drawing an optical fiber, when the preform 21 becomes small with proceeding the drawing, the upper space 31a becomes large. On the other hand, the temperature near the upper end of the preform 21 is increased by heating the vicinity of the lower end of the preform 21, and said temperature becomes higher when the preform becomes small. Because of the presence of the separating plate 30 comprising a quartz plate, the temperature is somewhat decreased above the separating plate, but it becomes 550xc2x0 C. or more near the lower end of the upper space 31a. At this time, the temperature near the upper end of the upper space 31a is about 200xc2x0 C. to form a considerable difference in temperature between the upper part and the lower part inside the upper space 31a, therefore convection is liable to be caused. The convection causes fluctuation in volume of the inert gas, and the fluctuation is transmitted to the lower space 31b by the flow of the inert gas through the gap 30a or the pore 30b of the separating plate 30. Thus, fluctuation in flow of the inert gas near the optical fiber occurs. As a result, the amount of heat transmission is changed by the fluctuation of the inert gas to easily cause fluctuation in viscosity and softened amount of glass, and thus it is difficult to suppress fluctuation in fiber diameter to a small value less than the prescribed value.
A furnace for drawing an optical fiber disclosed in Japanese Patent Laid-Open No. 2832/1997 will then be described. The furnace for drawing an optical fiber is shown in FIG. 10. In FIG. 10, the corresponding references as in FIG. 8 show the same components. Numeral 33 denotes an upper space above the preform, and 34 denotes an auxiliary heater. In the furnace for drawing an optical fiber, a preform 21 is arranged inside a muffle tube 28 and the inner tube 22 connected to an upper end thereof, being supported by hanging by the dummy rod 25, and the vicinity of a lower end of the preform 21 is heated and melted by a heater 29 arranged outside the muffle tube 28, so as to draw an optical fiber 21a downward.
An outer tube 23 is arranged outside the inner tube 22 concentrically, and an inert gas is blown into the inside of the inner tube via a gas blowing inlet 22a through a gas passage 24a formed with the outer tube 23 and the inner tube 22. Because the vicinity of the upper end of the preform 21 becomes a high temperature of 1,000xc2x0 C. or more by heating the vicinity of the lower end of the preform 21, a large temperature difference formed between the upper part and the lower part of the space 33 above the preform.
In order to decrease the temperature difference, the auxiliary heater 34 is arranged outside the upper end of the inner tube 22 to heat the vicinity of the upper end of the inner tube 22. Thus, the vertical temperature difference of the space 33 between the inner tube 22 and the dummy rod 25 above the preform is decreased by the heating by the auxiliary heater 34 to prevent the convection from occurring at the space 33, and fluctuation in diameter of the optical fiber 21a drawn from the preform 21 is decreased.
However, in the case of this furnace for drawing an optical fiber, because the space 33 above the preform becomes large as the drawing of a large scale preform proceeds, it is difficult to make the temperature uniform inside the space solely by an auxiliary heater 34 arranged outside the upper part of the inner tube 22.
It is then considered that several auxiliary heaters are arranged vertically not only at the upper part but also at the lower part of the inner tube, and by controlling the temperature of each auxiliary heater, the temperature of the space above the preform is made uniform. However, there are problems that cost of the apparatus becomes increased, and the temperature control becomes complicated.
The invention is to provide a furnace for drawing an optical fiber and a method for drawing an optical fiber to solve the problems associated with the conventional art described in the foregoing.
The furnace for drawing an optical fiber according to the invention comprises a muffle tube and an inner tube connected to an end of the muffle tube. The preform is arranged inside the muffle tube and the inner tube and supported by a dummy rod at an upper part thereof in such a manner that the preform descends with the dummy rod. The preform is heated from outside of the muffle tube by a heater, and melted so as to draw an optical fiber from a lower end of the preform. One set or plural sets of separating plates separating a space inside the inner tube above the preform into plural parts in an advancing direction of the preform are arranged inside the space, and a gas blowing inlet for blowing an inert gas into the inner tube and the muffle tube is provided at the wall of the inner tube at a part under the separating plates.
Therefore, the inert gas entered from the gas blowing inlet mainly flows downward, and thus the gas in the upper space of the separating plate above the preform less influences the conditions of the drawing of the preform. Accordingly, the drawing is stably continued, and fluctuation in fiber diameter is decreased. Therefore, an optical fiber produced by using this furnace for drawing an optical fiber has a substantially constant outer diameter in the longitudinal direction, and has small fluctuation in transmission characteristics. Owing to the use of a simple separating plate but not using a large member such as a seal piston, the cost of the apparatus is low, and since heavy sliding as in the seal piston does not occur, dust formed by sliding is so minimal that it doesn""t adversely affect the strength of the optical fiber.
While the separating plates comprise plural sets of separating plates arranged as being penetrated by the dummy rod, and the plural sets of separating plates descend with the descent of the dummy rod, the respective sets of the plural sets of separating plates are stopped on the inner wall surface of the inner tube one by one, so that the space inside the inner tube above the preform is respectively separated into an upper part and a lower part by the stopped separating plates. Thus, because the space inside the inner tube can be separated by plural positions into suitable sizes, the flow of the inert gas inside the inner tube can be further stabilized even when the preform becomes small and the space inside the inner tube is enlarged with proceeding the drawing of the optical fiber.
While the respective sets of separating plates may each comprise one disk-shaped plate, the sets of separating plates may each be constituted by two plate members of an outer member and an inner member. In this case, the outer member has an outer diameter that is the same as the inner diameter of the inner tube at a position where the separating plate is stopped, and has a center hole diameter that is larger than the outer diameter of dummy rod so as to absorb the deviation from the concentric condition of the inner tube and the dummy rod. The inner member has an outer diameter that is larger than the center hole diameter of the outer member and smaller than the outer diameter of the outer member, and has a center hole diameter larger than an outer diameter of the dummy rod by 2 to 10 mm.
When the dummy rod penetrates both the members with the inner member being placed at upper side and the outer member being placed at lower side, the upward inner member is supported by being placed on the outer member. By constituting each of the sets of separating plates of an outer member and an inner member, even when the concentric condition of the inner tube and the dummy rod is deviated by rolling of the preform to cause decentering, the upper member moves in the radial direction by sliding on the lower member, and no such phenomenon that the inner wall surface of the inner tube is damaged by the separating plate occurs.
Alternatively, one or plural sets of separating plates may be arranged near the lower end of the dummy rod or at the upper part of the preform by fixing to the dummy rod, the connecting part or the preform, and they descend with the descent of the preform without stopping on the way on the inner wall of the inner tube. Accordingly, the space between the separating plates and the preform can be unchanged and constant even when the preform is shortened, and thus the flow of the gas in the space above the preform can be stabilized. It is also possible in this case that the respective sets of separating plates are each constituted by an outer member and an inner member. In this case, however, the outer diameter of the outer member must be smaller than the inner diameter of the inner tube by 5 to 10 mm, and the center hole diameter of the outer member must be larger than the outer diameter of the dummy rod. The outer diameter of the inner member must be larger than the center hole diameter of the outer member but smaller than the outer diameter of the outer member. The center hole diameter of the inner member must be the same as or larger than the outer diameter of the dummy rod. The inner member is then supported by the dummy rod or the connecting part with the inner member being downward and the outer member being upward.
By constituting each of the respective sets of separating plates by the outer member and the inner member, even in the case where the concentric condition is deviated by rolling of the preform to cause decentering, the upper member moves in the radial direction by sliding on the lower member, and no such phenomenon that the inner wall surface of the inner tube is damaged by the separating plate occurs.
When plural protrusions are provided on an outer periphery of the separating plate, the sliding friction coefficient of the separating plate to the inner wall surface of the inner tube on descending can be reduced, so as not to damage the inner tube, because only the protrusions are in contact with the inner wall surface of the inner tube.
By forming the separating plate with a heat insulating material, heat transferred from the upper end of the heated preform to the upper space above the separating plate can be reduced, and thus the temperature of the upper space above the separating plate can be reduced. Therefore, the temperature difference between the upper part and the lower part in the upper space is also reduced, and the generation of convection of the inert gas due to the temperature difference can also be suppressed. As a result, the influence on fluctuation in gas flow near the lower part of the preform influenced by the convection of the inert gas in the upper space can be suppressed, and thereby fluctuation in heat transfer amount by the inert gas, and fluctuation in viscosity and softened amount of the glass are suppressed, so as to reduce fluctuation in diameter of the optical fiber. Furthermore, because the influence by the convection of the inert gas in the upper space is reduced, the inert gas atmosphere can be maintained and the fluctuation in fiber diameter can be suppressed by flowing only a small amount of the inert gas near the preform. Therefore, the amount of consumption of high cost inert gas, such as helium, is reduced, and thus an economical effect is also expected.
Furthermore, by arranging an auxiliary heater outside the vicinity of the upper end of the inner tube to heat the vicinity of the upper part of the inner tube, the temperature inside the upper space can be further uniform.


It is well known that a mixture of fluids having different densities may be separated from one another through use of a centrifugal separator. One specific use of such a separator is in the separation of oil from gas vented from a crank case forming part of an internal combustion engine.
With regard to this specific use of separators, there can be a tendency for the high pressure gasses found in the combustion chambers of an internal combustion engine to leak past the associated piston rings and into the crank casing of the engine. This continuous leaking of gas into the crank case can lead to an undesirable increase of pressure within the crank case and, as a consequence, to a need to vent gas from said casing. In large commercial vehicles, vented gas is generally reintroduced into the inlet manifold of the engine. However, the gas vented from the crank casing typically carries a quantity of engine oil (as droplets or a fine mist), which is picked up from the reservoir of oil held in the crank casing. More specifically, gas flowing between an engine cylinder and the associated piston tends to pick up lubricating oil located on the cylinder wall. Also, condensing of oil vapour by an engine's cylinder block cooling system generates an oil mist in the crank case.
In order to allow vented gas to be introduced into the inlet system without also introducing unwanted oil (particularly into a turbocharging system wherein the efficiency of the compressor can be adversely affected by the presence of oil), it is necessary to clean the vented gas (i.e. to remove the oil carried by the gas) prior to the gas being introduced into the inlet system. This cleaning process may be undertaken by a centrifugal separator, which is mounted on or adjacent the crank case and which directs cleaned gas to the inlet system and directs separated oil back to the crank case.
There are a number of problems associated with some prior art ALFDEX™ separators. These problems can be considered in three broad categories.
First, the fluid pathways through the separator give rise to pressure losses which adversely affect the flow capacity of the separator and, consequently, the size of engine with which the separator can be used.
Second, the arrangement of some of these prior art separators is such that, under certain conditions, cleaned gas can become contaminated before leaving the separator.
Third, certain manufacturing techniques and construction features associated with these prior art separators can lead to assembly difficulties and/or reliability problems.


This invention relates to a process for the melt-spinning of a filamentary structure from a synthetic polyamide polymer. More particularly, it is concerned with a continuous process for the formation of high strength polycaproamide filament, yarn or the like by melt-spinning a synthetic linear fiber-forming polycaproamide having excess number of carboxyl end groups over amino end groups.
U.S. Pat. No. 2,174,527 discloses that dibasic dicarboxylic acids when employed in excess in a diacid-diamine polyamide, serve to terminate the polymer, thereby minimizing further increase in polymer molecular weight.
U.S. Pat. No. 2,241,321 teaches polymerization of caprolactam in the presence of a diamine, followed by addition of sebacic acid and completion of the polymerization. the sebacic acid apparently acts as a chain-extending agent.
More recently, U.S. Pat. No. 3,386,967 discloses that a high strength polycaproamide yarn having an excess number of carboxyl end groups over amino end groups may be produced from a high molecular weight polymer prepared by polymerizing e-caprolactam and reacting the polymer with a dibasic carboxylic acid containing at least six carbon atoms. Because polycondensation of the polymer in the presence of a dibasic carboxylic acid is relatively slow, the acid is desirably included at the start of the polymerization reaction. Even so, equilibrium is approached in the polymerization reaction mixture at number average molecular weight not above about 20,000 under usual polymerization conditions, and special measures are required to carry the reaction further. One particularly useful method of accomplishing the required further reaction is to remove volatile by-products of the polymerization such as water by flowing an inert gas across the reaction mixture surface, desirably followed by application of vacuum.
Although the process of U.S. Pat. No. 3,386,967 constitutes a major contribution to this art, we have found that in continuous operation of the process on a commercial basis, particularly at maximum production rates, serious problems have been encountered in melt spinning due to the frequent occurrence of "nubs" in the fiber. The term "nubs" is conventionally applied and is used herein to mean enlarged sections of filament no more than several filament diameters in length. Nubs may be formed by a foreign, nonorientable substance which interferes with normal fiber stretch in a short section, resulting in an enlargement. Foreign substances which are believed to have contributed to nuts in the present instance include carbonized polymer and gels formed in the polymer. Gels appear to be the chief cause, i.e., the nubs are probably created by non-orientable gel from cross-linked polymer. Thermal degradation of the polymer may be an important causative factor.
The reactions in thermal degradation of polyamides containing dicarboxylic acid additives are not entirely understood. It is likely that thermal degradation produces a decomposition product which serves to form cross-links between amide groups and adjacent polymer chains. The decomposition reaction proceeds slowly, finally building up a three-dimensional network of molecules which may be called polymer gel and which eventually reaches the stage where it forms an infusible coating on the walls of the equipment.
A serious difficulty which arises from the formation of this polymer gel on the interior walls is that from time to time pieces break off and get into the flowing polymer stream where they produce damage to the spinning equipment.
The greatest difficulty, however, is caused by polymer gel which has progressed to the three-dimensional structural stage, but which has not yet reached the stage of being infusible. This kind of polymer gel is readily carried with the stream of flowing polymer. Being still molten or at least softened, it passes through the pump and even through the filter medium to show up either as discontinuities or as viscosity differences in the spun filament. When these filaments are later drawn, these defects may cause breaks in the filaments which either cause the whole thread to break or else form nubs which go through to be counted as quality defects in the final yarns.


Polymeric compositions are extensively used as insulation materials for high voltage wire and cable. Olefin homo- and copolymers are the insulation materials of choice for high voltages (5000+ volts) based on desirable electrical and physical properties such as dielectric strength; toughness, such as resistance to cutting and abrasion; ageing characteristics; resilience; and mininal cracking on mechanical stress. Polyethylene, polypropylene and blends thereof polymerized in different densitites as well as copolymers thereof with each other and other comonomers are usually used.
It has been noted that such polyolefin-based materials when used as insulation materials in high voltage distribution wires and cable are prone to deterioration under voltage stress in wet environment resulting in electrical failure. The latter deterioration may result from a degradation phenomenon identified as "water trees". Under high voltage wet-stress, microscopic channels, i.e. dendritic voids, appear in the insulation. These have a tree-like appearance--hence, the name. Such failure is most disadvantageous. This problem is now aggrevated in that many high voltage cables are buried for greater reliability (decrease of damage from high winds, ice storms, etc.) and for aesthetic reasons. Over extended periods of time, short circits have occurred in such buried cables resulting in loss of service. These cables have to be removed by excavation and replaced, a time consuming and costly operation.
Many classes of chemical compound additives have been disclosed in the prior art as effective voltage stabilizers, i.e. suppressants for electrical failure, water-treeing and/or electrical-treeing (microscopic dentrites caused by corona arcing). These prior art disclosures include voltage stabilizers based on silicon derivatives, furfuryloxy phosphites and high-molecular weight polyethylene oxide.
In the prior art, Kowasaki, U.S. Pat. No. 4,305,849, teaches the use of polyethylene glycols having molecular weights of from about 1,000 to 20,000 as voltage stabilizers.
Ashcraft et al in U.S. Pat. Nos. 4,144,202 and 4,263,158 teach the use of organosilane compounds containing azomethine groups as voltage stabilizers.
Turbett et al in U.S. Pat. No. 4,376,180 disclose the use of 3-(N-phenylaminopropyl-tridodecyloxysilane) as a voltage stabilizer.
Turbett in U.S. Pat. No. 4,440,671 discloses the use of a blend of hydrocarbon-substituted diphenyl amine and a high molecular weight polyethylene glycol for this purpose.
Braus et al, U.S. Pat. No. 4,514,535 disclose the use of tritetrahydrofurfuryloxy phosphite as a voltage stabilizer.
Beasley et al in U.S. Pat. No. 4,374,224 disclose the use of an organic carboxylic ester having at least one aromatic ring and at least three carboxylic ester groups as a voltage stabilizer.
U.S. Pat. No. 3,553,348 describes the use of filler minerals such as magnesium silicate, pretreated with alkyl and vinyl alkoxysilanes, as voltage stabilizers.
It will be noted from most of these prior art teachings that previous experimenters have relied upon a test based on a microscopic examination of the voltage stressed polymer. The number of "trees" and their length were utilized to judge the resistance deterioration of the insulation. These tests were based on the assumption that "tree" length and the number of trees could be used to approximate the relative useful life of the insulation. These tests, while rapid, are subject to many variables not quite analagous to the actual service conditions.
In contrast, the polymers of this invention and representative compounds of the above mentioned prior art have been tested and compared herein by the use of actual wires coated with the test material compositions. These wires are immersed in a water bath and subjected to high voltage until electrical failure. This test methodology is more closely analagous to the conditions leading to electrical failure of buried distribution cables, and thus provides a meaningful method of illustrating the improved performance characteristics of the instant compounds.


People routinely undergo surgery for treatment of a variety of medical conditions. In many cases, the patients are placed under general anesthesia for the surgical procedure. While under general anesthesia, the patient is unconscious and cannot respond or react to external stimuli or conditions. In some surgical procedures, there is a potential for these external conditions to cause trauma to the patient. For example, during certain orthopaedic surgical procedures, the surgeon must exert considerable pressure on various parts of the body, e.g., to the arms, legs, shoulder, and torso. In addition, the surgeon uses a variety of instruments during the procedure. The pressure on the body and use of surgical instruments create the potential for unintentional trauma to the patient, particularly to the head, face, ears, eyes, and neck area. The patient may receive pressure marks or sores from direct contact with surgical instruments and body positioning techniques. Any pressure applied to the ocular structures, even a short time, can cause damage or blindness to the eye. The body is typically covered at most by a blanket or cloth, which provides minimal protection.
Another challenge is the task of rolling the patient over from a supine position to a prone position on the operating table or from a cart onto the operating table. Depending on the procedure, the patient may be intubated, which creates a risk of neck injury during the roll-over process. After the procedure, the patient must again be rolled off the operating table onto a gurney. Still anesthetized, the risk of neck injury is again present if the head is not properly supported and manipulated during patient movement.
If an emergency develops while the patient is in the prone position, requiring the patient to be rolled to the supine position, valuable time can be lost trying to properly support the patient without injury to the neck, and without crimping the airway supply tubing and monitoring equipment communicating through the nose and mouth of the patient.
One approach found in U.S. Pat. No. 6,490,737 involves a molded helmet, which partially covers the patient's face and head. The helmet is particularly designed for procedures with the patient in the prone position and, in fact, the helmet can be rigidly mounted to the operating table, as shown in FIG. 8 of U.S. Pat. No. 6,490,737. However, in the prone position, the forehead and chin areas are exposed to continuous pressure by the weight of the patient's own head. If not relieved by regular movement of the face to allow blood flow, the pressure can cause localized ischemia to the chin and forehead area. In addition, the helmet leaves the eyes, cheeks, nose, and back of the head exposed and vulnerable to objects smaller than the openings in the helmet. The helmet is molded to a rigid form factor so the head is likely to shift in position relative to the helmet.
In the anesthetized state, the patient is unable to respond or react to any of these conditions. The surgeon, anesthesiologist, and surgical staff must be constantly aware of patient safety to avoid unnecessary trauma.
The operating room is typically maintained at a low temperature, in part for the comfort and alertness of the surgical team. The patient may experience body heat loss in the low temperature environment. The torso and upper and lower extremities are typically covered by a blanket for warmth. However, a significant amount of heat can be lost passively through the head and neck. A surgical cap can reduce some heat loss, but typically does not cover the face and certainly does not remove the potential for injury.


Without limiting the invention, its background is described in connection with a process for the manufacture of sub-100 nm devices using imprint lithography.
In manufacturing, lithography techniques that are used for large-scale production include photolithography and other application oriented lithography techniques, such as electron beam lithography, ion-beam and x-ray lithography, as examples. Imprint lithography is a type of lithography that differs from these techniques. Recent research has shown that imprint lithography techniques can print features that are smaller than 50 nm. As such, imprint lithography has the potential to replace photolithography as the choice for semiconductor manufacturing in the sub-100 nm regime. It can also enable cost effective manufacturing of various kinds of devices, including patterned magnetic media for data storage, micro optical devices, MEMS, biological and chemical devices, X-ray optical devices, etc.
Current research in the area of imprint lithography has revealed a need for devices that can perform orientation alignment motions between a template, which contains the imprint image, and a substrate, which receives the image. Of critical importance is the careful and precise control of the gap between the template and the substrate. To be successful, the gap may need to be controlled within a few nanometers across the imprinting area, while, at the same time, relative lateral motions between the template and the substrate must be eliminated. This absence of relative motion leads is also preferred since it allows for a complete separation of the gap control problem from the overlay alignment problem.
For the specific purpose of imprinting, it is necessary to maintain two flat surfaces as close to each other as possible and nearly parallel. This requirement is very stringent as compared to other proximity lithography techniques. Specifically, an average gap of about 100 nm with a variation of less than 50 nm across the imprinted area is required for the imprint process to be successful at sub-100 nm scales. For features that are larger, such as, for example, MEMS or micro optical devices, the requirement is less stringent. Since imprint processes inevitably involve forces between the template and the wafer, it is also desirable to maintain the wafer surface as stationary as possible during imprinting and separation processes overlay alignment is required to accurately align two adjacent layers of a device that includes multiple lithographically fabricated layers. Wafer motion in the x-y plane can cause loss of registration for overlay alignment.
Prior art references related to orientation and motion control include U.S. Pat. No. 4,098,001, entitled “Remote Center Compliance System;” U.S. Pat. No. 4,202,107, entitled “Remote Axis Admittance System,” both by Paul C. Watson; and U.S. Pat. No. 4,355,469 entitled “Folded Remote Center Compliant Device” by James L. Nevins and Joseph Padavano. These patents relate to fine decoupled orientation stages suitable for aiding insertion and mating maneuvers in robotic machines and docking and assembly equipment. The similarity between these prior art patents and the present invention is in the provision for deformable components that generate rotational motion about a remote center. Such rotational motion is generated, for example, via deformations of three cylindrical components that connect an operator and a subject in parallel.
The prior art patents do not, however, disclose designs with the necessary high stiffness to avoid lateral and twisting motions. In fact, such lateral motion is desirable in automated assembly to overcome mis-alignments during the assembly process. Such motion is highly undesirable in imprint lithography since it leads to unwanted overlay errors and could lead to shearing of fabricated structures. Therefore, the kinematic requirements of automated assembly are distinct from the requirements of high precision imprint lithography. The design shown in U.S. Pat. No. 4,355,469 is intended to accommodate larger lateral and rotational error than the designs shown in the first two patents, but this design does not have the capability to constrain undesirable lateral and twisting motions for imprint lithography.
Another prior art method is disclosed in U.S. Pat. No. 5,772,905 (the '905 patent) by Stephen Y. Chou, which describes a lithographic method and apparatus for creating ultra-fine (sub-25 nm) patterns in a thin film coated on a substrate in which a mold having at least one protruding feature is pressed into a thin film carried on a substrate. The protruding feature in the mold creates a recess of the thin film. First, the mold is removed from the film. The thin film is then processed such that the thin film in the recess is removed exposing the underlying substrate. Thus, the patterns in the mold are replaced in the thin film, completing the lithography. The patterns in the thin film will be, in subsequent processes, reproduced in the substrate or in another material which is added onto the substrate.
The process of the '905 patent involves the use of high pressures and high temperatures to emboss features on a material using micro molding. The use of high temperatures and pressures, however, is undesirable in imprint lithography since they result in unwanted stresses being placed on the device. For example, high temperatures cause variations in the expansion of the template and the substrate. Since the template and the substrate are often made of different materials, expansion creates serious layer-to-layer alignment problems. To avoid differences in expansion, the same material can be used but this limits material choices and increases overall costs of fabrication. Ideally, imprint lithography could be carried out at room temperatures and low pressures.
Moreover, the '905 patent provides no details relative to the actual apparatus or equipment that would be used to achieve the process. In order to implement any imprint lithography process in a production setting, a carefully designed system must be utilized. Thus, a machine that can provide robust operation in a production setting is required. The '905 patent does not teach, suggest or disclose such a system or a machine.
Another issue relates to separation of the template from the substrate following imprinting. Typically, due to the nearly uniform contact area at the template-to-substrate interface, a large separation force is needed to pull the layers apart. Such force, however, could lead to shearing and/or destruction of the features imprinted on the substrate, resulting in decreased yields.
In short, currently available orientation and overlay alignment methods are unsuitable for use with imprint lithography. A coupling between desirable orientation alignment and undesirable lateral motions can lead to repeated costly overlay alignment errors whenever orientation adjustments are required prior to printing of a field (a field could be for example a 1″ by 1″ region of an 8″ wafer).
Further development of precise stages for robust implementation of imprint lithography is required for large-scale imprint lithography manufacturing. As such, a need exists for an improved imprint lithography process. A way of using imprint lithography as a fabrication technique without high pressures and high temperatures would provide numerous advantages.


An important goal in animal husbandry is to develop biologically active agents which can increase the quantity and improve the quality of meat obtained from livestock animals.
xe2x80x9cIncreasing the quantityxe2x80x9d of food obtained from livestock animals refers to, inter alia, promoting the growth of livestock animals, increasing the efficiency of feed utilized in raising livestock animals and/or enhancing the production of lean body mass in livestock animals. Biologically active agents with these attributes are commonly referred to as xe2x80x9canabolic agentsxe2x80x9d.
xe2x80x9cImproving the qualityxe2x80x9d of food obtained from livestock animals refers to, inter alia, reducing the quantity of subcutaneous fat in meat and, in poultry, the size of the abdominal xe2x80x9cfat padxe2x80x9d. Subcutaneous fat can cause elevated cholesterol and triglyceride levels in individuals who consume large quantities of meat, has minimal nutritional value and decreases the overall yield of meat. Therefore, the reduction or elimination of this type of fat from meat is desirable. On the other hand, intramuscular fat, commonly referred to as xe2x80x9cmarblingxe2x80x9d, contributes positively to the flavor of meat and maintains a high Quality Grade. Marbling is therefore considered a desirable quality. Biologically active agents which are lipolytic can reduce subcutaneous fat while retaining the intramuscular fat.
Certain publications have appeared generally disclosing arylpropanolamines such as U.S. Pat. No. 5,013,761 and WO 97/10825. There continues to be a need for the development of agents which are anabolic and lipolytic to improve the economics of meat production by increasing the yield and improving the quality of meat obtained from livestock animals. Further increases in profitability could be achieved by the development of long-lasting anabolic/lipolytic agents which, because they require less frequent dosing, are more convenient and economical to use.
It has now been found that indazolyloxy propanolamimines such as those represented by Structural Formula (I) and (III) below are both anabolic and lipolytic when administered to livestock (Example 7 and Table 1). It has also been found that the anabolic and lipolytic effects of these compounds are longer lasting than other aryloxy propanolamines. Specifically, the percent decrease in serum urea nitrogen level (SUN) after forty-eight hours and the increase in non-esterified fatty acid levels (NEFA) after twenty-four hours in cattle treated with the indazolyloxy propanolamines of the present invention have been found to be significantly greater than for other aryloxy propanolamines (see Example 8 and Table 2). The percent decrease in SUN is indicative of anabolic activity and the increase in NEFA is indicative of lipolytic effects. Based on these results, novel compounds and novel methods of improving meat production from livestock animals are disclosed herein.
One embodiment of the present invention is a compound represented by Structural Formula (I):
and physiologically acceptable salts thereof; where R1 and R2 are independently xe2x80x94H or a C1-C4 straight chained or branched alkyl group;
Ring A, Ring B and Ring C are independently substituted or unsubstituted, provided, however, that Ring C is not substituted in the para position with a group represented by Structural Formula (II):
R3 and R4 are independently xe2x80x94H, a straight or branched C1-C4 alkyl or, taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring, and Ring D is substituted with zero, one, two or three additional substituents.
Another embodiment of the present invention is a compound represented by Structural Formula (III):
and physiologically acceptable salts thereof; where
R1 and R2 are independently xe2x80x94H, a C1-C4 straight chained or a branched alkyl group;
Ring A, Ring B, Ring C and Ring E are independently substituted or unsubstituted, provided, however, that Ring E is not substituted in the position meta to xe2x80x94Nxe2x80x94 and ortho to the carbon bonded to oxygen with xe2x80x94CONR3R4;
R3 and R4 are independently xe2x80x94H or a straight or branched chain C1-C4 alkyl group or, taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring.
Another embodiment of the present invention is a method of increasing the quantity and improving the quality of meat obtained from a livestock animal. The method comprises administering to the animal an effective amount of one or more compounds represented by Structural Formula (I). Another embodiment of the present invention is a method of increasing the quantity and improving quality of meat obtained from a livestock animal. The method comprises administering to the animal an effective amount of one or more compounds represented by Structural Formula (III).
The indazolyloxy propanolamines of the present invention have both anabolic and lipolytic activity and can therefore be administered to livestock to increase the output of meat and to decrease its fat content. Moreover, the duration of the anabolic and lipolytic activity of these indazolyloxy propanolamines is longer in vivo than other structurally related aryloxy propanolamines. Consequently, indazolyloxy propanolamines are more convenient and economical to use than other aryloxy propanolamines because indazolyloxy propanolamines need to be administered less frequently and/or at lower doses. The compounds of the present invention are intended for the treatment of healthy animals.
The present invention is directed to a compound represented by Structural Formula (I) and (III). Also included is a method of improving livestock production by administering one or more compounds of the present invention to the livestock.
In a preferred embodiment, the compound is represented by Structural Formula (IV):
Ring A, Ring B, Ring C, R1 and R2 are as described above for Structural Formula (I). Ring E is substituted or unsubstituted.
X is xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94.
In Structural Formula (IV), R1 and R2 are preferably methyl and Rings A-C have no further substitution.
In a preferred embodiment, the compound of the present invention is represented by Structural Formula (V):
X is xe2x80x94Nxe2x80x94 or xe2x80x94CHxe2x80x94.
Ring E is substituted or unsubstituted. Examples of suitable substituents for Ring E include halo, xe2x80x94CN, xe2x80x94OR5, C1-C4 alkyl, C1-C4 haloalkyl, xe2x80x94CO2R5, xe2x80x94CONR6R7, xe2x80x94CONH(C1-C4 alkyl), xe2x80x94SR5, xe2x80x94CSNR6R7, xe2x80x94CSNR6R7, xe2x80x94SO2R5, xe2x80x94SO2NR6R7, xe2x80x94SOR5, xe2x80x94NR6R7. Preferred substituents are xe2x80x94CN, xe2x80x94CONH2, xe2x80x94SO2CH3, xe2x80x94SO2NH2 or are represented by Structural Formulas (VI) or (VII):
xe2x80x94SR2CH3 is a more preferred substituent.
R5 is xe2x80x94H, C1-C4 alkyl or aryl.
R6 and R7 are independently xe2x80x94H, C1-C4 alkyl, aryl, xe2x80x94(CH2)naryl, or combine with the nitrogen atom to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl.
n is 0, 1, 2, or 3.
In another preferred embodiment, the compound of the present invention is represented by Structural Formula (IV) or (V), provided, however, that Ring E is not substituted in the position meta to xe2x80x94Xxe2x80x94 and ortho to the carbon bonded to oxygen with xe2x80x94CONR3R4. R3 and R4 are independently xe2x80x94H or a straight or branched chain C1-C4 alkyl group or, taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring.
Also included in the present invention are Compounds 1-5, shown in Tables 1 and 2.
Physiologically acceptable salts of the compounds disclosed herein, including the compounds represented by Structural Formulas (I),(III), (IV), (V) and Compounds 1-5, shown in Tables 1 and 2, are included. Salts can be formed from those compounds which comprise acidic functional groups by reacting with a suitable base. Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like. Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.
Because of the amine moiety, salts of the compounds disclosed herein can also be prepared by reacting with a suitable acid. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic, acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, 2-butyne-1,4 dioate, 3-hexyne-2, 5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, xcex2-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts.
When substituted, Rings A-E can have one, two or three substituents in addition to those shown in Structural Formulas (I)-(V). Suitable substituents are those which do not significantly decrease the anabolic and lipolytic properties of the compound. Examples of suitable substituents include halogens, hydroxy, xe2x80x94ORxe2x80x2, xe2x80x94SRxe2x80x2, xe2x80x94S(O)Rxe2x80x2, xe2x80x94S(O)2Rxe2x80x2, xe2x80x94COORxe2x80x2, xe2x80x94C(O)Rxe2x80x2, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OCONRxe2x80x2Rxe2x80x3, xe2x80x94OCONHRxe2x80x2, xe2x80x94NHCOORxe2x80x2, xe2x80x94NRxe2x80x3COORxe2x80x2, xe2x80x94NHRxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94CN, C1-C4 alkyl, C1-C4 haloalkyl, xe2x80x94CONRxe2x80x2Rxe2x80x3, xe2x80x94CONHRxe2x80x2, xe2x80x94CSNRxe2x80x2Rxe2x80x3, xe2x80x94CSNRxe2x80x2Rxe2x80x3, xe2x80x94SO2NRxe2x80x2Rxe2x80x3. Rxe2x80x2 and Rxe2x80x3 are independently xe2x80x94H, C1-C4 alkyl or aryl. In addition, when Rxe2x80x2 and Rxe2x80x3 are bonded to the same nitrogen atom (e.g, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94CONRxe2x80x2Rxe2x80x3 or xe2x80x94OCONRxe2x80x2Rxe2x80x3), then R and Rxe2x80x2, taken together with the nitrogen atom, can form a non-aromatic heterocyclic ring.
Aryl groups include carbocyclic aromatic groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl, and heteroaryl groups such as N-imidazolyl, 2-imidazolyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl and 5-oxazolyl.
Aryl groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples include 1-benzimidazolinyl, 2-benzimidazolonyl, 1-benzimidthioazolinyl, 2-benzimidthioazolonyl, 1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl, 2-benzimidazolyl, 2-quinolinyl, 3-quinolinyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl and 3-isoindolyl. Also included within the scope of the term aryl group, as it is used herein, is a group in which one or more carbocyclic aromatic rings and/or heteroaromatic rings are fused to a cycloalkyl or non-aromatic heterocyclic ring.
Non-aromatic heterocyclic rings are non-aromatic carbocyclic rings which include one, two or three heteroatoms selected from nitrogen, oxygen and sulfur in the ring that will afford a stable structure. The ring can be five, six, seven or eight-membered. Examples include 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahyrothiophenyl, 3-tetrahyrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl and 4-thiazolidinyl.
As used herein, aliphatic groups include straight chained, branched or cyclic C1-C20 hydrocarbons which are completely saturated or which contain one, two or three units of unsaturation.
Suitable substituents on an aliphatic group, aryl group (carbocyclic and heteroaryl), non-aromatic heterocyclic ring or benzyl group are those which do not significantly reduce the anabolic effects or alter the lipolytic effects of the compound. Examples include xe2x80x94OH, halogen (xe2x80x94Br, xe2x80x94Cl, xe2x80x94I and xe2x80x94F), xe2x80x94OR, xe2x80x94Oxe2x80x94COR, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COOH, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2, xe2x80x94COOR, xe2x80x94COR, xe2x80x94CHO, xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2, xe2x80x94SH, xe2x80x94SR and xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2. R is C1-C6 alkyl, benzyl, or phenyl.
A substituted non-aromatic heterocyclic ring can also have xe2x95x90O, xe2x95x90S, xe2x95x90NH or xe2x95x90NR where R is as defined above as a substituent. A substituted aliphatic, substituted aromatic, substituted non-aromatic heterocyclic ring or substituted benzyl group can have one, two or three substituents.
In the structural formulas depicted herein, the bond by which a chemical group or moiety is connected to the remainder of the molecule or compound is indicated by the following symbol:

For example, the corresponding symbol in Structural Formula (II) indicates the bond by which the oxygen of the pyridyloxy group is connected to Ring C of Structural Formula (I).
The present invention includes solvates of the compounds of Structural Formula I and the physiologically acceptable salts thereof. A particular compound of the present invention or a physiologically acceptable salt thereof may form solvates with water or common organic solvents. Such solvates are included within the scope of compounds of the present invention.
In addition, it will be appreciated that diastereomers exist for the compounds of Structural Formula I and, depending on the substituents, further diastereomers may exist. The compounds of the present invention include mixtures of two or more diastereomers as well as each individual stereoisomer.
It will also be appreciated that some of the heterocycles may exist in tautomeric forms. All such forms are included within the scope of the present invention.
As used herein, xe2x80x9ccrystallizingxe2x80x9d refers to providing a solvent or solvent mixture in which the indazolyloxy propanolamine compound is highly soluble and in which an ammonium salt(s) thereof is insoluble or only slightly soluble. The compound is dissolved in the solvent or solvent mixture and then converted to the ammonium salt by the addition of at least one equivalent of the appropriate acid, after which the ammonium salt precipitates. To minimize contamination of the precipitated product, between about 1.0 and about 1.1 equivalents of acid are preferably used. Impurities present in the indazolyloxy propanolamine are preferably highly soluble in the solvent or solvent mixture, resulting in a precipitated salt which is purified relative to the free base prior to precipitation. More preferably, the precipitated compound is crystalline.
Purification by acidic (or basic) extraction refers to dissolving a compound with a basic functional group such as an amine (or a compound with an acidic functional group, such as a carboxylic acid) in aqueous or alcoholic acid (or aqueous or alcoholic base, in the case of a compound with an acidic functional group). The aqueous solution can then be washed with organic solvents that are not miscible with water to remove organic impurities. The pH of the solution is then adjusted to the isoelectric point of the compound, thereby precipitating the compound or allowing its extraction into an organic solvent.
Purification by precipitation at the isoelectric point refers to adjusting the pH of an aqueous solution of a compound with both an acidic and basic functional group (e.g., an amino acid) to its isoelectric point, thereby causing the compound to precipitate from solution. xe2x80x9cIsoelectric pHxe2x80x9d is the pH at which the compound is electrically neutral and therefore least soluble in aqueous solution. Preferably, impurities present in the compound are highly soluble at the isoelectric point. As a result, the precipitated compound is purified relative to the compound prior to precipitation. More preferably, the precipitated compound is crystalline. Optionally, a compound with both an acidic and basic functional group can be purified by both by acidic (or basic) extraction and by precipitation at its isoelectric point.
Livestock animals are animals raised for food production. Ruminants or xe2x80x9ccud-chewingxe2x80x9d animals such as cows, bulls, heifers, steers, sheep, buffalo, bison, goats and antelopes are examples of livestock. Other examples of livestock include pigs and avians (poultry) such as chickens, ducks, turkeys and geese. Yet other examples of livestock include fish, shellfish and crustaceans raised in aquaculture. Also included are exotic animals used in food production such as alligators, water buffalo and ratites (e.g., emu, rheas or ostriches). The method of the present invention is preferably used with avians.
An xe2x80x9ceffective amountxe2x80x9d of a compound of the present invention is the quantity which, when administered to a livestock animal, increases the quantity of meat and/or quality of meat obtained from the animal.
Increasing the quantity of meat obtained refers to promoting a greater amount of growth in the animal with a treatment compared with the absence of the treatment. Alternatively, increasing the quantity of meat obtained refers to promoting formation of lean body mass. The formation of lean body mass is promoted, for example, when there is a higher ratio of muscle to fat as a result of a treatment than in the absence of the treatment. Alternatively, increasing the quantity of meat obtained refers to improving the efficiency of utilization of food. Food utilization is more efficient when there is a greater body weight gain per a given amount of feed consumed by an animal as a result of a treatment than in its absence. Thus, increasing the quantity of meat obtained from a livestock animal generally results in an improvement in the economics, e.g., in increase in the profitability of producing meat.
Increasing the quality of meat refers to an improvement in carcass quality of the animal. Improved carcass quality refers, for example, to the formation of less fatty tissue (subcutaneous fat), to a decreased size of the fat pad in poultry and/or to greater leanness (improved yield). Thus, improved carcass quality generally results in meat that is more healthy to consume, e.g., is less likely to cause elevated cholesterol and/or triglyceride levels. Improving the quality of meat can also improve the economics and increase the profitability of producing meat because high quality grade meat can command higher selling prices at market.
The effective amount to be administered will vary somewhat depending upon the particular animal species being treated and the particular active ingredient employed, but generally will be from about 0.5 to about 1000 parts per million (ppm: milligrams compound per kilogram food) of total daily feed intake. Such amount will provide a dosage of about 0.02 to about 50 mg/kg. A preferred embodiment employs about 0.5 to about 200 ppm, and more preferably from about 1 to about 40 ppm. For example, when practicing the method in animals such as poultry, the compound will be added to the daily feed ration at about 2 to 100 parts per million of the daily feed ration.
The method of the present invention is preferably practiced by orally administering an effective amount of a compound of the present invention to a livestock animal. Other routes of administration can be employed, for instance intranasal (e.g., by intranasal misting device), in ovo or subcutaneous, intramuscular or intravenous injection; however, such routes are less practical.
For oral administration, a compound of the present invention is preferably admixed with suitable carriers or diluents commonly employed in animal husbandry. Animal feedstuffs comprising a compound of the present invention are provided as a further embodiment of this invention. Typical carriers and diluents commonly employed in such feedstuffs include corn meal, corncob grits, soybean meal, alfalfa meal, rice hulls, soybean mill run, cottonseed oil meal, bone meal, ground corn, corncob meal, wheat middlings, limestone, dicalcium phosphate, sodium chloride, urea, distillers dried grain, vitamin and/or mineral mixes, cane molasses or other liquid carriers and the like. Such carriers promote a uniform distribution of the active ingredient, and more typically about 20 to about 98 percent by weight.
While the preferred method for orally administering the compounds of the present invention is via the daily feed rations, the compounds can be incorporated into salt blocks and mineral licks, as well as being added directly to link tank formulations or drinking water for convenient oral consumption. The compounds can additionally be formulated with polymorphous materials, waxes and the like for long-term controlled release, and administered to animals as a bolus or tablet only as needed to maintain the desired daily payout of active ingredient. Compounds can also be administered orally by gavage treatment and/or applied transdermally.
For parenteral administration, the compounds of the present invention can be admixed with conventional carriers such as water, propylene glycol, polyethylene glycols, n-methyl pyrrolidone, glycerol formal, corn oil, sesame oil, calcium stearate, polymeric materials and the like. Such formulations can be molded into pellets and administered as an injection or as a slow-release subcutaneous implant, sustained rumen delivery device or intranasal device. Such administrations can be made as often as needed to ensure the proper dosing of active ingredient to obtain the desired rate of growth promotion and improvement in leanness and feed efficiency.
The compounds of the present invention can be prepared by procedures disclosed in WO 97/10825 to Bell et al., WO 98/09625 to Crowell et al., U.S. Pat. Nos. 5,808,080 and 6,046,227. The entire teachings of these references are incorporated herein by reference. A reaction scheme for preparing these compounds is shown below:
X and Ring D in the Scheme are as described above.
The amination of the epoxides in the Scheme is carried out under conditions known in the art for this type of reaction. For example, the epoxide may be combined with the amine in an alcohol, preferably ethanol at room temperature, to the reflux temperature of the reaction mixture. For example, the reaction is carried out under conditions generally described in Atkins et al., Tetrahedron Letters 27:2451 (1986) the entire teachings of which are incorporated herein by reference. An example of specific conditions for reacting an epoxide with an amine is provided in Example 6.
Substituents which interfere with the reaction shown in the Scheme can be present, provided that they are first converted to a protected form. Suitable protecting groups are known to those skilled in the art and are disclosed in Green and Wuts, xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, 1991, the teachings of which are incorporated herein by reference.
An alternative method of preparing the compounds of the present invention involves deprotecting a cyclic sulfate-containing compound to reveal hydroxy substituents, and comprises combining the cyclic sulfate-containing compound with a trialkylsilyl halide in a solvent for a time sufficient to deprotect the hydroxyl group.
Specifically, the process comprises reacting a compound of the formula (VIII):
with thionyl halide in a solvent for a time sufficient to yield a sulfite compound of the formula (IX):
where Ring A and Ring B are as described above.
Suitable thionyl halides include thionyl bromide and thionyl chloride. Thionyl chloride is preferred. Typically, 2 equivalents of thionyl halide are used per mole of compound (VIII).
Any solvent can be used in this step, so long as it does not interfere with the reaction. THF is preferably used. The reaction is typically conducted until product is obtained, generally for about 120 to 240, preferably 180, minutes. The reaction can be conducted at any temperature, but generally is conducted at a temperature less than about 0xc2x0 C., preferably from about xe2x88x9210 to 0xc2x0 C., more preferably from about xe2x88x9210 to xe2x88x925xc2x0 C., most preferably from about xe2x88x929 to xe2x88x928xc2x0 C.
In a preferred embodiment, the NH group in the 1H-indazole ring is first N-protected prior to conversion of the compound to the corresponding sulfate. Selection of the protecting group is preferably made such that it can be removed under the same conditions as for removing the sulfate group to reveal a hydroxy group.
Conditions for N-protecting the nitrogen atoms depend on the particular protecting group chosen. Suitable reaction conditions are described in xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d Peter G. M. Wuts (Editor), Theodora W. Greene, 3rd ed. (April 1999), Vch Pub.
Thereafter, compound (IX) can be converted into corresponding sulfate compound of the formula (X):
where Ring A and Ring B are as described above.
Suitably, the conversion comprises combining sulfite compound (IX) with a catalytic amount of a ruthenium compound and an oxidizing agent in solvent for a time sufficient to oxidize said sulfite compound (IX) to a sulfate compound (X).
Suitable ruthenium compounds include ruthenium chloride or ruthenium oxide. Generally, about 0.001 to 0.25 equivalents of ruthenium compound are used per mole of sulfite compound (IX).
Suitable oxidizing agents include sodium periodate, sodium hypochlorite, sodium bromate, calcium hypochloride, sodium chlorate or ozone. Generally, about greater than about 2.0, preferably 2.5, equivalents of oxidizing agent are used per mole of sulfite compound (IX).
The conversion is typically conducted in any solvent that would not interfere with the reaction, such as CCl4, CHCl3, CH3CN, or water or mixtures thereof. The conversion is typically conducted for about 30 to 120, preferably 60, minutes. Preferably, the conversion is conducted in a mixture of CHCl3, CH3CN and water. The conversion is typically conducted at a temperature of from about xe2x88x9210 to 25xc2x0 C.
Thereafter, the sulfate compound (X) can be reacted with a primary amine of the formula (XI):
where X, Ring C and Ring E are as described above, in solvent for a time sufficient to yield a compound (XII):
Typically, about 0.9 to 2 equivalents of amine are used per mole of sulfate compound (X). Preferably, about 0.9 to 1.1 eq. are used. Most preferably, about 1.0 eq. (a stoichiometric amount) of amine is used.
Typically, any solvent can be used in this step, as long as it does not interfere with the reaction. Preferably, the reaction is conducted in CH3CN. The reaction is typically conducted for about 60-180, preferably 120, minutes at a temperature of from about 78 to 85xc2x0 C.
Finally, the compound (XII) can be combined with trialkylsilyl halide in solvent for a time sufficient to yield compound (IV):
where R1, R2, X, Ring A, Ring B, Ring C, and Ring E are as described above.
Suitable trialkylsilyl halides include trialkylsilyl iodide, trialkylsilyl bromide or trialkylsilyl chloride. Preferably, the trialkylsilyl halide is trimethylsilyl iodide.
The reaction may be carried out in any solvent, so long as the solvent does not interfere with the reaction. Preferably, the solvent is an aprotic solvent such as carbon tetrachloride, acetonitrile, dimethyl sulfoxide, dimethylformamide, sulfolane, tetrahydrofuran, diethyl ether, methyl-t-butyl ether, 1,2-dimethoxy-ethane, dioxane, chloroform, methylene chloride, toluene or acetone or mixtures thereof.
The reaction is typically conducted for 5-25, preferably 15, minutes at a temperature of less than 0xc2x0 C., preferably xe2x88x9210 to 0xc2x0 C., most preferably xe2x88x929 to xe2x88x928xc2x0 C.
A method of preparing the compounds of the present invention involves formation of salts of novel indazolyloxy propanolamines in which the amine group is substituted with an alkyl 2-[4-(2-yl-2-methylpropyl)phenoxy]pyridine-carboxylate group (hereinafter xe2x80x9cindazolyloxy propanolamine estersxe2x80x9d). These indazolyloxy propanolamine esters can be readily crystallized in high yield and in high purity, substantially free (typically less than 1 ppm) of epoxide precursors. In addition, the corresponding carboxylic acids of indazolyloxy propanolamine esters (hereinafter xe2x80x9cindazolyloxy propanolamine carboxylic acidsxe2x80x9d) can be purified by precipitation at their isoelectric point in high yield and high purity. Both indazolyloxy propanolamine esters and carboxylic acids can be prepared in high yield from readily accessible starting materials.
This method can be used to prepare an indazolyloxy propanolamine ester represented by Structural Formula (XIII):
and ammonium salts thereof.
R8 is a C1 to C6 straight or branched chain alkyl group or a C7 to C9 substituted or unsubstituted aralkyl group. Preferably, R8 is methyl or ethyl.
The method comprises the step of reacting an epoxide starting material with an amine starting material. The epoxide starting material is represented by Structural Formula (XIV):
and the amine starting material is represented by Structural Formula (XV):.
This method of can also be used to prepare an indazolyloxy propanolamine carboxylic acid or a carboxylate salt thereof from an indazolyloxy propanolamine ester represented by Structural Formula (XIII). The indazolyloxy propanolamine carboxylic acid is represented by Structural Formula (XVI):
The method comprises the step of hydrolyzing the xe2x80x94COOR8 group of the indazolyloxy propanolamine ester.
Because of the amine moiety present in the indazolyloxy propanolamines esters disclosed herein, ammonium salts of these compounds can be prepared by reacting with a suitable acid. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic, acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-1,4 dioate, 3-hexyne-2, 5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, xcex2-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate salts.
Carboxylate salts can be formed from the indazolyloxy propanolamines acids disclosed herein which have a carboxylic acid functional group by reacting with a suitable base. Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkylamines, and the like. Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.
Preferred carboxylate salts of the compound represented by Structural Formula (XVI) include alkali metal carboxylate salts such as the sodium carboxylate salt, the potassium carboxylate salt and the lithium carboxylate salt.
The preparation of the indazolyloxy propanolamine ester represented by Structural Formula (XIII) from the epoxide and amine represented by Structural Formulas (XIV) and (XV), respectively, is generally carried out in a solvent at room temperature to the reflux temperature of the reaction mixture. Temperatures of 40-140xc2x0 C. are generally preferred. The solvents that may be used in the reaction include: alcoholic solvents, such as methanol, ethanol or isopropanol, (with the preferred solvent corresponding to the particular ester being used in the reaction to prevent transesterification); aromatic solvents, such as benzene, toluene, xylenes, chlorobenzene, dichlorobenzene, other haloaromatics, nitrobenzene, benzonitrile, or trifluoromethylbenzene; or dipolar aprotic solvents, such as dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMAC) or N,N-dimethylformamide; or other solvents where the reagents are soluble and the temperature can be elevated to the range previously described. Equimolar amounts of epoxide and amine can be used. Alternatively, up to about a five fold excess of one reagent is used. Preferably, however, between about 1.1 to about 2.0 equivalents of amine relative to epoxide is preferred.
Indazolyloxy propanolamine esters, prepared as described above, can be purified by any suitable means, including by converting to a suitable ammonium salt and crystallizing, as described above.
Amine starting materials can be prepared as generally described in Examples 3 and 4. A phenoxide salt of the alkylamino phenol represented by Structural Formula (XVII) is reacted with a 2-halo pyridine ester represented by Structural Formula (XVIII):
R8 in Structural Formula (XVIII) is as described for Structural Formula (XIII). X is a halo group. The coupling reaction and the preparation of the compound represented by Structural Formula (XVII) can be carried out according to procedures described in the aforementioned WO 97/10825 to Bell et al., WO 98/09625 to Crowell et al., U.S. Pat. Nos. 5,808,080 and 6,046,227.
Generally, the reaction may be carried out by mixing the alkylamino phenol with a base in the presence of the 2-halopyridine ester. Equimolar amounts of the starting materials are preferably used. However, molar excesses up to about five or ten fold of one starting material relative to the other can be used. The coupling is performed by mixing the amino phenol with a base in a suitable solvent or solvent system. The reaction can be carried out at temperatures as low as room temperature, but is preferably carried out by heating the mixture at reflux while azeotropically removing water formed during the deprotonation step. The 2-halopyridine ester is then added and the reaction continued until the reaction is complete.
Suitable solvents include dipolar aprotic, ethereal, and aromatic solvents, as well as combinations thereof. Dipolar aprotic solvents include solvents such as DMSO, N,N-dimethylacetamide, N-methylpyrrolidinone, 1,3-dimethyl-2-imidazolindinone (DMI), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) with a lower boiling solvent to azeotropically remove water such as benzene, toluene, isooctane, xylenes or other solvents capable of forming binary azeotropes with water but which are inert under the reaction conditions. Other suitable compounds for azeotropic removal of water may be found in Advances In Chemistry Series 116xe2x80x94Azeotropic Data III, American Chemical Society: Washington D.C., 1973. Ethereal solvents include tetrahydrofuran, dioxane and 1,2-dimethoxyethane. Aromatic solvents include benzene, toluene, chlorobenzene, anisole and 1,2-dichlorobenzene. Preferred is the use of an aromatic solvent such as chlorobenzene containing 0.1-10 equivalents of a dipolar aprotic solvent such as N,N-dimethylacetamide. Suitable bases include alkali metal alkoxides, such as alkali metal methoxides, ethoxides and tert-butoxides (preferably corresponding to the alkyl group of the ester to prevent transesterification), alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide, or alkali metal carbonates, such as Na2CO3 or K2CO3. Although excesses of base up to at least about ten fold can be used, preferred is the use of stoichiometric quantities of hydroxide or alkoxide bases or 1.5-5 equivalents of K2CO3.
The preparation of the epoxide starting material represented by Structural Formula (XIV) can be carried out by reacting 4-hydroxyindazole with (2S)-(+)-glycidyl 3-nitrobenzenesulfonate in an inert solvent (e.g., acetone, methyl ethyl ketone, methyl isobutylketone, dimethyl sulfoxide, N,N-dimethylacetamide (DMAC) or DMF) and in the presence of a base. Although about equimolar amounts of the starting materials are preferred, molar excess up to about five to about ten-fold of one starting material relative to the other can also be used. Suitable bases include non-nucleophilic bases such as potassium carbonate, sodium carbonate and alkali metal alkoxides; potassium carbonate is preferred. Although an excess of base can be used, between about 1.05 and about 1.50 equivalents of K2CO3 are preferred. The reaction is carried out at temperatures ranging from about ambient temperature to about 40xc2x0 C., preferably about 30xc2x0 C. Other sulfonate esters can also be used (e.g., tosylate, nosylate or mesylate) as well as halides such as epibromohydrin or epichlorohydrin. The nosylate is preferred. Specific reaction conditions are described in Examples 1 and 2.
The hydrolysis of the indazolyloxy propanolamine ester represented by Structural Formula (XIII) to form the carboxylic acid represented by Structural Formula (XVI) or the carboxylate salt thereof can be carried out by any suitable means, including by procedures disclosed in Larock, R. C. Comprehensive Organic Transformations; VCH: New York, 1989, pp. 981-985; March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, third(3rd) edition, John Wiley Sons (1985), pages 375-76 and references cited therein, the entire relevant teachings of which are incorporated herein by reference. This reaction is referred to herein as the xe2x80x9chydrolysis reactionxe2x80x9d.
Preferably, the hydrolysis reaction is carried out in alcoholic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in methanol or ethanol. Methanolic sodium hydroxide is preferred. The hydrolysis can be carried out with one equivalent of base relative to indazolyloxy propanolamine ester. Alternatively, an excess of base, for example, an excess up to about ten to about twenty-fold can be used to form the carboxylate salt. Preferably, the excess of base is between about zero and about 30 percent. Generally, the reaction temperature varies between room temperature and the reflux temperature of the solvent, and is typically 40-70xc2x0 C. The carboxylic acid product (or carboxylate salt thereof) is isolated by conventional means, for example, by removal of the solvent in vacuo.
The indazolyloxy propanolamine carboxylic acid or carboxylate salt thereof can be purified by basic (or acidic) extraction, e.g., by dissolving in aqueous base (e.g., aqueous sodium hydroxide, potassium hydroxide or lithium hydroxide), and/or by precipitation at its isoelectric point. Preferably, the aqueous solution is extracted with one or more organic solvents which are not miscible with water to remove impurities. The pH of the aqueous solution can then adjusted to its isoelectric point with aqueous acid (e.g., aqueous HCl, H2SO4, acetic acid or a sulfonic acid), thereby causing the indazolyloxy propanolamine carboxylic acid to precipitate.
The indazolyloxy propanolamine carboxylic acids or carboxylate salts thereof can also be purified by using either cationic ion-exchange resins, such as AMB 15 (H form), 50WX2-400 (H form), or IR50S (H form) and eluting with an alcoholic solution of an alkali metal acetate, such as 6% (w/v) sodium acetate in methanol; or by using anionic ion-exchange resins, such as IRA900 (chloride form) or A21 (acetate form) and eluting with a basic solution of water and either alcohol or acetonitrile.
The individual optically active isomers of the compounds prepared by the present invention may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. This resolution can be carried out by derivatization with a chiral reagent followed by chromatography or by repeated crystallization. Removal of the chiral auxiliary by standard methods affords substantially optically pure isomers of the compounds of the present invention or their precursors. Further details regarding resolutions can be obtained in Jacques, et al., Enantiomers, Racemates, and Resolutions, John Wiley Sons, 1981.
The compounds employed as initial starting materials in the synthesis of the compounds of this invention are well known and, to the extent not commercially available, are readily synthesized by standard procedures commonly employed by those of ordinary skill in the art.
The invention is illustrated by the following examples, which are not meant to be limiting in any way.


MicroElectroMechanical System (MEMS) assemblies include microphones and speakers to mention two examples. These MEMS devices may be used in diverse applications such as within hearing aids and cellular phones.
In the case of a MEMS microphone, acoustic energy typically enters through a sound port in the assembly, vibrates a diaphragm and this action creates a corresponding change in electrical potential (voltage) between the diaphragm and a back plate disposed near the diaphragm. This voltage represents the acoustic energy that has been received. Typically, the voltage signal is then transmitted to an electric circuit (e.g., an integrated circuit such as an application specific integrated circuit (ASIC)). Further processing of the signal may be performed on the electrical circuit. For instance, amplification or filtering functions may be performed on the voltage signal by the integrated circuit.
As mentioned, sound typically enters the assembly through an opening or port. When a port is used, this opening also allows other unwanted or undesirable items to enter the port. For example, various types of contaminants (e.g., solder, flux, dust, and spit, to mention a few possible examples) may enter through the port. Once these items enter the assembly, they may damage the internal components of the assembly such as the MEMS device and the integrated circuit.
Previous systems have sometimes deployed particulate filters that prevent some types of debris from entering an assembly. Unfortunately, these filters tend to adversely impact the operation of the microphone. For instance, the performance of the microphone sometimes becomes significantly degraded when using these previous approaches. Microphone customers often elect to not use such microphones in their applications because of the degraded performance.
Skilled artisans will appreciate that elements in the figures are illustrated for simplicity and clarity. It will further be appreciated that certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not necessarily required. It will also be understood that the terms and expressions used herein have the ordinary meaning as is accorded to such terms and expressions with respect to their corresponding respective areas of inquiry and study except where specific meanings have otherwise been set forth herein.


A headphone having a noise-cancelling function (noise-cancelling headphone) includes a microphone and a noise-cancelling circuit (hereinafter referred to as “NC circuit”). The microphone collects external sounds (hereinafter referred to as “noises”) around the headphone. The NC circuit generates cancelling signals corresponding to the noises collected by the microphone. The headphone combines sound waves corresponding to the cancelling signals generated by the NC circuit and sound waves corresponding to the reproduced signals from a sound source such as a music player connected to the headphone, and then outputs the combined sound waves from a driver unit. That is, the headphone outputs musical sounds (hereinafter referred to as “reproduced sounds”) derived from the reproduced signals from the sound source with cancelling (muting) of the noises.
Examples of the scheme for generating cancelling signals include a feedback scheme (hereinafter referred to as FB) and a feedforward scheme (hereinafter referred to as FF).
A built-in microphone of the FB noise-cancelling headphone is disposed in the interior of a housing unit (ear piece) of the headphone and near the ear of the user. The NC circuit analyses in real-time the signals of the noises collected by the microphone and generates cancelling signals minimizing the noises at the position of the eardrum of the user. The FB noise-cancelling headphone collects the noises at the position near the ear of the user. Thus, the noise-cancelling effect of the FB noise-cancelling headphone is higher than that of the FF noise-cancelling headphone. In addition, the response of the FB noise-cancelling headphone to the variation of noise components is good.
However, when the built-in microphone of the FB noise-cancelling headphone collects the reproduced sounds in addition to the noises, and then the NC circuit generates cancelling signals, the sound quality of the reproduced sounds output from the headphone are degraded. In addition, the ear piece of the FB noise-cancelling headphone should be sealed in the state which the headphone is worn on the head of the user, to enhance the noise-cancelling effect. When the ear piece is sealed, the reproduced sounds output from the headphone may be muffled. Thus, the sound quality of the reproduced sounds are degraded. To address the problem, a FB noise-cancelling headphone generally includes a filter to correct the sound quality of the reproduced sounds.
On the other hand, a built-in microphone of the FF noise-cancelling headphone is disposed at the exterior of the housing unit of the headphone. The NC circuit analyses the signals of the noises collected by the microphone and predicts the variation in the noises that will reach the eardrum of the user wearing the headphone. The NC circuit generates cancelling signals based on the result of the prediction. The FF noise-cancelling headphone does not need the placement of the microphone on a limited space near the ear of the user. In addition, the built-in microphone of the FF noise-cancelling headphone is disposed at a position remote from the driver unit. Thus, the FF noise-cancelling headphone is less likely to collect the reproduced sound output from the driver unit and to generate cancelling signals from the reproduced sounds than the FB noise-cancelling headphone. That is, the sound quality of the reproduced sound output from the FF noise-cancelling headphone are less susceptible to the cancelling signals generated from the reproduced sounds than the sound quality of the reproduced sound output from the FB noise-cancelling headphone.
Unfortunately, the FF noise-cancelling headphone often indicates directionality of the noise-cancelling effect depending on the position of the built-in microphone. Unlike the built-in microphone of the FB noise-cancelling headphone, the built-in microphone of the FF noise-cancelling headphone is disposed at the exterior of the housing unit. Thus, the FF noise-cancelling headphone generates noises caused by wind pressure of the blowing of the wind, for example. In other words, the FF noise-cancelling headphone is susceptible to the influence of the wind around the headphone. As a result, the FF noise-cancelling headphone can cause a feeling of strangeness or discomfort to the user, when the noise-cancelling function is activated.
Schemes have been proposed to dispose a microphone in the interior of the housing unit of the FF noise-cancelling headphone to avoid the influence of the wind described above (for example, refer to Japanese Unexamined Patent Application No. 2010-109799).
The FF noise-cancelling headphone disclosed in Japanese Unexamined Patent Application No. 2010-109799 includes a driver unit, a baffle plate, and a microphone. The microphone is disposed behind the baffle plate to which the driver unit is attached (that is, in the interior of a rear air chamber). The baffle plate includes a flange portion and a groove. The flange portion is disposed on the forward portion and the rear portion in the thickness direction of the baffle plate. The groove is formed between the flange portion and along the outer circumference of the baffle plate. The flange portion that is disposed on the rear portion of the baffle plate has a sound collecting hole penetrating the flange portion in thickness direction. The sound collecting hole is in communication with the groove. The external noises are collected by the microphone through the groove and the sound collecting hole.