Coding of an audio signal represented by a respective set of sampled signal values for each of a plurality of sequential segments is disclosed. The sampled signal values are analyzed (40) to determine one or more sinusoidal components for each of the plurality of sequential segments. The sinusoidal components are linked (42) across a plurality of sequential segments to provide sinusoidal tracks. For each sinusoidal track, a phase comprising a generally monotonically changing value is determined and an encoded audio stream including sinusoidal codes (r) representing said phase is generated (46).

Referring now to FIG. 1, a parametric coding scheme in particular a sinusoidal coder is described in PCT Patent Application No. WO01/69593. In this coder, an input audio signal x(t) is split into several (overlapping) segments or frames, typically of length 20 ms. Each segment is decomposed into transient, sinusoidal and noise components. (It is also possible to derive other components of the input audio signal such as harmonic complexes although these are not relevant for the purposes of the present invention.)
In the sinusoidal analyser 130, the signal x2 for each segment is modelled using a number of sinusoids represented by amplitude, frequency and phase parameters. This information is usually extracted for an analysis interval by performing a Fourier Transform (FT) which provides a spectral representation of the interval including: frequencies; amplitudes for each frequency; and phases for each frequency where each phase is in the range {−π,π}. Once the sinusoidal information for a segment is estimated, a tracking algorithm is initiated. This algorithm uses a cost function to link sinusoids with each other on a segment-to-segment basis to obtain so-called tracks. The tracking algorithm thus results in sinusoidal codes CS comprising sinusoidal tracks that start at a specific time instance, evolve for a certain amount of time over a plurality of time segments and then stop.
In such sinusoidal coding, frequency information is usually transmitted for the tracks formed in the encoder. This can be done cheaply, since tracks are defined as having a slowly varying frequency and, therefore, frequency can be transmitted efficiently by time-differential encoding. (In general, amplitude can also be encoded differentially over time.)
In contrast to frequency, phase transmission is viewed as expensive. In principle, if the frequency is (nearly) constant, phase as a function of the track segment index should adhere to a (nearly) linear behaviour. However, when it is transmitted, phase is limited to the range {−π,π} as provided by the Fourier Transform. Because of this modulo 2π representation of phase, the structural inter-frame relation of the phase is lost and, at first sight appears to be a white stochastic variable.
However, since the phase is the integral of the frequency, the phase need, in principle, not be transmitted. This is called phase continuation and reduces the bit rate significantly.
In phase continuation, only the frequency is transmitted and the phase is recovered at the decoder from the frequency data by exploiting the integral relation between phase and frequency. It is known, however, that the phase can only be approximately recovered using phase continuation. If frequency errors occur, due to measurement errors in the frequency or due to quantisation noise, the phase, being reconstructed using the integral relation, will typically show an error having the character of a drift. This is because frequency errors have an approximately white noise character. Integration amplifies low-frequency errors and, consequently, the recovered phase will tend to drift away from the actually measured phase. This leads to audible artifacts.
This is illustrated in FIG. 2(a) where ψ and Ω are the real frequency and phase for a track. In both the encoder and decoder frequency and phase have an integral relationship represented by I. The quantisation process in the encoder is modelled as an additive white noise n. In the decoder, the recovered phase {circumflex over (ψ)} thus includes two components: the real phase ψ and a noise component ε2, where both the spectrum of the recovered phase and the power spectral density function of the noise ε2 have a pronounced low-frequency character.
Thus, it can be seen that in phase continuation, since the recovered phase is the integral of a low-frequency signal, the recovered phase is a low-frequency signal itself. However, the noise introduced in the reconstruction process is also dominant in this low-frequency range. It is therefore difficult to separate these sources with a view to filtering the noise n introduced during encoding.
The present invention attempts to mitigate this problem.

Audio coding via creation of sinusoidal tracks and phase determination


A process for the recovery of oil from a subsurface reservoir in combination with the production of liquid hydrocarbons from a hydrocarbonaceous stream involving:    (i) separating an oxygen/nitrogen mixture into a stream enriched in oxygen and an oxygen depleted stream;    (ii) partial oxidation of the hydrocarbonaceous feed at elevated temperature and pressure using enriched oxygen produced in step (i) to produce synthesis gas;    (iii) converting synthesis gas obtained in step (ii) into liquid hydrocarbons; and    (iv) recovering oil from a subsurface reservoir using at least part of the oxygen depleted gas stream produced in step (i).

Enhanced oil recovery (sometimes also called tertiary oil recovery) is the description applied by the oil industry to non-conventional techniques for getting more oil out of subsurface reservoirs than is possible by natural production mechanisms (primary oil recovery) or by the injection of water or gas (secondary oil recovery).
If oil is to move through the reservoir rock to a well, the pressure under which the oil exists in the reservoir must be greater than that at the well bottom. The rate at which the oil moves towards the well depends on a number of features, among which the pressure differential between the reservoir and the well, permeability of the rock, layer thickness and the viscosity of the oil. The initial reservoir pressure is usually high enough to lift the oil from the producing wells to the surface, but as the oil is produced, the pressure decreases and the production rate starts to decline. Production, although declining, can be maintained for a time by naturally occurring processes such as expansion of the gas in a gas cap, gas release by the oil and/or the influx of water. A more extensive description of natural production mechanisms can be found in the Petroleum Handbook, 6th edition, Elsevier, Amsterdam/New York, 1983, p. 91–97.
The oil not producible, or left behind, by the conventional, natural recovery methods may be too viscous or too difficult to displace or may be trapped by capillary forces. Depending on the type of oil, the nature of the reservoir and the location of the wells, the recovery factor (the percentage of oil initially contained in a reservoir that can be produced by natural production mechanisms) can vary from a few percent to about 35 percent. Worldwide, primary recovery is estimated to produce on average some 25 percent of the oil initially in place.
In order to increase the oil production by natural production mechanisms, techniques have been developed for maintaining reservoir pressure. By such techniques (also known as secondary recovery) the reservoir's natural energy and displacing mechanism which is responsible for primary production, is supplemented by the injection of water or gas. However, the injected fluid (water or gas) does not displace all the oil. An appreciable amount remains trapped by capillary forces in the pores of the reservoir rock and is bypassed. This entrapped oil is known as residual oil, and it can occupy from 20 to 50 percent, or even more, of the pore volume. See for a more general description of secondary recovery techniques the above-mentioned Petroleum Handbook, p. 94–96.
Enhanced oil recovery (sometimes called tertiary oil recovery) is the description applied by the oil industry to non-conventional techniques for getting more oil out of subsurface reservoirs than is possible by natural production mechanisms or secondary production mechanisms. Many enhanced oil recovery techniques are known. It covers techniques as thermal processes, miscible processes and chemical processes. Examples are heat generation, heat transfer, steam drive, steam soak, polymer flooding, surfactant flooding, the use of hydrocarbon solvents, high-pressure hydrocarbon gas, carbon dioxide and nitrogen. See for a more general description of secondary recovery techniques the above-mentioned Petroleum Handbook, p. 97–110.
The use of nitrogen in enhanced oil recovery processes is well known. At first waste gases as stack gas, flue gas and exhaust gas were used. These gasses usually contained not only nitrogen, but also carbon dioxide and optionally steam. See for instance U.S. Pat. No. 4,499,946. A problem, however, was the presence of certain waste products such as nitrogen oxides and sulphur oxides which give rise to corrosion and pollution problems. A paper by M. D. Rushing et al., entitled "Miscible Displacement with Nitrogen", Petroleum Engineer, November 1977, p. 26–30, describes a miscible oil displacement process involving the injection of high pressure nitrogen. As disclosed, pure nitrogen is injected into the reservoir and functions to initially strip relatively low molecular weight hydrocarbons from the reservoir oil. U.S. Pat. No. 4,434,852 describes the use of nitrogen and 2 to 20 percent by volume of light hydrocarbons in the enhanced oil recovery of subterranean oil reservoirs. Mixtures of nitrogen and carbon dioxide are described in U.S. Pat. Nos. 3,811,501 and 4,008,764. The injected gas may take the form of substantially pure nitrogen, such as produced by cryogenic fractionation of air as described by Rothrock et al., Nitrogen Floods Need Specialise Surface Equipment, Petroleum Engineer, August 1977, p. 22–26. As described above, the nitrogen gas may also take the form of flue gasses such as from boilers or internal combustion engines which typically will contain about 80–90% nitrogen, usually 88%, 5–15% carbon dioxide, usually 10%, 0–2% carbon monoxide, usually 1%, and the remainder hydrogen and trace amounts of other gasses.
As described, attention has been given to producing nitrogen cryogenically. A problem, however, is the need of a large, expensive cryogenic unit.
Several cryogenic concepts have been developed over the years to liquefy and separate air into its main constituents nitrogen, oxygen and rare gases. Refrigeration for cryogenic applications is produced by absorbing or extracting heat at low temperature and rejecting it to the atmosphere at higher temperatures. Three general methods for producing cryogenic refrigeration in large-scale commercial application are the liquid vaporisation cycle, the Joule-Thomson expansion cycle and the engine expansion cycle. The first two are similar in that they both utilise irreversible isenthalpic expansion of a fluid, usually through a valve. Expansion in an engine approaches reversible isenthalpic expansion with the performance of work. For more detailed discussion reference is made to Perry's Chemical Engineers Handbook, Sixth Edition, 12–49 ff. (McGraw-Hill, New York, 1984), Kirk-Othmer, Encyclopedia of Chemical Technology, Fourth Edition, Volume 7, p. 662 ff. (John Wiley and Sons, New York, 1993) and Ullmann's Encyclopedia of Industrial Chemistry, Fifth Edition, Volume A 18, p. 332 ff. (VCH, Weinheim, 1991).
Most commercial air separation plants are based on Linde's double distillation column process. This process is clearly described in the above references. In a typical example, feed air is filtered and compressed to a pressure usually between 5 and 10 bara. The compressed air is cooled and any condensed water is removed in a separator. To avoid freezing of water and carbon dioxide in the cryogenic part of the plant, the feed air is further passed through an adsorbent bed, usually activated alumina and/or molecular sieves, to remove the last traces of water and carbon dioxide. The purified air is than cooled down further, and fed to a first cryogenic distillation unit, usually at an intermediate stage. Crude liquid material from the bottom section of the first distillation unit, usually comprising between 40 and 50 mol percent oxygen, is fed to the second distillation unit (which second unit is usually on the top of the first distillation unit, the condenser of the first column usually acting as the reboiler for the second unit), usually also at an intermediate stage. The second distillation unit is operated at relatively low pressure (usually 1 to 2 bara). At the top of the first distillation unit almost pure liquid nitrogen is obtained which is typically fed to the second column at the top. Pure liquid oxygen is obtained at the bottom of the second distillation unit, while pure gaseous nitrogen is obtained from the top of the second column.
Many variations on the above concept are known. These include separation of air into gaseous products, liquid products and all kind of combinations thereof. Also the production of partly enriched oxygen and/or nitrogen streams together with almost pure oxygen and/or nitrogen streams, either in liquid or gaseous phase is well known. In addition there may be additional distillation units to separate any of the rare gases present in the feed air. Further, the methods for creating the low temperatures may vary in many ways. In this respect reference is made to the above cited literature references, and further to EP 798524, JP 08094245, EP 593703, EP 562893, U.S. Pat. No. 5,237,822, JP 02052980, EP 211957, EP 102190, SU 947595 JP 71020126 and JP 71020125.
The nitrogen produced in an air separation unit is usually vented to the atmosphere. This is at least partly due to the fact that, especially gas-to-liquids, plants (using so called stranded gas) are usually at remote locations, far away from industrial activities which could use the nitrogen. Up till now no suggestion has been made to use the nitrogen for enhanced oil recovery, while there are sufficient locations at which the nitrogen produced in the air separation unit could be used for enhanced oil recovery. This is the more remarkable as several suggestions have been made as to the use of other side products from gas-to-liquids plants, as energy and water.
Many publications are known describing processes for the conversion of (gaseous) hydrocarbonaceous feed stocks, as methane, natural gas and/or associated gas, into liquid products, especially methanol and liquid hydrocarbons, particularly paraffinic hydrocarbons. In this respect often reference is made to remote locations (e.g. in the dessert, tropical rairi-forest) and/or offshore locations, where no direct use of the gas is possible, usually due to the absence of large populations and/or the absence of any industry. Transportation of the gas, e.g. through a pipeline or in the form of liquefied natural gas, requires extremely high capital expenditure or is simply not practical. This holds even more in the case of relatively small gas production rates and/or fields. Reinjection of gas will add to the costs of oil production, and may, in the case of associated gas, result in undesired effects on the crude oil production. Burning of associated gas has become an undesired option in view of depletion of hydrocarbon sources and air pollution. Gas found together with crude oil is known as associated gas, whereas gas found separate from crude oil is known as natural gas or non-associated gas. Associated gas may be found as "solution gas" dissolved within the crude oil, and/or as "gas cap gas" adjacent to the main layer of crude oil. Associated gas is usually much richer in the larger hydrocarbon molecules (ethane, propane, butane) than non-associated gas.
In WO 91/15446 a process is described to convert natural gas, particularly remote location natural gas (including associated gas), into liquid hydrocarbons suitable for use as fuel. However, no optimally integrated, efficient, low-cost process scheme has been described. In WO 97/12118 a method and system for the treatment of a well stream from an offshore oil and gas field has been described. Natural gas is converted into syngas using pure oxygen in an autothermal reformer, a combination of partial oxidation and adiabatic steam reforming. The syngas (comprising a considerable amount of carbon dioxide) is converted into liquid hydrocarbons and wax. No fully and optimally integrated process scheme for a highly efficient, low capital process is described in this document.
In EP 1 004 746 a process has been described for the combined production of liquid hydrocarbons and the recovery of oil from a subsurface reservoir by partial oxidation of natural gas followed by conversion of the synthesis gas thus obtained into hydrocarbons and separating the hydrocarbons into liquid hydrocarbons and gaseous hydrocarbons (mainly C1–C4 hydrocarbons), and combusting and/or expanding these gaseous hydrocarbons to provide power for the secondary or enhanced recovery of oil. However, a further optimisation of the efficiency and the integration of the process is desired.
The present invention is directed to a process for the recovery of oil from a subsurface reservoir in combination with the production of liquid hydrocarbons from a hydrocarbonaceous stream, comprising:
(i) separating an oxygen/nitrogen mixture into a stream enriched in oxygen and an oxygen depleted stream;
(ii) partially oxidating the hydrocarbonaceous feed at elevated temperature and pressure using enriched oxygen produced in step (i) to produce synthesis gas;
(iii) converting synthesis gas obtained in step (ii) into liquid hydrocarbons;
(iv) recovering oil from a subsurface reservoir using at least part of the oxygen depleted gas stream produced in step (i).

Tertiary oil recovery combined with gas conversion process


A tablet based kiosk to securely support a tablet such as a personal computer to receive, transmit and display information or data comprising a tablet mount including a frame having a back frame member and a front frame member coupled together to retain or house the tablet therein and a card swipe scanner housing to operatively retain a card scanner or swipe to scan information from a card to transmit information from the tablet and card scanner such as payments to a remote site, and supported above the floor or other surface by a stand including a substantially vertical column coupled to the frame by an upper coupling assembly including a power supply housing and coupled to a base by a lower coupling assembly, and a lock mechanism to selectively lock the tablet and tablet mount to the stand.

1. Field of the Invention
A tablet based kiosk to house and support a tablet and card swipe or scanner to receive and transmit data or information to a remote site.
2. Description of the Prior Art
Personal computers are carried universally for the convenience of individual users. Such personal computers or tablets dedicated for a specific use may be employed with docking stations, in malls or other public locations to receive and transmit data to a remote site or sites.
Unfortunately, conventional docking stations generally do not have a means to secure the personal computer. Since such computers are not locked to the docking station, the personal computers are easily removed from the docking stations.
U.S. Pat. No. 5,506,393 shows a donation kettle that permits a contributor to make a donation comprising a display, keyboard, a surface for collecting a cash donation, a credit card and/or debit card donation processor. The donation kettle associates a donation with an account of a contributor, tallies information regarding a number of donations, and stores information regarding a donation, and a plurality of donations. The donation kettle is part of a donation kettle network which consists of a donation kettle, a terminal, and a communication link between the donation kettle and the terminal.
U.S. Pat. No. 7,079,384 relates to a portable computer and docking station locking structure in which the docking station has a lock provided inside the support arm controlled by a key. The portable computer has a lock hole in the back side adapted to receive the swivel locking member of the lock for enabling the portable computer to be locked to the docking station after setting of the portable computer in the support arm of the docking station.
U.S. Pat. No. 8,182,426 discloses a diagnostic system comprising a tablet type electronic device for ultrasonic diagnosis with docking station for mounting the electronic device. The docking station includes a receptacle section against which one side of the electronic device comes into abutment when mounting the electronic device and a hold-down section for holding down the electronic device releasably on the side opposite to the one side when mounting the electronic device.
US 2005/0213298 shows a docking station for a tablet computer comprising a docking assembly for positioning with three degrees of freedom and having a data connector for mechanically supporting and interfacing with the tablet computer. A support member couples the cradle assembly to an expansion base.
US 2006/0148575 shows an entertainment system comprising a video system having a video monitor and a video source, and a cradle secured within an automobile. The cradle is shaped and dimensioned for selectively receiving and securely holding the video system.
US 2006/0221565 discloses an ultra thin tablet computer and docking station system with an edge mounted battery with an optional extended battery.
US 2011/0192681 discloses a kiosk configured to accept a plurality of different types of connections corresponding to a plurality of different types of customer media. In one example, the kiosk includes a mount; a computer in a first position on the mount including a touchscreen, a card reader, and a processor; a storage medium coupled to the processor containing content; and a content transfer device coupled to the processor. The content transfer device is configurable to include at least one connection of a plurality of different types of connections corresponding to a plurality of different types of customer media. The kiosk further includes a panel in a second position on the mount adjacent to the computer including at least one connection mounting location, and the at least one connection is removably mounted to the panel at the connection mounting location. The processor stores the content in the storage medium, operates the touch screen to display a menu of the content and to record selections made by a customer from the menu, operates the card reader to read a payment card of the customer as payment for content associated with the customer selections, and transfers the content associated with the customer selections to a removable storage medium of the customer.
Additional examples of the prior art are found in U.S. Pat. No. 5,665,952; U.S. Pat. No. 5,696,366; U.S. Pat. No. 5,869,825; U.S. Pat. No. 5,909,794; U.S. Pat. No. 6,092,052; U.S. Pat. No. 8,160,922; US 2007/0244810; US 2008/0033855; US 2008/0195532; US 2008/0195533; US 2010/0312658; US 2012/0022955; US 2012/0185314 and US 2012/0232980.
While some of the prior art may contain some similarities relating to the present invention, none teach, suggest or include all of the advantages and unique features of the invention disclosed hereafter.


The present invention relates to novel xcex2-carboline derivatives of the general formula

The present invention relates to novel xcex2-carboline derivatives, useful as phosphodiesterase inhibitors. The invention further relates to synthesis of the xcex2-carboline derivatives and intermediates used in their preparation. The present invention additionally relates to use of the described derivatives for the treatment of diseases and conditions related to PDE, for example male erectile dysfunction.
Erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficiently rigid for satisfactory sexual intercourse. Currently it is estimated that approximately 7-8% of the male population suffers from some degree of ED, the equivalent of at least 20 million men in the United States alone. Since the likelihood of ED increases with age, it is projected that the incidence of this condition will rise in the future as the average age of the population increases.
Male erectile dysfunction may be the consequence of psychogenic and/or organic factors. Although ED is multi-factorial, certain sub-groups within the male population are more likely to present with the symptoms of the disorder. In particular, patients with diabetes, hypertension, heart disease, and multiple sclerosis have a particularly high prevalence of ED. In addition, patients who take certain classes of drugs such as antihypertensives, antidepressants, sedatives, and anxiolytics are more prone to suffer from ED.
Treatments for ED include a variety of pharmacologic agents, vacuum devices, and penile prostheses. Among the pharmacologic agents, papaverine, phentolamine, and alprostadil are currently used in practice. These agents are only effective after direct intracavernosal or intraurethral injection, and are associated with side effects such as priapism, fibrosis, penile pain and hematoma at the injection site. Vacuum devices are a noninasive alternative treatment for ED. These devices produce an erection by creating a negative pressure around the shaft of the penis resulting in an increased blood flow into the corpus cavernosum via passive arterial dilation. Although this form of therapy is frequently successful in ED of organic origin, complaints include the lack of spontaneity and the time involved in using a mechanical device, and difficulty and discomfort with ejaculation. A variety of semi-rigid or inflatable penile prostheses have been used with some success, particularly in diabetic men. These devices are generally considered when other treatment options have failed, and are associated with an increased risk of infection and ischemia.
Recently, the phosphodiesterase V (PDEV) inhibitor, sildenafil (Viagra(copyright)) was approved by the FDA as an orally effective medication for the treatment of ED. Sildenafil, 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3-n-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one and a number of related analogs and their use as antianginal agents are described in U.S. Pat. Nos. 5,250,534 and 5,346,901. The use of sildenafil and related analogs for treating male erectile dysfunction is described in PCT International Application Publication No. WO 94/28902, published Dec. 22, 1994. In clinical studies, the drug improved sexual function in about 70% of the men who suffer from ED of psychogenic or organic etiology. However, the drug showed less dramatic efficacy in patients who had undergone a radical prostatectomy, with improved erections in 43% of patients who took sildenafil versus 15% on placebo. In addition, the use of sildenafil is associated with several undesirable side effects including headache, flushing and disrupted color vision which result from non-selective effects on a variety of tissues. In spite of these shortcomings, the drug is viewed by patients as preferable to other treatments which involve the introduction of medication directly into the penis via injection, the use of an external device or a surgical procedure.
Daugan et.al, in U.S. Pat. No. 5,859,009 (EP 0740668 B1 and WO9519978) describe the synthesis of tetracyclic derivatives as inhibitors of cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate specifically phosphodiesterase, and their use in treating cardiovascular disorders. Daugan et.al., in WO97/03675 teach the use of tetracyclic derivatives for the treatment of impotence.
Bombrun et al., in WO 97/43287 describe a series of carboline derivatives, more specifically 2-(substituted alkyl carbonyl) substituted carboline derivatives and their use in treating cardiovascular disorders as inhibitors of cyclic guanosine 3,5-monophosphate, specifically phosphodiesterase.
Ellis et. al., in WO 94/28902 and EP0702555 B1 describes a series of pyrazolpyrimidinone derivatives and their use in treating erectile dysfunction. Campbell, S. F. in WO96/16657 teaches the use of bicyclic heterocyclic compounds for the treatment of impotence (pyrazolopyrimidones); while Campbell et al, in WO,96/16644 teach the use of selective cGMP PDE inhibitors for the treatment of erectile dysfunction.
Ohashi et al., in WO9745427 disclose tetracyclic pyridocarbazole derivatives having cGMP PDE inhibitory effects.
Fourtillan et. al., in WO 96/08490 A1 describe a series of carboline derivatives and their use in the treatment of diseases associated with melatonin activity disorders. Ueki et. al., in U.S. Pat. No. 5,126,448 describe pyridine and 1,2,3,4-tetrahydropyridine derivatives useful as psychotropic drugs having antianxiety effects. Atkinson et. al., in U.S. Pat. No. 3,328,412 describe 1-aryl- and 1-heteroaryl-2-acly-1,2,3,4-tetrahydro-xcex2-carboline derivatives having long lasting analgesic properties.
Sexually stimulated penile erection results from a complex interplay of physiological processes involving the central nervous system, the peripheral nervous system, and the smooth muscle. Specifically, release of nitric oxide from the non-adrenergic, non-cholinergic nerves and endothelium activates guanylyl cyclase and increases intracellular cGMP levels within the corpus cavernosum. The increase in intracellular cGMP reduces intracellular calcium levels, resulting in trabecular smooth muscle relaxation, which, in turn, results in corporal volume expansion and compression of the sub-tunical venules leading to penile erection.
PDEV has been found in human platelets and vascular smooth muscle, suggesting a role for this enzyme in the regulation of intracellular concentrations of cGMP in cardiovascular tissue. In fact, inhibitors of PDEV have been shown to produce endothelial-dependent vasorelaxation by potentiating the increases in intracellular cGMP induced by nitric oxide. Moreover, PDEV inhibitors selectively lower the pulmonary arterial pressure in animal models of congestive heart failure and pulmonary hypertension. Hence in addition to their utility in ED, PDEV inhibitors would likely be of therapeutic benefit in conditions like heart failure, pulmonary hypertension, and angina.
Agents that increase the concentration of cGMP in penile tissue, either through enhanced release or reduced breakdown of cGMP, are expected to be effective treatments for ED. The intracellular levels of cGMP are regulated by the enzymes involved in its formation and degradation, namely the guanylate cyclases and the cyclic nucleotide phosphodiesterases (PDEs). To date, at least nine families of mammalian PDEs have been described, five of which are capable of hydrolyzing the active, cGMP, to the inactive, GMP, under physiological conditions (PDEs I, II, V, VI, and IX). PDE V is the predominant isoform in human corpus cavernosum. Inhibitors of PDEV, therefore, would be expected to increase the concentration of cGMP in the corpus cavernosum and enhance the duration and frequency of penile erection.
Additionally, selective PDE inhibitors are known to be useful in the treatment of various disorders and conditions including male erectile dysfunction (ED), female sexual arousal dysfunction, female sexual dysfunction related to blood flow and nitric oxide production in the tissues of the vagina and clitoris, premature labor, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications.
Accordingly, it is an object of the invention to identify compounds which increase the concentration of cGMP in penile tissue through the inhibition of phosphodiesterases, specifically PDEV. It is another object of the invention to identify compounds which are useful for the treatment of sexual dysfunction, particularly erectile dysfunction and/or impotence in male animals and sexual dysfunction in female animals. Still another object of the invention is to identify methods for treating sexual dysfunction, especially erectile dysfunction, using the compounds of the present invention.
It is another object of the invention to identify compounds which are useful for the treatment of conditions of disorders mediated by PDEV, such as male erectile dysfunction, female sexual dysfunction, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication or diabetic complications.
We now describe a series of xcex2-carboline derivatives with the ability to inhibit phosphodiesterase type V in enzyme assays and increase the concentration of cGMP in cavernosal tissue in vitro.
The present invention provides novel xcex2-carboline derivative compounds useful as phosphodiesterase inhibitors. More particularly, the present invention is directed to compounds of the general formula (I):
wherein
R1 is independently selected from the group consisting of halogen, nitro, hydroxy, C1-C8alkyl, C1-C8alkoxy, xe2x80x94NH2, xe2x80x94NHRA, xe2x80x94N(RA)2, xe2x80x94Oxe2x80x94RA, xe2x80x94C(O)NH2, xe2x80x94C(O)NHRA, xe2x80x94C(O)N(RA)2, xe2x80x94NC(O)xe2x80x94RA, xe2x80x94SO2NHRA, xe2x80x94SO2N(RA)2, phenyl (optionally substituted with 1 to 3 RB) and heteroaryl (optionally substituted with 1 to 3 RB);
where each RA is independently is independently selected from the group consisting of C1-C8alkyl, aryl (optionally substituted with 1 to 3 RB), C1-C8aralkyl (optionally substituted with 1 to 3 RB) and heteroaryl (optionally substituted with 1 to 3 RB);
where each RB is independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C8alkyl, C1-C8alkoxy, C1-C8alkoxycarbonyl, carboxyC1-C8alkyl, C1-C8alkylsulfonyl, trifluoromethyl, trifluoromethoxy, amino, acetylamino, di(C1-C8alkyl)amino, di(C1-C8alkyl)aminoC1-C8alkoxy, di(C1-C8alkyl)aminoacetylC1-C8alkyl, di(C1-C8alkyl)aminoacetylamino, carboxyC1-C8alkylcarbonylamino, hydroxyC1-C8alkylamino, NHRA N(RA)2 and heterocycloalkylC1-C8alkoxy;
n is an integer from 0 to 4;
X is selected from the group consisting of O, S and NRD;
where RD is selected from the group consisting of hydrogen, hydroxy, xe2x80x94ORA, C1-C8alkyl (wherein the alkyl is optionally substituted with one to three substituent independently selected from halogen, carboxy, amino, C1-C8alkylamino, di(C1-C8alkyl)amino, C1-C8alkoxycarbonyl, heteroaryl or heterocycloalkyl), heteroaryl and heteroarylcarbonyl (wherein the heteroaryl may be optionally substituted with phenyl or substituted phenyl, where the phenyl substituents are one to three RB);
R2 is selected from the group consisting of C5-C10alkyl (optionally substituted with 1 to 3 RC), aryl (optionally substituted with 1 to 3 RB), heteroaryl (optionally substituted with 1 to 3 RB) and heterocycloalkyl (optionally substituted with 1 to 3 RB);
where each RC is independently selected from the group consisting of halogen, hydroxy, nitro, NH2, NHRA and N(RA)2;
Z is selected from the group consisting of CH2, CHOH and C(O); provided that when Z is CHOH or C(O), then X is NH;
R4 is selected from the group consisting of hydrogen, hydroxy, carboxy, C1-C6alkylcarbonyl, C1-C6alkoxylcarbonyl, di(C1-C8alkyl)aminoalkoxycarbonyl, di(C1-C8alkyl)aminoC1-C8alkylaminocarbonyl, and xe2x80x94CORF;
where RF is selected from the group consisting of C1-C8alkyl, NH2, NHRA, NRA2, xe2x80x94C1-C8alkylxe2x80x94NH2, xe2x80x94C1-C8alkyl-NHRA, xe2x80x94C1-C8alkyl-NRA2 and xe2x80x94NHxe2x80x94C1-C8alkyl-NRA2;
a is an integer from 0 to 1;
Y is selected from the group consisting of CH2, C(O), C(O)O, C(O)xe2x80x94NH and SO2;
xe2x80x83is selected from the group consisting of naphthyl, heteroaryl and heterocycloalkyl;
m is an integer from 0 to 2;
R3 is independently selected from the group consisting of halogen, nitro, C1-C8alkyl, C1-C8alkoxy, trifluoromethyl, trifluoromethoxy, phenyl (optionally substituted with 1 to 3 RB), phenyisulfonyl, naphthyl, C1-C8aralkyl, heteroaryl (optionally substituted with 1 to 3 RB), NH2, NHRA and N(RA)2;
provided that when
xe2x80x83is 2-furyl or 2-thienyl, then m is an integer from 1 to 2;
and pharmaceutically acceptable salts thereof.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
Exemplifying the invention are methods of treating sexual dysfunction, for example, male erectile dysfunction, impotence, female sexual dysfunction, for example female sexual arousal dysfunction, female sexual dysfunction related to blood flow and nitric oxide production in the tissues of the vagina and clitoris, premature labor and/or dysmenorrhea in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
An example of the invention is a method for increasing the concentration of cGMP in penile tissue through the inhibition of phosphodiesterases, specifically PDEV, in a male subject in need thereof comprising administering to the subject an effective amount of any of the compounds or pharmaceutical compositions described above.
Further exemplifying the invention is a method of producing endothelial-dependent vasorelaxation by potentiating the increases in intracellular cGMP induced by nitric oxide in a subject in need thereof comprising administering to the subject an effective amount of any of the compounds or pharmaceutical compositions described above.
Further illustrating the invention is a method of treating a condition selected from the group consisting of male erectile dysfunction (ED), impotence, female sexual dysfunction, female sexual arousal dysfunction, female sexual dysfunction related to blood flow and nitric oxide production in the tissues of the vagina and clitoris, premature labor, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
An example of the invention is the use of any of the compounds described above in the preparation of a medicament for: (a) treating sexual dysfunction, especially male erectile dysfunction, (b) treating impotence, (c) increasing the concentration of cGMP in penile tissue through inhibition of phosphodiesterase, especially PDEV and/or (d) treating a condition selected from the group consisting of premature labor, dysmenorrhea, cardiovascular disorders, atherosclerosis, arterial occlusive disorders, thrombosis, coronary rest stenosis, angina pectoris, myocardial infarction, heart failure, ischemic heart disorders, hypertension, pulmonary hypertension, asthma, intermittent claudication and diabetic complications in a subject in need thereof.
The present invention provides novel xcex2-carboline derivatives useful for the treatment of sexual dysfunction, particularly male erectile dysfunction (ED). Although the compounds of the present invention are useful primarily for the treatment of male sexual dysfunction or erectile dysfunction, they may also be useful for the treatment of female sexual dysfunction, for example female sexual arousal dysfunction, female sexual dysfunction related to blood flow and nitric oxide production in the tissue of the vagina and clitoris, and of premature labor and dysmenorrhea.
More particularly, the compounds of the present invention are of the formula (I):
wherein all variables are as defined above.
Preferably, n is 0. Preferably, m is an integer from 0 to 1.
In an embodiment of the present invention X is selected from S or NRD, wherein RD is selected from the group consisting of hydrogen, haloC1-C6alkyl, di(C1-C4alkyl)aminoC1-C6alkyl, heteroaryl, heteroarylC1-C4alkyl, heterocycloalkyC1-C4alkyl, carboxyC1-C4alkyl, C1-C4alkoxycarbonylC1-C4alkyl and heteroarylcarbonyl; wherein the heteroaryl is further optionally substituted with phenyl or substituted phenyl, wherein the substituents on the phenyl are one to two independently selected from RB; and wherein each RB is independently selected from the group consisting of halogen, nitro, C1-C4alkyl, C1-C4alkoxy, trifluoromethyl, trifluoromethoxy, amino and di(C1-C4alkyl)amino. Preferably, X is selected from S or NRD, where RD is selected from the group consisting of hydrogen, di(methyl)aminoethyl, di(methyl)amino-n-propyl, di(ethyl)aminoethyl, di(ethyl)amino-n-butyl, N-pyrrolidinylethyl, N-morpholinylethyl, 2-pyridylmethyl, 4-pyridylmethyl, 5-(4-methylphenyl)-2-pyrimidinyl, carboxymethyl, carboxyethyl, 4-chloro-n-butyl, 2-(5-(3-trifluoromethylphenyl)furyl)carbonyl, 2-(5-(3-nitrophenyl)furyl)carbonyl, methoxycarbonylmethyl, methoxycarbonylethyl and 2-benzoxazolyl. More preferably, X is NRD, where RD is selected from the group consisting of hydrogen, di(methyl)aminoethyl, 4-pyridylmethyl, 2-pyridylmethyl, N-morpholinylethyl, carboxyethyl, carboxymethyl, di(ethyl)aminoethyl, N-pyrrolidinylethyl and 5-(4-methylphenyl)-2-pyrimidinyl. Most preferably, X is NRD, where RD is selected from the group consisting of hydrogen, di(methyl)aminoethyl, N-morpholinylethyl, carboxymethyl and N-pyrrolidinylethyl;
Preferably, Z is selected from the group consisting of CH2 and C(O); provided that when Z is C(O), then X is NH.
Preferably, Y is selected from the group consisting of C(O), SO2 and CH2. More preferably, Y is selected from the group consisting of C(O) and CH2. Most preferably, Y is C(O).
In an embodiment of the present invention
is selected from the group consisting of naphthyl and heteroaryl. Preferably,
is selected from the group consisting of naphthyl, 2-pyrimidinyl, 2-furyl, 3-furyl, 2-benzofuryl, 2-theinyl, 2-benzothienyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 4-thiazolyl, 2-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-(1,2,5-triazolyl), 4-isoxazolyl, 2-pyridyl and 3-pyridyl. More preferably,
is selected from the group consisting of naphthyl, 2-pyrimidinyl, 2-furyl, 2-benzofuryl, 2-thienyl, 2-benzothienyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-thiazolyl, 4-thiazolyl and 2-pyridyl. Most preferably,
is selected from the group consisting of 2-pyrimidinyl, 2-furyl, 2-benzofuryl, 2-benzoxazolyl, 2-thiazolyl and 2-pyridyl.
In an embodiment of the present invention, R2 is selected from the group consisting of 3,4-methylenedioxyphenyl, 3,4-(difluoro)methylenedioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo-[1,4]-dioxin-6-yl, pyridyl, phenyl and substituted phenyl; wherein the phenyl substituents are one to two substituents independently selected from halogen, C1-C4alkyl, C1-C4alkoxy, trifluoromethyl, cyano, nitro, C1-C4alkoxycarbonyl, di(C1-C4alkyl)amino or di(C1-C4alkyl)aminoC1-C4alkoxy. Preferably, R2 is selected from the group consisting of phenyl, 3,4-methylenedioxyphenyl, 3,4-(difluoro)methylenendioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo-[1,4]-dioxin-6-yl, 4-pyridyl, 3-pyridyl, 4-cyanophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4-dimethoxyphenyl, 3-trifluoromethyl-4-chlorophenyl, 3,4-dichlorophenyl, 4-chlorophenyl, 4-methoxycarbonylphenyl, 3,4-dimethoxyphenyl, 4-(dimethylamino)phenyl and 4-(N-(3-dimethylamino)-n-propoxy)phenyl. More preferably, R2 is selected from the group consisting of 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl and 2,3-dihydrobenzo-[1,4]-dioxin-6-yl. Most preferably, R2 is selected from the group consisting of 3,4-methylenedioxyphenyl and 2,3-dihydrobenzofuryl.
Preferably, R4 is selected from the group consisting of hydrogen, carboxy, C1-C4alkoxycarbonyl, di(C1-C4alkyl)aminoC1-C4alkoxycarbonyl and di(C1-C4alkyl)aminoC1-C4alkylaminocarbonyl. More preferably, R4 is selected from the group consisting of hydrogen, carboxy, dimethylaminoethoxycarbonyl, dimethylaminoethylaminocarbonyl and methoxycarbonyl. Most preferably, R4 is hydrogen.
In an embodiment of the present invention, R3 is independently selected from the group consisting of halogen, nitro, C1-C4alkyl, C1-C4alkoxy, trifluoromethyl, C1-C4aralkyl, pyrazinyl, pyridyl, halogen substituted pyridyl, dimethyl substituted imidazolyl, phenyl, phenyisulfonyl and substituted phenyl; wherein the substituents on the phenyl are one or more substituents independently selected from halogen, hydroxy, C1-C4alkyl, C1-C4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino, acetylamino, C1-C4alkylsulfonyl, carboxyC1-C4alkylcarbonylamino, hydroxyC1-C4alkylamino, di(C1-C4alkyl)aminoC1-C4alkoxy, di(C1-C4alkyl)aminoacetylamino or heterocycloalkylC1-C4alkoxy. Preferably, R3 is independently selected from the group consisting of chloro, bromo, methyl, n-propyl, t-butyl, methoxy, trifluoromethyl, nitro, phenyl, benzyl, phenylsulfonyl, 4-hydroxyphenyl, 4-chlorophenyl, 4-methylphenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 5-trifluoromethylphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 2-nitro-4-chlorophenyl, 2-nitro-4-methylphenyl, 2-nitro-4-methylsulfonylphenyl, 3-acetylaminophenyl, 4-acetylaminophenyl, 4-(3-carboxy-n-propyl)carbonylaminophenyl, 2-chloro-5-trifluoromethylphenyl, 4-(4-hydroxy-n-butyl)aminophenyl, 2-(dimethylamino)acetylaminop the group consisting of bromo, t-butyl, methoxy, trifluoromethyl, nitro, phenyl, 4-chlorophenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 2-nitro-4-chlorophenyl, 2-nitro-4-methylphenyl, 2-nitro-4-methylsulfonylphenyl, 4-(3-carboxy-n-propyl)carbonylaminophenyl, 2-chloro-5-trifluoromethylphenyl, 4-hydroxy-n-butyl)aminophenyl, 2-2-(dimethylamino)acetylaminophenyl, 4-pyrazinyl 2-pyridyl and 2,3-dimethyl-3H-imidazol-4-yl. Most preferably, R3 is selected from the group consisting of t-butyl, methoxy, nitro, phenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl, 2-nitro-4-methylsulfonylphenyl, 2-(dimethylamino)acetylaminophenyl, 2-pyridyl and 2,3-dimethyl-3H-imidazol-4-yl.
For use in medicine, the salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable salts.xe2x80x9d Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methyinitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
As used herein, unless otherwise noted, xe2x80x9chalogenxe2x80x9d shall mean chlorine, bromine, fluorine and iodine.
The term xe2x80x9calkylxe2x80x9d, whether used alone or as part of a substituent group, shall mean straight or branched chain alkanes of one to ten carbon atoms, or any number within this range. For example, alkyl radicals include, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl and 2-methylpentyl.
The term xe2x80x9calkoxyxe2x80x9d shall denote an oxygen ether radical of the above described straight or branched chain alkyl group. For example, alkoxy radicals include methoxy, ethoxy, n-propoxy, n-butoxy, sec-butoxy, tert-butoxy, and the like.
The term xe2x80x9carylxe2x80x9d indicates an aromatic groups such as phenyl, naphthyl, and the like.
The term xe2x80x9caralkylxe2x80x9d denotes an alkyl group substituted with an aryl group. For example, benzyl, phenylethyl, and the like.
The term xe2x80x9cheteroarylxe2x80x9d as used herein represents a stable five or six membered monocyclic aromatic ring system containing one to three heteroatoms independently selected from N, O or S; and any nine or ten membered bicyclic aromatic ring system containing carbon atoms and one to four heteroatoms independently selected from N, O or S. The heteroaryl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to pyridyl, pyrimidinyl, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl,pyrazinyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, indazolyl, indolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl or isoquinolinyl. Particularly preferred heteroaryl groups include pyridyl, pyrazolyl, furyl, thiazolyl, thienyl, imidazolyl, isoxazolyl, pyrazinyl, pyrimidinyl, triazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl and benzoxazolyl.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein represents a stable three to eight membered monocyclic ring structure consisting of saturated carbon atoms. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The term xe2x80x9cheterocycloalkylxe2x80x9d represents a stable saturated or partially unsaturated, three to eight membered monocyclic ring structure containing carbon atoms and one to four, preferably one to two, heteroatoms independently selected from N, O or S; and any stable saturated, partially unsaturated or partially aromatic, nine to ten membered bicyclic ring system containing carbon atoms and one to four heteroatoms independently selected from N, O or S. The heterocycloalkyl may be attached at any carbon atom or heteroatom which results in the creation of a stable structure. Suitable examples of heterocycloalkyl groups include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, dithianyl, trithianyl, dioxolanyl, dioxanyl, thiomorpholinyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo-[1,4]-dioxin-6-yl, 2,3-dihydro-furo[2,3-b]pyridyl, 1,2-(methylenedioxy)cyclohexane, and the like. Particularly preferred heterocycloalkyl groups include pyrrolidinyl, morpholinyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl and 2,3-dihydrobenzo-[1,4]-dioxin-6-yl.
As used herein, the notation xe2x80x9c*xe2x80x9d shall denote the presence of a stereogenic center.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a xe2x80x9cphenylC1-C6 alkylaminocarbonylC1-C6alkylxe2x80x9d substituent refers to a group of the formula
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein. It is further intended that when n or m is  greater than 1, the corresponding R1 or R3 substituents may be the same or different.
The term xe2x80x9csexual dysfunctionxe2x80x9d as used herein, includes male sexual dysfunction, male erectile dysfunction, impotence, female sexual dysfunction, female sexual arousal dysfunction and female sexual dysfunction related to blood flow and nitric oxide production in the tissues of the vagina and clitoris.
The term xe2x80x9csubjectxe2x80x9d as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
Abbreviations used in the specification, particularly the Reactions and Examples, are as follows:
Compounds of formula (I) may be prepared according to the processes outlined in more detail below.
Compounds of formula (I) wherein (Y)a is C(O) may be prepared according to a process as outlined in Scheme 1.
More particularly, a compound of formula (II), wherein X is O, S or NH, a known compound or compound produced by known methods, is reacted with a suitably substituted aldehyde of formula (III), in an organic solvent such as DCM, THF, toluene, and the like, in the presence of an acid catalyst such as TFA, tosic acid, and the like, to produce the corresponding tricyclic compound of formula (IV).
The compound of formula (IV) is reacted with a suitably substituted compound of formula (V), wherein A is halogen, in the presence of a base such as triethylamine (TEA), diisopropylethylamine (DIPEA), sodium carbonate and the like, in an organic solvent such as dichloromethane (DCM), N,Nxe2x80x2-dimethylformamide (DMF), tetrahydrofuran (THF), and the like; or with a suitably substituted compound of formula (V), wherein A is hydroxy, in the presence of a coupling agent such as DCC, DIC, PyBop, PyBrop, and the like, in an organic solvent such as dichloromethane (DCM), N,Nxe2x80x2-dimethylformamide (DMF), tetrahydrofuran (THF), and the like; to produce the corresponding compound of formula (Ia).
Alternatively, compounds of formula (I), wherein X is O, S, or NH and (Y)a is C(O) may be prepared according to a process as outlined in Scheme 2.
More particularly, a compound of formula (II), wherein X is O, S or NH, is reacted with a suitably substituted compound of formula (VI), wherein A is halogen or hydroxy, in an organic solvent such as DCM, THF, DMF, and the like, to produce the corresponding compound of formula (VII).
The compound of formula (VII) is cyclized by treatment with POCl3, in an organic solvent such as toluene, benzene, and the like, followed by reduction with NaBH4, in an organic solvent such as ethanol, isopropanol, and the like, to produce the corresponding compound of formula (IV).
The compound of formula (IV) is then reacted with a suitably substituted compound of formula (V) to produce the compound of formula (Ia) as outlined in Scheme 1.
Compounds of formula (I), wherein X is O, S or NH and (Y)a is SO2 may be prepared according to a process as outlined in Scheme 3.
Accordingly, a suitably substituted compound of formula (IV) is reacted with a suitably substituted compound of formula (VIII), wherein A is halogen or hydroxy, a known compound or compound prepared by known methods, in an organic solvent such as DCM, chloroform, DMF, THF, and the like, to produce the corresponding compound of formula (Ib).
Compounds of formula (I) wherein X is O, S or NH and (Y)a is CH2 may be prepared according to a process as outlined in Scheme 4.
Accordingly, a suitably substituted compound of formula (Ia) is treated with a reducing agent such as LAH, diboron, and the like, preferably LAH, in an organic solvent such as methanol, THF, diethyl ether, and the like, preferably at a temperature in the range of about xe2x88x9220 to 40xc2x0 C., to produce the corresponding compound of formula (Ic).
Compounds of formula (I) wherein (Y)a is CH2 and X is NH, may alternatively be prepared according to a process as outlined in Scheme 5.
Accordingly, a compound of formula (IVa) is reacted with a suitably substituted compound of formula (IX), wherein Q is halogen, O-tosylate or O-mesolate, in an organic solvent such as DCM, THF, and the like, to produce the corresponding compound of formula (Id).
Compounds of formula (I), wherein X is O, S or NH and (Y)a is (Y)0 (i.e. wherein a is 0, such that Y is absent), may be prepared according to a process as outlined in Scheme 6.
More specifically, a compound of formula (IV), a known compound or compound produced by known methods, is reacted with a suitably substituted halide of formula (X), a known compound or compound prepared by known methods, in an organic solvent such as toluene, DMF, 1-methyl-2-pyrrolidinone, and the like, preferably at a temperature in the range of about 80 to 250xc2x0 C., to produce the corresponding compound of formula (Ie).
Compounds of formula (I) wherein X is NRD may be prepared by according to a process as outlined in Scheme 7.
Accordingly, a compound of formula (If) is reacted with a compound of formula (XI), wherein Z is halogen, hydroxy, O-toylate or O-mesolate and a base such as sodium hydride, potassium t-butoxide, and the like, in a solvent such DMF, 1-methyl-2-pyrrolidinone, and the like, to produce the corresponding compound of formula (Ig).
Compounds of formula (I) wherein Z is CHxe2x80x94OH or C(O) may be prepared according to a process as outlined in Scheme 8.
More particularly, a compound of formula (If) is treated with an oxidizing agent such as DDQ, chloranil, and the like, in a solvent such as THF, methanol, water, and the like, preferably at a temperature in the range of about xe2x88x9278 to about 30xc2x0 C., to produce a mixture of the corresponding compounds of formula (Ih) and (Ii). Preferably, the compounds of formula (Ih) and (Ii) are separated by known methods, such as recrystallization, column chromatography, and the like.
Compounds of formula (I) wherein
is 2-thiazolyl, may be prepared according to a process as outlined in Scheme 9.
Accordingly, a suitably substituted compound of formula (IVa) is reacted with Fmoc-NCS, in an organic solvent such as DCM, DMF, THF, and the like, preferably at room temperature, to produce the corresponding compound of formula (XII).
The compound of (XII) is reacted with 20% piperidine, in an alcohol such as methanol, ethanol, and the like, to produce the corresponding amine of formula (XIII).
The amine of formula (XIII) is reacted with a suitably substituted xcex1-halo methyl ketone of formula (XIV), in the presence of an organic solvent or mixture such as DMF, ethanol:dioxane, and the like, in the presence of a base such as TEA, DIPEA, and the like, preferably at a temperature of about 70xc2x0 C., to produce the corresponding compound of formula (Ij).
Compounds of formula (I) wherein (Y)a is C(O)O, may be prepared according to the process outlined in Scheme 10.
More particularly, a compound of formula (IV) is reacted with a suitably substituted chloroformate of formula (XV) or an anhydride of formula (XVI) in an organic solvent such as DCM, DMF, THF, and the like, to produce the corresponding compound of formula (Ik).
Compounds of formula (I) wherein (Y)a is C(O)xe2x80x94NH may be prepared according to a process as outlined in Scheme 11.
Accordingly, a compound of formula (IV) is reacted with a suitably substituted compound of formula (XVII), in an organic solvent such as DCM, DMF, THF, and the like, to produce the corresponding compound of formula (Im).
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The utility of the compounds to treat sexual dysfunction can be determined according to the procedures described in Example 10, 11 and 12 herein.
The present invention therefore provides a method of treating sexual dysfunction in a subject in need thereof, which comprises administering any of the compounds as defined herein in a quantity effective to treat sexual dysfunction. The compound may be administered to a patient by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral. The quantity of the compound which is effective for treating sexual dysfunction is between 0.1 mg per kg and 20 mg per kg of subject body weight.
The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 1 to about 1000 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
The method of treating sexual dysfunction, particularly male erectile dysfunction (ED) described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 1 mg and 1000 mg, preferably about 10 to 500 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
The compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of sexual dysfunction, particularly male erectile dysfunction (ED) is required.
The daily dosage of the products may be varied over a wide range from 1 to 1,000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 20 mg/kg of body weight per day. Preferably, the range is from about 0.2 mg/kg to about 10 mg/kg of body weight per day, and especially from about 0.5 mg/kg to about 10 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.
Unless otherwise indicated, 1H NMRs were run on a Bruker AC-300.

xcex2-carboline derivatives useful as inhibitors of phosphodiesterase

Abstract: wherein all the variables are as described within the specification, useful as phosphodiesterase inhibitors. The present invention further relates to use of the described derivatives for the treatment of diseases and conditions related to PDE, for example male erectile dysfunction.


A refrigerator is provided which can individually cool a freezing chamber and a refrigerating chamber by dividing a heat exchange region of an evaporator into a freezing chamber side region and a refrigerating chamber side region, forming individual circulation passages for supplying cool air from each region to the freezing chamber and the refrigerating chamber, and forming a freezing chamber fan and a refrigerating chamber fan on each circulation passage. Further, a method for controlling operation of the same is provided which can efficiently perform a cooling operation and reduce power consumption by effectively controlling the operations of each component.

In general, a refrigerator is one of the living necessaries which preserves food fresh for a predetermined period, by lowering a temperature of a freezing chamber or a refrigerating chamber by repeating a refrigeration cycle of compressing, condensing, expanding and evaporating refrigerants.
The refrigerator has a refrigeration cycle including basic components such as a compressor for compressing refrigerants into high temperature high pressure gas refrigerants, a condenser for condensing the refrigerants from the compressor into high temperature high pressure liquid refrigerants, an expansion valve for decompressing the refrigerants from the condenser into low temperature low pressure liquid refrigerants, and an evaporator for maintaining a low temperature in a freezing chamber or a refrigerating chamber, by absorbing heat from the freezing chamber or the refrigerating chamber by evaporating the refrigerants from the expansion valve into low temperature low pressure gas refrigerants.
FIG. 1 is a schematic front perspective view illustrating a conventional side-by-side type refrigerator, and FIG. 2 is a structure view illustrating a refrigeration cycle applied to the refrigerator of FIG. 1.
The conventional side-by-side type refrigerator in which a freezing chamber and a refrigerating chamber are disposed side by side will now be described with reference to FIGS. 1 and 2. A refrigeration cycle including a compressor 12, a condenser 14, an expansion valve 16 and an evaporator 18 is built in an inner wall, for generating cool air by the evaporator 18. The freezing chamber F maintaining about −18° C. by sucking most of the cool air, and the refrigerating chamber R maintaining about 0 to 7° C. by sucking part of the cool air are disposed side by side at both sides of a main body 2.
The refrigeration cycle includes basic components, and thus explanations thereof are omitted.
Here, the freezing chamber F and the refrigerating chamber R are divided by a cross wall 4. Part of the cross wall 4 is opened so that the cool air can flow between the freezing chamber F and the refrigerating chamber R.
The evaporator 18 is installed on the inner wall in the freezing chamber F, and a blast fan 22 is installed at the upper portion of the evaporator 18, for sending cool air generated in the evaporator 18 to the freezing chamber F or the refrigerating chamber R. Generally, an axial flow fan for sucking and discharging cool air in an axial direction is used.
The freezing chamber F and the refrigerating chamber R compose a cool air circulation structure for circulating cool air near the evaporator 18 through the freezing chamber F and the refrigerating chamber R by the operation of the blast fan 22, and returning the cool air to the evaporator 18.
The operations of the components of the refrigerator are controlled by a microcomputer (not shown). The microcomputer controls the whole components so that a temperature Tf of the freezing chamber F and a temperature Tr of the refrigerating chamber R can reach a set freezing temperature Tf0 and a set refrigerating temperature Tr0 setting by the user or automatically set.
In the conventional refrigerator, when a load is applied, the compressor 12 is operated according to a control signal from the microcomputer, and refrigerants are circulated though the compressor 12, the condenser 14, the expansion valve 16 and the evaporator 18, for cooling air near the evaporator 18 and generating cool air.
In addition, the blast fan 22 is operated according to a control signal from the microcomputer, so that most of the cool air near the evaporator 18 can be supplied to the freezing chamber F and part of the cool air can be supplied to the refrigerating chamber R. The cool air circulated in the freezing chamber F and the refrigerating chamber R to have a high temperature is resupplied to the evaporator 18.
In the conventional refrigerator, one evaporator 18 is installed in the freezing chamber F, and the cool air heat-exchanged through the evaporator 18 is partially distributed and supplied to the refrigerating chamber R on the passage of the freezing chamber F. Accordingly, when the inside temperature of any one of the freezing chamber F and the refrigerating chamber R does not satisfy the set freezing temperature Tf0 or the set refrigerating temperature Tr0, the compressor 12 and the blast fan 22 are operated to lower the temperature, thereby increasing power consumption or supercooling food.
For example, when the temperature Tf of the freezing chamber F reaches the set freezing temperature Tf0, if the temperature Tr of the refrigerating chamber R does not satisfy the set refrigerating temperature Tr0, the temperature Tr of the refrigerating chamber R must be lowered to reach the set refrigerating temperature Tr0 by operating the compressor 12 and the blast fan 22. Here, the cool air is also supplied to the freezing chamber F, to unnecessarily lower the temperature Tf of the freezing chamber F. In addition, power consumption increases.
On the other hand, when the temperature Tr of the refrigerating chamber R reaches the set refrigerating temperature Tr0, if the temperature Tf of the freezing chamber F does not satisfy the set freezing temperature Tf0, the temperature Tf of the freezing chamber F must be lowered to reach the set freezing temperature Tf0 by operating the compressor 12 and the blast fan 22. The cool air is also supplied to the refrigerating chamber R, to unnecessarily lower the temperature Tr of refrigerating chamber R. Moreover, food is supercooled.
In the conventional refrigerator, part of the cool air from the evaporator 18 is distributed to the refrigerating chamber R. A volume of the cool air distributed to the refrigerating chamber R is relatively smaller than a volume of the cool air distributed to the freezing chamber F. Therefore, a cooling speed of the refrigerating chamber R is reduced, to unnecessarily operate the compressor 12.
For example, when the temperature Tr of the refrigerating chamber R does not reach the set refrigerating temperature Tr0, the compressor 12 is operated until the temperature Tr of the refrigerating chamber R reaches the set refrigerating temperature Tr0. Accordingly, an excessive load is applied to the compressor 12 to reduce the temperature of the evaporator 18 lower than the temperature Tf of the freezing chamber F.

Refrigerator, and method for controlling operation of the same


A suture device is configured to guide a suture thread. The device includes a sleeve that defines an opening, and a plunger to which a suture thread can be attached. The plunger can be inserted into the opening of the sleeve, and movable between a retracted position and an advanced position. When the plunger is in the retracted position, a distal portion of the suture thread is located proximal with respect to the distal end of the suture device. When the plunger is in the advanced position, the distal portion of the suture thread is driven out the distal end of the suture device.

One problem associated with conventional suture devices is that the insertion of the suture thread into the eye in the needle can be cumbersome and time consuming for the operator. Another problem with conventional suture devices is that they cannot handle both monofilament and braided suture in one instrument. This means that during a procedure an operator may have to switch between instruments in an inefficient and time consuming manner and also follow a complicated procedure simplification.

Method and apparatus for guiding a suture thread


A non-pneumatic tire for a vehicle or other machine. The non-pneumatic tire may include an annular beam. The annular beam may include a plurality of layers of different elastomeric materials. The annular beam may be free of a substantially inextensible reinforcing layer running in a circumferential direction of the non-pneumatic tire. The annular beam may include a plurality of openings distributed in the circumferential direction of the non-pneumatic tire. Such an annular beam may be part of other annular devices.

Wheels for vehicles and other machines may comprise non-pneumatic tires (sometimes referred to as NPTs) instead of pneumatic tires.
Pneumatic tires are market leaders across a wide variety of size, speed, and load requirements. For example, radial pneumatic tires are found on automotive tires of 0.6 meter diameter that carry 0.5 metric tons, and also on tires used in mining operations of 4 meter diameter that carry 50 metric tons. Pneumatic tires are thus scalable.
Pneumatic tires offer high load capacity per unit mass, along with a large contact area and relatively low vertical stiffness. High contact area results in the ability to both efficiently generate high tangential forces and obtain excellent wear characteristics. However, pneumatic tires are also prone to flats.
Non-pneumatic tires offer flat-free operation, yet generally contain some compromise. For various reasons, non-pneumatic tires do not have a predominant market share in various industries because they tend to be expensive, heavy, have a poor ride quality, have limited speed capability under heavy load, and/or have lower traction potential, compared to pneumatic tires. For example, in construction and other field with large tires, in the common dimension 20.5 inch×25 inch (20.5 inches wide, 25 inch diameter wheel), currently available non-pneumatic tires weighs around 2000 lbs., whereas a pneumatic tire and steel wheel only weigh around 650 lbs.
Non-pneumatic tires in this size are usually solid, with the addition of circular cutouts in the tire sidewall to reduce the compressive stiffness of the structure. Because of this solid construction, heat build-up is problematic. Elastomers are generally good insulators, and therefore such structures tend to retain heat. This reduces their utility in practical use in some cases.
Other annular devices, such as, for instance, tracks for vehicles and/or conveyor belts, may in some cases be affected by similar considerations.
For these and other reasons, there is a need to improve non-pneumatic tires and other annular devices.

Non-pneumatic tire and other annular devices


An integrated light-speaker assembly suitable for connection into conventional electrical sockets. The combination includes an FM wireless receiver operating within a local area wireless transmission system. The speaker is mounted behind the light bulb, and when mounted into a conventional electrical socket, the assembly provides both sound and light, with the sound being provided by the local area wireless FM transmission system.

This invention relates to a speaker system arranged in a housing adapted to be inserted in a conventional electrical socket such as that used for light bulbs and floodlights.
900 MHz wireless transmission has enabled greater utilization of effective wireless FM audio transmission. A preferred 900 MHz system to be used in this invention is that identified in U.S. Pat. No. 5,410,735 entitled WIRELESS SIGNAL TRANSMISSION SYSTEMS, METHODS AND APPARATUS issued on Apr. 25, 1995 to Robert M. Borchardt et al. This patent is incorporated herein by reference.
An object of this invention is to provide a speaker which is connected to a conventional electrical bulb socket of the threaded or bayonet type so that power tothe speaker is provided by the power normally provided to the appliance placed in the socket. In a preferred embodiment, an appliance, such as an electric bulb, is integrated with a speaker in a single integral unit so that the same electrical socket powers both the electrical speaker as well as the electrical bulb. Additionally the device may include a rechargeable battery to enable it to operate without the light being powered.
This invention may find wide acceptance in environments in industrial, commercial and consumer environments where background music is played.

Speaker light unit connected to conventional electrical light socket


A method and apparatus for a dual power supply on a universal serial bus system using an overcurrent detect circuit. Dual power supplies in the universal serial bus system allows for greater flexibility of operation and is based on two separate power systems. The first power system is achieved using the power line on the bus connecting to the universal serial bus controller. The second power system is a separate power supply to power the downstream ports. Moreover, the universal serial bus system has an overcurrent and thermal error detect circuit based on the power system in order to achieve an efficient and cost effective method and apparatus in which to notify the universal serial bus controller of any error in the power system.

A. Field of the Invention
This invention relates to the operation of a communication network, and more particularly relates to a method and apparatus for powering components on the communication network.
B. Description of Related Art
The universal serial bus (USB) is a protocol for a serial bus. USB supports data exchange between a host computer and a wide range of simultaneously accessible peripherals. The attached peripherals share USB bandwidth through a host scheduled token based protocol. The USB allows peripherals to be attached, configured, used and detached while the host and other peripherals are in operation.
The USB transfers signal and power over a four wire cable with two wires for power (+5 Volts) and ground and the other two wires for data signaling. The USB in one configuration is 12 megabits per second and supports up to 128 devices. One of the purposes behind the universal serial bus is to provide ease of use to add PC peripherals. The USB is designed to handle a broad range of devices such as telephones (both analog, digital, and proprietary), modems, printers, mice, joysticks, scanners, keyboards, and tablets. Therefore, removed from the personal computer are the parallel, serial, graphics, modem, sound/game and mouse ports. The USB is designed so that external devices, such as a mouse or a keyboard may be correctly detected and properly configured upon attachment. Ordinarily, the topology of the USB system is tiered star. At each star is a universal serial bus repeater providing power for the devices, routing of signals in each direction and providing terminations for each line.
The universal serial bus repeater is a device which has one upstream port, a universal serial bus controller, and several downstream ports. The upstream port is toward the host, such as connected to a computer or other data communication device, and the downstream ports is toward a device. The universal serial bus controller performs the following functions: routing of the signals from the upstream port to the downstream ports and from the downstream ports to the upstream port; and error detection and recovery. The universal serial bus controller supports two power source modes (bus-powered or self-powered). Ordinarily, if the power required for the downstream ports and embedded functions is equal to or less than the power the bus can supply, the universal serial bus controller can be powered by the bus. If the power required for the downstream ports and embedded functions is more than what the bus can supply, the universal serial bus controller and the downstream ports are self-powered.
When the universal serial bus controller is self powered, the operator of the system must follow a special sequence in configuring the system. The operator must first connect the power source for the universal serial bus controller and the downstream ports. Then, the operator must connect the universal serial bus controller to the port on the computer. Otherwise, if the bus is connected to the universal serial bus controller without the universal serial bus controller being powered, the computer may determine that there is a problem with the universal serial bus controller since the computer detects that the universal serial bus controller is connected, but it is not responding due to a lack of power. Thus, the sequence of connecting the power supply and then the connector to the bus must be followed to avoid any potential errors.
Further, all self-powered universal serial bus controllers should implement overcurrent and thermal error protection for safety reasons. The universal serial bus controller should have a way to detect faults in the system such as an overcurrent or thermal error condition and report it to the universal serial bus software. Should the aggregate current drawn by a single downstream port or group of downstream ports exceed a preset value or the thermal value of the power supply be too high, the power should be removed from the downstream ports and the condition should be reported through the universal serial bus controller to the computer. Fault detect circuits, detecting overcurrent and thermal errors, are used to protect from catastrophic device failures, software errors that turn on devices when the current budget has been exceeded, and operator actions such as shorting out the connector pins. Known overcurrent limiting methods include poly fuses, standard fuses, or a solid state switch.
Moreover, the power supply which supplies power to the universal serial bus controller and the downstream ports in the self-powered mode are designed either with expensive power switches such as power transistors or switching chips. In this manner, the power which is supplied by the power supply can be turned on upon power up or turned off when an overcurrent is detected. Also, the power can be turned on or turned off by the software on the computer through the universal serial bus controller, which is contained within the universal serial bus controller.
Finally, when the universal serial bus controller and the downstream ports are in the self-powered mode, this limits the overall operation of the system. In the event of an overcurrent thermal error or other condition which requires the power supply to be removed, the power to the universal serial bus controller is removed as well. Thus, in order to have a reliable universal serial bus system, the power to the universal serial bus controller and the downstream ports should be reliable. It would therefore be desirable to have an improved method and apparatus for powering components on the communication network.

Fault detection on a dual supply system for a universal serial bus system