A process for producing steam for extracting heavy bitumen includes the steps of mixing carbon or hydrocarbon fuel, the fuel being crude oil, vacuum residue, Asphaltin, or coke with an oxidation gas, the gas being oxygen, oxygen enriched air or air-combusting the mixture under high pressure and high temperature and mixing low quality contaminated water containing organics and inorganic with the combusted mixture so as to control combustion temperature and to generate steam. The liquid phase is transferred to a gas phase so as to contain steam and carbon dioxide. The solids are separated from the gas phase. The super heated dry steam and gas mixture is ejected into an underground reservoir.

1. Field of the Invention
This application relates to a system and method that improves the SAGD facility with a system that can be added-on to an existing SAGD facility or as a new stand alone facility. The present invention relates to processes for producing steam from low quality rejected water containing high levels of dissolved inorganic solids or organics, such as oil.
Due to its simple direct contact, above ground adiabatic nature, combined with high pressure and temperature solid removal, the invention will minimize the amount of energy used to produce the mixture of steam and gas that is injected into the underground formation to recover heavy oil. This thermal efficiency minimizes the amount of greenhouse gases released into the atmosphere.
This thermal efficiency is achieved due to direct heat exchange. The condensed steam and the gases that will return back to the surface with the produced bitumen are at the temperature required for the oil recovery which is no higher than the underground reservoir temperature.
The present invention also relates to processes for making SAGD facilities more environmentally friendly by using low quality fuel and reducing the amount of greenhouse gas emissions by thermal efficiency and by injecting the CO2 into the formation, where a portion will remain permanently.
2. Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 37 CFR 1.98
Steam injection into deep underground formations has proven to be an effective method for producing heavy oil. This is typically done by SAGD or by Cyclic Steam Injection (called "huff and puff"). In recent years, the SAGD method has become more popular, especially for heavy oil sand formations. Presently steam injection it is the only method that is commercially used on a large scale.
The present invention can be uses together with prior art processes currently used in upstream Upraders and down stream production facilities, which are currently in use by the industry, and adds the adiabatic direct contact steam and CO2 generation unit to reduce the disadvantages of the prior art and to allow for expansion with the use of a low quality water supply, the use of reject water from the existing facility and the use of low quality fuel supplies. There is also no need for high quality separation and purification downstream oil removal processes.
In the present invention, the exothermal reactions and the treatment of the injected gas mixture are done in an adiabatic control area above ground. The underground portion of oil production is very complex, with many unknowns as it was created over millions of years until it reached steady-state equilibrium. As was shown in other areas, one way to exploit resources and to produce products is by improving the organization and control. Since underground combustion processes change the chemistry of the reservoir, it is difficult to control and further complicates the already complicated underground reservoirs.
The injection of pure steam, or as a mixture with other gases, creates the minimum necessary increase in the underground formation disorder. It does not increase the complexity of the underground reservoir beyond the minimum required to mobilize the oil from the sand. This might be the reason why only injection of steam, or steam and other gases, are implemented and found to be commercially effective with SAGD.
The present invention is designed to be incorporated with SAGD. However, it can be useful with cyclic steam injection or with any other method for injection of steam into the ground. The main disadvantages of existing commercial SAGD are the main drivers.
SAGD consume large quantities of water to extract the heavy oil using steam. The water-to-oil ratio needed to produce the oil from the ground is in the range of 2-4 barrels of water to one barrel of oil. The current prior art technology requires relatively high water quality, as required by the once-through steam generators (OTSGs) or boilers for scaling prevention. The source water requires expensive purification processes that create sludge and reject water. As part of the recycled water treatment, all oil traces must be removed to treat the water both in lime softeners and evaporators and, as in the case of hot or warm lime softeners, significant amounts of waste sludge are created. The treatment requires significant purification of the water to prevent scaling in the steam generation units. Any oily emulsions must be broken down by chemicals or filters to a very high degree of separation. The process usually requires a stream of "reject water" from the blowdown that is injected into disposals wells or treated in an additional evaporators and crystallizers to evaporate the water from the reject water. Low quality, high TSS source water requires an expansive treatment facility and creates large amounts of sludge or disposal water. The oil producing companies are typically drawing water from an area which is much larger than the area from which the oil is produced. The water is pumped from relatively high aquifers to produce the best water quality available.
Due to environmental concerns regarding production of fossil fuels, a fossil water may be utilized. A fossil water is water that left the surface millions of years ago. Fossil water is found in deep underground formations and typically contains significant amounts of dissolved materials that make it unattractive for use by oil producers with current water treatment technologies as it is be far more expensive water treatment facility and produces large quantities of sludge and waste. There is a need to provide the oil producers with the ability to utilize fossil water while minimizing environmental impact.
The prior art SAGD required expensive water treatment plants and water de-oiling separation. This results in expensive facilities and chemicals to minimize oil traces in the recycled water. Reject water is produced and injected into disposal wells. In the case of lime softeners, sludge is produced as well. An increasing portion of the SAGD construction and operation costs is the cost of the water treatment plant. At present, the most widespread commercial water treatment process in the SAGD industry is the use of lime softeners. In this process, lime, magnesium oxide and other materials are used for removal of the dissolved solids in the form of a slurry. This process requires constant chemical supply and creates significant amounts of slurry waste resulting in landfill costs and environmental impacts. Different processes include evaporators that require water de-oiling and reject water that must be disposed of in disposal wells, or evaporated and crystallized to produce solid waste in additional facility. There is a need to be able to use oily water and water-oil emulsion for the production of steam so as to reduce the water treatment plant complexity and associated capital costs, and so as to reduce the amount of chemicals used. There is need to be able as part from the steam production process to cause the waste to be solid waste that is easy to handle.
SAGD consumes a large amount of heat energy. In most commercial SAGDs, natural gas is used as the energy source for the steam production. Natural gas is a valuable resource and the extensive use of it for producing oil is expensive with significant environmental impact. There is prior art that teaches the production of steam by other means. In some prior art, the steam is produced by burning some of the extracted heavy oil for the production of steam. This is a problematic process since there is a need for flue gas treatment prior to releasing it to the atmosphere. Another option combines upstream and downstream technologies in the form of an SAGD and upgrader that uses a gasification process to gasify the "barrel bottom" to produce syngas for the production of steam in the traditional way. Currently there is one commercial project that use this method. However, in the prior art, the steam generation is carried out by using co-generation, OTSG or boilers, where instead of burning natural gas for producing the steam, they burn the syngas as a source of energy. There is a need to use the heavy oil or the heavy asphaltin parts of the heavy oil for steam production.
In the prior art, a traditional gasifier is used to produce syngas. This is costly to install and operate and requires significant utilities to support it. The syngas is used as a fuel source to produce steam, using the traditional methods.
The SAGD technology consumes a significant amount of energy to produce the steam for the processes that are released to the atmosphere. The uses of OTSG, boilers or gas turbines with steam generation causes only a portion of the heat from the burning hydrocarbon to be injected underground to the reservoir. Flue gases and its carbon dioxide are released to the atmosphere. This issue becomes more and more significant due to global warming. There is a need to reduce carbon dioxide emissions as much as possible. The burning or gasification of other fuels or by-product waste will solve the problem of burning natural gas but it will not solve this issue since the amount of carbon dioxide released is equivalent to that released by burning natural gas. There is a need for minimizing the carbon dioxide release by: (1) using less steam; (2) producing the steam in an overall more efficient manner so as to minimize the aboveground heat losses; and (3) injecting the carbon dioxide with the produced steam to the reservoir where some of it will permanently remain. Down hole direct contact steam generators of the prior art produce steam by direct contact underground combustion process with water injection. These have several disadvantages. Any maintenance or cleaning requires a shut down of the wheel and drilling completion rigs to pull out the equipment. The water and fuel that is used must be of high quality so as to prevent the creation of solids that can plug the well over time. The maintenance of such systems is complicated. Any operation outside of optimal design conditions can have problems with corrosion and solids creation.
The above ground direct contact steam generators of the prior art generate reject water similar to the reject water generated by Once Through Steam Generation (OTSG). This system utilizes low quality water and low quality fuel. The reject water in the form of blowdown water can contain organic or inorganic materials. The blowdown can be either released to a disposal formation or crystallized to evaporate the remaining water. These prior art processes can not be integrated with prior art SAGD since they can not consume its reject flows or consume low quality solid fuels, such as coke or asphaltin.
It is an object of the present invention to provide a system and method that improves SAGD facilities by an add on to an existing SAGD facility.
It is another object of the present invention to provide a system and method that produces steam from low quality rejected water containing high levels of dissolved inorganic solids or organics.
It is another object of the present invention to provide a system and method that utilizes low grade fuel.
It is a further object of the present invention to provide a system and method that removes produced solids by converting the liquids to a gas phase under high pressures.
It is another object of the present invention to provide a system and method that minimizes the amount of energy used to produce the mixture of steam and gas that is injected into the underground formation to recover heavy oil.
It is a further object of the present invention to provide a system and method that minimize the amount of greenhouse gases that are released to the atmosphere.
It is still another object of the present invention to provide a system and method that enhance thermal efficiency as a result of direct heat exchange.
It is still a further object of the present invention to provide a system and method that serves to make the SAGD facilities more environmentally friendly by using low quality fuel and the reduction in greenhouse gases.
It is still a further object of the present invention to provide a system and method which minimizes water treatment costs.
These and other objects and advantages of the present invention will become apparent from a reading of the attached specification and appended claims.

This patent is subject to a terminal disclaimer.

Integrated system and method for steam-assisted gravity drainage (SAGD)-heavy oil production using low quality fuel and low quality water


Anti-pruritic pharmaceutical formulations containing kappa agonist compounds and methods of prevention or treatment of pruritus in a mammal with the anti-pruritic formulations.

1. Field of the Invention
This invention relates to pharmaceutical formulations containing kappa agonist compounds and to their medical use as anti-pruritic agonist at kappa opioid receptors.
2. Reported Developments
A) Antihyperalgesic Kappa Agonists
Opium and its derivatives are potent analgesics that also have other pharmacological effects, and exert their effects by interacting with high-affinity receptors.
It has been shown by investigators that there are at least three major opioid receptor types in the central nervous system (hereinafter CNS) and in the periphery. These receptors, known as mu (.mu.), delta (.delta.) and kappa (.kappa.), have distinct pharmacological profiles, anatomical distributions and functions. [See, for example: Wood, P. L., Neuropharmacology, 21, 487-497, 1982; Simon, E. J., Med. Res. Rev., 11, 357-374, 1991; Lutz et al, J. Recept. Res. 12, 267-286; and Mansour et al, Opioid I, ed. Herz,. A. (Springer, Berlin) pp. 79-106, 1993.] The .delta. receptors are abundant in CNS and mediate analgesia, gastrointestinal motility and various hormonal functions. The .mu. receptors bind morphine-like drugs and mediate the opiate phenomena associated with morphine, including analgesia, opiate dependence, cardiovascular and respiratory functions, and several neuroendocrine effects.
The .kappa. receptors have a wide distribution in CNS and mediate a spectrum of functions including the modulation of drinking, water balance, food intake, gut motility, temperature control and various endocrine functions. They also produce analgesia [See, for example: Leander et al, J. Pharmacol. Exp. Ther. 234, 463-469, 1985; Morley et al, Peptides 4, 797-800, 1983; Manzanares et al, Neuroendocrinology 52, 200-205, 1990; and Iyengar et al, J. Pharmacol. Exp. Ther, 238, 429-436, 1986.]
Most clinically used opioid analgesics such as morphine and codeine act as .mu. receptor agonists. These opioids have well-known, undesirable and potentially dangerous dependence forming side effects. Compounds which are .kappa.-receptor agonists act as analgesics through interaction with .kappa. opioid receptors. The advantage of these agonists over the classical .mu. receptor agonists, such as morphine, lies in their ability to cause analgesia while being devoid of morphine-like behavioral effects and addiction liability.
B) Antihyperalgesic Kappa Agonists as Anti-Pruritic Agents
The prior art has investigated the physiology and treatment of pruritus as illustrated hereunder.
Itch is a well known sensory state associated with the desire to scratch. As with pain, itch can be produced by a variety of chemical, mechanical, thermal or electrical stimuli. In addition to the difference in the sensory quality of itch and pain, they also differ in that (1) itch, unlike pain, can only be evoked from the superficial layers of skin, mucosa, and conjunctiva, and (2) itch and pain usually do not occur simultaneously from the same skin region; in fact, mildly painful stimuli, such as scratching, are effective in eliminating itch. In addition, the application of histamine to skin produces itch but not pain. Itch and pain are further dissociated pharmacologically: itch appears to be insensitive to opiate and non-steroidal anti-inflammatory drug (NSAID) treatment, both of which are effective in treating pain.
Although itch and pain are of a class in that both are modalities of nociception transmitted by small unmyelinated C fibers, evidence that itch is not just a variety of low-threshold pain is overwhelming. Itch leads to the reflex or urge to scratch; pain leads to withdrawal. Removal of the epidermis eliminates itch but causes pain. Analgesics, particularly opiods, relieve pain but often cause itch (see, for example J. Am. Acad. Derm. 24: 309-310, 1991). There can be no doubt that itching is of eminent clinical importance; many systemic and skin diseases are accompanied by persistent or recurrent itch attacks. Current knowledge suggests that itch has several features in common with pain but exhibits intriguing differences as well (see, for example, W. Magerl, IASP Newsletter, pp. 4-7, September/October 1996).
McMahon et al (TINS, Vol. 15, No. 12, pp. 497-501, 1992) provides a description of stimuli (Table a) and a comparison of the established features of itch and pain (Table b):
TABLE a ______________________________________ Stimuli that can elicit or augment itch ______________________________________ Physical Mechanical. Light touch, pressure, suction. Thermal. Warming. Electrical. Focal transcutaneous repetitive stimulation, transcutaneous constant current stimulation, intraneural microstimulation. Chemical Non-specific irritants. Acids, alkalis. Inflammatory mediators. Histamine, kallikrein, bradykinin, prostaglandins. Histamine-releasing substances. Compound 48/80, protamine, C3a. Peptidases. Mucunain, papain, trypsin, mast cell chymase. Neuropeptides. Substance P, vasoactive intestinal polypeptide , neurotensin, secretin. Opioids. Morphine, .beta.-endorphin, enkephalin analogues. ______________________________________
TABLE b ______________________________________ Comparison of the established features of itch and pain ITCH PAIN ______________________________________ Psychophysiology Tissue Skin. Mucous Most tissues membranes Stimulus See Table a Many stimuli Intraneural microstimulation Occasionally Yes Secondary sensations Allokinesis (itchy Hyperalgesia skin) Psychogenic modification Pronounced Present Counterstimuli Scratching, pain, Tactile stimuli, cooling cooling Neurophysiology Primary afferent neurones C-- and A.delta.-fibres C-- and A.delta.-fibres Flare size Large Small Spinal pathway Anterolateral funiculus Anterolateral funiculus Protective reflexes Scratching, sneezing Flexion, guarding Autonomic reflexes Yes Yes Pharmacology Capsaicin sensitivity Yes Chemogenic pain; yes NSAID sensitivity Probably not Yes Morphine sensinvity No Yes ______________________________________ Abbreviation: NSAID, nonsteroidal antiinflammatory drugs.
Experimental focal itch stimuli are surrounded by a halo of seemingly unaffected tissue where light tactile stimuli are capable of eliciting itch-like sensations. The term itchy skin or allokinesis has been coined for these secondary sensations that are reminiscent of the features of secondary hyperalgesia evolving around a painful focus. A crucial observation is that itch and pain usually do not coexist in the same skin region and a mild noxious stimulus such as scratching is in fact the singly most effective way to abolish itch. This abolition of itch can be prolonged producing an `antipruritic state`. Although mild scratch is often not painful, microneurographic recordings from humans have directly determined that such stimuli are among the most effective ways to excite cutaneous unmyelinated nociceptive afferents. (See, for example:
Shelly, W. B. and Arthur, R. P. (1957) Arch. Dermatol. 76, 296-323; PA1 Simone, D. A. et al. (1987) Somatosens. Res. 5, 81-92; PA1 Graham, D. T. , Goodell, H. and Wolff, H. G. (1951) J. Clin. Invest. 30, 37-49; PA1 Simone, D. A., Alreja, M. and LaMotte, R. H. (1991) Somatosens, Mot. Res. 8, 271-279; PA1 Torebjork, E (1985) Philos. Trans. R. Soc. London Ser. B 308, 227-234; and PA1 Vallbo, A. B., Hagbarth, K. E., Torebjork, H. E. and Wallin, B. G. (1979) Physiol. Rev. 59, 919-957). PA1 A is a single chemical bond (-), --(CH.sub.2).sub.q, CH(CH.sub.3)-- or --X(CH.sub.2).sub.n PA1 Ar is an aromatic, hetero-aromatic, bicyclic-aromatic, tricyclic-aromatic group or diphenyl methyl each of which may be unsubstituted or substituted with a member selected from the group consisting of H, halo, trifluoromethyl, nitro, C.sub.1 -C.sub.3 -alkoxy, hydroxy, azido, C.sub.1 -C.sub.3 -alkyl, methanesulfonyl, cyano, amino, C.sub.1 -C.sub.3 -alkoxycarbonyl, C.sub.1 -C.sub.3 -alkanoyloxy, and C.sub.1 -C.sub.3 -carboxacylamino of the formula --NHC(O)R.sub.7 PA1 R.sub.1 and R.sub.2 are independently H, C.sub.1 -C.sub.3 -alkyl or allyl; PA1 R.sub.1 and R.sub.2, taken together with the nitrogen to which they are bonded, complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, 3-fluoropyrrolidinyl, morpholinyl, piperidinyl, and 3,4-dehydropiperidinyl; PA1 R.sub.3, R.sub.4, R.sub.5, R.sub.6 are independently H, hydroxy, OR.sub.8 or OC(.dbd.O)R.sub.9 ; PA1 R.sub.5 and R.sub.6 taken together may form the group --E--CH.sub.2 --CH.sub.2 --E--; PA1 R.sub.5 and R.sub.6 taken together form a ring ##STR2## where Z is selected from the group consisting of oxygen (--O--), NR.sub.10, sulfur (--S--), sulfinyl (--S(O)--), and sulfonyl (--S(O).sub.2 --); PA1 E is N.about.OH, N.about.OC(O)CH.sub.3, O, S, with the proviso that when E is bivalent sulfur or oxygen, R.sub.5 and R.sub.6 cannot both be hydrogen; PA1 R.sub.8 is C.sub.1 -C.sub.3 -alkyl; PA1 R.sub.9 is H or C.sub.1 -C.sub.3 -alkyl; and PA1 R.sub.10 is H, or C.sub.1 -C.sub.3 -alkyl. PA1 Ar denotes an aromatic or hetero-aromatic group such as pyridine, thiophene, a bicyclic-aromatic group such as naphthalenes, benzofurans, benzothiophines, a tricyclic-aromatic group such as anthracenes and fluorenes; and halo denotes F, Cl, Br or I. PA1 A is ##STR4## or, --CH.sub.2 CH.sub.2 -- provided that in Formula A, when n is 1, A may also be --O-- or --S--; B, C and D are independently selected from the group consisting of H, OH, OCOR.sup.5, OCH.sub.2 CH.sub.2 OR.sup.5, OR.sup.6, R.sup.6, CH.sub.2 OR.sup.6, CH.sub.2 COR.sup.7, Cl, F, Br, I, NH.sub.2, NHR.sup.8, NR.sup.8 R.sup.9, SH, SR.sup.6, CH.sub.2 SR.sup.6 and OC(S)N(CH.sub.3).sub.2 ; or PA1 two of B, C and D when on adjacent carbon atoms taken together form a fused benzo ring; PA1 X and Y are independently selected from the group consisting of H, OCH.sub.3, Cl, F, Br, I, NO.sub.2, CF.sub.3, CN, SO.sub.2 R.sup.10, and SO.sub.2 CF.sub.3 ; or PA1 X and Y taken together with the benzene ring form ##STR5## R and R.sup.1 independently are selected from the group consisting of H, and alkyl of 1 to 3 carbon atoms; PA1 R.sup.2 is H; alkyl of 1 to 6 carbon atoms; CH.sub.2 CF.sub.3 ; alkenylmethyl of 3 to 6 carbon atoms; hydroxyalkenylmethyl of 2 to 5 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; cyclopropylmethyl; cyclobutylmethyl, or phenylalkyl of 7 to 9 carbon atoms; or R.sup.2 can be taken together with R.sup.1 and the nitrogen to which they are attached to be 1-azetidinyl; 1-pyrrolidinyl optionally substituted at the 3-position by OH, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or alkanoyloxy of 1 to 3 carbon atoms; 1-piperazinyl optionally substituted at the 4-position by alkyl of 1 to 3 carbon atoms; 1-morpholino; 2,5-dihydro-1H-pyrrol-1-yl; 3-azabicyclo[3.1.0]hexan-3-yl; or 3-azabicyclo[3.2.0]heptan-3-yl; PA1 R.sup.3 is H, but if n is 1 and A is CH.sub.2, R.sup.3 may also be CH.sub.3, CH.sub.2 OH, CHO, or COR.sup.11 ; PA1 R.sup.4 is H, alkyl of 1 to 6 carbon atoms, --CH.sub.2 OH--, CHO, or COR.sup.12 ; PA1 R.sup.5 is alkyl of 1 to 6 carbon atoms, phenyl, or mono-substituted phenyl; PA1 R.sup.6, R.sup.8, R.sup.9, R.sup.10 and R.sup.13 are independently an alkyl group of 1 to 3 carbon atoms; and PA1 R.sup.7, R.sup.11 and R.sup.12 independently are selected from the group consisting of H, OH, OR.sup.13, NHR.sup.13, and NR.sub.2.sup.13 ; or PA1 a stable N-oxide or a pharmaceutically acceptable salt thereof. PA1 A is --CH.sub.2 --, --O--, or --S--; PA1 B is OH, OCOR.sup.5, OCH.sub.2 CH.sub.2 OR.sup.5, OR.sup.6, CH.sub.2 OR.sup.6, or CH.sub.2 COR.sup.7 ; PA1 C is H, OH, or OR.sup.6 ; and PA1 R.sup.1 and R.sup.2 independently are selected from H or alkyl of 1 to 3 carbon atoms or are taken together with the nitrogen to which they are attached to form the group 1-azetidinyl, 1-pyrrolidinyl, 1-(2,5-dihydro-1H-pyrrolyl) or 1-piperidinyl. PA1 R is unsubstituted phenyl or phenyl substituted with one to three substituents selected from the group consisting of halogen, C.sub.1-6 alkyl, hydroxy, --O--CO--NH.sub.2, --O--CO--NHalkyl, --O--CO--N(alkyl).sub.2, C.sub.1-6 alkoxy, trifluoromethyl, C.sub.1-4 -alkoxy-C.sub.1-4 alkyloxy, carboxy-C.sub.1-4 alkyloxy, nitrile, nitro and amino; or mono or dialkyl amino, amide, sulfonamide, carboxamide; or mono or disubstituted carboxamide, ureido; or mono and di-alkylsubstituted ureido; or PA1 R represents an alkyl or cycloalkyl group having up to 7 carbon atoms. The cycloalkyl moiety, where present, can be optionally substituted by one or more substituents selected from the group consisting of from hydroxy, amino, amidino, guanidino, aminocarbonyl, carboxy, C.sub.1-6 alkoxy, (C.sub.1-6 alkoxy)carbonyl, (C.sub.3-6 alkenyloxy)carbonyl, (C.sub.3-6 alkynyloxy)carbonyl, C.sub.1-6 alkanoyloxy, C.sub.1-6 alkylsulfide, C.sub.1-6 alkylsulfoxide, C.sub.1-6 alkylsulfone, C.sub.1-6 (monoalkylamino)carbonyl, C.sub.1-6 acylamino, C.sub.1-6 acylmethylamino and C.sub.1-6 monoalkylamino; or PA1 R represents the group --D--R.sup.8 in which D represents a single bond, --CH.sub.2 --, --CH(CH.sub.3)--, --CH.sub.2 O--, --CH(CH.sub.3)O--, --CH.sub.2 S--, --CH(CH.sub.3)S--, --CH.sub.2 NH-- or --CH(CH.sub.3)NH-- and R.sup.8 represents a 4-6 membered heterocyclic ring containing up to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, the heterocyclic ring optionally being substituted on nitrogen or sulfur by oxygen or on nitrogen by hydroxy or C.sub.1-3 alkyl and/or the ring optionally being substituted on carbon by one or more substituents selected from the group consisting of amino, hydroxy, thio (and their tautomers), cyano, halogen, C.sub.1-3 alkoxy, C.sub.1-3 monoalkylamino, C.sub.1-3 acylamino, C.sub.1-3 acylmethylamino, and C.sub.1-3 alkylthio; PA1 R.sup.1 and R.sup.2 are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.3-5 alkenyl, C.sub.3-5 alkynyl, and C.sub.4-7 cycloalkylallyl group; or R.sup.2 can be taken together with R.sup.1 and the nitrogen to which they are attached to form a heterocyclic ring which may optionally contain a further heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur (i.e. 1-azetidinyl; 1-pyrrolidinyl optionally substituted at the 3-position by OH, --CH.sub.2 OH, tri(C.sub.1 -C.sub.6 alkyl)silyloxy, acyloxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or C.sub.1-6 alkanoyloxy; 1-piperazinyl optionally substituted at the 4-position by alkyl of 1 to 3 carbon atoms; 1-morpholino; 2,5-dihydro-1H-pyrrol-1-yl; 3-azabicyclo[3.1.0]hexan-3-yl; or 3-azabicyclo[3.2.0]heptan-3-yl); PA1 R.sup.3 represents hydrogen, C.sub.1-7 alkyl, --CH.sub.2 -phenyl or heterocyclic (the phenyl or heterocyclic substituted with one to three substituents selected from the group consisting of halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy and methoxycarbonyl; mono-, di- or tri-halomethyl; cyano; COR.sup.9 ; CH.dbd.NOR.sup.10 ; OR.sup.10 ; SR.sup.10 ; CH.sub.2 CN; CH.sub.2 OR.sup.10 ; CH.sub.2 SR.sup.10 ; CH.sub.2 S(O)R.sup.10 ; CH.sub.2 S(O).sub.2 R.sup.10 ; CH.sub.2 N(R.sup.10)R.sup.11 ; CH.sub.2 (R.sup.10)R.sup.11 ; CH.sub.2 OR.sup.10 OH; CH.sub.2 N(COR.sup.10)OH; CH.sub.2 NR.sup.10 COR.sup.11 ; CH.sub.2 NR.sup.10 S(O).sub.2 R.sup.11 ; or CH.sub.2 OCOR.sup.10, wherein R.sup.9 is hydrogen, hydroxy, amino, NHOH, NHOCH.sub.3, pyridylamino, NHN(CH.sub.3).sub.2, C.sub.1-4 alkoxy, benzyloxy, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, C.sub.1-4 alkyl or C.sub.1-4 alkylthio; R.sup.10 and R.sup.11 are each hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or C.sub.7-11 phenylalkyl), or OR.sup.12, wherein R.sup.12 is hydrogen, C.sub.1-4 alkyl or a hydroxy protecting group; PA1 X represents --CO--, or --SO.sub.2 --; and PA1 Y represents a single bond (in this case, only one of R.sup.4 -R.sup.6 is attached), a tetrahedral carbon, --OC--, --SC--, --S(O)C--, --S(O).sub.2 C--, or --CH.sub.2 C--; and PA1 R.sup.4, R.sup.5, and R.sup.6 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, C.sub.1-4 alkylenedioxy, C.sub.1-8 cyclic and acyclic alkyl; substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic group (i.e. phenyl, naphthyl, biphenyl, indanyl, 1-tetralone-6-yl, furyl, thienyl, pyridyl, thiazolyl, benzofuryl or benzothienyl, substituted with one to three substituents selected from the group consisting of halo, cyano, --OCONH.sub.2, --OCONHalkyl, --OCON(alkyl).sub.2, --OCOalkyl, --NHCHO, --NHCOalkyl, ureido, --NHCONHalkyl, --NalkylCONHalkyl, --NHCON(alkyl).sub.2, --NalkylCON(alkyl).sub.2, --NHSO.sub.2 alkyl, --COalkyl, --CONH.sub.2, --CONHalkyl, --CON(alkyl).sub.2, --CH.sub.2 CONH.sub.2, --CH.sub.2 CONHalkyl, --CH.sub.2 CON(alkyl).sub.2, --OCH.sub.2 CONH.sub.2, --OCH.sub.2 CONHalkyl, --OCH.sub.2 CON(alkyl).sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, amino, hydroxy, nitro, trifluoromethyl, --SO.sub.2 alkyl, --SOalkyl, and mesyl; or R.sup.5 and R.sup.6 can together form the following structure ##STR8## wherein R.sup.13 and R.sup.14 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, mono-, di- or tri-halomethyl, amino, --NHalkyl, --N(alkyl).sub.2, --NHCOalkyl, ureido, nitro, and methylenedioxy; and PA1 D represents --CH--, --O--, --S--, --NH, --CHCH.sub.2 --, --CH.dbd.CH--, --CH.sub.2 NH--, or --CH.sub.2 Nalkyl--. PA1 R.sub.3 is hydrogen, C.sub.1-6 alkyl or phenyl; or R.sub.3 together with R.sub.1 forms a --(CH.sub.2).sub.3 -- or --(CH.sub.2).sub.4 -- group; PA1 R.sub.4 is C.sub.1-6 alkyl, or phenyl; PA1 R.sub.5 is hydrogen, or together with R.sub.4 forms a C.sub.2-5 linear polymethylene group; PA1 R.sub.6 represents hydroxy, C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 carboxyalkyl, phenyl, oxo, amino, carboxy, amido, --COR.sub.13, --CO.sub.2 R.sub.13 or --COCO.sub.2 R.sub.13 (where R.sub.13 represents a hydrogen atom or an unsubstituted or substituted C.sub.1-10 hydrocarbon moiety); --NRxCORx (where Rx represents C.sub.1-6 alkyl), optionally substituted ethylene; or R.sub.6 together with the E atom to which it is attached, forms a 5 or 6-membered ring containing one or more heteroatoms; R.sub.7 is hydrogen, or together with R.sub.6 forms an optionally substituted or unsubstituted single or fused aryl or heterocyclic ring, containing from 5 to 12 ring atoms and comprising up to four heteroatoms in the ring selected from the group consisting of oxygen, nitrogen and sulphur, which may be substituted with hydrogen, C.sub.1-6 alkyl, --CH.sub.2 OR.sub.14, halogen, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkoxycarbonyl, thiol, C.sub.1-6 alkylthio, --OCOR.sub.15, --NHCOR.sub.16, --NHSO.sub.2 R.sub.17 or --CH.sub.2 SO.sub.2 NR.sub.18 R.sub.19, PA1 in which each of R.sub.14 to R.sub.19 is independently hydrogen, C.sub.1-6 alkyl, aryl or aralkyl, PA1 A is aryl or heteroaryl ring, optionally mono or disubstituted with C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.1-6 haloalkyl, C.sub.2-6 haloalkenyl, C.sub.2-6 haloalkynyl, aryl, aralkyl, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, thiol, C.sub.1-6 alkylthio, C.sub.1-6 haloalkylthio, halogen, nitro, cyano, carboxy, aryloxy, aralkoxycarbonyl, carbamoyl, sulfonyl or sulfamoyl; PA1 E represents methylene, sulphur, oxygen or an imino; PA1 R.sub.8 is hydrogen or C.sub.1-6 alkyl; and PA1 R.sub.9 is hydrogen or together with R.sub.8 may form the group --(CRaRa)m--C(.dbd.Y)-- wherein Ra is hydrogen or C.sub.1-6 alkyl having up to a maximum of 3 alkyl groups; PA1 m is 1, 2, or 3; and PA1 Y represents two hydrogens or oxygen. PA1 R.sup.1 represents an allyl group having 1-5 carbon atoms, a cycloalkylalkyl group having 4-7 carbon atoms, a cycloalkenylalkyl group having 5-7 carbon atoms, an aryl group having 6-12 carbon atoms, an aralkyl group having 7-13 carbon atoms, an alkenyl group having 4-7 carbon atoms, an allyl group, a furan-2-ylalkyl group having 1-5 carbon atoms, or a thiophen-2-ylalkyl group having 1-5 carbon atoms; PA1 R.sup.2 represents a hydrogen atom, a hydroxy group, a nitro group, an alkanoyloxy group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkyl group having 1-5 carbon atoms, or --NR.sup.9 R.sup.10 wherein R.sup.9 represents a hydrogen atom or an alkyl group having 1-5 carbon atoms, and R.sup.10 represents a hydrogen atom; an alkyl group having 1-5 carbon atoms, or --C(.dbd.O)R.sup.11 wherein R.sup.11 represents a hydrogen atom, a phenyl group or an alkyl group having 1-5 carbon atoms; PA1 R.sup.3 represents a hydrogen atom, a hydroxy group, an alkanoyloxy group having 1-5 carbon atoms, or an alkoxy group having 1-5 carbon atoms; PA1 A represents --XC(.dbd.Y)--, --XC(.dbd.Y)Z--, --X--, --XSO.sub.2 --, or --OC(OR.sup.4)R.sub.4 -- (where, X, Y and Z each independently represent NR.sup.4, S or O wherein R.sup.4 represents a hydrogen atom, a straight-chain or branched chain alkyl group having 1-5 carbon atoms or an aryl group having 6-12 carbon atoms, and wherein R.sup.4 may be identical or different; PA1 B represents a valence bond, a straight-chain or branched chain alkylene group having 1-14 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, a trifluoromethyl group and a phenoxy group, and wherein 1 to 3 methylene groups may be replaced with carbonyl groups), an acyclic unsaturated hydrocarbon containing from 1 to 3 double bonds and/or triple bonds and having 2-14 carbon atoms (which may be substituted with at least one substituent group selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, a trifluoromethyl group and a phenoxy group, and wherein from 1 to 3 methylene groups may be replaced with carbonyl groups), or a straight-chain or branched chain saturated or unsaturated hydrocarbon group containing from 1 to 5 thioether, ether and/or amino bonds and having 1-14 carbon atoms (wherein hetero atoms are not bonded directly to A, and 1 to 3 methylene groups may be replaced with carbonyl groups); PA1 R.sup.5 represents a hydrogen atom or an organic group (which may be substituted with at least one or more substituent groups selected from the group consisting of an alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, an isothiocyanate group, a trifluoromethyl group and a methylenedioxy group); or PA1 R.sub.5 is ##STR11## wherein Q is N, O or S; PA1 R.sup.6 represents a hydrogen atom; PA1 R.sup.7 represents a hydrogen atom, a hydroxy group, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, or R.sup.6 and R.sup.7 together represent --O--, --CH.sub.2 -- or --S--; PA1 R.sup.8 represents a hydrogen atom, an alkyl group having 1-5 carbon atoms, or an alkanoyl group having 1-5 carbon atoms. The general formula (V) includes the (+) form, (-) form and (.+-.) form of compounds. PA1 R.sup.1 is an alkyl group having 1-5 carbon atoms, a cycloalkylmethyl group having 4-7 carbon atoms, a cycloalkenylmethyl group having 5-7 carbon atoms, a phenylalkyl group having 7-13 carbon atoms, an alkenyl group having 4-7 carbon atoms, an allyl group, a furan-2-yl-alkyl group having 1-5 carbon atoms or a thiophen-2-yl-alkyl group having 1-5 carbon atoms, while particularly preferred compounds are those wherein R.sup.1 is methyl, ethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentenylmethyl, cyclohexenylmethyl, benzyl, phenethyl, trans-2-butenyl, 2-methyl-2-butenyl, allyl, furan-2-yl-methyl or thiophen-2-yl-methyl groups; PA1 R.sup.2 is hydrogen, hydroxy, nitro, acetoxy, methoxy, methyl, ethyl, propyl, amino, dimethylamino, acetylamino or benzoylamino groups, while particularly prefered compounds are those wherein R.sup.2 is hydrogen, hydroxy, nitro, acetoxy, methyl or dimethylamino groups; PA1 R.sup.3 is hydrogen, hydroxy, acetoxy or methoxy; PA1 A is --NR.sup.4 C(.dbd.O--, --NR.sup.4 C(.dbd.S)--, --NR.sup.4 C(.dbd.O)O--, --NR.sup.4 C(.dbd.O)NR.sup.4 --, --NR.sup.4 C(.dbd.S)NR.sup.4 --, --NR.sup.4 C(.dbd.O)S--, --OC(.dbd.O)--, --OC(.dbd.O)O--, --SC(.dbd.O)--, --NR.sup.4 --, --O--, --NR.sup.4 SO.sub.2 -- or --OSO.sub.2 --, while particularly preferred compounds are those wherein R.sup.3 is --NR.sup.4 C(.dbd.O)--, --NR.sup.4 C(.dbd.S)--, --NR.sup.4 C(.dbd.O)O--, --NR.sup.4 C(.dbd.O)NR.sup.4 --, --NR.sup.4 C(.dbd.S)NR.sup.4 -- or --NR.sub.4 SO.sub.2 --; PA1 R.sup.4 is hydrogen, a straight-chain or branched alkyl group having 1-5 carbon atoms or a phenyl group, while particularly particularly preferred compounds are those wherein R.sup.4 is a straight-chain or branched alkyl group having 1-5 carbon atoms, particularly methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups; or PA1 R.sup.4 is ##STR12## wherein Q is N, O or S; PA1 B is --(CH.sub.2).sub.n -- (n=0-6), --(CH.sub.2).sub.n --C(.dbd.O)-- (n=1-4), --CH.dbd.CH--(CH.sub.2).sub.n -- (n=0-4), --C.tbd.C--(CH.sub.2).sub.n -- (n=0-4), --CH.sub.2 O--, --CH.sub.2 --S--, --CH.sub.2 --O--(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2 --, --CH.sub.2 --O--CH.sub.2 --NH--CH.sub.2 --O--CH.sub.2 -- or --CH.sub.2 --O--CH.sub.2 --S--CH.sub.2 --O--CH.sub.2 --, while particularly preferred compounds are those wherein B is --(CH.sub.2).sub.n -- (n=0-6), --CH.dbd.CH(CH.sub.2).sub.n -- (n=0-4), --C.tbd.C--(CH.sub.2).sub.n -- (n=0-4), --CH.sub.2 --O-- or --CH.sub.2 --S--; PA1 R.sup.5 is hydrogen or an organic group having the basic skeleton indicated in (Formula V-1) (which may be substituted with at least one or more substituent groups selected from the group consisting of an alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, an amino group, a nitro group, a cyano group, an isothiocyanate group and a trifluoromethyl group), while particularly preferred compounds are those wherein R.sup.5 is hydrogen, phenyl, 3,4dichlorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4bromophonyl, 3-bromophenyl, 2-bromophenyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 4-trifuoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-mothoxy, 3-furanyl, 2-furanyl, 3-thienyl, 2-thienyl, cyclopentyl or cyclohexyl groups.
Physiologically, there is evidence that substance P released from nociceptor terminals can cause the release of histamine from mast cells. Activation of mast cells, with release of the pruritogen histamine, occurs in immediate type hypersensitivity diseases, such as anaphylactic reactions and urticaria. Urticarial eruptions are distinctly pruritic and can involve any portion of the body, and have a variety of causes beyond hypersensitivity, including physical stimuli such as cold, solar radiation, exercise and mechanical irritation. Other causes of prutitus include: chiggers, the larval form of which secretes substance that creates a red papule that itches intensely; secondary hyperparathyroidism associated with chronic renal failure; cutaneous larva migrans, caused by burrowing larvae of animal hookworms; dermal myiasis, caused by maggots of the horse botfly, which can afflict horseback riders; onchocerciasis ("river blindness") caused by filarial nematodes; pediculosis, caused by lice infestations; enterobiasis (pinworm) infestations, which afflict about 40 million Americans, particularly school children; schistosome dermatitis (swimmer's itch); psoriasis; poison ivy, and asteatotic eczema ("winter itch"). The role of histamine or other endogenous pruritogens in mediating itch associated with these and other pruritic conditions, such as atopic dermatitis, its not yet well established. For atopic dermatitis, in particular, it appears that itch is not inhibited by antihistamines, but by cyclosporin A, a drug which inhibits the production of cytokines which have been proposed as potential pruritogens.
Current therapies for the treatment of itch include a variety of topical and systemic agents, such as steroids, antihistamines, and some psychotherapeutic tricyclic compounds, such as doxepin hydrochloride. Many such agents are listed in PDR Generics (see Second Edition, 1996, p. cv for a listing of said agents). The limitations of these agents are well known to medical practitioners, and are summarized in the "Warnings" and "Precautions" sections for the individual agents listed in PDR Generics. In particular, the lack of complete efficacy of antihistamines is well known, but antihistamines are frequently used in dermatology to treat prutitus due to urticaria, atopic dermatitis, contact dermatitis, psoriasis, and a variety of other conditions. Although sedation has been a frequent side effect of conventional systemically administered antihistamines, a new generation of antihistamines have been developed that are nonsedating, apparently due to their inability to cross the blood-brain barrier.
Intravenous administration of opiate analgesics, such as morphine and hydromorphone has been associated with pruritus, urticaria, other skin rashes, and wheal and flare over the vein being injected. These itch and itch-related reactions are believed to be due to a histamine-releasing property of these opiates, via mast cell degranulation. These opiates are thought to act upon the mu subtype of opiate receptor, but the possibility of interactions at the other principal opiate receptor subtypes (delta and kappa) cannot be excluded since these and other pruritogenic analgesics are not pure mu agonists. The cellular loci of the receptor type(s) mediating the itching effect is not known, although the mast cell is a possible candidate since opiates cause histamine release from these cells. However, some investigators have suggested that the frequent inability of antihistamines to block morphine-induced itching suggests a non-histaminergic mediation of opiate-induced itching--mechanism which could involve central opiate receptors. Although i.v. morphine only occasionally results in generalized itching (in about 1% of patients), prutitus is more prevalent in opiate analgesia with epidural (8.5%) or intraspinal (45.8%) administration. (See, for example: Bernstein et al., "Antipruritic Effect of an Opiate Antagonist, Naloxone Hydrochloride", The Journal of Investigative Dermatology, 78:82-83, 1982; and Ballantyne et al., "Itching after epidural and spinal opiates", Pain, 33: 149-160, 1988.)
To date, treatment with opiates has not only proven useless in the treatment of itch, but appears to exacerbate itch in mammals. The consistent findings from human studies indicate that whether by central or peripheral mechanisms, opiates appear to promote rather than prevent itching, and that opiate antagonists have antipuritic activity.
Human clinical studies have generally shown that opiates cause itching and there is evidence that these effects can be reproduced in animal models, where itching sensations per se cannot be reported, but scratching behavior can be observed. (See, for example: Thomas et al., "Microinjection of morphine into the rat medullary dorsal horn produces a dose-dependent increase in facial-scratching", Brain Research, 695: 267-270, 1996; Thomas et al., "Effects of central administration of opioids on facial scratching in monkeys", Brain Res., 585: 315-317, 1992; and Thomas et al., "The medullary dorsal horn: A site of action of opioids in producing facial scratching in monkeys", Anesthesiology, 79: 548-554, 1993).
We have now discovered that certain kappa agonists, which are substantially devoid of central nervous system effects, possess anti-pruritic activity in addition to antihyperalgesic activity. Accordingly, the present invention also provides safe and effective compositions for the prevention and treatment of pruritus.
Compounds having kappa opioid agonist activity are disclosed in the following references all of which are incorporated herein by reference:
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EPA 0 260 555 PA0 (.+-.)-N-[2-(N,N'-dimethylamino)cyclohexyl]-N-methyl-2-(4-trifluoromethylph enyl)acetamide; PA0 (.+-.)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-propyl-2-(3-methoxyphenyl)ac etamide; PA0 (.+-.)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(4-azidopbenyl)acet amide; PA0 (.+-.)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl )acetamide; PA0 (.+-.)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(4-methoxyphenyl)ac etamide; PA0 (.+-.)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(2-naphthyl)acetami de; PA0 (.+-.)-N-[2-(N-cyclopropyl-N-methylamino)cyclohexyl]-2-(4-azidophenyl)aceta mide; PA0 (.+-.)-N-(2-(3-acetoxy-1-pyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorop henyl)acetamide; PA0 (.+-.)-N-[2-(N-pyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acet amide; PA0 (.+-.)-N-[2-(3-hydroxypyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophen yl)acetamide; PA0 (.+-.)-N-[2-[N'-(3-hydroxy-1-azetidinyl]cyclohexyl]methyl-2-(3,4-dichloroph enyl)acetamide; PA0 (.+-.)-N-[2-(N',N'-diethylamino)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl) acetamide; PA0 (.+-.)-N-[2-(N'-pyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)pro pionamide; PA0 (.+-.)-N-[2-(4-methyl-1-piperazinylcyclopentyl]-2-(3,4-dichlorophenyl)aceta mide; PA0 (.+-.)-N-[2-(N,N-dimethylamino)cyclohexyl]-2-(3,4-dichlorophenyl)acetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-7 -yl]-benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4dioxaspiro[4.5]dec-8- yl]-benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-6 -yl]-benzeneacetamide; PA0 (.+-.)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec.8.yl]- benzeneacetamide; PA0 (.+-.)-3.fluoro-N-ethyl-N-[7-(1-azetidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]ben zeneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.4]-non- 8-yl)-benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.6]-unde c-8-yl]-benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.6]-unde c-7-yl]-benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[9-(1-pyrrolidinyl)-1,4-dioxaspiro[4.6]-unde c-8-yl]-benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-[4methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenze acetamide; PA0 (.+-.)-3,4-dichloro-N-[5-methoxy-2-(1-pyrrolidinyilcyclohexyl]-N-methylbenz eneacetamide; PA0 (.+-.)-3,4-dichloro-N-methyl-N-[4-oxo-2-(1-pyrrolidinyl)cyclohexyl]-benzene acetamide; PA0 (.+-.)-4-bromo-N-methyl-N-[2-(N',N'-dimethylamino)4-oxo-cyclohexyl]benzenea cetamide; PA0 (.+-.)-N-[4-acetyloxy-2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichloro-N-methylbe nzeneaceamide; PA0 (.+-.)-N-[4-acetyloxy-2-aminocyclohexyl]-3,4-difluoro-N-methylbenzeneacetar nide; PA0 (.+-.)-3,4-dichloro-N-[5-(hydroxyimino)-2-(1-pyrrolidinyl)cyclohexyl]-N-met hylbenzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl benzeneacetamide which can also be named: PA0 (.+-.)-3,4-dichloro-N-methyl-N-[4oxo-2-(1-pyrrolidinyl)cyclohexyl]benzeneac etamide, dimethyl ketal; PA0 (.+-.)-3,4-dichloro-N-[5,5-diethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylb enzeneacetamide; PA0 (.+-.)-(1.alpha.,2.beta.)-3,4-dichloro-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)c yclohexyl]-N-methyl benzeneacetamide; PA0 (.+-.)-4-trifluoromethyl-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-m ethylbenzeneacetamides; PA0 (.+-.)-3-trifluoromethyl-N-[4,4-diethoxy-2-(1-pyrrolidinyl)-cyclohexyl]-N-m ethylbenzeneacetamide; PA0 (.+-.)-3-hydroxy-4-methyl-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N- methylbenzeneacetamide; PA0 (.+-.)-4-methanesulfonyl-N-[4,4-dimethoxy-2-(1-piperidinyl)-cyclohexyl]-N-m ethylbenzamide; PA0 (.+-.)-4-acetyloxy-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)-cyclohexyl-N-methylb enzeneacetamide; PA0 (.+-.)-N-[4,4-bis(methylthio)-2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichloro-N- methylbenzeneacetamide; PA0 (.+-.)-N-[5,5-bis(ethylthio)-2-(1-pyrrolidinyl)cyclohexyl]-3,4-di-chloro-N- methylbenzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-[4-methylthio-2-(1-pyrrolidinyl)cyclohexyl]-N-methylb enzeneacetamide; PA0 (.+-.)-3,4dichloro-N-[5-ethylthio-2-(1-pyrrolidinyl)cyclohexyl]-N-methylben zeneacetamide; PA0 (.+-.)-3,4-dichloro-N-[6-methylthio-2-(1-pyrrolidinyl)cycloheptyl]-N-methyl benzeneacetamide; PA0 (.+-.)-3,4-dichloro-N-[4-mercapto-2-(1-pyrrolidinyl)cyclohexyl]-N-methylben zeneacetamide; PA0 [1R-(1.beta.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)c yclohexyl]-N-methyl-4-benzofuranacetamide; PA0 [1S-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-4-benzofuranacetamide; PA0 [1R-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-4-benzofuranacetamide; PA0 [1S-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-4-benzofuranacetamide; PA0 [1R-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-benzo[b]thiophene-4-acetamide; PA0 [1S-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-benzo[b]thiophene-4-acetamide; PA0 [1R-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-benzo[b]thiophene-4-acetamide; PA0 [1S-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-benzo[b]thiophene-4-acetamide; PA0 [1R-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-1-naphthaleneacetamide; PA0 [1S-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-1-naphthaleneacetamide; PA0 [1R-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-1-naphthaleneacetamide; PA0 [1S-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-1-naphthaleneacetamide; PA0 [1R-(1.alpha.,2.beta.,4.beta.,5.beta.)]-3,4-dichloro-N-[4,5-dimethoxy-2-(1- pyrrolidinyl)cyclohexyl]-N-methybenzeneacetamide; PA0 [1S-(1.alpha.,2.beta.,4.beta.,5.beta.)]-3,4-dichloro-N-[4,5-dimethoxy-2-(1- pyrrolidinyl)cyclohexyl]-N-methybenzeneacetamide; PA0 [1R-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-3,4-dichloro-N-[4,5-diethoxy-2-(1 -pyrrolidinyl)cyclohexyl]-N-methybenzeneacetamide; PA0 [1S-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-3,4-dichloro-N-[4,5-dimethoxy-2-( 1-pyrrolidinyl)cyclohexyl]-N-methybenzeneacetamide; PA0 [1R-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide; PA0 [1S-(1.alpha.,2.beta.,4.beta.,5.beta.)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide; PA0 [1R-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide; PA0 [1S-(1.alpha.,2.beta.,4.alpha.,5.alpha.)]-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide; PA0 (.+-.)-(1.alpha.,2.beta.,4.beta.)-N-methyl-N-[4methoxy-2-(1-pyrrolidinyl)cy clohexyl]-4-benzofuranacetamide; PA0 (.+-.)-(1.alpha.,2.beta.,4.alpha.)-N-methyl-N-[4-methoxy-2-(1-pyrrolidinyl) cyclohexyl]-4-benzofuranacetamide; PA0 (.+-.)-(1.alpha.,2.beta.,5.beta.)-N-methyl-N-[5-methoxy-2-(1-pyrrolidinyl)c yclohexyl]-4-benzofuranacetamide; PA0 (.+-.)-(1.alpha.,2.beta.,5.alpha.)-N-methyl-N-[5-methoxy-2-(1-pyrrolidinyl) cyclohexyl]-4-benzofuranacetamide; PA0 (.+-.)-(1.alpha.,2.beta.,4.alpha.)-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexy l]-N-methyl-9H-fluorene-9-carboxamide; PA0 (.+-.)-(1.alpha.,2.beta.,5.beta.)-N-[5-methoxy-2-(1-pyrrolidinyl)cyclohexyl ]-N-methyl-9H-fluorene-9-carboxamide; PA0 (.+-.)-N-methyl-2-(1-naphthalenyloxy)-N-[2-(1-pyrrolidinyl)cyclohexyl]aceta mide; PA0 (.+-.)-N-methyl-2-(2-naphthalenyoxy)-N-[2-(1-pyrrolidinyl)cyclohexy]jacetam ide; PA0 (.+-.)-1,2dihydro-N-methyl-N-[2-(1-pyrrolidinyl)cylohexyl]-1-acenaphthylenc arboxamide, (isomer I, mixture of (1.alpha.,2.beta.) and (1.beta.,2.alpha.) forms); PA0 (.+-.)-1,2-dihydro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-1-acenaphthyle necarboxamide, (isomer II, mixture of (1.alpha.,2.beta.) and (1.beta.,2.alpha.) forms); PA0 (.+-.)-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-1,2-dihydro-N-methyl- 1-acenaphthylenecarboxamide (isomer I, mixture of (1.alpha.,2.beta.,4.beta.,5.beta.) and (1.beta.,2.alpha.,4.alpha.,5.alpha. forms); PA0 (.+-.)-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-1,2-dihydro-N-methyl- 1-acenaphthylenecarboxamide (isomer II, mixture of (1.alpha.,2.beta.,4.beta.,5.beta.) and (1.beta.,2.alpha.,4.alpha.,5.alpha. forms); PA0 (.+-.)-1,2-dihydro-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-ac enaphthylenecarboxamide (isomers I and II, mixtures of (1.alpha.,2.beta.,4.beta.) and (1.beta.,2.alpha.,4.alpha.) forms); PA0 (.+-.)-1,2-dihydro-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-ac enaphthylenecarboxamide (isomers I and II, mixtures of (1.beta.,2.alpha.,4.alpha.) and (1.alpha.,2.beta.,4.beta.) forms); PA0 (.+-.)-trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-9H-fluorene-9-carbox amide; PA0 (.+-.)-trans-1,3-dihydro-N-methyl-1-oxo-N-[2-(1pyrrolidinyl)cyclohexyl]-4-i sobenzofuranacetamide; PA0 (.+-.)-(1.alpha.,2.beta.,4.beta.,5.beta.)-N-[4,5-dimethoxy-2-(1-pyrrolidiny l)cyclohexyl]-1,3-dihydro-N-methyl-1-oxo-4-isobenzofuranacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1-o xaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-4-methoxy-N-methyl-N-[7-(1-pyrrolidinyl) -1-oxaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-2-nitro-N-[7-(1-pyrrolidinyl)-1 -oxaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-3-nitro-N-[7-(1-pyrrolidinyl)-1 -oxaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-4-nitro-N-[7-(1-pyrrolidinyl)-1 -oxaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspir o[4.5]dec-8-yl]-3-(trifluoromethyl)benzeneacetamide; PA0 (.+-.)-(5.alpha.,6.alpha.,7.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-oxaspiro[4.5]dec-6-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.beta.,8.alpha.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidin yl)-1-oxaspiro[4.5]dec-7-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-1,N-dimethyl-[7-(1-pyrrolid inyl)-1-azaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1 -azaspiro[4.5dec-8-yl]benzamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-thiaspiro[4.5]dec-8-yl]benzamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide, 1-oxide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-1-thiaspiro[4.5]dec-8-yl]benzeneacetamide, 1,1-dioxide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyrrolidinyl)-1-azaspir o[4.5]dec-8-yl]4-trifluoromethylbenzeneacetamide; PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[8-(1-pyrrolidinyl)-1-thiaspi ro[4.5]dec-7-yl]-3-trifluoromethylbenzeneacetamide; PA0 [5R-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4. 5]dec-8-yl]-1H-indene-3-acetamide; PA0 [5S-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4. 5]dec-8-yl]-1H-indene-3-acetamide; PA0 [5R-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4. 5]dec-8-yl]-1H-indene-3-acetamide; PA0 [5S-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4. 5]dec-8-yl]-1H-indene-3-acetamide; PA0 [5R-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-1H-indole-3-acetamide; PA0 [5S-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-1H-indole-3-acetamide; PA0 [5R-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-1H-indole-3-acetamide; PA0 [5S-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(-pyrrolidinyl)-1-oxaspiro[4 .5]dec-8-yl]-1H-indole-3-acetamide; PA0 [5R-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-2-benzofuranacetamide; PA0 [5S-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-2-benzofuranacetamide; PA0 [5R-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-2-benzo[b]furanacetamide; PA0 [5S-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-2-benzo[b]furanacetamide; PA0 [5R-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-3-benzo[b]furanacetamide; PA0 [5S-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-3-benzo[b]furanacetamide; PA0 [5R-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-3-benzo[b]furanacetamide; PA0 [5S-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-3-benzo[b]furanacetamide; PA0 [5R-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-4-benzo[b]furanacetamide; PA0 [5S-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-4-benzo[b]furanacetamide; PA0 [5R-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]4-benzo[b]furanacetamide; PA0 [5S-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-4-benzo[b]furanacetamide; PA0 [5R-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro[4 .5]dec-8-yl-4-benzo[b]thiophene-4-acetamide; PA0 [5S-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro[4 .5]dec-8-yl-4-benzo[b]thiophene-4-acetamide; PA0 [5R-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro[4 .5]dec-8-yl-4-benzo[b]thiophene-4-acetamide; PA0 [5S-(5.alpha.,7.beta.,8.alpha.)]-N-Methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro[4 .5]dec-8-yl-4-benzo[b]thiophene-4-acetamide; PA0 (-)-(5.alpha.,7.alpha.,8.beta.)]-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[ 4.5]dec-8-yl]-4-benzo[b]furanacetamide; PA0 (-)-(5.alpha.,7.alpha.,8.beta.)]-N-7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8- yl-4-benzo[b]thiophene-4-acetamide; PA0 (.+-.)-(5.alpha.,6.alpha.,7.beta.)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidin yl)-2-oxaspiro[4.5]dec-6-yl]benzeneacetamide; PA0 (.+-.)-(5.alpha.,6.alpha.,7.beta.)-3,4-dichloro-N-methyl-N-[6-(1-pyrrolidin yl)-2-oxaspiro[4.5]dec-7-yl]benzeneacetamide; and PA0 (.+-.)-(5.alpha.,7.alpha.,8.beta.)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidin yl)-2-oxaspiro[4.5]dec-7-yl]benzeneacetamide. PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-methoxy-1,2,3,4- tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride or the methansulfonic acid salt; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4-tetrahydro naphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-6-methoxy-1,2,3,4- tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-6-hydroxy-1,2,3,4- tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)-trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4-tetrahydr onaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2,3-dihydro-2-(pyrrolidin-1-yl)-1H-ind en-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[3,4-dihydro-3-(pyrrolidin-1-yl)-2H-ben zopyran4-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-hydroxy-1,2,3,4- tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-propionyloxy-1,2 ,3,4-tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-benzoyloxy-1,2,3 ,4-tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-6,7-dihydroxy-1,2, 3,4-tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-N-methyl-N-[3,4-dihydro-3-(pyrrolidin-1-yl)-2H-benzopyran-4-yl] -benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4-dichloro-N-methyl-N-[3,4dihydro-8-methoxy-3-(pyrrolidin-1-y l)-2H-benzopyran-4yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-(N,N-dimethylthio carbamoyloxy)-1,2,3,4-tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride; PA0 (.+-.)trans-3,4dichloro-N-methyl-N-[2-(2,5-dihydro-1H-pyrrol-1-yl)-5-methox y-1,2,3,4-tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride, and PA0 (.+-.)trans-3-nitro-N-methyl-N-[2,3-dihydro-2-(pyrrolidin-1-yl)-1H-inden-1- yl]-benzeneacetamide hydrochloride. PA0 N-methyl-N-{[1S]-1-phenyl-2-[(3S)-(3-hydroxypyrrolidin-1-yl)]ethyl}-2,2-dip henylacetamide hydrochloride, PA0 3,4dichloro-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]benzeneacetam ide hydrochloride, PA0 N-methyl-N-{[1S]-1-phenyl-2-[(3S)-(3-hydroxypyrrolidin-1-yl)]ethyl }-2-aminophenylacetamide hydrochloride, PA0 3,4-dichloro-N-methyl-N-[(1S)-1-isopropyl-2-(1-pyrrolidinyl)ethyl]benzeneac etamide hydrochloride, PA0 3,4-dichloro-N-methyl-N-[(1S)-1-(O-acetic acid-3-hydroxyphenyl)-2-(1-pyrrolidinyl)ethyl]benzeneacetamide hydrochloride, and PA0 N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]-2,2-diphenylacetamide hydrochloride PA0 (.+-.)1-(Pyrrolidin-1-yl)methyl-2-(3,4dichlorophenyl)-acetyl-4,4-dimethyl-1 ,2,3,4-tetrahydroisoquinoline; PA0 (.+-.)8-[(3,4-Dichlorophenyl)acetyl]-7-(1-pyrrolidinylmethyl)-1,4-dioxa-8-a za[4.5]spirodecane; PA0 (.+-.)Methyl 4-[3,4dichlorophenyl)acetyl]-3-(1-pyrrolidinylmethyl)-1-piperazinecarboxyl ate 1-[(3,4-Dichlorophenyl)acetyl]-2-[(3-oxo-1-pyrolidinyl)methyl]-piperidine; PA0 (.+-.)[S-(RR)]-(-)5-[(3,4-Dichlorophenyl)acetyl]-4,5,6,7-tetrahydro-4[(3-hy droxy-1-pyrolidinyl)methyl]furo[3,2-c]pyridine; PA0 (.+-.)[S-(RS)]-4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(3-hydroxy-1-pyro lidinyl)methyl]pyridine; PA0 (.+-.)2-[(3,4-Dichlorophenyl)acetyl]-1,2,3,4-tetrahydro-1-(1-pyrolidinyl)me thyl)-5-isoquinolinol; PA0 (.+-.)4-(Pyrolidin-1-yl)methyl-5-(3,4-dichlorophenyl)acetyl-4,5,6,7-tetrahy drothieno[3,2,c]pyridine; PA0 (.+-.)1-[(5,6-Dichloro-3-oxoindan-1-carbonyl)-2-pyrrolidin-1-ylmethyl)piper idine; PA0 (.+-.)2-(3,4-Dichlorophenyl)acetyl-3-(pyridin-1-yl)methyl-decahydroisoquino line; and PA0 (.+-.)1-(4-Trifluoromethylphenyl)acetyl-2-(3-hydroxypyrolidin-1-yl)methyl-4 ,4-dimethyl piperidine. PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-3-phenylpropionamido)morphinan; PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-trans-3-(3-furyl)acrylamido)morphinan; PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-trans-3-cyclohexylacrylamido)morphinan; PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-trans-3-(4-trifuoromethylphenyl)acrylamido)morphinan; PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-trans-3-(3-thiophenyl)acrylamido)morphinan; PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-trans-3-phenylacrylamido)morphinan; PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-trans-2-hexenamido)morphinan; and PA0 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methy l-phenylpropiolamido)morphinan.

Kappa agonist anti-pruritic pharmaceutical formulaitons and method of treating pruritus therewith


An active arc suppression circuit and systems and methods of use to suppress arcing in an electro-mechanical apparatus. The preferred circuit includes an electro-mechanical switch and a solid state shunt switch for temporarily shunting current around the electro-mechanical switch for a predetermined period of time. The preferred circuit also includes an electro-mechanical switch controller for delaying the activation of the electro-mechanical switch until after the predetermined period of time for shunting current through the solid state shunt switch has commenced. The preferred circuit may be used with power control equipment and systems, including in remotely controllable systems for telecommunications, computing, and other networks. In a particularly preferred embodiment, multiple such circuits may be disposed in a power controller housing to provide independent active arc suppression control of multiple power outputs also disposed in the power controller housing.

There is a growing need for competitive local exchange carriers to manage remote power control functions of internetworking devices at telephone company (telco) central offices. Competitive local exchange carriers (CLECs), incumbent local exchange carriers (ILECs), independent telephone companies, and other next generation service providers are now all offering a digital subscriber line (DSL) service that promises high-speed Internet access for both homes and businesses. DSL is expected to replace integrated services digital network (ISDN) equipment and lines, and DSL competes very well with the T1 line that has historically been provided by ILECs. A DSL drop costs about $40-60 per month, and is expected to quickly become the dominant subscriber-line technology.
The DSL service is provided by a switch that is co-located in a telco central office, that is, a digital subscriber line access multiplexer (DSLAM). Many new competitive local exchange carriers are now deploying DSL service in several states. They are installing digital subscriber line access multiplexers in many locations. Such digital subscriber line access multiplexers are now available from a number of different manufacturers, for example, Paradyne, Copper Mountain, Ascend, etc.
Nearly all such digital subscriber line access multiplexers are powered by 48-VDC battery power and all have operator console ports. And for emergencies, these DSLAMs usually have two independent 48-VDC battery power supplies, for example, an A-channel and a B-channel. Most commercial DSLAMs are also controlled by large operating systems that host various application software. Unfortunately, this means most DSLAMs have the potential to fail or lock-up, for example, due to some software bug.
When a digital subscriber line access multiplexer does lock-up, the time-honored method of recovering is to cycle the power, that is, reboot. But when a digital subscriber line access multiplexer is located at a telco central office, such location practically prevents it being easy to reboot manually.
There are many large router and ATM switch farms around the country that are equipped by the leading vendors, for example, Cisco, Bay Networks/Nortel, Ascend, Lucent, Fore, etc. So each of these too has the potential to lock-up and need rebooting, and each of these is very inconvenient to staff or visit for a manual reboot when needed.
Server Technology, Inc., of Reno, Nev., markets a 48-VDC remote power manager and intelligent power distribution unit that provides for remote rebooting of remote digital subscriber line access multiplexers and other network equipment in telco central offices and router farms. The SENTRY 48-VDC is a network management center that eliminates the dispatching of field service technicians to cycle power and rectify locked-up digital subscriber line access multiplexers.
Statistics show that seventy percent or more of all network equipment lock-ups can be overcome by rebooting, for example, cycling power off and on. A remote power controller, like the SENTRY, can reduce network outages from hours to minutes.
In a typical installation, the telco central office provides the competitive local exchange carriers with bare rack space and a 48-VDC power feed cable that can supply 60-100 amps. The single power input is conventionally distributed through a fuse panel to several digital subscriber line access multiplexers in a RETMA-type equipment rack. Individual fuses in such fuse panel are used to protect each DSLAM from power faults.
But such fuses frequently weld themselves to their sockets in the fuse panel due to loose contacts and high amperage currents. It is ironic therefore that many digital subscriber line access multiplexers do not have power on/off switches. Thus the fuse often must be pried out and put back in or replaced so the DSLAM can be powered-off for rebooting. But when the fuse is welded, removing the fuse without damaging the fuse panel can be nearly impossible.
The Server Technology SENTRY 48-VDC accepts from the telco or other site host an A-power feed cable and B-power feed cable. Internally, DC-power is distributed to a set of "A" and "B" rear apron output terminal blocks that are protected by push-to-reset circuit breakers. The fuse panel is no longer required. The A-feed and B-feed are then matched to the newer digital subscriber line access multiplexers that also require A-power supply and B-power supply inputs.
Sometimes digital signaling lines can lose the carrier. In such cases, the respective DSLAM must be rebooted to restore the DS3 line. A technician is conventionally required to visit the DSLAM, and use a console port to monitor how the software reboots, and if communications are correctly restored to the DS3.
A SENTRY 48-VDC can be used to remotely power-off the digital subscriber line access multiplexer in the event the carrier is lost. A companion asynchronous communications switch can be used to establish a connection to the DSLAM's console port. Power can be cycled to the DSLAM, and the asynchronous communications switch used to monitor the reboot operation to make certain that the carrier to the DS3 line is restored. The asynchronous communications switch is a low-cost alternative to the expensive terminal server typically used for console port access. The reboot process and the console port monitoring process can both be managed from an operations center, without the need to dispatch technical personnel to the remote location.
The floor space that a competitive local exchange carrier's equipment rack sits upon is very expensive, so the equipment placed in the vertical space in a rack ("U-space") must be as compact as possible. A typical rack may house several digital subscriber line access multiplexers, a terminal server, a fuse panel, and 48-VDC modems. A SENTRY 48-VDC uses "2 U or 3 U" (3.5 or 5.25 inches) of vertical RETMA-rack space, and combines the functions of a fuse panel, a terminal server, and a modem. As many as sixteen 10-amp devices, eight 20 amp devices, or four 35-amp devices can be supported.
Power controllers, like the Server Technology SENTRY, have long used electro-mechanical relays to open and close the 48-volt supply lines to the network equipment. Unfortunately, the same physical phenomena that welds the fuses in their holders can also weld or destroy the contacts of these relays.
Most electric welders generate the high heats necessary to fuse metal together by arcing a direct current (DC) low voltage (under 50-volts) and high current (over 50-amps) across an electrode gap. Such conditions occur in a power controller's relay, especially when the relay contacts are opening. The mass inertia of the contact mechanism has to be overcome before the contacts can open. The contacts accelerate apart, but are moving only very slowly at the start. Electric arcs, once generated, will continue even though the electrode separation distance is increased. This is the so-called Jacob's Ladder effect. The ionized air and the heated contacts increase the distance an arc can bridge. The arcing stops only after the contacts are very wide apart.
In contrast, a pair of open relay contacts will not arc until the contacts get very close to one another. By this time, the contact closure is moving at its near maximum velocity. So the remaining gap that needs to be closed up when the arc commences will vanish quickly.
One prominent prior art arc suppression circuit consists of a capacitor in series with a resistor and a diode in parallel interconnecting the input and the output of the electro-mechanical relay. This type of conventional circuit shunts some electricity around the electro-mechanical relay when it is activated, reducing the extent of arcing that might otherwise take place. This conventional circuit is, however, relatively slow acting circuit (in passive response to the activation of the electro-mechanical relay to open or stop the flow of current from, for example, the input to the output) and does not completely eliminate all arcing between separating contacts in an electro-mechanical relay. Over an extended period of activation of this type of electro-mechanical relay circuit with passive arc suppression, electro-mechanical relay contacts often burn up and fail.

Active arc-suppression circuit, system, and method of use


A system, method, and computer program product are provided for performing peer discovery of HAIPE devices. A local enclave network fronted by a HAIPE device is addressed from the perspective of a “black” network using a “black” address associated with the HAIPE device. In order to properly address a network device within the local enclave, the “black” address associated with the fronting HAIPE device is determined. This is facilitated by mapping the address of the network device to the address of the HAIPE device, and propagating this mapping using the BGP routing protocol.

1. Field of the Invention
The present invention relates generally to networks and, more particularly, to the operation of end-to-end secure networks.
2. Description of the Background Art
The High Assurance Internet Protocol Encryption ("HAIPE") is the primary encryption device used to provide end-to-end security for the Global Information Grid ("GIG") environment. A HAIPE device operates at the IP layer of the TCP/IP protocol stack and represents a boundary between a common encrypted IP "black core" (e.g., the general Internet) and protected "red enclaves" at the perimeter.
This HAIPE device breaks the normal routing function such that traffic generated in one red enclave cannot be directly routed to other red enclaves. To support end-to-end traffic forwarding, a HAIPE device must be able to discover the "cipher-text" ("CT") address of the HAIPE fronting the destination red enclave, this CT address corresponding to the address of the fronting HAIPE as seen from the black network. Once the CT address is known, the source HAIPE can establish a secure communication channel with the destination HAIPE, and end-to-end secure traffic between a source red enclave and a destination red enclave may be transmitted.
An approach for providing HAIPE peer discovery is the "Routing Based Peer HAIPE Discovery" ("RBD"), which uses Border Gateway Protocol ("BGP") to send PT-to-CT mapping information to other enclaves. The fronting HAIPE of the source red enclave is operable to discover the "plain-text" ("PT") addresses of networked systems within the red enclave using an intra-enclave routing protocol, this PT address corresponding to the address of any systems as seen from within the red enclave. The fronting HAIPE is also able to obtain its own CT address and to create PT-to-CT address mappings using the aforementioned information, which is then provided to a discovery server. The discovery server is itself protected by a HAIPE, but does not necessarily reside in the source red enclave. The discovery server is operable to exchange and further populate the PT-to-CT mapping information with other discovery servers using BGP. Accordingly, when a first workstation located in a first enclave wants to establish communications with a second workstation in a second enclave, the first workstation knowing the PT address of the second workstation, the first workstation could use this mapping to determine the CT address corresponding to the fronting HAIPE which must be contacted in order to establish the communications channel.
By its nature, peer discovery of IP crypto is uni-directional. When a first workstation located in a first enclave wants to establish communications with a second workstation in a second enclave, the first workstation expects the second workstation to provide a reply. For the second workstation to reply, its fronting HAIPE must discover the fronting HAIPE of the first enclave. The peer discovery process at the fronting HAIPE of the second enclave adds latency to communication between the first and second workstation. We name this problem the "double discovery issue."
Accordingly, what is desired is a means of providing optimization of HAIPE peer discovery on reply communications.


A battery terminal for fixing a circular electrode engaging portion thereof to an outer surface of a battery post, wherein a rotatable nut interposed between the tightening plates in such a manner that a supporting shaft projecting from each of opposed side walls of the rotatable nut is rotatably inserted through each of the opposed through-holes formed on the tightening plates; and a tightening tool, having an approximately trapezoidal cut-out portion which is formed on each of side walls thereof and has a pair of tapered surfaces which are brought into contact with an outer surface of each of the tightening plates; and a bolt-installing through-hole, formed on an upper surface thereof, through which a bolt is tightened into the rotatable nut, the bolt being tightened, via the bolt-installing through-hole of the tightening tool, into the rotatable nut located at a desired angle by means of the shafts of the rotatable nut.

1. Field of the Invention
The present invention relates to a battery terminal to be installed on an electrode (battery post) of a battery mounted on a car or the like and more particularly to the battery terminal to be installed on the battery post in a desired direction, for example, vertically, obliquely or horizontally.
2. Description of the Related Arts
As shown in FIG. 7, a battery post 2 projecting upward from the upper surface of a battery 1 is inserted into an electrode engaging portion 3a of a battery terminal 3. A bolt 4 is horizontally inserted into a bolt opening of a substrate 3b and that of a tightening plate 3c. A nut 6 is tightened horizontally on the bolt 4 with an impact wrench 5 disposed horizontally. Then, the electrode engaging portion 3a is pressed against the battery post 2 to fix the battery terminal 3 to the battery post 2.
In recent years, component parts are installed in the engine room of the car in a high density. For example, projections such as an air duct higher than the battery post or electric wires are installed in the periphery of the battery. In tightening the nut 6 on the bolt 4, with the bolt 4 and the impact wrench 5 disposed horizontally, the following problems occur: The impact wrench 5 may contact other parts and thus it is difficult to tighten the nut 6 on the bolt 4 or it is impossible to tighten the nut 6 thereon if there is no space in which the impact wrench 5 can be placed horizontally.
If the impact wrench 5 and other parts interfere with each other while the plus side of the battery post is being tightened, a short circuit occurs when the impact wrench 5 interferes with the minus side thereof. Even a fire may occur in the car. Therefore, it is necessary to alter the configurations of other parts so as to prevent the interference between the impact wrench 5 and other parts.
In order to overcome the above-described problems, the following battery terminal is proposed in Examined Japanese Patent Laid-Open Utility Model Publication No. 4-7567 as shown in FIG. 8: That is, the bolt 4 is inclined at an acute angle with respect to the axis of the electrode engaging portion 3a of the battery terminal 3, and the nut 6 is tightened obliquely downward toward the head of the bolt 4 by the impact wrench 5.
The following battery terminal is also proposed in Examined Japanese Utility Model Publication No. 4-9736 as shown in FIGS. 9A and 9B: That is, the battery terminal comprises a substrate 3b'; a tightening plate 3c' opposed to each other and inversely tapered; and a crimping plate 7 inversely tapered and stretching over the substrate 3b' and the tightening plate 3c'. The bolt 4 is tightened downward on the crimping plate 7 so that the crimping plate 7 presses substrate 3b' and the tightening plate 3c' downward. In this manner, an electrode engaging portion 3a' is pressed against the battery post 2.
In the above described battery terminal shown in FIG. 8, since the nut 6 is tightened downward obliquely, the substrate 3b and the tightening plate 3c are formed by imparting torsion thereto so that they incline with respect to the axial direction of the electrode engaging portion 3a. The direction in which the twisted substrate 3b and the tightening plate 3c are moved toward each other is different from the direction in which the electrode engaging portion 3a is pressed against the peripheral surface of the battery post 2. Therefore, the force generated by the nut 6 tightened on the bolt 4 cannot be preferably applied to the direction in which the electrode engaging portion 3a is pressed against the peripheral surface of the battery post 2.
In the battery terminal shown in FIGS. 9A and 9B, both sides of the crimping plate 7 are inversely tapered. As a result, the force generated by the nut 6 tightened on the bolt 4 acts outward as well as inward and thus, the sides 7a and 7b of the crimping plate 7 do not preferably apply tightening force inward to the substrate 3b' and the tightening plate 3c'. As a result, there is a disadvantage that the electrode engaging portion 3a' cannot be reliably pressed against the battery post 2.
In the battery terminal disclosed in Examined Japanese Patent Laid-Open Utility Model Publications No. 4-7567, the nut is tightened only obliquely. In the battery terminal disclosed in Examined Japanese Patent Laid-Open Utility Model Publications No. 4-9736, the bolt is tightened only laterally or vertically. The installing position of main bodies of battery terminals are varied depending on the kind of a car. For example, an operator has difficulty in tightening the bolt vertically when the distance between the operator and the battery is long. The operator has also difficulty in tightening the bolt obliquely when the distance between the operator and the battery is short. The operator has also difficulty in tightening the bolt laterally because there is often a small space into which an impact wrench for tightening the bolt is inserted. Thus, it is necessary to select a battery terminal in installing it on the battery depending on the kind of a car.


An apparatus, circuit arrangement and method for emulating a hardware design by time division multiplexing data communicated between an emulator and a runtime assist unit (RTAU), such as a behavior card. Data from the emulator may be received directly at the general purpose registers of the RTAU. A programmable delay may be used in conjunction with a step generator to initiate concurrent cycle processes. Code executed by the RTAU may be coded in assembly, and external interrupts that might otherwise affect the determined processing time of the RTAU task are disabled. The time multiplexing reduces card port, cabling and processing cycle requirements.

Electronics designers commonly rely on simulators and emulators to test their designs for both operability and compatibility with existing systems or interfacing components. A simulator typically comprises a general purpose computer workstation that runs a simulation program. The program uses software to simulate, or model, the circuits of the design to be evaluated. The program thus simulates input signals and outputs data representative of signals produced by the circuits in response to the input signals.
Simulators by themselves, however, have been found to be relatively inefficient and lacking in processor speed, particularly for large and complex designs, and can require prohibitively long periods of time to complete a simulation. To help alleviate these limitations, accelerator hardware can be interfaced with a workstation. An accelerator is typically an electronic circuit board system that performs the concurrent processing, or operations that model circuit logic. The workstation can then concentrate the majority of its available processing power on sequential operations, i.e., operations that apply test vector data and otherwise simulate sequentially occurring activities with respect to a simulation.
A further improvement in processing efficiency can be gained by providing an emulator, or an emulator/accelerator combination. An emulator is a large scale hardware configuration typically implemented in field programmable gate arrays (FPGAs) or some other type of software configurable custom hardware. Because the logic is modeled in hardware (e.g., FPGAs) that approaches the same degree of parallel operation that the actual circuit being modeled would exhibit, the emulator/accelerator can perform the concurrent operations much faster than an accelerator alone.
Emulator are capable of emulating many types of computer system hardware and other logic, including, for example, memory devices. One emulator type, for example, executes a logic model embodied in suitable software that reflects a combination of a user model logic portion and non user model logic portion. The user model logic portion may be derived from (e.g., compiling) a netlist for the hardware design under test. Accordingly, this portion represents the functionality of the hardware design. The non user model logic portion is peripheral to the hardware design itself and is included for the purpose of providing peripheral functions to the emulation, such as high speed multiplexed data communication between the emulator/accelerator and a host workstation.
The chief advantage of including an emulator is that it can perform the concurrent operations in parallel with the sequential operations performed by the workstation to which it is connected. In some cases, an emulator can be interfaced to target hardware. Such hardware may comprise a portion of the system that is being tested or otherwise evaluated. For example, the target hardware may be a personal computer in which a microprocessor has been removed and replaced with cables connecting it to the emulator.
Emulator systems may include one or more behavior cards for performing the sequential operations, thereby taking that portion of the load off the workstation. The behavior card can apply test vectors or model sequential devices, e.g., a memory. Thus, the emulator performs the concurrent operations while the behavior card performs the sequential operations. The two preferably operate in parallel. Nevertheless, the two do not operate asynchronously with respect to each other. Rather, attempts are made to synchronize them with each other by operating in lock step fashion, i.e., a handshake. On each cycle of the emulation, the emulator produces a "STEP" or "BEGIN_CYCLE" signal. In response to this signal, the behavior card generates a "HALT" signal, which indicates that the behavior card has begun processing data it received from the emulator on the previous cycle and needs the emulator to wait until it has finished doing so. When it has finished, the behavior card drops the HALT signal. In response to the HALT signal being dropped, the emulator can reassert the STEP signal when it is ready to begin another emulation cycle. In addition, if the behavior card asserts the HALT signal but detects an error condition, requires more input data before it can continue, or otherwise needs to suspend the emulation, it can assert a "STOPPED" signal. This signal provides an indication of such a condition to the workstation and to any other behavior cards in the system.
While such timing and hardware implementations have improved the processing times of simulation environments, there remain improvements that can be made to emulation systems. For instance, the communication of bit values between an emulator and a behavior card during a processing cycle conventionally requires a wire to be dedicated to each bit value. The thousands of bit values potentially implicated in an emulation cycle can translate into thousands of wires bundled into hundreds or thousands of cables. These cables, in turn, require a large number of ports to accommodate the cable connections. This multitude of cables and ports can dramatically raise implementation costs, financially burdening developers and dissuading users from realizing the benefits of emulation techniques. There is consequently a need for an improved manner of emulating a hardware design that addresses the above identified problems.

Time multiplexed interface for emulator system

International Business Machines Corporation


A printed circuit board includes an uncured substrate material with closed voids which are disposed with a through-hole. When the through-hole is formed, voids which exist in the substrate material open from inner wall of the through-hole to form a hollow-shaped part. By filling the through-hole and the hollow-shaped part with conductive paste, the adhesion improves by the increased holding effect between the conductive paste and the wall surface of the through-hole.

Recently, following the tendency of electronic devices towards compact size and higher mounting density, multilayer printed circuit boards have been strongly demanded, not only for industrial but also for consumer use. This type of multilayer printed circuit boards requires employing inner-via-hole connections between a plurality of circuit patterns and also requires high reliability.
A conventional method of manufacturing a double sided printed circuit board is described as follows. FIGS. 8 (a) to (e) are cross-sectional views showing a method of manufacturing a conventional double sided printed circuit board. First, an insulating substrate 801 such as glass-epoxy is provided as shown in FIG. 8 (a). Then, copper foils 802 are applied on both sides of insulating substrate 801 as shown in FIG. 8 (b). Subsequently, insulating substrate 801 and copper foils 802 are bonded to each other through heating and pressurization. Thereafter, by using a conventional technique such as etching or the like, copper foils 802 are formed into a first circuit pattern 805 and a second circuit pattern 806 as illustrated in FIG. 8 (c). Next, as shown in FIG. 8 (d), through-holes 803 are drilled at places where first circuit pattern 805 and second circuit pattern 806 will be electrically connected. After that, conductive paste 804 is filled into through-holes 803 by a printing process as shown in FIG. 8 (e), and the paste is hardened.
In the manner as described above, first circuit pattern 805 and second circuit pattern 806 are connected by conductive paste 804 filled into through-holes 803, and thus, a double sided printed circuit board 807 is obtained.
However, the above-mentioned conventional structure has the problem that adhesion between the conductive paste and the wall surface of the through-hole is poor. In addition, there is a gap in coefficient of thermal expansion between the conductive paste and the insulating substrate so that a boundary face of the conductive paste and the through-hole breaks due to the thermal shock of solder dipping. As a result, a failure in continuity occurs.

Printed circuit board and method of manufacturing the same

Matsushita Electric Industrial Co., Ltd.


A car-navigating map displaying apparatus and method which produces a continuous representation of a road is disclosed. The apparatus comprises a storage storing data of a map including a plurality of areas at different levels of detailedness, a determinant determining whether or not there is a boundary of the areas having different levels of detailedness on the screen of a display, and controller controlling the display to display the entire map on the screen at a lower level of detailedness when the determinant determines that there is the boundary of the areas on the screen of the display.

1. Field of the Invention
The present invention relates to an apparatus and a method of displaying a car-navigating map.
2. Description of the Related Art
In making a car-navigating map of an area including a city, level of detailedness of the map is usually determined by the population of the city. For example, levels of detailedness of car-navigating maps for predetermined areas are classified so that a somewhat detailed car-navigating map is prepared for an area including a city of a population of 200,000 or more and a more detailed car-navigating map is prepared for an area including a city for which The Japanese Geographical Survey Institute issued a map of a scale of 1/10,000.
When a car-navigating map displaying system, for example, establishes the three levels of level A, level B and level C of detailedness and a motorcar goes to an area of level B through an area of level A or to an area of a lower level, for example, from the area of level B to the area of level C lower than level B, there is a problem that a representation of the same road to be traveled by the motorcar may be discontinued between the areas of the different levels.
This problem will be described with reference to FIGS. 8 and 9 hereinafter. As shown in FIGS. 8 and 9, it is assumed that the system displays all of roads b and c at level B and continues to display the roads b at level B but displays none of the roads at level C. When a automotive vehicle or motorcar X now travels along a road c1 toward north and a current position of the motorcar X is in the area of level B as shown in FIG. 8, the system displays the road c1. However, the system discontinues displaying the road c1 in the area of level C as the motorcar X approaches a boundary between the areas of levels B and C as shown in FIG. 9. Thus, such discontinuity in displaying a road due to a difference between levels of detailedness may mislead a driver of the motorcar X to judge that a traveled road reaches an end.

Apparatus and method of displaying car-navigating map