A cryogenic air separation system wherein liquid oxygen is vaporized against condensing feed air and against condensing nitrogen which is taken from a higher pressure column and returned to the top of the higher pressure column, thus supplying added reflux for the air separation and enabling column system operation with improved flexibility and reduced energy usage.

The demand for high pressure oxygen gas is increasing due to the greater use of high pressure oxygen in partial oxidation processes such as coal gasification for power generation, hydrogen production, and steelmaking. Often nitrogen is also employed in these processes.
Oxygen gas is produced commercially in large quantities generally by the cryogenic rectification of air. One way of producing the oxygen gas at high pressure is to compress the product oxygen gas from the cryogenic rectification plant. This, however, is costly both in terms of the capital costs for the product oxygen compressor and also in terms of the operating costs to power the product oxygen compressor. Another way of producing high pressure oxygen gas is to operate the cryogenic rectification plant at a higher pressure thus producing the oxygen at a higher initial pressure and reducing or eliminating downstream compression requirements. Unfortunately, operating the cryogenic rectification plant at a higher pressure reduces the efficiency of the production process because component separation depends on the relative volatilities of the components which decrease with increasing pressure. This is particularly the case when high pressure nitrogen product is also desired from the cryogenic rectification plant because the removal of nitrogen from the high pressure distillation column as product reduces the amount of reflux which may be employed thus reducing oxygen recovery.
In response to this problem there have been developed air separation processes wherein liquid oxygen is pressurized, such as by pumping or by hydrostatic means, and vaporized against an air stream which is either partially or totally condensed. This markedly reduces the compression costs for the elevated pressure oxygen gas product.
One problem with such systems is that the condensed air enters the high pressure column of the air separation plant near the bottom of the column. The air undergoes practically no distillation compared to air entering as a vapor at the bottom of the high pressure column. As a result, nitrogen, which is usually available as liquid nitrogen reflux for operation of the high pressure column and the low pressure column when all air enters the high pressure column as a vapor, is not separated from the liquid air. Since the reflux ratio of the high pressure column is fixed by the purity of reflux withdrawn from the top of the column and the number of equilibrium stages present in the column, there is produced less reflux for operation of the upper column resulting in the loss of product.
Nitrogen from the column system may be used in place of feed air to vaporize the liquid oxygen. However such an arrangement often results in the generation of more reflux than needed for the column system thus wasting power. Moreover, if the nitrogen is taken from the lower pressure column, significant power and capital costs are incurred in order to get the nitrogen to the requisite pressure for the product vaporization.
Accordingly, it is an object of this invention to provide a cryogenic rectification system which can produce product gas with improved efficiency over results attainable with conventional systems, especially at elevated product pressure.
It is another object of this invention to provide a cryogenic rectification system which can produce gas with improved efficiency wherein the amount of reflux generated may be adjusted to optimize the system performance.

Cryogenic rectification system with hybrid product boiler


Disclosed is an aqueous solution of a chromium salt, in which the oxalic acid content is 8% by weight or less relative to chromium. In the aqueous solution of the chromium salt, the total organic carbon content is 4% by weight or less relative to chromium. The chromium salt is preferably a chromium chloride, a chromium phosphate, or a chromium nitrate. The chromium chloride preferably contains a basic chromium chloride represented by the composition formula Cr(OH)xCly (wherein 0<x≦2, 1≦y<3, and x+y=3). The chromium phosphate is preferably one represented by the composition formula Cr(H3−3/nPO4)n (wherein n is a number satisfying 2≦n≦3). The chromium nitrate is preferably a basic chromium nitrate represented by the composition formula Cr(OH)x(NO3)y (wherein 0<x≦2, 1≦y<3, and x+y=3).

Among various aqueous solutions of chromium salts, aqueous solutions of chromium nitrate are known to be used as surface treatment agents for metals. Aqueous solutions of chromium phosphate are used as treatment solutions for forming chemical conversion coatings on zinc-plated surfaces of various metals, such as iron, nickel, and copper (refer to Patent Document 1).
In a known method for producing a chromium salt, such as chromium nitrate, chromium phosphate, or chromium chloride, ore is subjected to alkali oxidizing roasting to prepare a sodium dichromate solution, sulfuric acid is added to the sodium dichromate solution, which is then subsequently reduced with an organic substance to produce a chromium sulfate solution, caustic soda or soda ash is added thereto to form a precipitate of chromium hydroxide or chromium carbonate, which is subsequently subjected to filtration and water washing, and then nitric acid, phosphoric acid, or hydrochloric acid is added thereto for dissolution. In another known method, chromium ore is reduced in an electric furnace using a carbon reductant to produce high-carbon ferrochromium, the high-carbon ferrochromium is extracted with sulfuric acid, the resulting solution is electrolyzed to obtain metallic chromium, and nitric acid or hydrochloric acid is added to the metallic chromium to produce chromium nitrate or chromium chloride.
Furthermore, with respect to chromium nitrate, a production method is also known, which includes the steps of preparing a mixed solution of chromium trioxide and nitric acid by mixing nitric acid with chromium trioxide in a stoichiometric amount required to produce chromium nitrate or more, and adding an excessive amount of an organic reducing agent composed of an alcohol, an aldehyde, or a carboxylic acid, which is derived from a carbohydrate selected from monosaccharides, disaccharides, and starches, or a mixture of these, to the mixed solution of chromium trioxide and nitric acid prepared in the previous step to reduce chromium trioxide, thereby producing chromium nitrate (for example, refer to Patent Document 2).
With respect to chromium chloride, the present applicant has proposed a method in which an aqueous solution of chromic acid is allowed to react with an organic reducing agent capable of substantially completely decomposing into carbon dioxide gas and water by reaction with hydrochloric acid and chromic acid, thereby producing a high-purity aqueous solution of chromium chloride (for example, refer to Patent Document 3).
Among known methods, in the method in which chromium hydroxide is dissolved in nitric acid, it is very difficult to perform water washing of the precipitate of chromium hydroxide produced by adding caustic soda or soda ash to chromium sulfate, and it is not possible to remove impurities, such as sodium and sulfate salts, in chromium hydroxide. This problem remains to be solved.
In the method according to Patent Document 2, for example, mixing of nitric acid with chromium trioxide in a stoichiometric amount required to produce chromium nitrate or more is effective in decreasing the amount of hexavalent chromium. However, depending on the conditions, the added reducing agent may react with nitric acid instead of chromium trioxide, resulting in generation of NOx. Consequently, not only a de-NOx system may be required, but also sudden reaction may cause dangerous conditions.
Patent Document 1: Japanese Unexamined Patent Application Publication No. 2003-268562
Patent Document 2: Japanese Unexamined Patent Application Publication No. 2002-339082
Patent Document 3: Japanese Unexamined Patent Application Publication No. 1-176227

Aqueous solution of chromium salt and method for producing same


An adaptable audio instruction system and method allows for tailoring and modification to audio sequences used for audio instruction of users. The tailoring and modification abilities of the system regard content and presentation details of the audio sequences to comply with user preferences and user progress in learning content contained in the audio sequences.

Audio based systems can be used to present fixed audio sequences for instructional purposes. Such fixed audio sequences can be related to a foreign language or other material to be learned. The fixed audio sequences can be stored on analog tapes or digital files and played on tape players or digital audio players, respectively. Digital audio players can include computers and/or portable devices. The digital audio files can include, but are not limited to mp3, wav, aiff, au, vorbis, wma, aac, apple, ape and other lossy and lossless compression formats.
Various formats can be used to present the fixed audio sequences. One such format includes a series of audio content pairs that are presented in a time sequenced order when the audio sequence is played. Each of the audio content pairs include a first audio content played first in the time sequenced order and a second audio content played after the first audio content is played.
For instance, in the case of foreign language instruction, for each audio content pair, the first audio content may be a particular word or phrase in a first language and the second audio content may be the equivalent word or phrase in a second language. Other content may include for each audio content pair a question or other sort of cue for either the first audio content or the second audio content and an answer or other sort of response for the other of the first audio content and the second audio content.
Each audio content pair can include a pause positioned in the time sequenced order between the first audio content and the second audio content of the pair. This type of pause is referred to herein as an intra-pause. Intra-pauses can be used by a hearer to think of or verbalize the second audio content of a audio content pair after the first audio content of the pair has been played but before the second audio content is played.
Pauses can be also placed in the time sequenced order before and after each of the pairs. These pauses are referred to herein as inter-pauses. Inter-pauses are used to separate audio content pairs from one another, but are otherwise typically indistinguishable as to type from intra-pauses other than the differing placement in the time sequence order of the intra-pauses compared with the inter-pauses.
As the fixed audio sequences are initially heard by an individual, all the material may be unfamiliar. After the initial and subsequent presentations of the fixed audio sequences, the material as a whole becomes more familiar to the individual and in particular, some portions of the material are typically learned by the individual more quickly than other portions.
Unfortunately, the fixed audio sequences of the audio tapes and digital audio files remain in the same state to be re-played identically to when they were first heard by the individual rather than being modified to the changing state of learning of the individual. For instance, even though the individual will learn some portions of the material faster than others, the initial fixed order of the audio sequence with the original content selection is continually re-played. Audio content that is already learned by the individual must be heard again in order to hear accompanying audio content that is not yet learned thereby reducing efficiency and effectiveness of the audio based instruction.

Adaptable audio instruction system and method


A thermoplastic resin composition comprising an aromatic polysulfone resin and at least one resin selected from aromatic polyester resins, wherein the amount of alkali metal which exists in the aromatic polysulfone resin as a terminal phenolate is 50 ppm or less, and molded article thereof. This composition is excellent in heat resistance and melt-mold processability.

1. Field of the Invention
The present invention relates to a thermoplastic resin composition that is excellent in mechanical properties, heat resistance, moldability, molded-article appearance, etc., and a molded article made therefrom.
2. Description of the Related Art
For the object of improving the chemical resistance of an aromatic polyester resin or improving the impact resistance and flowability during mold processing of an aromatic polysulfone resin, various thermoplastic resin compositions comprising an aromatic polyester resin and an aromatic polysulfone resin have been proposed.
For example, JP-B-45-39181, discloses that chemical resistance and thermal-stress brittleness are improved by mixing an aromatic polysulfone resin with an aromatic polycarbonate resin, compared to each resin alone.
JP-B-49-13855 discloses that a composition comprising an aromatic polysulfone resin and an aromatic polycarbonate resin is excellent in heat-deformation resistance compared with ABS resin.
JP-A-54-28361 discloses that a composition comprising an aromatic polycarbonate resin having a weight average molecular weight of larger than 60000, and an aromatic polysulfone resin is improved in chemical resistance and temperature of deflection under load compared with each resin alone.
JP-A-60-51739 discloses that a composition comprising an aromatic polysulfone resin and an aromatic polycarbonate resin having a specific structure is excellent in mechanical properties, and has improved chemical resistance.
However, in these compositions, there have been problems, such that the originally expected physical properties cannot be obtained. These problems have resulted from (1) decomposition of an aromatic polycarbonate resin or an aromatic polyester resin in the production process by melt-kneading, or (2) difficulties encountered in melt-molding operations such as injection molding, extrusion molding, etc. due to a viscosity fall or gas generation accompanying a decomposition.
An object of the present invention is to provide a thermoplastic resin composition which is excellent in heat resistance and melt-mold processability.
As a result of extensive studies to solve the above problems, the present inventors found that the above object can be attained with using a composition comprising an aromatic polysulfone resin containing only a small amount of alkali metals existing as terminal phenolate and an aromatic polyester resin.
That is, the present invention relates to a thermoplastic resin composition comprising an aromatic polysulfone resin and at least one resin selected from an aromatic polyester resin, wherein the amount of alkali metal which exists in an aromatic polysulfone resin as a terminal phenolate is 50 ppm or less based on the total amount of the aromatic polysulfone resin, and a molded article thereof.
The aromatic polyester resins used in the present invention are a polycarbonate resin, a polyalkylene polyarylate resin, a polyarylate resin, and a liquid crystal polyester resin.
The polycarbonate resin is a homopolymer having a repeating unit represented by the following Formula (1), a copolymer thereof, or a mixture containing such a homopolymer and copolymer.
In Formula (1), A is a divalent aromatic group which is the residue of a dihydric phenol as a raw material. A dihydric phenol which can be used in order to manufacture such an aromatic polycarbonate is a single or plural nucleus aromatic compound containing two hydroxyl groups as functional groups attached directly on the aromatic carbon atoms. Examples of such a dihydric phenol include: bisphenol A, bis(4-hydroxyphenyl)methane, 2,2-bis(4-hydroxy-3-methylphenyl)propane, 2,2-(3,5,3xe2x80x2,5xe2x80x2-tetrachloro-4,4xe2x80x2-hydroxyphenyl)propane, 2,2-(3,5,3xe2x80x2,5xe2x80x2-tetrabromo-4,4xe2x80x2-hydroxyphenyl)propane, 1,1-bis(4-hydroxyphenyl)cyclohexane, hydroquinone, resorcinol, biphenyl-4,4xe2x80x2-diol, and the like, although the present invention is not limited thereto.
Use of a homo-polycarbonate or co-polycarbonate using at least 30 mol % bisphenol A as a dihydric phenol is preferable in the present invention.
The polyalkylene polyarylate resin used in the present invention is a polyester synthesized from a dihydric alcohol, or a derivative thereof, and an aromatic dicarboxylic acid, or a derivative thereof, and said polyalkylene polyarylate resin is a homopolymer or copolymer having a repeating unit represented by following Formula (2) or a mixture containing such a homopolymer and copolymer.
"Parenopenst"Oxe2x80x94Bxe2x80x94Oxe2x80x94COxe2x80x94Dxe2x80x94CO"Parenclosest"xe2x80x83xe2x80x83Formula (2)
In Formula (2), B is an alkylene group which is a dihydric alcohol residue of the raw material.
As examples of the dihydric alcohol which can be used in order to manufacture the aromatic polyester, ethylene glycol, propylene glycol, butane-1,4-diol, propane-1,3-diol, 2-ethylpropane-1,3-diol, 2,2-dimethylpropane-1,3-diol, pentane-1,5-diol, hexane-1,6-diol, cyclohexane-1,4-dimethanol, 3-ethylpentane-2,4-diol, 2-methylpentane-2,4-diol, and the like are mentioned, although the present invention is not limited thereto. The term xe2x80x9cdihydric alcohol derivativexe2x80x9d as used herein means a diester, such as an alkyl- or phenyl-diester of the above dihydric alcohol. Also mixtures thereof can be used in the present invention, if so desired.
In Formula (2), D is a divalent aromatic group which is the residue of an aromatic dicarboxylic acid of a raw material. As examples of the aromatic dicarboxylic acid which can be used in order to manufacture such aromatic polyesters, terephthalic acid, isophthalic acid, phthalic acid, biphenyl-4,4xe2x80x2-dicarboxylic acid, naphthalene-2,6-dicarboxylic acid, oxydiphenyl-4,4xe2x80x2-dicarboxylic acid, ethylenedioxyphenyl-4,4xe2x80x2-dicarboxylic acid, thiodiphenyl-4,4xe2x80x2-dicarboxylic acid, and the like are mentioned, although the present invention is not limited thereto. The hydrogen atom of the aromatic nuclei can be optionally substituted with an alkyl group having 1-6 carbon atoms an alkenyl group having 3-10 carbon atoms, a phenyl group or a halogen atom.
Among the polyalkylene polyarylate resin of the present invention there are included: a polyethylene terephthalate resin containing at least 80% by weight, suitably at least 90% by weight of ethylene-glycol unit based on the dihydric alcohol component, and containing at least 80% by weight, suitably at least 90% by weight of terephthalic acid unit based on the aromatic dicarboxylic acid component;
a polybutylene terephthalate resin containing at least 80% by weight, suitably at least 90% by weight of 1,4-butanediol unit based on the dihydric alcohol component, and containing at least 80% by weight, suitably at least 90% by weight of terephthalic acid unit based on the aromatic dicarboxylic acid component; and a polyethylene naphthalate resin containing at least 80% by weight, suitably at least 90% by weight of ethylene-glycol unit based on the dihydric alcohol component, and containing at least 80% by weight, suitably at least 90% by weight of 2,6-naphthalene dicarboxylic acid unit based on the aromatic dicarboxylic acid component.
The polyarylate resin used in the present invention is a polyester synthesized from dihydric phenol or its derivative, and an aromatic dicarboxylic acid, or a derivative thereof, and is a homopolymer or a copolymer having a repeating unit represented by the following Formula (3), and a mixture containing such a homopolymer or copolymer
"Parenopenst"Oxe2x80x94Exe2x80x94Oxe2x80x94COxe2x80x94Dxe2x80x94CO"Parenclosest"xe2x80x83xe2x80x83Formula (3)
In Formula (3), E is a divalent aromatic group which is the residue of dihydric phenol of a raw material.
Examples of dihydric phenol which can be used in order to manufacture such a polyarylate resin include: bis(4-hydroxyphenyl)-methane, bis(4-hydroxy-3-methylphenyl)-methane, bis(4-hydroxy-3,5-dichlorophenyl)-methane, bis(4-hydroxy-3,5-dibromophenyl)-methane, bis(4-hydroxy-3,5-difluorophenyl)-methane, bis(4-hydroxyphenyl)-ketone, bis(4-hydroxyphenyl)-sulfide, bis(4-hydroxyphenyl)-sulfone, 4,4-dihydroxydiphenylether, 1,1-bis(4-hydroxyphenyl)-ethane, 2,2-bis(4-hydroxyphenyl)-propane, 2,2-bis(hydroxy-3-methylphenyl)-propane, 2,2-bis(4-hydroxy-3-chlorophenyl)-propane, 2,2-bis(4-hydroxy-3,5-dichlorophenyl)-propane, 2,2-bis(4-hydroxynaphtyl)-propane, bis(4-hydroxyphenyl-phenylmethane, bis(4-hydroxyphenyl)-diphenylmethane, and bis(4-hydroxyphenyl)-4-methylphenylmethane, 1,1-bis(4-hydroxyphenyl)-2,2,2-trichloroethane, bis(4-hydroxyphenyl)-4-chlorophenylmethane, 1,1-bis(4-hydroxyphenyl)-cyclohexane, bis(4-hydroxyphenyl)-cyclohexylmethane, 4,4-dihydroxydiphenyl, 2,2-dihydroxydiphenyl, dihydroxynaphthalenes such as 2,6-dihydroxynaphthalene, hydroquinone, resorcinol, 2,6-dihydroxytoluene, 2,6-dihydroxychlorobenzene, and 3,6-dihydroxytoluene. The derivative of dihydric phenol is a diester, such as alkyl or phenyl diester of the above dihydric phenol, and mixtures of the dihydric phenols and derivatives thereof may be used if so desired.
In Formula (3), D is a divalent aromatic group which is the residue of an aromatic dicarboxylic acid of a raw material, and examples thereof are as above-mentioned. For example, among them, a suitable polyarylate resin contains at least 80% by weight, preferably at least 90% by weight of 2,2-bis(4-hydroxyphenyl)-propane based on the dihydric phenol component, and contains terephthalic acid and isophthalic acid as an aromatic dicarboxylic acid unit.
The liquid crystal polyester used in the present invention is a polyester called thermotropic liquid crystalline polymer, and examples thereof include;
(1) a polyester of a combination of an aromatic dicarboxylic acid, aromatic diol and aromatic hydroxycarboxylic acid,
(2) a polyester of a combination of different kinds of aromatic hydroxycarboxylic acids,
(3) a polyester of a combination of an aromatic dicarboxylic acid and aromatic diol,
(4) a polyester obtained by reacting an aromatic hydroxycarboxylic acid with a polyester such as polyethylene terephthalate, and the like. And, each of them forms an anisotropic molten material at a temperature of not higher than 400xc2x0 C. In place of these aromatic dicarboxylic acid, aromatic diol and aromatic hydroxycarboxylic acid, ester-forming derivatives thereof are also sometimes used.
Examples of the repeating structural unit of the above-described liquid crystal polyester include, but are not limited to, the following units.
Repeating Structural Units Derived From Aromatic Hydroxycarboxylic Acids:
Repeating Structural Units Derived From Aromatic Dicarboxylic Acids:
Repeating Structural Units Derived From Aromatic Acids:
Repeating Structural Units Derived From Diols:
"Brketopenst"Oxe2x80x94CH2CH2xe2x80x94"Brketclosest", "Brketopenst"Oxe2x80x94CH2CH2CH2CH2xe2x80x94O"Brketclosest"
A liquid crystal polyester which is particularly preferable in view of a balance between heat resistance, mechanical properties and processability is one which comprises the repeating structural unit represented by (A1) in an amount of at least 30% by mol.
Concretely, liquid crystal polyesters containing repeating structural units in combinations represented by the following formulae (a) to (f) are preferable.
(a): (A1), (B1) or a mixture of (B1) and (B2), (C1).
(b): (A1), (A2).
(c): Combination (a) wherein a part of (A1) is replaced by (A2).
(d): Combination (a) wherein a part of (B1) is replaced by (B3).
(e): Combination (a) wherein a part of (C1) is replaced by (C3).
(f): Combination (b) to which structural units (B1) and (C1) are further added.
Liquid crystal polyesters having the basic structures (a) and (b) are described respectively in JP-B-47-47870 and JP-B-63-3888.
The aromatic polysulfone resin used in the present invention comprises an arylene unit, an ether bond and a sulfone bond as components thereof. The arylene unit is defined as a polyarylene compound located disorderly or orderly together with an ether bond and a sulfone bond. The following repeating units are included herewith as typical examples thereof. However, the present invention is not limited thereto.
The compound (II) contains a random copolymer. In the formula, R1 represents an alkyl group having 1-6 carbon atoms, an alkenyl group having 3-10 carbon atoms, a phenyl group, or a halogen atom; p is an integer of 0 to 4; m and n represent average number of repeating units, and m and n are within the range of 0.1 to 100; each R1 on the same or different nucleus may differ mutually; p may differ each mutually.
This compound contains a random copolymer. In the formula, R1 represents an alkyl group having 1-6 carbon atoms, an alkenyl group having 3-10 carbon atoms, a phenyl group, or a halogen atom; p is an integer of 0 to 4; q, m and n represent average number of repeating units, q is a numeral of 1 to 3, m and n are within the range of 0.1 to 100; each R1 on the same or different nucleus may differ mutually; and each p may differ mutually.
As for the aromatic polysulfone resin used in the present invention, the value of (m/m+n) in the repeating unit represented by (II) or (III) is preferably not less than 0.8. Moreover, q in the structural unit of (III) is preferably 1. Among them, a polysulfone having the repeating units of (I) and (II) is preferable, and a polysulfone having the repeating unit of (I) is more preferable.
The aromatic polysulfone resin used in the present invention contains the alkali metal, which exists as terminal phenolate in an amount of 50 ppm or less, preferably not more than 40 ppm and not less than 5 ppm, based on the total amount of the aromatic polysulfone resin. When the alkali metal which exists as terminal phenolate is more than 50 ppm, the heat resistance of the composition is inferior, and it is not preferable. Terminal structures other than phenolate are determined according to the process of each resin. For example, Cl, OH, OR (R is an alkyl group), and the like are mentioned, but the present invention is not limited thereto.
Examples of the method for obtaining aromatic polysulfone resins containing alkali metal which exists as terminal phenolate in an amount of 50 ppm or less based on the total amount of the aromatic polysulfone resin are:
a method of converting the end groups to Cl, in case of dehydrochlorination polycondensation of a divalent phenolate (obtained, for example, by heat-melting of dihydric phenol, such as 4,4xe2x80x2-dihydroxydiphenylsulfone and bisphenol A, with potassium carbonate or sodium hydroxide, with stirring) and a dichloro compound (for example, 4,4xe2x80x2-dichlorodiphenylsulfone) by charging excess amount of the dichloro compound in the production process, maintaining satisfactory polymerization time, and completing the reaction;
a method of converting the end groups to OR (R is an alkyl group) by charging a compound represented by RCl (R is an alkyl group) in the second half of polycondensation; and
a method of converting the end groups to hydroxyl groups by washing the aromatic polysulfone resin containing terminal phenolates more than 50 ppm with water or aqueous acetic-acid solution.
The amount of the aromatic polyester resin in the resin composition of the present invention compounds is 5-55% by weight on the basis of the total weight of the aromatic polysulfone resin and the aromatic polyester resin, more suitably 25-45% by weight.
In the present invention, if necessary, one or more of the types of typical additives described below can be added to the compositions of the present invention.
Fibrous or needlelike reinforcements such as glass fiber, silica alumina fiber, alumina fiber, carbon fiber, aluminum borate whisker, etc.; inorganic fillers, such as talc, mica, clay, glass bead, etc.; mold release agents, such as a fluoropolymer, metallic soaps, etc.; colorants, such as dye, pigment, etc.; antioxidant, heat stabilizer, ultraviolet absorber, antistatic agent, and a surfactant.
Moreover, there can be added a small amount of thermoplastic resin, for example, polyethylene, polypropylene, polyvinyl chloride, ABS resin, polystyrene, methacrylic resin, polyamide, polyester, polyphenylene sulfide, polyetherketone, polyphenylene ether and modifications thereof, polyether imide, and the like, either alone or in combinations of two or more of them. There can also be added a small amount of thermosetting resin, for example, phenol resin, epoxy resin, cyanate resin, isocyanate resin, polyimide resin, and the like, either alone or in combination of two or more of them. A small amount of rubber component can also be added if so desired.
The formulation method of the raw material for obtaining a resin composition of the present invention is not especially limited. Usually, an aromatic polycarbonate resin, an aromatic polysulfone resin, if necessary, reinforcements, such as glass fiber, an inorganic filler, a mold release agent and a heat stabilizer, etc., are mixed with a Henschel mixer, a tumbling mixer, or the like, and melt-kneaded using an extruder. As a method of melt-kneading, it is possible that all raw materials are mixed together and fed to an extruder. It is also possible that raw materials such as inorganic fillers and reinforcements like glass fiber etc., can be fed separately from raw materials mainly that are composed of resins.
The preparation method of a molded article molded made from or by using the thermoplastic resin composition of the present invention is not especially limited. As methods for melting, solidifying and shaping resins, an extrusion molding, injection molding, a blow molding and the like are mentioned. Among them, especially injection molding is preferably used. Further, the extrusion-molded article may be processed by cutting or pressing if so desired.
The thermoplastic resin composition of the present invention can be suitably used for manufacturing parts for a car, an airplane, etc., industrial instruments, household electric appliances products, tableware and medical instruments, OA/AV instruments, and electron/electronic parts, for example, IC trays, IC sockets, etc., for which heat resistance is especially required.

Aromatic polysulfone resin composition and molded article containing the same


Described herein are compounds that are useful as protein kinase inhibitors having the formula:

The present invention is in the field of medicinal chemistry and relates to pyrazole compounds that are protein kinase inhibitors, especially inhibitors of ERK, compositions containing such compounds and methods of use. The compounds are useful for treating cancer and other disease states that are alleviated by protein kinase inhibitors.
Mammalian mitogen-activated protein (MAP)1 kinases are serine/threonine kinases that mediate intracellular signal transduction pathways (Cobb and Goldsmith, 1995, J Biol. Chem., 270, 14843; Davis, 1995, Mol. Reprod. Dev. 42, 459). Members of the MAP kinase family share sequence similarity and conserved structural domains, and include the ERK (extracellular signal regulated kinase), JNK (Jun N-terminal kinase), and p38 kinases. JNKs and p38 kinases are activated in response to the pro-inflammatory cytokines TNF-alpha and interleukin-1, and by cellular stress such as heat shock, hyperosmolarity, ultraviolet radiation, lipopolysaccharides and inhibitors of protein synthesis (Derijard et al., 1994, Cell 76, 1025; Han et al., 1994, Science 265, 808; Raingeaud et al., 1995, J Biol. Chem. 270, 7420; Shapiro and Dinarello, 1995, Proc. Natl. Acad. Sci. USA 92, 12230). In contrast, ERKs are activated by mitogens and growth factors (Bokemeyer et al. 1996, Kidney Int. 49, 1187).
ERK2 is a widely distributed protein kinase that achieves maximum activity when both Thr183 and Tyr185 are phosphorylated by the upstream MAP kinase kinase, MEK1 (Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478). Upon activation, ERK2 phosphorylates many regulatory proteins, including the protein kinases Rsk90 (Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848) and MAPKAP2 (Rouse et al., 1994, Cell 78, 1027), and transcription factors such as ATF2 (Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247), Elk-1 (Raingeaud et al. 1996), c-Fos (Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952), and c-Myc (Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162). ERK2 is also a downstream target of the Ras/Raf dependent pathways (Moodie et al., 1993, Science 260, 1658) and may help relay the signals from these potentially oncogenic proteins. ERK2 has been shown to play a role in the negative growth control of breast cancer cells (Frey and Mulder, 1997, Cancer Res. 57, 628) and hyperexpression of ERK2 in human breast cancer has been reported (Sivaraman et al., 1997, J Clin. Invest. 99, 1478). Activated ERK2 has also been implicated in the proliferation of endothelin-stimulated airway smooth muscle cells, suggesting a role for this kinase in asthma (Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 589).
The JNK family of (MAP)1 kinases have been implicated in having a role in mediating cellular response to a variety of disorders including cancer (Oncogene 1996, 13, 135-42), hepatic disorders (Hepatology 1998, 28,1022-30), cardiovascular disease (Circ. Res. 1998, 83, 167-78; Circulation 1998, 97:1731-7; J. Biol. Chem. 1997, 272, 28050-6; Circ. Res. 1996, 79, 162-73; Circ. Res. 1996, 78, 947-53; J. Clin. Invest. 1996, 97, 508-14), and immunological disorders (J. Immunol. 1999, 162, 3176-87; Eur. J. Immunol. 1998, 28, 3867-77; J. Exp. Med. 1997, 186, 941-53; Eur. J. Immunol. 1996, 26, 989-94, among others).
Aurora2 is a serine/threonine protein kinase that has been implicated in human cancer, such as colon, breast and other solid tumors. This kinase is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, aurora2 may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, the aurora2 protein has been found to be overexpressed. See Bischoff et al., EMBO J., 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of xcex1 and xcex2 isoforms that are each encoded by distinct genes [Coghlan et al., Chemistry and Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has been implicated in various diseases including diabetes, Alzheimer""s disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be caused by, or result in, the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role.
KDR is a tyrosine kinase receptor that also binds VEGF (vascular endothelial growth factor) (Neufeld et al., 1999, FASEB J., 13, 9). The binding of VEGF to the KDR receptor leads to angiogenesis, which is the sprouting of capillaries from preexisting blood vessels. High levels of VEGF are found in various cancers causing tumor angiogenesis and permitting the rapid growth of cancerous cells. Therefore, suppressing VEGF activity is a way to inhibit tumor growth, and it has been shown that this can be achieved by inhibiting KDR receptor tyrosine kinase.
AKT, also known as protein kinase B, is a serine/threonine kinase that plays a central role in promoting the survival of a wide range of cell types [Khwaja, A., Nature, pp. 33-34 (1990)]. It has been shown by Zang, et al, that human ovarian cancer cells display elevated levels of AKT-1 and AKT-2. Inhibition of AKT induces apoptosis of these human ovarian cancer cells which demonstrates that AKT may be an important target for ovarian cancer treatment [Zang, Q. Y., et al, Oncogene, 19 (2000)] and other proliferative disorders. The AKT pathway has also been implicated in motoneuronal survival and nerve regeneration [Kazuhiko, N., et al, The Journal of Neuroscience, 20 (2000)].
There is a high unmet medical need to develop protein kinase inhibitors, especially ERK inhibitors, that are useful in treating the various conditions associated with ERK activation, especially considering the currently available, relatively inadequate treatment options for the majority of these conditions.
Accordingly, there is still a great need to develop potent inhibitors of protein kinase, including ERK inhibitors, that are useful in treating various conditions associated with protein kinase activation.
It has now been found that compounds of this invention and compositions thereof are effective as protein kinase inhibitors, especially as inhibitors of ERK. These compounds have the general formula I:
or a pharmaceutically acceptable derivative thereof, wherein:
R1 is selected from R, halogen, N(R8)2, OR, NRCOR, NRCON(R8)2, CON(R8)2, SO2R, NRSO2R, or SO2N(R8)2;
T is selected from a valence bond or a linker group; each R is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons;
R2 is selected from hydrogen, CN, halogen, aryl, aralkyl, heteroaryl, heterocyclyl, an optionally substituted acyclic aliphatic chain group having one to six carbons, or an optionally substituted cyclic aliphatic group having four to ten carbons;
R3 is selected from R, OH, OR, N(R8)2, halogen, or CN;
Q is a valence bond, J, or an optionally substituted C1-6 alkylidene chain wherein up to two nonadjacent carbons of the alkylidene chain are each optionally and independently replaced by J;
J is selected from xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94C(O)C(O)xe2x80x94, xe2x80x94NRCONR8xe2x80x94, xe2x80x94N(R)N(R8)xe2x80x94, xe2x80x94C(xe2x95x90O)NR8xe2x80x94, xe2x80x94NRC(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R)Oxe2x80x94, xe2x80x94ON(R8)xe2x80x94, xe2x80x94OC(xe2x95x90O)N(R8)xe2x80x94, xe2x80x94N(R)COOxe2x80x94, xe2x80x94SO2N(R8)xe2x80x94, xe2x80x94N(R)SO2xe2x80x94, or xe2x80x94N(R8)xe2x80x94;
R4 is selected from xe2x80x94R8, xe2x80x94R5, xe2x80x94NH2, xe2x80x94NHR5, xe2x80x94N(R5)2, or xe2x80x94NR5(CH2)yN(R5)2;
each R5 is independently selected from R6, R7, xe2x80x94(CH2)yCH(R6)(R7), xe2x80x94(CH2)yR6, xe2x80x94(CH2)yCH(R6)2, xe2x80x94(CH2)yCH(R7)2, or xe2x80x94(CH2)yR7;
y is 0-6;
each R6 is an optionally substituted group independently selected from an aliphatic, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, or heterocyclylalkoxy, group;
each R7 is independently selected from an optionally substituted hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl; and
each R8 is independently selected from R, or two R8 on the same nitrogen taken together with the nitrogen optionally form a four to eight membered, saturated or unsaturated heterocyclic ring having one to three heteroatoms.
As used herein, the following definitions shall apply unless otherwise indicated. Also, combinations of substituents or variables are permissible only if such combinations result in stable compounds.
The term xe2x80x9caliphaticxe2x80x9d as used herein means straight chained, branched or cyclic C1-C12 hydrocarbons which are completely saturated or which contain one or more units of unsaturation. For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The term xe2x80x9calkylxe2x80x9d and xe2x80x9calkoxyxe2x80x9d used alone or as part of a larger moiety refers to both straight and branched chains containing one to twelve carbon atoms. The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d used alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms. The terms xe2x80x9chaloalkylxe2x80x9d, xe2x80x9chaloalkenylxe2x80x9d, and xe2x80x9chaloalkoxyxe2x80x9d means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term xe2x80x9chalogenxe2x80x9d means F, Cl, Br, or I. The term xe2x80x9cheteroatomxe2x80x9d means N, O, or S and shall include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
The term xe2x80x9carylxe2x80x9d, used alone or as part of a larger moiety as in xe2x80x9caralkylxe2x80x9d, refers to aromatic ring groups having five to fourteen members, such as phenyl, benzyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl, and heterocyclic aromatic groups or heteroaryl groups such as 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, or 3-thienyl. The term xe2x80x9caryl ringxe2x80x9d also refers to rings that are optionally substituted.
Aryl groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other rings. Examples include tetrahydronaphthyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzoisoxazolyl, and the like. Also included within the scope of the term xe2x80x9carylxe2x80x9d, as it is used herein, is a group in which one or more carbocyclic aromatic rings and/or heteroaryl rings are fused to a cycloalkyl or non-aromatic heterocyclic ring, for example, indanyl or tetrahydrobenzopyranyl.
Non-aromatic heterocyclic rings are non-aromatic carbocyclic rings in which one or more ring carbons are replaced by a heteroatom such as nitrogen, oxygen or sulfur in the ring. The ring can be five, six, seven or eight-membered and/or fused to another ring, such as a cycloalkyl or aromatic ring. Examples include 3-1H-benzimidazol-2-one, 3-(l-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxane, benzotriazol-1-yl, benzopyrrolidine, benzopiperidine, benzoxolane, benzothiolane, and benzothiane. The term xe2x80x9cheterocyclic ringxe2x80x9d, whether saturated or unsaturated, also refers to rings that are optionally substituted.
An aryl group (carbocyclic and heterocyclic) or an aralkyl group, such as benzyl or phenethyl, may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl group include a halogen, xe2x80x94R, xe2x80x94OR, xe2x80x94SR, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, xe2x80x94OPh, substituted xe2x80x94OPh, xe2x80x94NO2, xe2x80x94CN, xe2x80x94N(R)2, xe2x80x94NRN(R)2, xe2x80x94NRCON(R)2, xe2x80x94NRCOR, xe2x80x94NRCO2(aliphatic), xe2x80x94CO2R, xe2x80x94COR, xe2x80x94C(O)C(O)R, xe2x80x94CON(R)2, xe2x80x94CONRN(R)2, xe2x80x94S(O)2R, xe2x80x94SON(R)2, xe2x80x94S(O) (aliphatic), xe2x80x94SO2N(R)2, or xe2x80x94NRS (O)2R, where each R is independently selected from hydrogen, an aliphatic group or a substituted aliphatic group.
An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Examples of suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring include those listed above for the unsaturated carbon as well as the following: xe2x95x90O, xe2x95x90S, xe2x95x90NNHR, xe2x95x90NNR2, xe2x95x90Nxe2x80x94, OR, xe2x95x90NNHCOR, xe2x95x90NNHCO2(aliphatic), xe2x95x90NNHSO2 (aliphatic), or xe2x95x90NR, where each R is independently selected from hydrogen, an aliphatic group or a substituted aliphatic group.
The term xe2x80x9calkylidene chainxe2x80x9d refers to an optionally substituted, straight or branched, carbon chain that may be fully saturated or have one or more units of unsaturation. The optional substituents are as described above for an aliphatic group. Optional substituents of the C1-6 alkylidine chain of Q include those described above for an aliphatic group.
The term xe2x80x9clinker groupxe2x80x9d means an organic moiety that connects two parts of a compound. Linkers are typically comprised of an atom such as oxygen or sulfur, a unit such as xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94, or a chain of atoms, such as an alkylidene chain. The molecular mass of a linker is typically in the range of about 14 to 200. Examples of linkers include a saturated or unsaturated C1-6 alkylidene chain which is optionally substituted, and wherein up to two saturated carbons of the chain are optionally replaced by xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CONHxe2x80x94, CONHNHxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94NHCO2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHCONHxe2x80x94, xe2x80x94OC(xe2x95x90O)xe2x80x94, xe2x80x94OC(xe2x95x90O)NHxe2x80x94, xe2x80x94NHNHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94SO2NHxe2x80x94, or NHSO2xe2x80x94.
It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.
Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention.
One embodiment of this invention relates to compounds of formula II:
wherein R1, R2, R3, R4, T, and Q are as described above.
A preferred embodiment of this invention relates to compounds having the formula:
wherein T, R2, and R4 are as described above and R1 and R3 are each hydrogen.
Preferred compounds include those having one or more, and most preferably all, of the following features: (a) Q is xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, or xe2x80x94CONHxe2x80x94; (b) T is a valence bond; (c) R1 is hydrogen or NHR; (d) R2 is an optionally substituted aryl ring, more preferably an optionally substituted phenyl ring; (c) R3 is hydrogen; (e) R4 is selected from R5, xe2x80x94NHR5, xe2x80x94N(R5)2, xe2x80x94NR5R6, xe2x80x94NHCHR5R6, or xe2x80x94NHCH2R5; and/or (f) R5 is an optionally substituted group selected from aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl group, (CH2)yR6, (CH2)yR7, or (CH2)yCH(R6)(R7).
Examples of substitutions of the R2 phenyl group include halo, nitro, alkoxy, and amino.
When R4 is R5, examples of preferred R5 groups include pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, and piperazin-1-yl wherein each group is optionally substituted. When R4 is xe2x80x94NHR5 or xe2x80x94N(R5)2, preferred R5 groups further include (CH2)yR6, (CH2)yR7, and (CH2)yCH(R6)(R7). Examples of preferred R6 and R7 include pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, tetrahydrofuran-2-yl, cyclohexyl, phenyl, xe2x80x94CH2OH, xe2x80x94(CH2)2OH, and isopropyl, wherein each group is optionally substituted.
Exemplary structures of formula II, wherein R1 and R3 are each H, are set forth in Table 1 below.

wherein T, R, R2, and R4 are as described above.
Preferred II-B compounds include those having one or more, and most preferably all, of the following features: (a) T is a valence bond; (b) R3 is hydrogen; and/or (c) R2 is an optionally substituted aryl ring, more preferably an optionally substituted phenyl ring.
Exemplary structures of formula II-B, wherein R3 is H, are set out in Table 2 below.
The present compounds may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general Schemes I and II and the synthetic examples shown below.
Scheme I above shows a general synthetic route that was used for preparing the compounds of this invention when R2 is an optionally substituted phenyl group. In step (a), an optionally substituted benzoyl chloride was combined with compound 1 in dichloromethane and aluminum trichloride to form compound 2. A wide variety of substitutions on the phenyl ring are amenable to this reaction. Examples of suitable R2 groups include, but are not limited to, those set forth in Table 1 above.
The formation of amide 4 was achieved by treating compound 2 with an amine 3 in DMF. When amine 3 was a primary amine, the reaction proceeded at ambient temperature. When amine 3 was a secondary amine, the reaction was heated at 50xc2x0 C. to achieve complete reaction and afford amide 4.
The formation of enamine 5 at step (c) was achieved by treating amide 4 with (Me2N)2xe2x80x94Otxe2x80x94Bu at ambient temperature. Alternatively, the reaction to form enamine 5 at step (c) was also achieved by using dimethylformamide-dimethylacetal (DMFxe2x80x94DMA). The reaction sing DMFxe2x80x94DMA requires elevated temperature to afford enamine 5 whereas using (Me2N)2xe2x80x94OtBu has the advantage of proceeding at ambient temperature to afford the enamine 5 in higher purity.
The formation of the pyrazole compound 6 at step (d) was achieved by the treatment of enamine 5 with hydrazine hydrate at elevated temperature. The compounds of formula II synthesized by this method, as exemplified in Table 1, were isolated by preparatory HPLC (reverse phase, 10xe2x86x9290% MeCN in water over 15 minutes). The details of the conditions used for producing these compounds are set forth in the Examples.
Scheme II above shows a general synthetic method that may be used for preparing compounds of formula II-B, using compound II-B-16 as an example. This method is modified from that of Jira, T., et al, Pharmazie, pp. 401-406 (1994). Compounds of formula II-B may also be prepared by methods similar to those of Woller, J., et al, Pharmazie, pp. 937-940 (1996), Rychmans, T., et al, Tetrahedron, pp. 1729-1734 (1997), and Tupper, D. E., et al, Synthesis, pp. 337-341 (1997).
According to another embodiment, the invention provides a method of inhibiting kinase activity in a biological sample. This method comprises the step of contacting said biological sample with a compound of this invention.
The term xe2x80x9cbiological samplexe2x80x9d, as used herein includes cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. The term xe2x80x9cbiological samplexe2x80x9d also includes living organisms, in which case xe2x80x9ccontacting a compound of this invention with a biological samplexe2x80x9d is synonymous with the term xe2x80x9cadministrating said compound (or composition comprising said compound) to a mammal.xe2x80x9d
Another aspect of this invention relates to a method for treating a disease state in mammals that is alleviated by treatment with a protein kinase inhibitor, which method comprises administering to a mammal in need of such a treatment a therapeutically effective amount of a compound having the formula
or a pharmaceutically acceptable derivative thereof, wherein:
R1 is selected from R, halogen, N(R8)2, OR, NRCOR, NRCON(R8)2, CON(R8)2, SO2R, NRSO2R, or SO2N(R8)2;
T is selected from a valence bond or a linker group;
each R is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons;
R2 is selected from hydrogen, CN, halogen, aryl, aralkyl, heteroaryl, heterocyclyl, an optionally substituted acyclic aliphatic chain group having one to six carbons, or an optionally substituted cyclic aliphatic group having four to ten carbons;
R3 is selected from R, OH, OR, N(R8)2, halogen, or CN;
Q is a valence bond, J, or an optionally substituted C1-6 alkylidene chain wherein up to two nonadjacent carbons of the alkylidene chain are each optionally and independently replaced by J;
J is selected from xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94C(O)C(O)xe2x80x94, xe2x80x94NRCONR8xe2x80x94, xe2x80x94N(R)N(R8)xe2x80x94, xe2x80x94C(xe2x95x90O)NR8xe2x80x94, xe2x80x94NRC(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R)Oxe2x80x94, xe2x80x94ON(R8)xe2x80x94, xe2x80x94OC(xe2x95x90O)N(R8)xe2x80x94, xe2x80x94N(R)COOxe2x80x94, xe2x80x94SO2N(R8)xe2x80x94, xe2x80x94N(R)SO2xe2x80x94, or xe2x80x94N(R8)xe2x80x94;
R4 is selected from xe2x80x94R8, xe2x80x94R5, xe2x80x94NH2, xe2x80x94NHR5, xe2x80x94N(R5)2, or xe2x80x94NR5(CH2)yN(R5)2;
each R5 is independently selected from R6, R7, xe2x80x94(CH2)yCH(R6)(R7), xe2x80x94(CH2)yR6, xe2x80x94(CH2)yCH(R6)2, xe2x80x94(CH2)yCH(R7)2, or xe2x80x94(CH2)yR7;
y is 0-6;
each R6 is an optionally substituted group independently selected from an aliphatic, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, or heterocyclylalkoxy, group;
each R7 is independently selected from an optionally substituted aliphatic, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl;
and each R8 is independently selected from R, or two R8 on the same nitrogen taken together with the nitrogen optionally form a four to eight membered, saturated or unsaturated heterocyclic ring having one to three heteroatoms.
One embodiment comprises administering a compound of formula II. A preferred embodiment comprises administering a compound of formula II-A, and most preferably a compound listed in Table 1. Another preferred embodiment comprises administering a compound of formula II-B, and more preferably a compound listed in Table 2. Pharmaceutical compositions useful for such methods are described below.
The present method is especially useful for treating a disease state that is alleviated by the use of an inhibitor of ERK, JAK, JNK, Aurora, GSK, KDR, or AKT. As used herein, unless otherwise indicated, the terms xe2x80x9cERKxe2x80x9d, xe2x80x9cJAKxe2x80x9d, xe2x80x9cJNKxe2x80x9d, xe2x80x9cAuroraxe2x80x9d, xe2x80x9cGSKxe2x80x9d, xe2x80x9cKDRxe2x80x9d, and xe2x80x9cAKTxe2x80x9d refer to all isoforms of the respective enzymes including, but not limited to, ERK1, ERK2, ERK3, ERK4, ERK5, ERK6, ERK7, JAK1, JAK2, JAK3, JAK4, JNK1, JNK2, JNK3, Aurora1, Aurora2, GSK3-alpha, GSK3-beta, KDR, AKT-1, AKT-2, and AKT-3.
The activity of the compounds as protein kinase inhibitors, for example as ERK inhibitors, may be assayed in vitro, in vivo or in a cell line. Using ERK as an example, in vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of activated ERK. Alternate in vitro assays quantitate the ability of the inhibitor to bind to ERK and may be measured either by radiolabelling the inhibitor prior to binding, isolating the inhibitor/ERK complex and determining the amount of radiolabel bound, or by running a competition experiment where new inhibitors are incubated with ERK bound to known radioligands. One may use any type or isoform of ERK, depending upon which ERK type or isoform is to be inhibited.
The compounds of this invention are potent inhibitors of ERK as determined by enzymatic assay. These compounds have also been shown to inhibit ERK in a cell proliferation assay. The details of the conditions used for both the enzymatic and the cell proliferation assays are set forth in the Examples hereinbelow.
The compounds of this invention are also inhibitors of JNK, Aurora, GSK, KDR, and AKT as determined by enzymatic assay. The details of the conditions used for this assay are set forth in the Examples hereinbelow. Without being bound by theory, the compounds of this invention are also expected to inhibit other protein kinases.
The protein kinase inhibitors of this invention, or pharmaceutical salts thereof, may be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions effective to treat or prevent a protein kinase-mediated condition which comprise the protein kinase inhibitor in an amount sufficient to detectably inhibit protein kinase activity and a pharmaceutically acceptable carrier, are another embodiment of the present invention. The term xe2x80x9cdetectably inhibitxe2x80x9d, as used herein means a measurable change in activity between a sample containing said inhibitor and a sample containing only a protein kinase.
The term xe2x80x9cERK-mediated conditionxe2x80x9d, as used herein means any disease state or other deleterious condition in which ERK is known to play a role. Such conditions include, without limitation, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer""s disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone-related diseases. The term xe2x80x9ccancerxe2x80x9d includes, but is not limited to the following cancers: breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin""s, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, and leukemia.
Compounds of the present invention are also useful as inhibitors of related kinases. The term xe2x80x9crelated kinasesxe2x80x9d refer to protein kinases having residues which are similar to those residues which line the ERK binding site. Without wishing to be bound by theory, applicants speculate that this inhibitory activity is due to the close structural similarity between the active sites of ERK and related kinases. The alignment of the ERK sequence with other kinases can be derived from common software programs such as the xe2x80x9cbestfitxe2x80x9d program available from Genetics Computer Group. This program uses the local homology algorithm described by Smith and Waterman in Advances in Applied Mathematics 2; 482 (1981).
Related kinases inhibited by the compounds of this invention would contain residues, identified by the above standard protein sequence alignment software, corresponding to the ERK residues: I31, E33, G34, A35, Y36, G37, M38, V39, A52, K54, R67, T68, E71, L75, I84, I86, I103, Q105, D106, L107, M108, E109, D111, K114, D149, K151, S153, N154, L156, C166, and D167, with a similarity score of 80% or greater. The similarity score may be determined using standard amino acid substitution tables such as those described by Dayhoff (Dayhoff, M. O., et al, Atlas of Protein Sequence and Structure, 1979) and Blosom-Henikoff (Blosum-Henikoff, S and Henikoff, J. G., PNAS, 1992,89:10915-10919). The term xe2x80x9crelated kinasesxe2x80x9d also includes those containing residues with a similarity score of 80% or greater to the following ERK residues: I31, G37, A52, I103, E109, and N154.
Compounds of the present invention are also useful as inhibitors of JAK-family kinases. Without wishing to be bound by theory, applicants speculate that this inhibitory activity is due to the close structural similarity between the active sites of ERK and JAK as determined by the standard methods described above.
It has been found, from in-house x-ray crystal structure experiments with ERK-bound inhibitors, that three amino-acid residues in the ERK active site form key hydrogen bonding interactions with these types of inhibitors. These three amino-acid residues are M108, D106, and Q105. This amino acid numbering corresponds to the Swiss-Prot database entry for accession #P28482. The Swiss-Prot database is an international protein sequence database distributed by the European Bioinformatics Institute (EBI) in Geneva, Switzerland. The database can be found at www.ebi.ac.uk/swissprot.
The backbone atoms of M108 and D106, and the associated interactions, are common to all kinases. M108 provides both a hydrogen bond donor and acceptor and D106 provides a hydrogen bond acceptor through its backbone CO. An inhibitor that could form a hydrogen-bond to one or more of these hydrogen-bonding groups within the active site would be expected to bind to the enzyme and, therefore, show inhibition.
The Q105 glutamine residue is implicated in a subset of kinases that includes ERK and JAK as determined by examination of the alignment data obtained from the above mentioned software programs. Q105 provides a key hydrogen-bond accepting side-chain CO. Modeling experiments reveal that for both ERK and JAK, the hydrogen bond donor of the Ht-ring is within hydrogen-bonding distance to the Q105 residue. Because of these similar active-site interactions, the ERK inhibitors of the present invention inhibit JAK as well. Accordingly, these compounds are useful for treating JAK-mediated conditions.
The term xe2x80x9cJAK-mediated conditionxe2x80x9d, as used herein, means any disease state or other deleterious condition in which JAK is known to play a role. Such conditions include, without limitation, allergic disorders such as asthma and atopic dermatitis, autoimmune diseases such as SLE lupus and psoriasis, and conditions associated with organ transplantations.
The compounds of this invention are also useful as inhibitors of JNK-family kinases. Accordingly, these compounds are useful for treating JNK-mediated conditions. The term xe2x80x9cJNK-mediated conditionxe2x80x9d, as used herein, means any disease state or other deleterious condition in which JNK is known to play a role. Such conditions include, without limitation, apoptosis-driven neurodegenerative diseases such as Alzheimer""s Disease, Parkinson""s Disease, ALS (Amyotrophic Lateral Sclerosis), epilepsy and seizures, Huntington""s Disease, traumatic brain injuries, as well as ischemic and hemorrhaging stroke, heart disease, immunodeficiency disorders, inflammatory diseases, allergic disorders, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases, viral diseases, disorders relating to cell death and hyperplasia including reperfusion/ischemia in stroke, heart attacks, and organ hypoxia, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer, liver disease including hepatic ischemia, heart disease such as myocardial infarction and congestive heart failure, pathologic immune conditions involving T cell activation and neurodegenerative disorders.
The compounds of this invention are also useful as inhibitors of Aurora. Accordingly, these compounds are useful for treating Aurora-mediated conditions. The term xe2x80x9cAurora-mediated conditionxe2x80x9d, as used herein, means any disease or other deleterious condition in which Aurora is known to play a role. Such conditions include, without limitation, cancer. The term xe2x80x9ccancerxe2x80x9d includes, but is not limited to the following cancers: colon and ovarian.
The compounds of this invention are also useful as inhibitors of GSK family kinases. Accordingly, these compounds are useful for treating GSK-mediated conditions. The term xe2x80x9cGSK-mediated conditionxe2x80x9d, as used herein, means any disease state or other deleterious condition in which GSK is known to play a role. Such conditions include, without limitation, diabetes, Alzheimers disease, neurodegenerative diseases, and CNS disorders such as manic depressive disorder and schizophrenia.
The compounds of this invention are also useful as inhibitors of KDR family kinases. Accordingly, these compounds are useful for treating KDR-mediated conditions. The term xe2x80x9cKDR-mediated conditionxe2x80x9d, as used herein, means any disease state or other deleterious condition in which KDR is known to play a role. KDR-mediated diseases or conditions include, but are not limited to, cancer such as brain cancer, genitourinary tract cancer, lymphatic system cancer, stomach cancer, cancer of the larynx, lung cancer, pancreatic cancer, breast cancer, Kaposi""s sarcoma, and leukemia; endometriosis, benign prostatic hyperplasia; vascular diseases such as restenosis and atherosclerosis; autoimmune diseases such as rheumatoid arthritis and psoriasis; ocular conditions such as proliferative or angiogenic retinopathy and macular degeneration; and inflammatory diseases such as contact dermatitis, asthma and delayed hypersensitivity reactions.
The compounds of this invention are also useful as inhibitors of AKT family kinases. Accordingly, these compounds are useful for treating AKT-mediated conditions. The term xe2x80x9cAKT-mediated conditionxe2x80x9d, as used herein, means any disease state or other deleterious condition in which AKT is known to play a role. AKr-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders.
In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention may also be employed in compositions to treat or prevent the above-identified disorders.
A xe2x80x9cpharmaceutically acceptable derivative or prodrugxe2x80x9d means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N+(C1-4 alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term xe2x80x9cparenteralxe2x80x9d as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.
Sterile injectable forms of the compositions of this invention may be aqueous or an oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. optically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
The amount of protein kinase inhibitor of this invention that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between about 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of inhibitor will also depend upon the particular compound in the composition.
The kinase inhibitors of this invention or pharmaceutical compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a composition comprising a kinase inhibitor. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Implantable devices coated with a kinase inhibitor of this invention are another embodiment of the present invention.
According to another embodiment, the invention provides methods for treating or preventing an ERK-, JAK-, JNK-, Aurora-, GSK-, KDR-, or AKT-mediated condition, or disease state, comprising the step of administering to a patient one of the above-described pharmaceutical compositions. The term xe2x80x9cpatientxe2x80x9d, as used herein, means a mammal, preferably a human.
Preferably, that method is used to treat or prevent a condition, or disease state, selected from cancers such as cancers of the breast, colon, prostate, skin, pancreas, brain, genitourinary tract, lymphatic system, stomach, larynx and lung, including lung adenocarcinoma and small cell lung cancer, stroke, diabetes, hepatomegaly, cardiomegaly, cardiovascular disease, Alzheimer""s disease, cystic fibrosis, and viral disease, or any specific disease or disorder described above.
Depending upon the particular condition, or disease state, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention. For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the inhibitors of this invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.
Other examples of agents the inhibitors of this invention may also be combined with include, without limitation, anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; agents for treating diabetes such as insulin, insulin analogues, alpha glucosidase inhibitors, biguanides, and insulin sensitizers; and agents for treating immunodeficiency disorders such as gamma globulin.
These additional agents may be administered separately, as part of a multiple dosage regimen, from the inhibitor-containing composition. Alternatively, these agents may be part of a single dosage form, mixed together with the inhibitor in a single composition.

Pyrazole compositions useful as inhibitors of ERK

Abstract: where R1-4, Q, and T are described in the specification. The compounds are useful for treating disease states in mammals that are alleviated by a protein kinase inhibitor, particularly diseases such as cancer, inflammatory disorders, restenosis, and cardiovascular disease.


A surgical hand piece has a source of ultrasonic energy provided to a connecting body having a first passage with one end to receive fluid from a first source and the other end at the connecting body distal end. A work tip has first and second tubes each having at least one opening at its distal end and the proximal end of one or both of the tubes connected to the connecting body distal end to receive the ultrasonic energy and to selectively receive or discharge fluid from either the first or second source as controlled by a valve. A cannula is provided which is adapted to be placed in an opening in the cornea through which the work tip extends during the removal of cataracts from the eye by phacoemulsification. The cannula may be equipped with channels that permit additional infusion of fluid into the eye during the procedure, which infusion also cools the surrounding corneal tissue to protect against heat generated by the ultrasonic vibration of the work tip.

The use of ultrasonic instruments in surgical applications is well known. One widely used type of instrument is an ultrasonic hand piece that is used in ophthalmic applications, such as in the removal of cataracts from the eye by phacoemulsification.
FIG. 6 depicts one such type of prior art ultrasonic hand piece as shown in U.S. Pat. No. 4,504,264 of Kelman. This hand piece has a housing 10 of, for example, plastic or metal, within which is supported a transducer means 11 for generating mechanical vibrations upon excitation with an alternating-current electrical signal. The transducer 11 is shown as a magnetostrictive transducer with an electrical coil 12 wound about each leg of a stack of metal laminations so that longitudinal mechanical vibrations are produced. The transducer can also be of the piezoelectric type. There is a connecting body 16 of, for example, titanium, having a reduced diameter distal end portion, which also can be an attached separate portion. The connecting body forms an acoustic impedance transformer for conveying the longitudinal vibrations of the transducer 11 for application to an operative tool or working tip 14 connected to the distal end of the connecting body 16.
The work tip 14 is at least partially external of the housing 10. It is connected, such as by a screw thread, to the narrowed distal end of the connecting body 16 so as to be coupled to the transducer 11 so as to be longitudinally vibrated thereby. The working tip 14 is an elongated, hollow tip of a suitable metal, such as titanium, that is capable of supporting ultrasonic vibrations. It has a distal end of a desired shape to be placed against the tissue to be removed. The work tip 14 has a base portion 15 in threaded engagement with the distal end of the connecting body 16. The tip 14 can be interchanged by use of the screw threads.
The distal end of the tip 14 is shown surrounded by a sleeve 17, which may be made of a material such as silicone, whose proximal end 18 is supported in threaded engagement on a reduced diameter end of the housing 10. If desired, the proximal end of sleeve 17 can be engaged more proximally along the length of the housing 10. The connecting body 16 has two elastomeric 0-rings 19, 20 on its outer surface. These provide a fluid-tight seal between the connecting body 16 and the transducer means 11. A plurality of screws 51 are shown disposed around the axis of the housing 10 for preventing longitudinal displacement (other than vibration) or rotational movement of the vibratory structure within the housing and also for radial centering of the vibratory structure within the housing. Other types of conventional mounting arrangements can be used.
The hand piece also illustratively has electrical input terminals 40, 41 for applying a suitable electrical signal to the magnetostrictive transducer 11. Cooling water is shown provided inside the housing 10 from an inlet 42 to an outlet 43 and within a chamber between 0-ring 19 and a grommet 50 for circulation around the transducer and connecting body. This is not always necessary and is not used in most present day hand pieces.
The sleeve 17 around the tip 14 forms a first fluid passage 21 between the tip 14 and the sleeve for irrigation fluid. An inlet 22 is provided on the housing or sleeve distally of the 0-ring 20 for supplying the irrigation fluid to the passage 21 from a fluid supply, e.g., a bag of saline solution (not shown).
A passage 23 is formed through the connecting body 16 that is in communication with a central passage 25 of the work tip 14. An outlet 24 on the housing or sleeve receives a suction (aspiration) force that is applied to the passage 23 in the connecting body and the central passage 25 in the work tip. A chamber 31 is formed between the spaced 0-rings 19, 20 on the body 16 and the housing 10, with which the aspiration force from outline 24 communicates. Thus the aspiration force is from the source (e.g., a suction pump not shown), into the chamber 31 between the 0-rings, through the passage 23 in the connecting body and the passage 25 in the work tip 14. Tissue that is emulsified by the work tip is aspirated from the operating site by the aspiration flow force. In particular, saline solution introduced into the eye through fluid passage 21 and tissue displaced by the vibration force of the tip 14, is drawn into the distal end of passage 25 and passes out of the hand piece through outlet 24. It should be noted that passage 25 is located concentrically within passage 21.
As indicated, other apparatus (not shown) for use with the hand piece include the suction pump for producing the aspiration fluid (suction), the treatment fluid supply (irrigation fluid, such as a saline liquid), an oscillator for applying an electrical signal to the vibratory structure and control apparatus therefore. All of these are of conventional construction.
Considering now the operation of the hand piece of FIG. 6. When an electrical signal having a frequency of, for example, 40,000 cycles/second is applied to the coil 12 around the magnetostrictive transducer 11, the transducer 11 vibrates longitudinally at 40,000 cycles per second, thereby vibrating the connecting bodies 13, 16 and the work tip 14. Treatment fluid is supplied through inlet 22 and fluid passage 21 to bathe the tissue in the operating site region around the working tip 14. Suction force is applied through inlet 24 and passage 23 to the working tip 14 passage 25 to withdraw the tissue fragmented by the work tip along with some of the treatment fluid.
Instruments of the type described above are often used in cataract surgery in which the eye lens is removed from the eye capsule and an intra-ocular lens (IOL) is then implanted. In such a procedure before the IOL is implanted it has been found to be desirable to cleanup lens substance and lens epithelial cells (LEC's) in the capsular bag and to remove them. Doing this procedure provides a more stable and long-term fixation for certain types of IOL's in the capsular bag. One manner of accomplishing the cleanup is to use a combination of irrigation of the capsular bag interior with a liquid together with the application of low power ultrasonic energy. This dislodges the unwanted cells and substances so that they can be removed from the capsular bag by the aspiration fluid flow.
In a cleanup procedure it is advantageous if the flow of the irrigation liquid can be made more directional than would be possible using the hand piece with the outer sleeve through which the liquid flows and exits from around the work tip that produces the ultrasonic energy. It is also better if the aspiration force is lower. As a result, typically a different tip from the one illustrated in FIG. 6, which breaks up the tissue, is used for the cleanup. Thus, the surgeon must remove the first work tip and place a new work tip in the eye. This second insertion into the eye increases the possibilities of infection and trauma. In an alternative prior art embodiment it is possible to use a separate lumen or probe that conveys only the irrigation liquid and a separate probe with a work tip. However, this has a disadvantage in that the surgeon would have to keep inserting and withdrawing the ultrasonic work tip and irrigation probe from the eye. As a result, this would also subject the patient to the increased possibilities of infection and trauma.
As shown in the present inventor's own U.S. Pat. No. 7,083,589, the surgical instrument may be provided with a coupler body located between the connecting body and the work tip. In such a case the aspiration fluid flow is provided from the work tip aspiration passage through the coupler to an outlet without coming into contact with the interior of the connecting body. Irrigation fluid can be provided through a portion of the housing that surrounds the proximal part of the work tip so as to form a chamber which is in communication with a separate passage in the work tip. The coupler is detachably connected to the connecting body. This allows the removal of the work tip, which becomes a single use part, so that the rest of the instrument can be reused by replacing the work tip without having to sterilize the connecting body. However, the portion of the housing surrounding the work tip and which forms the chamber for irrigation fluid, also needs to be replaced in this design.
Accordingly a need exists for a surgical hand piece that can provide both ultrasonic energy to emulsify tissue, cells and other substances which are aspirated by an aspiration fluid and an irrigation liquid that can be applied to part of the operating site being cleaned in a more directional and controlled manner. Further, it would be beneficial if the work tip were made replaceable in a more convenient manner, e.g., without having to replace part of the housing.

Surgical hand piece with dual lumen work tip for use with infusion cannula


A water bike apparatus powered by at least human energy or a motor and comprising motion-inducing flotation elements with steering elements and with no stationary flotation elements necessary for flotation of the apparatus.

There is a need for water vehicles that are more compact and more maneuverable than those currently available. Particularly, there is a need for a water bike where the flotation elements responsible for maintaining the water bike on the surface of a body of water also are responsible for moving the water bike through that body of water.
Presently, water bikes comprise stationary floatation elements responsible for at least in part keeping the water bike afloat on a body of water. This can result in a water bike that is bulker than necessary. In addition, the maneuverability can often be hampered.
There is still a need for a water vehicle in which all of the floatation elements necessary to allow the vehicle to float upon a body of water also are configured to provide motion of the water bike upon that body of water.