The present invention is concerned with the compounds of formula

This application is a National Stage application under 35 U.S.C. 371 of PCT/EP99/09154 filed Nov. 22, 1999, which claims priority from EP 98.203.929.9, filed Nov. 23, 1998.
The present invention concerns IL-5 inhibiting 6-azauracil derivatives useful for treating eosinophil-dependent inflammatory diseases; to processes for their preparation and compositions comprising them. It further relates to their use as a medicine.
Eosinophil influx, leading to subsequent tissue damage, is an important pathogenic event in bronchial asthma and allergic diseases. The cytokine interleukin-5 (IL-5), produced mainly by T lymphocytes as a glycoprotein, induces the differentiation of eosinophils in bone marrow and, primes eosinophils for activation in peripheral blood and sustains their survival in tissues. As such, IL-5 plays a critical role in the process of eosinophilic inflammation. Hence, the possibility that inhibitors of IL-5 production would reduce the production, activation and/or survival of eosinophils provides a therapeutic approach to the treatment of bronchial asthma and allergic diseases such as, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and also other eosinophil-dependent inflammatory diseases.
Steroids, which strongly inhibit IL-5 production in vitro, have long been used as the only drugs with remarkable efficacy for bronchial asthma and atopic dermatitis, but they cause various serious adverse reactions such as diabetes, hypertension and cataracts. Therefore, it would be desirable to find non-steroidal compounds having the ability to inhibit IL-5 production in human T-cells and which have little or no adverse reactions.
U.S. Pat. No. 4,631,278 discloses xcex1-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetonitriles and U.S. Pat. No. 4,767,760 discloses 2-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-diones, all having anti-protozoal activity, in particular, anti-coccidial activity. EP 831,088 discloses 1,2,4-triazine-3,5-diones as anticoccidial agents. Unexpectedly, the 6-azauracil derivatives of the present invention prove to be potent inhibitors of the production of IL-5.
The present invention is concerned with the compounds of formula
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
p represents an integer being 0, 1, 2 or 3;
q represents an integer being 0, 1, 2, 3 or 4;
xe2x80x94Axe2x80x94Bxe2x80x94 represents xe2x80x94(CH2)rxe2x80x94, xe2x80x94(CH2)txe2x80x94Oxe2x80x94, xe2x80x94(CH2)txe2x80x94S(xe2x95x90O)uxe2x80x94 or xe2x80x94(CH2)txe2x80x94NR3xe2x80x94;
r represents 2, 3 or 4;
each t independently represents 1, 2 or 3;
u represents 0, 1 or 2;
X1 represents O, S, NR3 or a direct bond;
each R1 independently represents C1-6alkyl, halo, polyhaloC1-6alkyl, hydroxy, mercapto, C1-6alkyloxy, C1-6alkylthio, C1-6alkylcarbonyloxy, aryl, cyano, nitro, Het3, R6, NR7R8 or C1-4alkyl substituted with Het3, R6 or NR7R8;
each R4 independently represents C1-6alkyl, halo, polyhaloC1-6alkyl, hydroxy, mercapto, C1-6alkyloxy, C1-6alkylthio, C1-6alkylcarbonyloxy, aryl, cyano, nitro, Het3, R6, NR7R8 or C1-4alkyl substituted with Het3, R6 or NR7R8;
R2 represents aryl, Het1, C3-7cycloalkyl, cyano, C1-6alkyl, xe2x80x94C(xe2x95x90Q)xe2x80x94X2xe2x80x94R15 or C1-6alkyl substituted with one or two substituents selected from hydroxy, cyano, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxy, C1-6alkylsulfonyloxy, C1-6alkyloxycarbonyl, C3-7cycloalkyl, aryl, aryloxy, arylthio, Het1, Het1oxy, Het1thio and xe2x80x94C(xe2x95x90Q)xe2x80x94X2xe2x80x94R15;
each R3 independently represents hydrogen or C1-4alkyl;
each R15 independently represents hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl or C1-6alkyl substituted with aryl, halo, hydroxy or Het1; where X2 is a direct bond, R15 may also be halo or Het1; where X2 is NR5, R15 may also be hydroxy; where X2 is C(xe2x95x90O)xe2x80x94NHxe2x80x94NH or NHxe2x80x94NHxe2x80x94C(xe2x95x90O), R15 may be replaced by R11;
each Q independently represents O, S or NR3;
each X2 independently represents O, S, NR5, C(xe2x95x90O)xe2x80x94NHxe2x80x94NH, NHxe2x80x94NHxe2x80x94C(xe2x95x90O) or a direct bond;
R5 represents hydrogen, C1-6alkyl, C1-6alkyloxy or arylC1-6alkyl;
each R6 independently represents C1-6alkylsulfonyl, aminosulfonyl, mono- or di-(C1-4alkyl)aminosulfonyl, mono- or di(benzyl)aminosulfonyl, polyhaloC1-6alkylsulfonyl, C1-6alkylsulfinyl, phenylC1-4alkylsulfonyl, piperazinylsulfonyl, aminopiperidinylsulfonyl, piperidinylaminosulfonyl, N-C1-4alkyl-N-piperidinylaminosulfonyl or mono-or di(C1-4alkyl)aminoC1-4alkylsulfonyl;
each R7 and each R8 are independently selected from hydrogen, C1-4alkyl, hydroxy-C1-4alkyl, dihydroxyC1-4alkyl, aryl, arylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkylcarbonyl, aminocarbonyl, arylcarbonyl, Het3carbonyl, C1-4alkylcarbonyloxy-C1-4alkyl-carbonyl, hydroxyC1-4alkylcarbonyl, C1-4alkyloxycarbonylcarbonyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het3aminocarbonyl, Het3aminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Y-C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, Het3 and R6;
each Y independently represents O, S, NR3, or S(O)2;
R9 and R10 are each independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, dihydroxyC1-4alkyl, phenyl, phenylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkylcarbonyl, aminocarbonyl, phenylcarbonyl, Het3carbonyl, C1-4alkylcarbonyloxyC1-4alkylcarbonyl, hydroxyC1-4alkylcarbonyl, C1-4alkyloxycarbonylcarbonyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, Het3aminocarbonyl, Het3aminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Y-C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, Het3 and R6;
each R11 independently being selected from hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C1-4alkyloxy, formyl, trihaloC1-4alkylsulfonyloxy, R6, NR7R8, C(xe2x95x90O)NR7R8, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Y-C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, aryl, aryloxy, arylcarbonyl, C3-7cycloalkyl, C3-7cycloalkyloxy, phthalimide-2-yl, Het3, Het4 and C(xe2x95x90O)Het3;
R12 and R13 are each independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, dihydroxyC1-4alkyl, phenyl, phenylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkylcarbonyl, phenylcarbonyl, C1-4alkylcarbonyloxyC1-4alkylcarbonyl, hydroxyC1-4alkylcarbonyl, C1-4alkyloxycarbonylcarbonyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, phenylaminocarbonyl, phenylaminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Y-C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14 and R6;
each R14 independently represents hydrogen, C1-4alkyl, C3-7cycloalkyl, aminocarbonylmethylene, mono-or di(C1-4alkyl)aminocarbonylmethylene, mono- or di(C3-7cycloalkyl)aminocarbonylmethylene, azetidin-1-ylcarbonylmethylene, pyrrolidin-1-ylcarbonylmethylene, piperidin-1-ylcarbonylmethylene or homopiperidin-1-ylcarbonylmethylene;
aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, C1-4alkyl, C3-7cycloalkyl, C1-4alkyloxy, formyl, polyhaloC1-4alkyl, NR9R10, C(xe2x95x90O)NR9R10, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, R6, xe2x80x94Oxe2x80x94R6, phenyl, Het3, C(xe2x95x90O)Het3 and C1-4alkyl substituted with hydroxy, C1-4alkyloxy, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Y-C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, Het3 or NR9R10;
Het1 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het2, R11 and C1-4alkyl optionally substituted with one or two substituents independently selected from Het2 and R11;
Het2 represents a heterocycle selected from pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl; wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from R11 and C1-4alkyl optionally substituted with one or two substituents independently selected from R11;
Het3 represents a monocyclic heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl; wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, piperidinyl, NR12R13, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, R6 and C1-4alkyl substituted with one or two substituents independently selected from hydroxy, C1-4alkyloxy, phenyl, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Y-C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, R6 and NR12R13;
Het4 represents a monocyclic heterocycle selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; polyhaloC1-4alkyl is defined as polyhalosubstituted C1-4alkyl, in particular C1-4alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl; polyhaloC1-6alkyl is defined as polyhalosubstituted C1-6alkyl. The term C1-4alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; C2-6alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 2 to 6 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like.
Het1, Het2, Het3 and Het4 are meant to include all the possible isomeric forms of the heterocycles mentioned in the definition of Het1, Het2, Het3 and Het4, for instance, pyrrolyl also includes 2H-pyrrolyl; triazolyl includes 1,2,4-triazolyl and 1,3,4-triazolyl; oxadiazolyl includes 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl; thiadiazolyl includes 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl; pyranyl includes 2H-pyranyl and 4H-pyranyl.
The heterocycles represented by Het1, Het2, Het3 and Het4 may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. Thus, for example, when the heterocycle is imidazolyl, it may be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is thiazolyl, it may be 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; when it is triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,4-triazol-1-yl and 1,3,4-triazol-2-yl; when it is benzthiazolyl, it may be 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl and 7-benzthiazolyl.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.
The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide. For example, one or more nitrogen atoms of any of the heterocycles in the definition of Het1, Het2 and Het3 may be N-oxidized.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For example, a hydroxy substituted triazine moiety may also exist as the corresponding triazinone moiety; a hydroxy substituted pyrimidine moiety may also exist as the corresponding pyrimidinone moiety.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible stereoisomeric forms in which the compounds of formula (I) can exist. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration, used herein in accordance with Chemical Abstracts nomenclature. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
The compounds of formula (I) and some of the intermediates in the present invention contain one or more asymmetric carbon atoms. The pure and mixed stereochemically isomeric forms of the compounds of formula (I) are intended to be embraced within the scope of the present invention.
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I)xe2x80x9d is meant to also include their N-oxide forms, their pharmaceutically acceptable addition salts, and their stereochemically isomeric forms.
An interesting group of compounds are those compounds of formula (I) wherein the 6-azauracil moiety is connected to the phenyl ring in the para or meta position relative to the
substituent; preferably in the para position.
Another interesting group contains those compounds of formula (I) wherein one or more of the following restrictions apply:
p is 0, 1 or 2;
q is 0 or 1;
xe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94(CH2)rxe2x80x94 or xe2x80x94(CH2)txe2x80x94Oxe2x80x94;
X1 is S, NR3 or a direct bond; more in particular a direct bond;
each R1 independently is halo, polyhaloC1-6alkyl, C1-6alkyl, C1-6alkyloxy or aryl, preferably, chloro or methyloxy, more preferably chloro;
R2 is Het1, cyano, xe2x80x94C(xe2x95x90Q)xe2x80x94X2xe2x80x94R15 or C1-6alkyl substituted with one or two substituents selected from hydroxy, cyano, xe2x80x94C(xe2x95x90Q)xe2x80x94X2xe2x80x94R15, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxy, C1-6alkylsulfonyloxy, C1-6alkyloxycarbonyl, C3-7cycloalkyl, aryl, aryloxy, arylthio, Het1oxy and Het1thio; more in particular Het1, cyano, xe2x80x94C(xe2x95x90Q)xe2x80x94X2xe2x80x94R15 or C1-6alkyl substituted with Het1;
R4 is hydrogen or halo;
R15 is hydrogen or C1-6alkyl, and when X2 is a direct bond, R15 may also be halo, and when X2 is C(xe2x95x90O)xe2x80x94NHxe2x80x94NH, R15 may also be phenyl;
R6 is C1-6alkylsulfonyl or aminosulfonyl;
R7 and R8 are each independently hydrogen, C1-4alkyl, Het3 or R6;
R9 and R10 are each independently hydrogen, C1-4alkyloxyC1-4alkyl, C1-4alkylcarbonyl, aminocarbonyl, Het3carbonyl, Het3 or R6;
R11 is cyano, nitro, halo, C1-4alkyloxy, formyl, NR7R8, C(xe2x95x90O)NR7R8, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, aryl, arylcarbonyl, Het3, Het4 and C(xe2x95x90O)Het3, more in particular aryl, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14,
R14 is hydrogen or C1-4alkyl;
aryl is phenyl optionally substituted with one, two or three substituents each independently selected from nitro, cyano, halo, hydroxy, C1-4alkyl, C3-7cycloalkyl, C1-4alkyloxy, formyl, polyhaloC1-4alkyl, NR9R10, C(xe2x95x90O)NR9R10, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Oxe2x80x94R6, phenyl, C(xe2x95x90O)Het3 and C1-4alkyl substituted with hydroxy, C1-4alkyloxy, C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, Het3 or NR9R10, more in particular phenyl optionally substituted with halo or C1-4alkyl;
Het1 is a monocyclic heterocycle selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl, in particular imidazolyl, oxadiazolyl, thiazolyl, pyrimidinyl or pyridinyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het2, R11 and C1-4alkyl optionally substituted with Het2 or R11; preferably Het1 is oxadiazolyl or thiazolyl each independently and optionally substituted with one, or where possible, two or three substituents each independently selected from R11 and C1-4alkyl optionally substituted with R11;
Het2 is an aromatic heterocycle; more in particular furanyl, thienyl, pyridinyl or benzothienyl, wherein said aromatic heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from R11 and C1-4alkyl;
Het3 is piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl each independently and optionally substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, C1-4alkyl, C1-4alkylcarbonyl, piperidinyl and C1-4alkyl substituted with one or two substituents independently selected from hydroxy, C1-4alkyloxy and phenyl;
Het4 is thienyl.
Special compounds are those compounds of formula (I) wherein p is 1 or 2 and each R1 is chloro; more preferably p is 2 and the two chloro substituents are in the ortho positions relative to the
substituent.
Particular compounds are those compounds of formula (I) wherein the 6-azauracil moiety is in the para position relative to the
substituent, and p is 2 whereby both R1 substituents are chloro positioned ortho relative to the
substituent.
Other particular compounds are those compounds of formula (I) wherein X1 is a direct bond and R2 is cyano or a monocyclic heterocycle selected from thiazolyl and oxadiazolyl, wherein said monocyclic heterocycles each independently may optionally be substituted with one or two substituents each independently selected from R11 and C1-4alkyl optionally substituted with R11.
Other preferred compounds are those compounds of formula (I) wherein xe2x80x94Axe2x80x94Bxe2x80x94 is (CH2)2.
More preferred compounds are those compounds of formula (I) wherein xe2x80x94X1xe2x80x94R2 is optionally substituted 2-thiazolyl or 3-oxadiazolyl, the 6-azauracil moiety is in the para position relative to the
substituent, and p is 2 whereby both R1 substituents are chloro positioned ortho relative to the
substituent.
In order to simplify the structural representation of the compounds of formula (I),
will hereinafter be represented by the symbol D.
Compounds of formula (I) can generally be prepared by reacting an intermediate of formula (II) wherein W1 is a suitable leaving group such as, for example, a halogen atom, with an appropriate reagent of formula (III).
Said reaction may be performed in a reaction-inert solvent such as, for example, acetonitrile, N,N-dimethylformamide, acetic acid, tetrahydrofuran, ethanol or a mixture thereof. Alternatively, in case the reagent of formula (III) acts as a solvent, no additional reaction-inert solvent is required. The reaction is optionally carried out in the presence of a base such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium bicarbonate, sodiumethanolate and the like. Convenient reaction temperatures range between xe2x88x9270xc2x0 C. and reflux temperature.
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.
Some of the compounds and intermediates of the present invention can be prepared according to or analogous to the procedures described in EP-A-0,170,316, EP-A-0,232,932 and PCT/EP98/04191.
For instance, compounds of formula (I) may generally be prepared by cyclizing an intermediate of formula (IV) wherein L is a suitable leaving group such as, for example, C1-6alkyloxy or halo, and E represents an appropriate electron attracting group such as, for example, an ester, an amide, a cyanide, C1-6alkylsulfonyloxy and the like groups; and eliminating the group E of the thus obtained triazinedione of formula (V). The cyclization can suitably be carried out by refluxing the intermediate (IV) in acidic medium such as acetic acid and in the presence of a base such as, for example, potassium acetate.
Depending on its nature, E can be eliminated using various art-known elimination procedures. For example when E is an amide or a cyano moiety, it can be hydrolized to a carboxylic moiety by for instance refluxing the intermediate bearing the E group in hydrochloric acid and acetic acid. The thus obtained intermediate can then be further reacted with mercaptoacetic acid or a functional derivative thereof to obtain a compound of formula (I). Said reaction is conveniently carried out at elevated temperatures ranging up to reflux temperature.
A suitable way to prepare intermediates of formula (IV) involves the reaction of an intermediate of formula (IV) with sodium nitrite or a functional derivative thereof in an acidic medium such as for example hydrochloric acid in acetic acid, and preferably in the same reaction mixture, further reaction the thus obtained intermediate with a reagent of formula (VII) wherein L and E are as defined above, in the presence of a base such as, for example, sodium acetate.
An interesting subgroup comprises those compounds of formula (I) wherein xe2x80x94X1xe2x80x94R2 is an optionally substituted 2-thiazolyl moiety, said compounds being represented by formula (I-a). The optionally substituted 2-thiazolyl moiety can be incorporated in the compounds of formula (I-a) at different stages of the preparation process.
For instance, scheme 1 depicts three possible ways to prepare compounds of formula (I-a).
A first pathway involves the reaction of the cyano moiety in an intermediate of formula (VIII) to the corresponding thioamide using H2S gas in a suitable solvent such as, for example, pyridine and in the presence of a base such as, for example, triethylamine, thus obtaining an intermediate of formula (IX-a). This thioamide can then be cyclized with an intermediate of formula (XI) wherein W is a suitable leaving group such as, for example, a halogen, e.g. bromo, in a suitable solvent such as, for example, ethanol. The amino moiety in the resulting 2-thiazolyl derivative of formula (IX-b) can then be further reacted as described hereinabove to form a 6-azauracil ring, thus obtaining a compound of formula (I-a).
A second pathway to form compounds of formula (I-a) involves first the protecting of the amino moiety in an intermediate of formula (VIII) by introducing a suitable protective group P such as, for example, an alkylcarbonyl group, using art-known protection techniques. In the example of P being a alkylcarbonyl group, the intermediates of formula (VIII) can be reacted with the corresponding anhydride of formula alkyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94C(xe2x95x90O)-alkyl in an appropriate solvent such as, for example, toluene. The thus obtained intermediate of formula (X-a) can then be further reacted according to the first pathway described hereinabove. The final step, before formation of the 6-azauracil ring can be initiated after having deprotected the amino moiety using art-known deprotection techniques. In the example of P being a alkylcarbonyl group, the intermediates of formula (X-c) may be deprotected by reacting them in a suitable solvent such as, for example, ethanol, in the presence of an acid such as, for example, hydrochloric acid.
A third pathway involves first the formation of the 6-azauracil ring as described hereinabove but starting from an intermediate of formula (VIII), and subsequently reacting the thus formed compound of formula (I) wherein xe2x80x94X1xe2x80x94R2 is cyano, said compounds being represented by formula (I-c), with H2S and further reacting the compound of formula (I) wherein xe2x80x94X1xe2x80x94R2 is a thioamide, said compounds being represented by formula (I-d), with an intermediate of formula (XI) as described in the first pathway, to finally form a compound of formula (I-a).
Another interesting subgroup within the present invention are those compounds of formula (I) wherein xe2x80x94X1xe2x80x94R2 is an optionally substituted 1,2,4-oxadiazol-3-yl moiety, said compounds being represented by formula (I-b-1). The optionally substituted 1,2,4-oxadiazol-3-yl moiety can be incorporated at the same stages of the reaction procedure as depicted for the 2-thiazolyl derivatives in scheme 1.
For instance, analogous to one of the three pathways shown in scheme 1, compounds of formula (I-b) can be prepared by reacting an intermediate of formula (VIII) as depicted in scheme 2.
In said scheme 2, the cyano group of an intermediate of formula (VIII) is reacted with hydroxylamine or a functional derivative thereof in a suitable solvent such as, for example, methanol, and in the presence of a base such as, for example, sodium methanolate. The thus formed intermediate of formula (XIII-a) is then reacted with an intermediate of formula (XIV) wherein W is a suitable leaving group such as, for example, a halogen, e.g. chloro, in an appropriate solvent such as, for example, dichloromethane, and in the presence of a base, such as, for example, N,N-(1-methylethyl)ethaneamine. The resulting intermediate of formula (XIII-b) is then cyclized to a 3-oxadiazolyl derivative of formula (XIII-c). The amino moiety in the intermediates of formula (XIII-c) can then be transformed to the 6-azauracil ring as described above.
Still another interesting subgroup within the present invention are those compounds of formula (I) wherein xe2x80x94X1xe2x80x94R2 is an optionally substituted 1,3,4-oxadiazol-2-yl moiety, said compounds being represented by formula (I-b-2).
For instance, compounds of formula (I-b-2) can be prepared as depicted in scheme 3.
The nitrile moiety in an intermediate of formula (XV) is transformed into a carboxylic acid ester moiety using art-known techniques. For instance, the nitrile derivative may be refluxed in a mixture of sulfuric acid and an alcoholic solvent such as, for example, methanol and ethanol. The carboxylic acid ester derivative of formula (XVI-a) may further be reacted with an intermediate of formula (XX) in a reaction-inert solvent such as, for example, N,N-dimethylformamide, and in the presence of a base such as, for example, sodium hydride, thus obtaining an intermediate of formula (XVI-b) of which the ester may be converted into its corresponding carboxylic acid of formula (XVI-c). Said intermediate of formula (XVI-c) may be reacted with a chlorinating agent such as, for example, thionyl chloride, to form an acylchloride derivative of formula (XVI-d). Subsequently, the acyl chloride may be reacted with a hydrazine derivative of formula (XVII) in a suitable solvent such as, for example, dichloromethane, and in the presence of a base such as, for example N,N-(1-methylethyl)ethaneamine. The thus formed intermediate of formula (XVI-e) may be cyclized to a 1 ,2,4-oxadiazol-2-yl derivative of formula (XVI-f) in the presence of phosphoryl chloride. As a final step before the formation of the 6-azauracil ring as described above, the nitro group in the intermediates of formula (XVI-g) is reduced to an amino group using art-known reduction techniques such as, for instance, reducing the nitro group with hydrogen in methanol and in the presence of a catalyst such as Raney Nickel.
Yet another interesting subgroup within the present invention are those compounds of formula (I) wherein xe2x80x94X1xe2x80x94R2 is xe2x80x94NHxe2x80x94R2, said compounds being represented by formula (I-c-1). Scheme 4 depicts a suitable pathway to obtain compounds of formula (I-c-1).
In said scheme 4, the cyano moiety of an intermediate of formula (XI-a) is hydrolized to the corresponding amide using art-known techniques such as, for instance, hydrolysis in the presence of acetic acid and sulfuric acid. The thus formed amide in the intermediates of formula (XVIII-a) can be transformed in an amine using (diacetoxyiodo)benzene or a functional derivative thereof in a suitable solvent such as, for example a mixture of water and acetonitrile. The amine derivative of formula (XVIII-b) can then be reacted with benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate as described in Tetrahedron Letters No. 14 (1975) 1219-1222 to obtain a compound, or with a functional derivative thereof such as, for instance, an isothiocyanate, in an appropriate solvent such as, for example, tetrahydrofuran.
Intermediates of formula (VIII) can be prepared as depicted in scheme 5.
An intermediate of formula (XIX) and an intermediate of formula (XX) may be reacted in a suitable solvent such as, for example, N,N-dimethylformamide, in the presence of a base such as, for example sodium hydride, to form an intermediate of formula (XV-a). The nitro moiety in the intermediates of formula (XV-a) may be reduced to an amino group using art-known reduction techniques such as, for example, reducing the nitro group with hydrogen in methanol and in the presence of a catalyst such as Raney Nickel.
The compounds of formula (I) can also be converted into each other following art-known procedures of functional group transformation such as, for example, those mentioned in PCT/EP98/04191 and the ones exemplified in the experimental part hereinafter.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g. counter-current distribution, liquid chromatography and the like.
Some of the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
Some of the intermediates and starting materials as used in the reaction procedures mentioned hereinabove are known compounds and may be commercially available or may be prepared according to art-known procedures.
IL-5, also known as eosinophil differentiating factor (EDF) or eosinophil colony stimulating factor (Eo-CSF), is a major survival and differentiation factor for eosinophils and therefore thought to be a key player in eosinophil infiltration into tissues. There is ample evidence that eosinophil influx is an important pathogenic event in bronchial asthma and allergic diseases such as, cheilitis, irritable bowel disease, eczema, urticaria, vasculitis, vulvitis, winterfeet, atopic dermatitis, pollinosis, allergic rhinitis and allergic conjunctivitis; and other inflammatory diseases, such as eosinophilic syndrome, allergic angiitis, eosinophilic fasciitis, eosinophilic pneumonia, PIE syndrome, idiopathic eosinophilia, eosinophilic myalgia, Crohn""s disease, ulcerative colitis and the like diseases.
The present compounds also inhibit the production of other chemokines such as monocyte chemotactic protein-1 and -3 (MCP-1 and MCP-3). MCP-1 is known to attract both T-cells, in which IL-5 production mainly occurs, and monocytes, which are known to act synergetically with eosinophils (Carr et al., 1994, Immunology, 91, 3652-3656). MCP-3 also plays a primary role in allergic inflammation as it is known to mobilize and activate basophil and eosinophil leukocytes (Baggiolini et al., 1994, Immunology Today, 15(3), 127-133).
The present compounds have no or little effect on the production of other chemokines such as IL-1, IL-2, IL-3, IL-4, IL-6, IL-10, xcex3-interferon (IFN-xcex3) and granulocyte-macrophage colony stimulating factor (GM-CSF) indicating that the present IL-5 inhibitors do not act as broad-spectrum immunosuppressives.
The selective chemokine inhibitory effect of the present compounds can be demonstrated by in vitro chemokine measurements in human blood of which the test results for IL-5 are presented in the experimental part hereinafter. In vivo observations such as the inhibition of eosinophilia in mouse ear, the inhibition of blood eosinophilia in the Ascaris mouse model; the reduction of serum IL-5 protein production and splenic IL-5 mRNA expression induced by anti-CD3 antibody in mice and the inhibition of allergen- or Sephadex-induced pulmonary influx of eosinophils in guinea-pig are indicative for the usefulness of the present compounds in the treatment of eosinophil-dependent inflammatory diseases.
The present inhibitors of IL-5 production are orally active compounds.
In view of the above pharmacological properties, the compounds of formula (I) can be used as a medicine. In particular, the present compounds can be used in the manufacture of a medicament for treating eosinophil-dependent inflammatory diseases as mentioned hereinabove, more in particular bronchial asthma, atopic dertmatitis, allergic rhinitis and allergic conjunctivitis.
In view of the utility of the compounds of formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from eosinophil-dependent inflammatory diseases, in particular bronchial asthma, atopic dertmatitis, allergic rhinitis and allergic conjunctivitis. Said method comprises the systemic or topical administration of an effective amount of a compound of formula (I), a N-oxide form, a pharmaceutically acceptable addition salt or a possible stereoisomeric form thereof, to warm-blooded animals, including humans.
The present invention also provides compositions for treating eosinophil-dependent inflammatory diseases comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous, or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. Application of said compositions may be by aerosol, e.g. with a propellent such as nitrogen, carbon dioxide, a freon, or without a propellent such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab. In particular, semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ xcex1-, xcex2- or xcex3-cyclo-dextrins or their derivatives. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions. In the preparation of aqueous compositions, addition salts of the subject compounds are obviously more suitable due to their increased water solubility.
Appropriate cyclodextrins are xcex1-, xcex2-, xcex3-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclo-dextrin are substituted with C1-6alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated xcex2-CD; hydroxyC1-6alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyC1-6alkyl, particularly carboxymethyl or carboxy-ethyl; C1-6alkylcarbonyl, particularly acetyl; C1-6alkyloxycarbonylC1-6alkyl or carboxyC1-6alkyloxyC1-6alkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; C1-6alkylcarbonyloxyC1-6alkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are xcex2-CD, randomly methylated xcex2-CD, 2,6-dimethyl-xcex2-CD, 2-hydroxyethyl-xcex2-CD, 2-hydroxyethyl-xcex3-CD, 2-hydroxypropyl-xcex3-CD and (2-carboxymethoxy)propyl-xcex2-CD, and in particular 2-hydroxypropyl-xcex2-CD (2-HP-xcex2-CD).
The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl.
The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The M.S. value can be determined by various analytical techniques, preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10.
The average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The D.S. value can be determined by various analytical techniques, preferably, as measured by mass spectrometry, the D.S. ranges from 0.125 to 3.
Due to their high degree of selectivity as IL-5 inhibitors, the compounds of formula (I) as defined above, are also useful to mark or identify receptors. To this purpose, the compounds of the present invention need to be labelled, in particular by replacing, partially or completely, one or more atoms in the molecule by their radioactive isotopes. Examples of interesting labelled compounds are those compounds having at least one halo which is a radioactive isotope of iodine, bromine or fluorine; or those compounds having at least one 11C-atom or tritium atom.
One particular group consists of those compounds of formula (I) containing a radioactive halogen atom. In principle, any compound of formula (I) containing a halogen atom is prone for radiolabelling by replacing the halogen atom by a suitable isotope. Suitable halogen radioisotopes to this purpose are radioactive iodides, e.g. 122I, 123I, 125I, 131I; radioactive bromides, e.g. 75Br, 76Br, 77Br and 82Br, and radioactive fluorides, e.g. 18F. The introduction of a radioactive halogen atom can be performed by a suitable exchange reaction or by using any one of the procedures as described hereinabove to prepare halogen derivatives of formula (I).
Another interesting form of radiolabelling is by substituting a carbon atom by a 11C-atom or the substitution of a hydrogen atom by a tritium atom.
Hence, said radiolabelled compounds of formula (I) can be used in a process of specifically marking receptor sites in biological material. Said process comprises the steps of (a) radiolabelling a compound of formula (I), (b) administering this radiolabelled compound to biological material and subsequently (c) detecting the emissions from the radiolabelled compound. The term biological material is meant to comprise every kind of material which has a biological origin. More in particular this term refers to tissue samples, plasma or body fluids but also to animals, specially warm-blooded animals, or parts of animals such as organs.
The radiolabelled compounds of formula (I) are also useful as agents for screening whether a test compound has the ability to occupy or bind to a particular receptor site. The degree to which a test compound will displace a compound of formula (I) from such a particular receptor site will show the test compound ability as either an agonist, an antagonist or a mixed agonist/antagonist of said receptor.
When used in in vivo assays, the radiolabelled compounds are administered in an appropriate composition to an animal and the location of said radiolabelled compounds is detected using imaging techniques, such as, for instance, Single Photon Emission Computerized Tomography (SPECT) or Positron Emission Tomography (PET) and the like. In this manner the distribution of the particular receptor sites throughout the body can be detected and organs containing said receptor sites can be visualized by the imaging techniques mentioned hereinabove. This process of imaging an organ by administering a radiolabelled compound of formula (I) and detecting the emissions from the radioactive compound also constitutes a part of the present invention.
In general, it is contemplated that a therapeutically effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, in particular from 0.05 mg/kg to 10 mg/kg body weight. A method of treatment may also include administering the active ingredient on a regimen of between two or four intakes per day.

Abstract: the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein p is 0 to 3; q is 0 to 4; xe2x80x94Axe2x80x94Bxe2x80x94 represents xe2x80x94(CH2)rxe2x80x94, xe2x80x94(CH2)txe2x80x94Oxe2x80x94, xe2x80x94(CH2)txe2x80x94S(xe2x95x90O)uxe2x80x94 or xe2x80x94(CH2)txe2x80x94NR3xe2x80x94; r is 2 to 4; t is 1 to 3; u is 0 to 2; X1 is O, S, NR3 or a direct bond; R1 and R4 are C1-6alkyl, halo, polyhaloC1-6alkyl, hydroxy, mercapto, C1-6alkyloxy, C1-6alkylthio, C1-6alkylcarbonyloxy, aryl, cyano, nitro, Het3, R6, NR7R8 or substituted C1-4alkyl; R2 is aryl, Het1, C3-7cycloalkyl, cyano, optionally substituted C1-6alkyl, xe2x80x94C(xe2x95x90Q)xe2x80x94X2xe2x80x94R15; R3 is hydrogen or C1-4alkyl; R15 is hydrogen, optionally substituted C1-6alkyl, C3-7cycloalkyl, aryl; where X2 is a direct bond, R15 may also be halo or Het1; where X2 is NR5, R15 may also be hydroxy; where X2 is C(xe2x95x90O)xe2x80x94NHxe2x80x94NH or NHxe2x80x94NHxe2x80x94C(xe2x95x90O), R15 may be replaced by R11; Q is O, S or NR3; X2 is O, S, NR5, C(xe2x95x90O)xe2x80x94NHxe2x80x94NH, NHxe2x80x94NHxe2x80x94C(xe2x95x90O) or a direct bond; R5 is hydrogen, C1-6alkyl, C1-6alkyloxy or arylC1-6alkyl; R6 is a sulfonyl or sulfinyl derivative; R7 and R8 are independently hydrogen, optionally substituted C1-4alkyl, aryl, a carbonyl containing moiety, C3-7cycloalkyl, xe2x80x94Y-C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, Het3 and R6; R11 is hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C1-4alkyloxy, formyl, trihaloC1-4alkylsulfonyloxy, R6, NR7R8, C(xe2x95x90O)NR7R8, C1-4alkanediyl-C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R14, xe2x80x94Y-C1-4alkanediyl-C(xe2x95x900)xe2x80x94Oxe2x80x94R14, aryl, aryloxy, arylcarbonyl, C3-7cycloalkyl, C3-7cycloalkyloxy, phthalimide-2-yl, Het3, Het4 and C(xe2x95x90O)Het3; aryl is optionally substituted phenyl; Het1, Het2, Het3 and Het4 are optionally substituted heterocycles; to processes for their preparation and compositions comprising them. It further relates to their use as a medicine.


The apparatus transforms between a hand truck configuration and a tripod configuration. The apparatus includes a base frame, wheel axles, a base plate, a plurality of handle rods, and a center rod. The base frame is formed by lateral side supports, a top support member, upper and lower axle support bars, and a middle support member. The middle support member has a receptacle engaging a tool attachment. The base plate is made integral with the base frame, and the base frame extends orthogonally from a top planar surface of the base plate. The handle rods and center rod also extend orthogonally from the top planar surface in the hand truck configuration with the handle rods fixed to the top support member. Handle rods and center rod pivot at angles from the top planar surface in the tripod configuration. The apparatus transforms and inverts between configurations.

1. Field of the Invention
The present invention relates to hand trucks. In particular, the present invention relates to a convertible multi-function hand truck. Even more particularly, the present invention relates to an apparatus convertible back and forth between a hand truck configuration and a heavy duty tripod configuration.
2. Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 37 CFR 1.98.
A hand truck is a familiar transportation apparatus used to move equipment. A hand truck may also be known as a "dolly", "sack truck" or "trolley". The hand truck is generally an L-shaped cart with handles on a vertical portion, wheels at the base, and a ledge on a horizontal portion. The load to be carried is placed on the ledge and rests against the vertical portion. The hand truck pivots on the wheels, so that the load is supported by the ledge and the vertical portion. The load can now be moved by the wheels of the hand truck, and the handles allow manual control of the direction and speed of movement. The hand truck is a basic lever with the load tilted over the pivot of the wheels.
Hand trucks or dollies are normally used to move heavy equipment that is difficult to carry by hand or even impossible to carry by individuals. In the plumbing and electrical repair industry, a hand truck is used to transport generators, heavy tool boxes, and heavy duty tools. When transporting heavy equipment, such as pipe benders and vices, the hand truck must also be transported. Each piece of equipment includes a stand or tripod, which supports the actual tool. A saw table has a stand to set on the ground. A vice requires a heavy duty tripod to anchor the vice in place. A pipe bending head also requires a strong stand to stabilize on the ground, when a pipe is being bent. Once the equipment is loaded onto a truck or other service vehicle, the hand truck must also be stowed on the truck, so that the equipment can be unloaded at the work site.
Hand trucks are fabricated from various materials, such as tubular steel, tubular aluminum, and even some plastics. Hand trucks can be light weight for certain types of equipment and supply transportation. Some hand trucks can be heavy for other types of equipment. There can be manipulation of features of the hand truck for particular uses.
Specialized hand trucks are known in the prior art.
U.S. Pat. No. 6,471,220, issued to Babb on Oct. 29, 2002, describes a cart and stand for supporting and transporting a metal working apparatus, such as a threading machine. The threading machine is heavy, and the cart configuration makes the threading machine mobile. The tripod configuration supports and stabilizes the threading machine. The apparatus is inverted for the different configuration.
U.S. Pat. No. 7,726,669, issued to Alexander on Jun. 1, 2010, describes an apparatus for a collapsible table and dolly. The transforming dolly is shown to form a general work surface for various tools. The apparatus is comprised of a vertical support, which acts as a handle during transport; a pair of wheels; a table mounted to one or more arms, which may be collapsed parallel to the vertical support during transport and extended when in use; a further pair of support legs hingedly mounted to the bottom of the table at the opposite end from the vertical support; and a wheel base.
U.S. Pat. No. 5,931,483, issued to Haynes on Aug. 3, 1999, describes a foldable bowling caddy. There is a foldable bowling caddy comprised of two legs, a series of flat racks, two wheels, and a third leg pivotally mounted as to form a tripod. When the device is extended for use, the racks are flat to accept bowling balls in a step-wise fashion, and the device rests on three legs in a tripod position.
U.S. Pat. No. 5,257,892, issued to Branch on Nov. 2, 1993, describes a multi-purpose transporting device. The device is comprised of a hand truck suitable for both horizontal cart and vertical dolly use. The transformation happens only by flipping orientation of the hand truck. On one side, the device is a hand truck. On the other side, the device is a tripod with an inverted platform.
Other prior art references disclose other variation of hand trucks and tripods for heavy tools. U.S. Pat. No. 5,718,440, issued to Roxbury on Feb. 17, 1998, describes a pipe vice transportation dolly mounted on a tripod. U.S. Pat. No. 7,648,155, issued to Wise on Jan. 19, 2010, describes a universal mobile saw stand. U.S. Pat. No. 4,565,382, issued to Sherman on Jan. 21, 1986, describes a combined portable table and hand truck. U.S. Pat. No. 4,106,590, issued to Terran on Aug. 15, 1978, describes a combined hand truck and ladder.
It is an object of the present invention to provide an embodiment of an apparatus with a hand truck configuration and a tripod configuration.
It is another object of the present invention to provide an embodiment of an apparatus convertible between a hand truck configuration and a tripod configuration.
It is still another object of the present invention to provide an embodiment of a hand truck transforming into a tripod.
It is an object of the present invention to provide an embodiment of an apparatus with dual hand truck and stand functions.
It is another object of the present invention to provide an embodiment of an apparatus with dual hand truck and stand functions, dependent upon configuration of the apparatus.
It is an object of the present invention to provide an embodiment of an apparatus with a hand truck configuration and a tripod configuration, which supports multiple heavy duty tools.
It is another object of the present invention to provide an embodiment of an apparatus with a hand truck configuration and a tripod configuration with a universal attachment for heavy duty tools.
It is another object of the present invention to provide an embodiment of an apparatus with a hand truck configuration and a tripod configuration with a receptacle for removable engagement to heavy duty tool attachments.
It is an object of the present invention to provide an embodiment of an apparatus with a stable and strong hand truck configuration, which can transform into a stable and strong tripod configuration.
It is another object of the present invention to provide an embodiment of a hand truck to transform into a stable and strong tripod configuration in order to support heavy duty tools and machinery.
These and other objects and advantages of the present invention will become apparent from a reading of the attached specification and appended claims.

Apparatus having a hand truck configuration and a tripod configuration


A plasma generating apparatus for an extreme-ultraviolet laser that can generate high temperature plasma at high efficiency, and can form long plasma to be recombined by rapid cooling of the high temperature plasma. A shield plate including a narrow slit is disposed adjacent to a high temperature plasma source, and the high temperature plasma is discharged through the slit. Both high efficiency plasma generation and rapid expansion thereof can be simultaneously achieved by discharging high temperature plasma through the narrow slit. The rapid expansion makes it possible to form a long plasma having a large gain in an extreme-ultraviolet region. The high temperature plasma source can be readily realized by irradiating it with an exciting laser beam from behind the opposite side of the slit with regard to the high temperature plasma source directly or through a transmitting window. A closure provided in front of the slit can prevent a liquid or gas from flowing out of the slit before it is changed into plasma. This makes it possible to use a liquid or gas as a plasma source material.

1. Field of the Invention
The present invention relates to a plasma generating apparatus and method for an extreme-ultraviolet laser.
2. Description of the Related Art
Since the invention of a laser, efforts to shorten wavelengths of lasers have been continued, and as the wavelengths of lasers have been shortened, fields of laser application have been gradually widened. Recently, in particular, extreme-ultraviolet lasers (which are often called an "X-ray laser") whose wavelength is less than 100 nm, have been extensively studied. To shorten the wavelengths of lasers, a great exciting power no less than fourth power of the reciprocal of a laser wavelength is required. This presents many physical and technical problems that must be solved before an extreme-ultraviolet laser is realized. One promising extreme-ultraviolet laser is a recombination laser. This laser attempts to achieve an extreme-ultraviolet amplification by rapidly cooling a high temperature plasma. The most rapid cooling method is an adiabatic expansion cooling, if the size of the initial hot plasma is small enough. This method is based on the principle that the temperature drop takes place when gases are subjected to free expansion because thermal motion of particles are changed into translational motion, accompanying the density reduction by the expansion. To achieve sufficient amplification of an extreme-ultraviolet laser, the degree of population inversion achieved in nonequilibrium state must be great. This requires that the temperature of a plasma must be dropped faster than the speed of progress toward the thermal equilibrium. That is, a rapid expansion is required.
A greater density reduction is accomplished when a cylindrical plasma expands radially than when a plane plasma expands linearly. Accordingly, greater amplification power of an extreme-ultraviolet laser will be expected with a cylindrical plasma. The difference anticipated with the plane plasma and the cylindrical plasma has been experimentally confirmed (T. Tomie et al., X-ray lasers 1990, ed. by G. Tallents, Institute of Physics Conference Series 116, 1990). The cylindrical plasma from which a rapid expansion is expected can be generated by irradiating a thin fiber by an exciting laser. It was experimentally confirmed that 18 nanometer extreme-ultraviolet light was amplified using a seven micrometer diameter carbon fiber as a target (C. Chenais-Popovics, et al., Physical Review Letters, volume 59, number 19 (1987)).
Although C. Chenais-Popovics et al., reported a moderate degree of amplification of extreme ultraviolet light of 18 nanometer wavelength using a seven micrometer diameter by eight millimeter long carbon fiber as a target, several centimeter long plasma is required to achieve a sufficient amplification and to realize a practical extreme-ultraviolet laser of sufficient energy. Since light travels in straight lines, the plasma must also maintain the straightness in order to amplify extreme-ultraviolet light rays. However, it is inevitable for a thin, seven micrometer diameter fiber to bend, and hence, it is almost impossible to generate more than two centimeter long straight plasma by a fiber target. Furthermore, it is impossible for a thin fiber to absorb exciting laser energy with high efficiency: in experiments, absorption fractions less than only 10% have been achieved.

Plasma generating apparatus and method for extreme-ultaviolet laser

Agency of Industrial Science and Technology


Stamp for microcontact printing. The stamp includes a bulk portion having first and second surfaces, the first surface including a pattern of features to be transferred and the second surface including a different pattern of features. The features on the second surface have a lower stiffness than the features on the first surface. The dual-face stamp design of the invention provides an alternative location for dimensional errors to be absorbed, making microcontact printing a more robust production process.

This invention relates to microcontact printing and more particularly to an elastomeric stamp that provides improved process performance when very small (micrometer or nanometer) printing features are desired.
Microcontact printing is a lithographic method employing an elastomeric stamp and applicable to a variety of ink/substrate combinations [1-4]. After inking, applying, and removing the stamp, the resulting pattern can act as an etch resist, deposition catalyst, or as a final pattern itself. Most notably, applications include low-cost or flexible semiconductors, low-cost or flexible displays, advanced engineered surfaces, and the biological devices.
Dimensional inaccuracies in a stamp or substrate limit the feasible feature scales in microcontact printing; even infinitesimal variations in the stamp thickness have been shown to impact contact area, contact pressure and feature collapse.
A variety of stamping methods and machines [5-8] have been documented in the prior art. However, none of these machines, nor prior research investigations in stamp and pattern transfer integrity [9-12], have accounted for the sensitivity of the process to errors in stamp, substrate, or superstrate dimensions.
Traditional microcontact printing stamps are made of polydimethylsiloxane (PDMS) by casting the PDMS over a patterned surface, for example a wafer patterned with photoresist. This process results in a stamp with features imparted on one side, which is then mounted to a machine using the backside of the stamp or used in manual application. The incompressible elastomeric body of these stamps can develop significant contact pressure when compressed between printing plates or printing rolls. At micrometer scale displacements sufficient pressure develops to collapse the features on the stamp, destroying the intended transfer pattern.
The present invention enables accurate pattern transfer in situations in which pattern integrity would be compromised in traditional stamps.


A piezoelectric device includes a piezoelectric film, and electrodes through which an electric field can be applied to the piezoelectric film along the thickness direction of the piezoelectric film. The piezoelectric film contains a ferroelectric phase in which the thickness direction and a normal of a plane determined by the spontaneous-polarization axis and the axis makes an angle θm satisfying the condition that −45 degrees<θm<+45 degrees and θm≠0 degrees. Further, the spontaneous-polarization axis or the axis may be perpendicular to the thickness direction of the piezoelectric film.

1. Field of the Invention
The present invention relates to a piezoelectric device which takes advantage of reversible non-180-degree domain rotation. The present invention also relates to a process for producing the above piezoelectric device, and a liquid discharge device using the above piezoelectric device.
2. Description of the Related Art
Currently, the piezoelectric devices constituted by a piezoelectric body and electrodes are used as, for example, piezoelectric actuators installed in inkjet recording heads. In such piezoelectric devices, the piezoelectric body expands and contracts in response to increase and decrease in the strength of an electric field applied from the electrodes to the piezoelectric body. For example, perovskite oxides such as PZT (lead titanate zirconate) are known as materials suitable for the piezoelectric body. The piezoelectric materials are ferroelectric materials, which exhibit spontaneous polarization even when no electric field is applied.
In the conventional piezoelectric devices, the field-induced strain (i.e., the piezoelectric stain along the spontaneous-polarization axis of the ferroelectric body) is commonly utilized by applying an electric field along the direction of the spontaneous-polarization axis, i.e., the direction of the applied electric field is commonly identical to the direction of the spontaneous-polarization axis. However, since the magnitude of displacement is limited in the case where only the field-induced strain of the ferroelectric body is utilized, demands for greater displacement is increasing.
In the above circumstances, piezoelectric devices taking advantage of the non-180-degree domain rotation (such as the 90-degree domain rotation) have been proposed. In the case where the 180-degree domain rotation is utilized, the orientation of the spontaneous-polarization axis merely turns upside down. Therefore, the 180-degree domain rotation does not contribute to increase in the piezoelectric strain beyond the field-induced strain. On the other hand, the non-180-degree domain rotation such as the 90-degree domain rotation increases the piezoelectric strain beyond the field-induced strain.
Although the non-180-degree domain rotation per se is conventionally known, the non-180-degree domain rotation is conventionally considered to have poor usability since the non-180-degree domain rotation is normally irreversible. However, Japanese Unexamined Patent Publication No. 2004-363557 (hereinafter referred to as JP2004-363557) and X. Ren, "Large Electric-field-induced Strain in Ferroelectric Crystals by Point-defect-mediated Reversible Domain Switching", Nature Materials, Vol. 3, pp. 91-94, 2004 (hereinafter referred to as the nonpatent reference 1) disclose piezoelectric materials in which movable point defects are located so that the symmetry in the short-range order of the movable point defects coincides with the crystal symmetry in ferroelectric phases.
JP2004-363557 and the nonpatent reference 1 disclose preparation of:
(1) A sample of a monocrystal of BaTiO3 which is produced by the flux technique, cooled, and aged at a temperature not higher than the Curie temperature (as disclosed as "EXAMPLE 1" in JP2004-363557);
(2) A sample of a monocrystal of BaTiO3 doped with a small amount of potassium (i.e., (BaK)TiO3), which is produced by the flux technique, cooled, and aged at a temperature not higher than the Curie temperature (as disclosed as "EXAMPLE 2" in JP2004-363557);
(3) A ceramic sample of (Pb, La)(Zr, Ti)O3 (PLZT) aged for 30 days at room temperature (as disclosed as "EXAMPLE 3" in JP2004-363557); and
(4) A ceramic sample of BaTiO3 doped with a small amount of iron (i.e., Fe—BT), which is aged for 5 days at 80° C. (as disclosed as "EXAMPLE 5" in JP2004-363557).
It is reported that tetragonal phases forming a-domains (in each of which the spontaneous-polarization axis is perpendicular to the direction of an applied electric field) are formed in the above samples, and reversible 90-degree rotation of the a-domains occurs. In addition, "FIG. 7" in JP2004-363557 shows that the magnitude of the piezoelectric strain which can be achieved by use of the reversible 90-degree domain rotation in a ferroelectric substance is far greater than the magnitude of the piezoelectric strain which can be achieved by use of only the normal piezoelectric strain along the polarization axis (produced by the application of an electric field along the polarization axis of the ferroelectric substance).
In addition, R. Chu et al., "Ultrahigh Piezoelectric Response Perpendicular to Special Cleavage Plane in BaTiO3 Single Crystals", Applied Physics Letters, Vol. 86, pp. 012905-1-012905-2, 2005 (hereinafter referred to as the nonpatent reference 2) and J. J. Liu et al., "Engineering Domain Configurations for Enhanced Piezoelectricity in Barium Titanate Single Crystals," Applied Physics Letters, Vol. 88, pp. 032904-1-032904-3, 2006 (hereinafter referred to as the nonpatent reference 3) disclose structures which are slightly tilted from the attitudes of a-domains, and in which reversible 90-degree domain rotation can occur.
Specifically, the abstract and some other portions of the nonpatent reference 2 indicate that while the piezoelectric constant d33(001) of a BaTiO3 monocrystal (having a c-domain) is measured to be 87 pC/N by applying an electric field to the crystal along the [001] direction (perpendicular to the (001) face of the crystal), the piezoelectric constant d33(270) of the same BaTiO3 monocrystal is measured to be 2000 pC/N (i.e., more than twenty times greater than the above piezoelectric constant d33(001)) by cleaving the monocrystal along the (270) plane and applying an electric field to the cleaved monocrystal along the [720] direction (perpendicular to the (270) face of the crystal). The (270) face is tilted from the (100) face by 16 degrees.
Further, the nonpatent reference 3 indicates values of the piezoelectric constants calculated in consideration of both of the field-induced strain and the reversible 90-degree domain rotation which are caused by application of an electric field to a BaTiO3 monocrystal along the [n1 n2 0] direction, and the piezoelectric constant d33 has been shown to reach the maximum value of 1300 pC/N when the electric field is applied to the crystal along a direction which is tilted from the [100] axis (i.e., the a-axis) by 5 or 85 degrees. (See page 032904-3, left column, line 7 and FIG. 4 in the nonpatent reference 3.) FIG. 12A shows the a-axis, the b-axis (i.e., the [010] axis), the [n1 n2 0] direction (along which the electric field is applied), and the angle q between the a-axis and the [n1 n2 0] direction.
FIG. 12B schematically indicates a unit cell in a tetragonal crystal having a tilted domain as indicated in the nonpatent references 2 and 3. The unit cell indicated in FIG. 12B has the shape of a rectangular parallelepiped which is elongated in the depth direction in the illustration. In the tilted domain structure indicated in each of the nonpatent references 2 and 3, the c-axis (as the spontaneous-polarization axis) is perpendicular to the direction along which the electric field is applied to the tetragonal crystal, and is not tilted from the c-axis of the normal a-domain, and the a-axis and the b-axis are tilted from the a-axis and the b-axis of the normal a-domain. In other words, the (110) face in each of the nonpatent references 2 and 3, which is determined by the a-axis and the b-axis, is tilted from the (110) face of the normal a-domain. (The (110) face of the normal a-domain is illustrated in the upper part of FIG. 3.) In FIGS. 12B and 3, PS indicates the direction of the spontaneous-polarization axis.
However, the techniques disclosed in JP2004-363557 and the nonpatent references 1 to 3 have the following problems (1) to (4).
(1) Since the size and weight of the electronic devices are decreasing and the functions of the electronic devices are being sophisticated, development of the piezoelectric devices for reducing the size and weight of the piezoelectric devices and improving the functions of the piezoelectric devices are proceeding. For example, in the field of the inkjet recording heads, techniques for increasing the density of arrangement of piezoelectric devices are currently being studied in order to improve image quality. For this purpose, techniques for producing piezoelectric devices having a thin piezoelectric film, instead of the bulk piezoelectric body, are also being studied.
However, JP2004-363557A and the nonpatent references 1 and 2 disclose only the results of studies on bulk monocrystals and bulk ceramics, and do not refer to films and application of the reversible non-180-degree domain rotation to piezoelectric films.
(2) The nonpatent references 2 and 3 do not disclose a method for forming a piezoelectric film having a tilted domain structure as mentioned before (in which the c-axis as the spontaneous-polarization axis is perpendicular to the direction along which the electric field is applied, and is not tilted from the c-axis of the normal a-domain, and the a-axis and the b-axis are tilted from the a-axis and the h-axis of the normal a-domain).
(3) The technique disclosed in the nonpatent reference 2 (in which a monocrystal is cleaved along a high-index face (i.e., the (270) face)) requires laborious and expensive processes, and has difficulty in fine processing on the order of micrometers and integration on a substrate.
(4) The nonpatent reference 3 indicates only the results of theoretical calculation, discloses no concrete process for producing even a bulk crystal, and does not indicate whether or not the results of theoretical calculation match with the actual piezoelectric characteristics. When a piezoelectric film is formed on a substrate, it is necessary to consider the stress and the like which the substrate imposes on the piezoelectric film. However, since the piezoelectric film is not considered in the nonpatent reference 3, the substrate is not considered in theoretical calculation. Therefore, even when the results of theoretical calculation are assumed to match with the actual piezoelectric characteristics, it is unknown whether or not the piezoelectric films have theoretically calculated characteristics.

Piezoelectric device, process for producing the piezoelectric device, and liquid discharge device


When a semiconductor chip is mounted using ultrasonic vibration, a method of mounting makes it possible to bond the semiconductor chip and bonding patterns with sufficient bonding strength without making the construction of a circuit board complex. The method of mounting a semiconductor chip causes ultrasonic vibration to act on the semiconductor chip to mount the semiconductor chip on a circuit board by flip-chip bonding. As the circuit board, a circuit board is used where protrusion patterns are provided at positions on bonding patterns to which the semiconductor chip is bonded corresponding to antinodes of vibration for a case where the bonding patterns resonate due to ultrasonic vibration applied by the semiconductor chip.

1. Field of the Invention
The present invention relates to a method of mounting a semiconductor chip, and in particular to a method of mounting a semiconductor chip by flip-chip bonding using ultrasonic vibration.
2. Related Art
When mounting a semiconductor chip onto a circuit board by flip-chip bonding, a method of mounting that applies ultrasonic vibration to the semiconductor chip is carried out. When mounting a semiconductor chip using ultrasonic vibration, there is a known problem that the bonding strength of the bonded parts depends on the applied direction of the ultrasound and the arrangement of the wiring patterns (bonding patterns) for mounting that are formed on the circuit board.
FIG. 6 is a plan view showing a state where a semiconductor chip 20 is flip-chip bonded on a circuit board 10 when looking from above, with the arrow showing the direction of vibration for the ultrasound.
FIG. 7A is a cross-sectional view showing one bonding pattern 12 (a bonding pattern in the part A in FIG. 6) whose longitudinal direction is parallel to the direction of vibration (the direction of the arrow) for the ultrasonic vibration, and FIG. 7B is a cross-sectional view showing one bonding pattern 12 (a bonding pattern in the part B in FIG. 6) whose longitudinal direction is perpendicular to the direction of vibration of the semiconductor chip 20.
As shown in FIG. 7A, for a bonding pattern 12 disposed so that the longitudinal direction is parallel with the direction of vibration for the ultrasonic vibration, even if ultrasonic vibration is applied, the bonding pattern 12 resists excitation, and accordingly when flip-chip bonding is carried out, the required frictional force is achieved between the bump 22 and the bonding pattern 12, resulting in increased strength for the bond between the bump 22 and the bonding pattern 12. On the other hand, as shown in FIG. 7B, for a bonding pattern 12 disposed so that the longitudinal direction is perpendicular to the direction of vibration of the ultrasonic vibration, the bonding pattern 12 is susceptible to moving so as to track the ultrasonic vibration, resulting in decreased strength for the bond between the bump 22 and the bonding pattern 12.
In this way, when semiconductor chips are mounted using ultrasonic vibration, to solve the problem of decreased strength for bonds between bumps and bonding patterns disposed with the lengthwise direction perpendicular to the direction of vibration for the ultrasonic vibration, a method (see Patent Document 1) where dummy patterns extend from the bonding patterns in the direction in which the ultrasonic vibration is applied and a method (see Patent Document 2) where via holes are formed on each side of the bonded parts where the bumps are bonded or filled vias are formed below the bonded parts have been proposed.
Patent Document 1
Japanese Laid-Open Patent Publication No. 2004-311637
Patent Document 2
Japanese Laid-Open Patent Publication No. 2002-94241
The method where protrusion patterns extend from the bonding patterns described above in a direction in which ultrasonic vibration is applied increases the strength of the bonds between the bonding patterns and the base layer and makes the bonding patterns resistant to excitation when the ultrasonic vibration is applied, resulting in increased strength for the bonds between the bumps and the bonding patterns. However, a method where the protrusion patterns are disposed simply corresponding to the positions on the bonding patterns at which the bumps are bonded is not thought to be effective in view of the case where the bonding patterns resonate due to the ultrasonic vibration applied to mount the semiconductor chip.
With the method where the formation positions of the via holes are adjusted relative to the bonding patterns, there are the problems that the construction of the circuit board becomes complex and limitations are placed on the designs of components due to the via holes being formed at predetermined positions.


Disclosed is a leak detection cable that has an outer jacket layer and a four wire construction in a flat wire configuration that is twisted in a helix. Detection cables are disposed on the exterior surface adjacent openings of the jacket to allow for detection of aqueous fluids. The wire is twisted in a helix to allow adjacent detector wires to easily detect aqueous fluids. Disparate materials are used for the jacket and the coatings of the wires, to allow the jacket to be easily removed from the wires without affecting the integrity of the coatings of the wires. The four flat wire configuration is sized and spaced for easy connection to an insulation displacement connector.

Leak detection cables have been used to detect moisture in various applications. For example, leak detection cables may be used to detect leakage from appliances that leak water, such as dishwashers, hot water heaters, etc., in normal household applications, as well as in commercial applications. Leak detection systems may be used to automatically cut off water supplies, such as electrical and gas supplies, as well as providing notification for maintenance and repair services. These systems have been valuable in preventing flood damage and other damage.


A time-of-flight range sensing system for a vehicle such as a mobile robot comprised of a number of sensors that are situated at preset locations and aligned with particular orientations on the vehicle. Each sensor may consist of single or multiple transmitting transducers and single or multiple receiving transducers. Each sensor provides a means for changing the effective sensing volume of the sensors or it has two or more separate processing channels for processing the time-of-flight information with several different effective sensing volumes using the sensor signal processor. The sensor signal processor also provides a means for collecting information regarding the echo signal peak value and the noise present in the received signal before reception of the first echo. A sensor array processor excites the transducers, measures the time-of-flight of arrival of the first echo above a predetermined threshold and combines the data from the multiple signal processing channels so as to increase the range data gathering speed and to improve the fidelity of the range data received. The sensor array processor determines from the range data received and the signal and noise information the position and orientation of gross geometric features in the environment (flat surfaces, posts inside corners and outside corners) relative to the sensor array. This information may be used by a navigation control processor to avoid collisions, recognize features in the environment, or map the environment.

An autonomous vehicle or a sensor assisted vehicle is comprised of some type of sensor system for sensing the environment through which the vehicle navigates. The sensor system preferably has the ability to sense objects in the path of movement of the vehicle so that the vehicle control system can take appropriate action. The sensor system may also be used to sense objects at the sides and to the rear of the vehicle. The vehicle control system may use this sensor information to:
1. alter the speed or steering of the vehicle to avoid collision with objects in the environment,
2. determine position and orientation of features or objects in the environment in order to search for and or follow those features. Examples of such features are walls to be followed down a corridor, door openings for finding passages out of rooms, and corners of walls to find branches in corridors, and smaller objects such as posts that are to be avoided,
3. determine the position and orientation of features of objects in the environment in order to form an associative map that indicates where objects and features are in the environment,
4. determine the position and orientation of objects in the environment that the vehicle's control system will use as navigational landmarks, for registration of the vehicle's drive system while it is following a particular trajectory or to memorize and later locate a particular position in the environment.
Sensor systems that perform the sensing function required for such an application are time-of-flight ranging systems (ultrasound, light, radio waves), as well as laser ranging apparatus and passive scene analysis using computer vision. The ultrasound time-of-flight systems have been preferred because of their low cost.
Most often ultrasonic systems use the time-of-flight technique to measure the distance between the sensor and an object. One or more sensors are excited to send a burst of sound and the same or several other sensors are used to receive the echoes from the environment. Since the velocity of sound in air is known, the time between the emission of the sound burst and the reception of the first echo from an object may be used to determine the distance between the object and the detector.
However, there are a number of problems associated with ultrasonic detectors.
For example, it is difficult to obtain reliable and consistent range signals in most environments. This is due mainly to the specular reflections experienced by ultrasonic signals in most indoor environments. (The wavelength of sound in air is larger than the roughness of most indoor surfaces.)
In order to obtain the angular resolution required to determine the angular position of objects with respect to the vehicle, sensors may be positioned around the vehicle, or concentrated and pointed in the direction of motion of the vehicle. The speed of range data collection is limited by the speed of sound in air (about 340 meters per second, depending mainly on temperature and humidity) and the potential for errors due to the chance of a sound burst from one sensor causing an echo contribution to another sensor. This effect is called crosstalk.
System designers may excite the sensors in a manner that minimizes crosstalk. For example, in a system with a circular array of 24 sensors, orthogonally positioned sensors would be fired simultaneously--four at a time, and range data collected from them. Hence 24 sensors would need 6 excitations to capture the range data from all sensors.
In an attempt to further increase range data acquisition speed, some designers reduce the depth of view for all sensors. This means that the sensor array processor only monitors the echo data lines from the sensors long enough to measure the time of arrival of echoes from objects closer than 1 or 2 meters. In addition, a delay time may be added between firings to allow the previous sound emissions to decay. These techniques require careful adjustment of transducers excitation patterns, delays between firings, and depth of view to avoid crosstalk.
Due to the unreliable nature of the range signals, in order to determine position of objects and features in the environment, a type of temporal and spatial averaging has been used. This involves a vehicle which has a number of sensors positioned around its perimeter. The sensors are excited repetitively while the vehicle moves around the environment. Measurement devices attached to the vehicle's wheels are used to determine the relative motion of the vehicle. Range information regarding potential targets in the environment are recorded along with their positions relative to the vehicle in a two dimensional (2D), map-like representation. As the vehicle moves, the sensors view different volumes of space. This information is used to increase or decrease the probability of a target's appearance within a particular location. Using this system, over the course of time and movement in the environment, a more reliable idea of the position of objects is gained.
This system has a number of problems. It is time consuming, requiring data to be collected over a period of time and required movement in order to determine whether or not the sonar data are reliable.
It requires significant data collecting and storage. Over the course of time or for a large area, a large amount of data may be collected before there are data from sensors in other positions that confirm or deny the position of objects in the environment. To reduce storage requirements and increase processing speed, the granularity of the grid for the two dimensional map may be increased (i.e. cell locations within the map are increased in size). Unfortunately this also reduces the resolution of the system.
Errors due to inaccuracies in the dead reckoning system during movement cause the range data to be distorted.

Method of determining range data in a time-of-flight ranging system


In the method for propelling an aircraft, to obtain electric energy, a fuel is combusted, and an electric machine is used, wherein the fuel is used to cool at least one part of the electric machine and contains natural gas. The propulsion system is configured to propel an aircraft, in particular according to the above-mentioned method. The propulsion system has an electric machine configured to obtain electric energy by combusting a fuel. The propulsion system further includes a natural gas tank configured to supply the fuel formed with natural gas, and a cooling device configured to cool at least one part of the electric machine. The aircraft has such a propulsion system.

Serial hybrid-electric aircraft propulsion systems require electric machines with a particularly low power-to-weight ratio. To minimize the power-to-weight ratio, it is known to form a rotor of the electric machine from a superconductive material and to operate it at a temperature of 20 K.
To cool the rotor to 20 K, it is known to use cooling devices with refrigeration machines, which cool down the rotor from ambient temperature to 20 K.
However, such cooling devices have a high mass, which consequently disadvantageously increases the mass of the aircraft propulsion system and therefore the aircraft.

Method for propelling an aircraft, propulsion system, and aircraft