The present invention relates to compounds of formula 1

This invention relates to a series of quinolin-2-one derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as agents to combat tumors in which Ras contributes to transformation. Mutated, oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837, 1993). The compounds of the present invention exhibit activity as inhibitors of the enzyme farnesyl protein transferase and are therefore believed to be useful as anti-cancer and anti-tumor agents. Further, the compounds of the present invention may be active against any tumors that proliferate by virtue of farnesyl protein transferase.
The present invention relates to compounds of formula 1
and to pharmaceutically acceptable salts, prodrugs and solvates thereof wherein:
the dashed line indicates that the bond between C-3 and C4 of the quinolin-2-one ring is a single or double bond;
R1 is selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)qC(O)R12,xe2x80x94(CR13R14)qC(O)OR15, xe2x80x94(CR13R14)qOR12, xe2x80x94(CR13R14)qSO2R15, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5 and q is an integer from 1 to 5, said cycloalkyl, aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R1 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R6 groups;
R2 is halo, cyano, xe2x80x94C(O)OR15, or a group selected from the substituents provided in the definition of R12;
each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), and xe2x80x94(CR13R14)tC3-C10 cycloalkyl), and wherein in the foregoing R3, R4, R5, R6, and R7 groups t is an integer from 0 to 5; the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
R8 is H, xe2x80x94OR12, xe2x80x94NR12R13, xe2x80x94NR12C(O)R13, cyano, xe2x80x94C(O)OR13, xe2x80x94SR12, xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, or C1-C6 alkyl, wherein said heterocyclic and alkyl moieties are optionally substituted by 1 to 3 R6 substituents;
R9 is xe2x80x94(CR13R14)t(imidazolyl) wherein t is an integer from 0 to 5 and said imidazolyl moiety is optionally substituted by 1or 2 R6 substituents;
each R10 and R11 is independently selected from the substituents provided in the definition of R6;
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5; said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, C2-C10 alkenyl and C1-C6 alkoxy;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94(CR13R14)q or (CR13R14)t each is independently defined for each iteration of q or t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H; and,
provided that where R1 is not xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), wherein t is an integer from 0 to 5, optionally substituted as provided in the definition of R1 above, then R8 is triazolyl optionally substituted by 1 or 2 R6 groups, or at least one of R3, R4 and R5 is xe2x80x94CHxe2x95x90NOR12 or xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2 and R12 is as defined above.
Preferred compounds of formula 1 include those wherein R3 is xe2x80x94CHxe2x95x90NOR12. More preferred compounds include those wherein R1 is H, C1-C6 alkyl, or cyclopropylmethyl; R2 is H; and R8 is xe2x80x94NR12R13, xe2x80x94OR12, or a heterocyclic group selected from triazolyl, imidazolyl, pyrazolyl, and piperidinyl, wherein said heterocyclic group is optionally substituted by an R6 group. Even more preferred are those compounds wherein R9 is imidazolyl optionally substituted by C1-C6 alkyl; R8 is hydroxy, amino, or triazolyl; R1 is cyclopropylmethyl; and R4, R5, R10 and R11 are each independently selected from H and halo.
Other preferred compounds formula 1 include those wherein R1 is cyclopropylmethyl. More preferred compounds include those wherein R2 is H; and R8 is xe2x80x94NR12R13, xe2x80x94OR12, or a heterocyclic group selected from triazolyl, imidazolyl, pyrazolyl, and piperidinyl, wherein said heterocyclic group is optionally substituted by an R6 group.
Other preferred compounds of formula 1 include those wherein R8 is triazolyl optionally substituted by an R6 group. More preferred compounds include those wherein R1 is H, C1-C6 alkyl, or cyclopropylmethyl; R2 is H; R9 is imidazolyl optionally substituted by C1-C6 alkyl; and R4, R5, R10 and R11 are each independently selected from H and halo.
Specific preferred compounds include the following:
3-{6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl}-benzaldehyde O-methyl-oxime;
3-{6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl}-benzaldehyde O-ethyl-oxime;
4-(3-Chloro-phenyl)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one;
6-[Amino-(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one;
4-(3-Chloro-phenyl)-6-[(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-[1,2,4]triazol-1-yl-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one;
and the pharmaceutically acceptable salts, prodrugs and solvates of the foregoing compounds, as well as stereoisomers of the foregoing compounds.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 1, as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in inhibiting farnesyl protein transferase. In one embodiment of this method, the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin""s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 1, as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
The present invention also relates to a method for the treatment of an infection in a mammal, including a human, that is facilitated by farnesyl protein transferase, such as hepatitus delta virus or malaria, which comprises administering to said mammal a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof.
This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the formula 1, as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in inhibiting farnesyl protein transferase, and a pharmaceutically acceptable carrier. In one embodiment of said composition, said abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin""s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said pharmaceutical composition, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the formula 1, as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises a therapeutically effective amount of a compound of formula 1, as defined above, or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier and an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
This invention also relates to a pharmaceutical composition for the treatment of an infection in a mammal, including a human, that is facilitated by farnesyl protein transferase, such as malaria or hepatitus delta virus, comprising an amount of a compound of the formula 1, as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier.
xe2x80x9cAbnormal cell growthxe2x80x9d, as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs; and (4) any tumors that proliferate by virtue of farnesyl protein transferase.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, unless otherwise indicated, refers to the act of treating as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein, unless otherwise indicated, includes cyclic alkyl moieties wherein alkyl is as defined above.
The term xe2x80x9calkenylxe2x80x9d, as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term xe2x80x9c4-10 membered heterocyclicxe2x80x9d, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms, generally 1 to 4 heteroatoms, each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties. An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the compounds listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
Where R13 and R14 are as (CR13R14)q or (CR13R14)t each is independently defined for each iteration of q or t in excess of 1. This means, for instance, that where q or t is 2 alkylene moieties of the type xe2x80x94CH2CH(CH3)xe2x80x94, and other asymmetrically branched groups, are included.
The term xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of formula 1. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of carboxylic acid groups and hydrochloride salts of amino groups. Other pharmaceutically acceptable salts of amino groups are hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. The preparation of such salts is described below.
The subject invention also includes isotopically-labelled compounds, and the pharmaceutically acceptable salts thereof, which are identical to those recited in formula 1, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H 3H, 13C, 14C, 15N, 18O, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula 1 of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
This invention also encompasses pharmaceutical compositions containing and methods of treating bacterial infections through administering prodrugs of compounds of the formula 1. Compounds of formula 1 having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of formula 1. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, omithine and methionine sulfone.
Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. The amide and ester moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in D. Fleisher, R. Bong, B. H. Stewart, Advanced Drug Delivery Reviews (1996) 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in R. P. Robinson et al., J. Medicinal Chemistry (1996) 39, 10.
Certain compounds of formula 1 may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula 1, and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of formula 1, the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. In particular, the carbon to which the R8 and R9 groups are attached represents a potential chiral center; the present invention encompasses all stereoisomers based on this chiral center. The compounds of formula 1 may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof. Certain compounds of formula 1 may also include oxime moieties, such as where R3, R4, R5, R6 or R7 is xe2x80x94CHxe2x95x90NOR12, that exist in E or Z configurations. The present invention includes racemic mixtures of compounds of formula 1 that include such oxime moieties or specific E or Z isomers of such compounds.
The compounds of formula 1 may be prepared as described below.
With reference to Scheme 1 below, the compounds of formula 1 may be prepared by hydrolysing an intermediate ether of formula 2, wherein R is C1-C6 alkyl, according to methods familiar to those skilled in the art, such as by stirring the intermediate of formula 2 in an aqueous acid solution. An appropriate acid is, for example, hydrochloric acid. The resulting quinolinone of formula 1 wherein R1 is hydrogen may be transformed into a quinolinone wherein R1 has a meaning as defined above apart from hydrogen by N-alkylation methods familiar to those skilled in the art.
With reference to Scheme 2 below, the compounds of formula 1(b), which are compounds of formula 1 wherein R8 is hydroxy, may be prepared by reacting an intermediate ketone of formula 3 with an intermediate of the formula Hxe2x80x94R9, wherein R9 is as defined above and wherein in the imidazolyl moiety of said R9 group a free nitrogen atom may be protected with an optional protective group, such as a sulfonyl group (for example, a dimethylamino sulfonyl group) which can be removed after the addition reaction. Said reaction requires the presence of a suitable strong base, such as sec-butyl lithium, in an appropriate solvent, such as tetrahydrofuran, and the presence of an appropriate silane derivative, such as chloro-tert-butyldimethylsilane. The silyl group can be removed with a fluoride source such as tetrabutyl ammonium fluoride. Other procedures with protective groups analogous to silane derivatives can also be applied.
With reference to Scheme 3 below, compounds of formula 1(b-1), which are compounds of formula 1 wherein the dotted line is a bond and R1 is hydrogen, can be prepared by reacting an intermediate of formula 21 with an intermediate of formula Hxe2x80x94R9, wherein R9 is as described above. The resulting intermediate of formula 22 undergoes ring opening of the isoxazole moiety by stirring it with an acid, such as TiCl3, in the presence of water. Subsequent treatment of the resulting intermediate of formula 23 with a suitable reagent, such as R2CH2COCl or R2CH2COOC2H5, wherein R2 is as defined above, yields either directly a compound of formula 1(b-1) or an intermediate which can be converted to a compound of formula 1(b-1) by treatment with a base, such as potassium tert-butoxide.
Intermediates of formula 21 can be prepared by treating an intermediate of formula 16, referred to below with respect to Scheme 9, under acidic conditions.
With reference to Scheme 4 below, compounds of formula 1 wherein R8 is a radical of formula xe2x80x94NR12R13 wherein R12 and R13 are as described above (said compounds are represented below by formula 1(g)), may be prepared by reacting an intermediate of formula 13, wherein W is an appropriate leaving group, such as halo, with a reagent of formula 14. Said reaction may be performed by stirring the reactants in an appropriate solvent, such as tetrahydrofuran.
Compounds of formula 1(g), or other embodiments of formula 1, wherein the dotted line represents a bond can be converted into compounds wherein the dotted line does not represent a bond by hydrogenation methods familiar to those skilled in the art. Compounds wherein the dotted line does not represent a bond may be converted into compounds wherein the dotted line represents a bond by oxidation methods familiar to those skilled in the art.
With reference to Scheme 5 below, compounds of formula 1 wherein R8 is hydroxy (said compounds being represented by formula 1(b)) may be converted into compounds of formula 1(c), wherein R12 has the meaning described above except it is not hydrogen, by methods known to those skilled in the art, including O-alkylation or O-acylation reactions; such as by reacting the compound of formula 1(b) with an alkylating reagent such as R12xe2x80x94W, wherein R12 is as described above, in appropriate conditions, such as in a dipolar aprotic solvent, such as DMF, in the presence of a base, such as sodium hydride. W is a suitable leaving group, such as a halo group or a sulfonyl group.
As an alternative to the above reaction procedure, compounds of formula 1(c) may also be prepared by reacting a compound of formula 1(b) with a reagent of formula R12xe2x80x94OH, wherein R12 is as described above, in acidic medium.
Compounds of formula 1(b) may also be converted into compounds of formula 1(g), wherein R12 is hydrogen and R13 is replaced with C1-C6 alkylcarbonyl, by reacting compounds of formula 1(b) in acidic medium, such as sulfuric acid, with C1-C6 alkyl-CN in a Ritter-type reaction. Further, compounds of formula 1(b) may also be converted into compounds of formula 1(g), wherein R12 and R13 are hydrogen, by reacting a compound of formula 1(b) with ammonium acetate and subsequent treatment with NH3(aq.).
With reference to Scheme 6 below, compounds of formula 1(b), referred to above, may also be converted into compounds of formula 1(d), wherein R8 is hydrogen, by submitting a compound of formula 1(b) to appropriate reducing conditions, such as stirring in trifluoroacetic acid in the presence of an appropriate reducing agent, such as sodium borohydride, or, alternatively, stirring the compound of formula 1(b) in acetic acid in the presence of formamide. Further, the compound of formula 1(d) wherein R8 is hydrogen may be converted into a compound of formula 1(e) wherein R12 is C1-C10 alkyl by reacting the compound of formula 1(d) with a reagent of formula 5, wherein W is an appropriate leaving group, in an appropriate solvent, such as diglyme, in the presence of a base, such as potassium tert-butoxide.
With reference to Scheme 7 below, compounds of formula 2 may be prepared by reacting a nitrone of formula 6 with the anhydride of a carboxylic acid, such as acetic anhydride, thus forming the corresponding ester on the 2-position of the quinoline moiety. Said quinoline ester can be hydrolyzed in situ to the corresponding quinolinone using a base, such as potassium carbonate.
Alternatively, compounds of formula 1 can be prepared by reacting a nitrone of formula 6 with a sulfonyl containing electrophilic reagent, such as p-toluenesulfonylchloride, in the presence of a base, such as aqueous potassium carbonate. The reaction initially involves the formation of a 2-hydroxy-quinoline derivative which is subsequently tautomerized to the desired quinolinone derivative. The application of conditions of phase transfer catalysis, which are familiar to those skilled in the art, may enhance the rate of the reaction.
Compounds of formula 1 may also be prepared by an intramolecular photochemical rearrangement of compounds of formula 6, referred to above. Said rearrangement can be carried out by dissolving the reagents in a reaction-inert solvent and irradiating at a wavelength of 366 nm. It is advantageous to use degassed solutions and to conduct the reaction under an inert atmosphere, such as oxygen-free argon or nitrogen gas, in order to minimize undesired side reactions or reduction of quantum yield.
The substituents of the compounds of formula 1 may be converted to other substituents falling within the scope of formula 1 via reactions or functional group transformations familiar to those skilled in the art. A number of such transformations are already described above. Other examples are hydrolysis of carboxylic esters to the corresponding carboxylic acid or alcohol; hydrolysis of amides to the corresponding carboxylic acids or amines; hydrolysis of nitrites to the corresponding amides; amino groups on imidazole or phenyl moieties may be replaced by hydrogen by diazotation reactions familiar to those skilled in the art, and subsequent replacement of the diazo-group by hydrogen; alcohols may be converted into esters and ethers; primary amines may be converted into secondary or tertiary amines; double bonds may be hydrogenated to the corresponding single bond.
With reference to Scheme 8 below, intermediates of formula 3, referred to above, may be prepared by reacting a quinolinone derivative of formula 8 with an intermediate of formula 9, or a functional derivative thereof, under appropriate conditions, such as in the presence of a strong acid (for example, polyphosphoric acid) in an appropriate solvent. The intermediate of formula 8 may be formed by cyclization of an intermediate of formula 7 by stirring in the presence of a strong acid, such as polyphosphoric acid. Optionally, said cyclization reaction may be followed by an oxidation step, which can be performed by stirring the intermediate formed after cyclization in an appropriate solvent, such as a halogenated aromatic solvent (for example, bromobenzene), in the presence of an oxidizing agent, such as bromine or iodine. At this stage, the R1 substituent may be changed to a different moiety by a functional group transformation reaction familiar to those skilled in the art.
With reference to Scheme 9 below, intermediates of formula 3(a-1), which are intermediates of formula 3 wherein the dotted line is a bond and R1 and R2 are hydrogen, can be prepared starting from an intermediate of formula 17, which is conveniently prepared by protecting the corresponding ketone. Said intermediate of formula 17 is stirred with an intermediate of formula 18 in the presence of a base, such as sodium hydroxide, in an appropriate solvent, such as an alcohol (for example, methanol). The resulting intermediate of formula 16 will undergo hydrolysis of the ketal and ring opening of the isoxazole moiety by stirring the intermediate of formula 16 with an acid, such as TiCl3, in the presence of water. Subsequently, acetic anhydride can be used to prepare an intermediate of formula 15, which will undergo ring closure in the presence of a base, such as potassium tert-butoxide.
Intermediates of formula 3(a-1) can be converted to intermediates of formula 3(a), which are intermediates of formula 3 wherein the dotted line represents a bond, R2 is hydrogen, and R1 is other than hydrogen as defined above, using N-alkylation procedures familiar to those skilled in the art.
With reference to Scheme 10 below, an alternative method of preparing intermediates of formula 3(a-1), wherein R1 is hydrogen, begins with an intermediate of formula 16 which can be converted to an intermediate of formula 19 using catalytic hydrogenation conditions, such as by using hydrogen gas and palladium on carbon in a reaction-inert, solvent such as tetrahydrofuran (THF). The intermediates of formula 19 can be converted into an intermediate of formula 20 by submitting the intermediate of formula 19 to an acetylation reaction, such as by treatment with the anhydride of a carboxylic acid (for example, acetic anhydride) in a reaction-inert solvent, such as toluene, and subsequent treatment with a base, such as potassium tert-butoxide, in a reaction-inert solvent, such as 1,2-dimethoxyethane. The intermediate of formula 3(a-1) can be obtained by subjecting the intermediate of formula 20 to acidic conditions.
With reference to Scheme 11 below, the intermediate of formula 2, referred to above, may be prepared by reacting an intermediate of formula 10, wherein W is an appropriate leaving group, such as halo, with an intermediate ketone of formula 11. This reaction is done by converting the intermediate of formula 10 into a organometallic compound, by stirring it with a strong base such as butyl lithium, and subsequently adding the intermediate ketone of formula 11. Although this reaction gives at first instance a hydroxy derivative (R8 is hydroxy), said hydroxy derivative can be converted into other intermediates wherein R8 has another definition by performing functional group transformations familiar to those skilled in the art.
With reference to Scheme 12 below, the intermediate nitrones of formula 6 can be prepared by N-oxidizing a quinoline derivative of formula 12 with an appropriate oxidizing agent, such as m-chloro-peroxybenzoic acid or H2O2, in an appropriate solvent, such as dichloromethane.
Said N-oxidation may also be carried out on a precursor of a quinoline of forumula 12.
The intermediate of formula 12 may be metabolized in vivo into compounds of formula 1 via intermediates of formula 6. Hence, intermediates of formula 12 and 6 may act as prodrugs of compounds of formula 1. Such prodrugs are within the scope of the present invention.
With reference to Scheme 13 below, the compound of formula 26 can be prepared by reacting a compound of formula 25 with an intermediate of formula 27 where R12 is H or phenyl. This reaction requires the presence of a suitable base, such as tert-butyl lithium (when R12=H) or lithium 2,2,6,6,-tetramethylpiperidine (when R12=phenyl), in an appropriate solvent, such as THF. The xe2x80x94SR12 group can be reductively removed from the compound of formula 26 with RANEY(trademark) nickel or oxidatively with nitric acid or aqueous hydrogen peroxide in acetic acid.
The compounds of formula 1 and some of the intermediates described above may have one or more stereogenic centers in their structure. Such stereogenic centers may be present in a R or a S configuration. Oxime moieties, such as where R3, R4, R5, R6 or R7 is xe2x80x94CHxe2x95x90NOR12, may exist in E or Z configurations.
The compounds of formula 1 as prepared in the above processes are generally racemic mixtures of enantiomers which can be separated from one another following resolution procedures familiar to those skilled in the art. The racemic compounds of formula 1 may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomerics forms of the compounds of formula 1 involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs sterospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecfic methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of formula 1 that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula 1 from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is readily obtained. The desired acid addition salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid. Cationic salts of the compounds of formula 1 are similarly prepared except through reaction of a carboxy group with an appropriate cationic salt reagent, such as sodium, potassium, calcium, magnesium, ammonium, N,Nxe2x80x2-dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine, tromethamine, or diethanolamine.
The compounds of formula 1 and their pharmaceutically acceptable salts and solvates (hereinafter referred to, collectively, as xe2x80x9cthe therapeutic compoundsxe2x80x9d) can be administered orally, transdermally (e.g., through the use of a patch), parenterally or topically. Oral administration is preferred. In general, compounds of the formula 1 and their pharmaceutically acceptable salts and solvates are most desirably administered in dosages ranging from about 1.0 mg up to about 500 mg per day, preferably from about 1 to about 100 mg per day in single or divided (i.e., multiple) doses. The therapeutic compounds will ordinarily be administered in daily dosages ranging from about 0.01 to about 10 mg per kg body weight per day, in single or divided doses. Variations may occur depending on the weight and condition of the person being treated and the particular route of administration chosen. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
The therapeutic compounds may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the two routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the novel therapeutic compounds of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a therapeutic compound in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
Additionally, it is also possible to administer the therapeutic compounds topically and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The therapeutic compounds may also be administered to a mammal other than a human. The dosage to be administered to a mammal will depend on the animal species and the disease or disorder being treated. The therapeutic compounds may be administered to animals in the form of a capsule, bolus, tablet or liquid drench. The therapeutic compounds may also be administered to animals by injection or as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. As an alternative the therapeutic compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
The compounds of formula 1 exhibit activity as Ras farnesylation inhibitors and are useful in the treatment of cancer and the inhibition of abnormal cell growth in mammals, including humans. The activity of the compounds of formula 1 as Ras farnesylation inhibitors may be determined by their ability, relative to a control, to inhibit Ras farnesyl transferase in vitro. This procedure is described below.
A crude preparation of human farnesyl transferase (FTase) comprising the cytosolic fraction of homogenized brain tissue is used for screening compounds in a 96-well assay format. The cytosolic fraction is prepared by homogenizing approx. 40 grams fresh tissue in 100 ml of sucrose/MgCl2/EDTA buffer (using a Dounce homogenizer; 10-15 strokes), centrifuging the homogenates at 1000 grams for 10 minutes at 4G, re-centrifuging the supernatant at 17,000 grams for 15 minutes at 4G, and then collecting the resulting supernatant. This supernatant is diluted to contain a final concentration of 50 mM Tris HCl (pH 7.5), 5 mN DTT, 0.2 M KCl, 20 mM ZnCl2, 1 mM PMSF and re-centrifuged at 178,000 grams for 90 minutes at 4G. The supernatant, termed xe2x80x9ccrude FTasexe2x80x9d was assayed for protein concentration, aliquoted, and stored at xe2x88x9270xc2x0 C.
The assay used to measure in vitro inhibition of human FTase is a modification of the method described by Amersham LifeScience for using their Farnesyl transferase (3H) Scintillation Proximity Assay (SPA) kit (TRKQ 7010). FTase enzyme activity is determined in a volume of 100 ml containing 50 mM N-(2-hydroxy ethyl) piperazine-N-(2-ethane sulfonic acid) (HEPES), pH 7.5, 30 mM MgCl2, 20 uM KCl, 5 mM Na2HPO4, 5 mM dithiothreitol (DTT), 0.01% Triton X-100, 5% dimethyl sulfoxide (DMSO), 20 mg of crude FTase, 0.12 mM [3H]-farnesyl pyrophosphate ([3H]-FPP; 36000 dpm/pmole, Amersham LifeScience), and 0.2 mM of biotinylated Ras peptide KTKCVIS (Bt-KTKCVIS) that is N-terminally biotinylated at its alpha amino group and was synthesized and purified by HPLC in house. The reaction is initiated by addition of the enzyme and terminated by addition of EDTA (supplied as the STOP reagent in kit TRKQ 7010) following a 45 minute incubation at 37xc2x0 C. Prenylated and unprenylated Bt-KTKCVIS is captured by adding 10 ml of steptavidin-coated SPA beads (TRKQ 7010) per well and incubating the reaction mixture for 30 minutes at room temperature. The amount of radioactivity bound to the SPA beads is determined using a MicroBeta 1450 plate counter. Under these assay conditions, the enzyme activity is linear with respect to the concentrations of 40 the prenyl group acceptor, Bt-KTKCVIS, and crude FTase, but saturating with respect to the prenyl donor, FPP. The assay reaction time is also in the linear range.
The test compounds are routinely dissolved in 100% dimethyl sulfoxide (DMSO). Inhibition of farnesyl transferase activity is determined by calculating percent incorporation of tritiated-farnesyl in the presence of the test compound vs. its incorporation in control wells (absence of inhibitor). IC50 values, that is, the concentration required to produce half maximal farnesylation of Bt-KTKCVIS, is determined from the dose-responses obtained.

Quinolin-2-one derivatives useful as anticancer agents

Abstract: and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are as defined herein. The above compounds of formula 1 are useful in the treatment of hyperproliferative disorders, such as cancer, in mammals. The invention also relates to pharmaceutical compositions containing the compounds of formula 1 and to methods of inhibiting abnormal cell growth, including cancer, in a mammal by administering the compounds of formula 1 to a mammal requiring such treatment.


The invention relates to transmission and reception of clock synchronization data in a wireless communication system. According to the invention a device for transmitting clock synchronization data obtains at least one time reference of a wireless communication system clock, controls transmission of a frequency reference of the wireless communication system clock via an air interface of the wireless communication system, and provides transmission of the time reference via a transport network associated with the wireless communication system, while the base station receives the frequency reference, locks an own oscillator to the frequency of the frequency reference, receives the time reference from the transport network and adjusts timing that is controlled by the oscillator based on the time reference.

The size of wireless communication systems in terms of the number of nodes they include have increased rapidly in recent years. One type of communication system where this trend is especially strong is the cellular system.
One reason for this growth is the reduction in size of some system nodes, such as base stations. Base stations can nowadays be fairly small and cover a small area. This allows great flexibility in the systems but also puts high demands on them.
As the size of the base stations decrease there is desire to make them as simple as possible in order to keep the costs down. However, they must still have a first-rate functionality.
One area where this is evident is the issue of clocks and timing.
A base station used in a wireless communication system needs a stable frequency reference to be able to communicate with mobile stations at a reasonable bitrate. Demand for higher bitrates is increasing over time, depending of new end user features that requires large amount of data to be transferred to and from the mobile stations.
This leads to the requirement of more bandwidth and higher frequencies, which emphasises the need for exact timing.
This exact timing can in many instances be obtained using an oscillator that is heated and kept at a specific temperature with the help of a temperature regulation device, such as an Oven.
Yet another solution is to use a Global Positioning System (GPS) receiver for time and frequency synchronization of the local oscillator.
The use of GPS is for instance described in U.S. Pat. No. 7,606,541.
Stable oscillators are costly and require volume/space in the device. Warming the oscillator will first of all require the additional arrangement needed for keeping a certain temperature, which adds to the cost and the complexity. However, it will also draw extra energy, which even further raises the costs. The time until a stable frequency can be generated is further rather long depending of time sample integrating and oscillator warming, which means that valuable time may be lost before the required accuracy is obtained.
When synchronization is solved with the help of a GPS, the obvious drawback is that the GPS signal is not always available, typically not in indoor systems. Furthermore, there is here a requirement of additional receivers for receiving GPS signals.
As can be seen, there is therefore a need for alternative ways of obtaining accurate timing of a base station.


A high Q whispering gallery mode resonator with ion-implanted voids is described. A resonator device includes a resonator disk formed of an electrooptic material. The resonator disk includes a top surface, a bottom surface substantially parallel to the top surface, and a side structure between the top surface and the bottom surface. The side structure includes an axial surface along a perimeter of the resonator disk, where a midplane passes through the axial surface dividing the axial surface into symmetrical halves. The whispering gallery mode resonator disk includes voids localized at a particular depth from the top surface. At least one of the voids localized at the particular depth from the top surface is located at an outer extremity towards the perimeter of the resonator disk. The resonator device can further include a first electrode on the top surface and a second electrode on the bottom surface.

Various conventional architectures employ a laser that is injection locked to a resonator. For instance, the laser can emit a light beam that is sent to the resonator. The laser and the resonator are optically coupled, such that the light beam from the laser is provided to the resonator, circulates inside the resonator undergoing total internal reflection, and is provided back from the resonator to the laser. When injection locked, the frequency of the laser is a slave to the frequency of the resonator (e.g., the resonator can cause the laser to emit a light beam at substantially similar frequency as compared to the frequency of the resonator).
An exemplary resonator that can be utilized for injection locking is a high quality factor (Q) whispering gallery mode resonator. Due to electrooptic properties and size of such a resonator, frequency of a whispering gallery mode resonator can be linearly modulated with a relatively narrow linewidth. According to an example, a voltage in a sawtooth waveform applied to the resonator can cause the laser injection locked to the resonator to emit a light beam with a frequency that follows the sawtooth waveform.
Conventional whispering gallery mode resonators can intrinsically support a plurality of modes per each free spectral range (FSR). Mode positions in the traditional resonators can be determined by resonator geometry, which can have variations due to limited fabrication precision. Accordingly, many fabricated resonators can have side modes near a working mode (e.g., within a certain frequency range), which can render such resonators unusable. Thus, resonator production yield for conventional resonators can be detrimentally impacted.

This patent is subject to a terminal disclaimer.

Optical resonator with localized ion-implanted voids


The present invention provides a method for a local area network router, that allows communication between a number of remotely located users, and a plurality of peripheral devices connected to the local area network router. Users may access the local area network using wireless devices or the Internet. The peripheral devices, which may include a wide variety of multi-media storage, playback, printing, or other functions, are connected to the router via local interfaces, which communicate with the peripheral devices via established protocols. Each of the peripheral devices is provided with an IP address, which facilitates direct communication of the users with the peripheral devices and permits direct communication with the devices over the Internet. Data packets destined for the IP address of a peripheral device are router through the local interface, which converts the data utilizing compatible communication protocols for the target peripheral device.

1. Field of the Invention
The invention relates to methods and apparatus for providing multi-user access to devices and the Internet.
2. Description of the Related Art
It is increasingly desirable to couple computer and digital devices together and to the Internet using TCP/IP protocols. One instance of this is multiple computers provided with radio modems providing wireless communication. Wireless communication between users and a network provides some significant advantages over the similar communication networks utilizing completely hardwired connections. Since there are no permanent wires or cables connecting users to a hub or router in the network, the costs of installing wire and cable are eliminated, as are any costs associated with expanding or changing the office or workplace facility in the future. Wireless solutions also provide mobility for users who must take their PC to various locations on the job site and cannot be tied to a single, non-mobile workstation.
Currently, wireless communication between users and a network may take place via a wireless network access point. This access point is simply an adapter device that converts the incoming radio communications from users' PCs to signals understood by a network, and gives the remote PC users access to all devices connected (hard wired) to the network beyond the access point. This concept is illustrated in FIG. 1A of the prior art. Users may have portable 10A or desktop 10B PCs equipped with wireless modems. These modems transmit to and receive from wireless access point 12 which has a single Ethernet connection 14 to a local area network 16. This access point 12 is a dedicated hardware device specifically designed to provide multi-user wireless communication with a single Ethernet LAN connection.
Once a user is connected to the LAN 16, they would have access to a number of peripheral devices such as printers, network hard drives, scanners, cable modems, telephone modems, etc. But all of these devices normally require a second interface to connect to the LAN. For example, a printer connected to the network would require an interface device that has an Ethernet connection input (from the LAN) and a standard UART (universal asynchronous receiver transmitter) driven LPT (line printer terminal) parallel port (to be connected to the printer). In addition, the LAN usually requires various servers and switching hubs designed to identify and route traffic to end target devices.
FIG. 1B (prior art) illustrates a similar system marketed by Compex, that allows a standard PC 18 to be converted to an access point for an Ethernet based LAN 16. A "kit" provided by the manufacturer includes a wireless transceiver pair; one for a user's PC 10A or 10B, and a mating compatible PCI bus interface circuit card that is installed in PC 18. Also included in the "kit" is software that enables the network communication between user's PC 10 and LAN 16. Connection to peripheral devices attached to LAN 16 would have to be made through LAN 16. Connection to peripheral devices attached to the LAN 16 would have to be made through interface adapters, as discussed previously.
FIG. 1C (prior art) illustrates another current product manufactured by companies like Lucent, 3Com, and Cisco Systems. A wireless residential gateway 20 provides an access point for an Ethernet 14 based LAN 16, along with a standard V.90 modem connection 22 that can communicate via standard telephone lines 14, and RS232 serial port connections 26. This device provides connectivity to other communication technologies besides a LAN, but access to any peripheral device attached to the RS232 serial port 26, for example, will still require another piece of hardware or additional components to connect to the widest variety of devices, since most will not provide compatible connectivity via a serial port.
FIG. 1D (prior art) illustrates a product that provides wireless communication between users 10 and a USB (universal serial bus) based network. A wireless USB adapter 28 can be connected to a USB hub 30, which in turn is connected to multiple USB devices 32. Currently, a wide variety of USB devices exists such as scanners, DVD/CD readers/writers, removable storage, and printers. But not all devices are compatible with USB systems, and USB is not desirable for high speed data transfers, as might be required for hard disk drives or full color scanners.
FIG. 1E (prior art) illustrates a product that provides wireless communication to a cable modem or DSL (digital subscriber line) connection. Wireless base station and cable router 34 is connected to cable ort DSL line 36, and is designed exclusively for this purpose. Other types of peripherals cannot be executed.
FIG. 1F (prior art) illustrates a product that provides wireless communication between users 10 and a IEEE 1394 (Fire Wire) based network. A wireless IEEE 1394 adapter 200 can be connected to a IEEE 1394 hub 210, which in turn is connected to multiple IEEE 1394 devices 220. A wide variety of IEEE 1394 devices are available such as scanners, DVD/CD readers/writers, removable storage, and printers. But not all devices are compatible with IEEE 1394 systems, and IEEE 1394 is not a cost-effective solution when a high transfer rate is not required, such as when connecting a keyboard and a mouse to a computer.
As illustrated in the examples cited above, a wireless PC user has a large number of adapters to purchase if they want to connect to a multiplicity of devices. They can connect to a multiplicity of devices. They can purchase discrete adapters to connect directly to each end use device (such as a printer or scanner), or purchase a single access point adapter to connect to a LAN, then a number of discrete adapters to connect the end use devices to the LAN. While the current methodologies offer the highest degree of flexibility in configuring the system, it is at a penalty of high cost and significant complexity. The complexity aspect is also reflected in the software needed to run such a network, especially if numerous adapters from a number of different manufacturers are present.
It would be of further interest to have users, connected to the Internet, to also have access to a multiplicity of multi-media peripheral devices, without the expense and complexity of an Ethernet based LAN system equipped with discrete adapters to support a multiplicity of peripheral device protocols.
What is needed is an apparatus and method that allows multiple users to connect via wireless modems and the Internet to a single multiple access router, which enables the shared communication with a number of multi-media and peripheral devices.

Method and apparatus for a flexible peripheral access router


Children's ride-on vehicles having improved motor assemblies. The vehicles are reduced-scale vehicles, often formed substantially from molded plastic, that are sized for use by children and which include battery-powered motor assemblies. The vehicles may include a noise-suppression device that is adapted to reduce electromagnetic noise, a cutoff device that is adapted to selectively restrict operation of the motor assembly, or both devices. In some embodiments, the cutoff device may be a temperature-sensitive cutoff device and/or a current-sensitive cutoff device. In some embodiments, the device is disposed within a motor housing provided with the vehicle.

Children's ride-on vehicles are reduced-scaled vehicles that are designed for use by children. For example, children's ride-on vehicles include a seat adapted to accommodate one or more children and steering and drive assemblies that are adapted to be operated by a child sitting on the seat. One type of drive assembly that is often used in children's ride-on vehicles includes a battery-powered motor assembly that is adapted to drive the rotation of one or more of the vehicle's wheels. Typically, the vehicle will include an actuator, such as a foot pedal, push button or other user input device, which enables a child to select when power is delivered to the motor assembly. Some drive assemblies further include other user input devices, such as a speed selector and/or a direction selector, which are operated by a child sitting on the vehicle's seat to select the speed and/or direction at which the vehicle travels.


A thin film transistor substrate includes an active pattern which is disposed on a base substrate and includes a channel, a source electrode and a drain electrode, the channel which includes an oxide semiconductor, the source electrode and the drain electrode connected the channel, a gate electrode overlapped with the channel, a passivation layer which covers the source electrode, the drain electrode and the gate electrode and a fluorine deposition layer disposed between the active pattern and the passivation layer.

1. Field
Exemplary embodiments of the invention relate to thin film transistor substrate and a method of manufacturing the thin film transistor. More particularly, exemplary embodiments of the invention relate to a thin film transistor substrate including an oxide semiconductor, and a method of manufacturing the thin film transistor.
2. Description of the Related Art
A thin film transistor is used for various electronic devices such as a flat panel display. The thin film transistor is used as a switching device or a driving element in the flat panel display including a liquid crystal display, an organic light emitting diode display, an electrophoretic display or the like, for example.
The thin film transistor includes a gate electrode, a source electrode, a drain electrode and a channel layer providing a channel between the source electrode and the drain electrode. The channel layer includes a semiconductor layer including amorphous silicon, polycrystalline silicon, oxide semiconductor or the like.
Amorphous silicon has a relatively low electron mobility, which may be about 1 square centimeters per volt second (cm2/V·s) to about 10 cm2/V·s so that a thin film transistor including amorphous silicon has relatively low driving characteristics. In contrast, polycrystalline silicon has a relatively high electron mobility, which may be about 10 cm2/V·s to about hundreds cm2/V·s. However, a crystallization process is added for forming polycrystalline silicon. Thus, it is difficult to form a uniform polycrystalline silicon layer on a large-sized substrate and manufacturing costs are high.
Oxide semiconductor may be formed by a low-temperature process, and may be formed easily large-scaled, and has high electron mobility. Thus, the thin film transistor including the oxide semiconductor has been being researched and developed actively.

Thin film transistor substrate and method of manufacturing the same


A DC power distribution system can be configured to utilize a variable number of AC power distribution units. Installation of a converter unit in place of a PDU and resetting of associated switches permits inexpensive and rapid reconfiguration of the system without interrupting power supply to current receiving units. Techniques such as mechanical keying and sense switches minimize the possibility of human error in the reconfiguring operation.

A common technique for the distribution of DC power to large, multi-component computer systems or electronics systems is to provide a common power rail. (The term "rail," as used herein, includes both the hot path and return path.) This rail can be energized with DC power with a minimum number of connections to a power source yet can supply power to as few or as many components or units as the system requires. The impact of any interruption of the power to the rail during operation, however, can be substantial.
Various systems have been developed to render the power supplied through a common rail more reliable or fault tolerant. The power distribution system can include batteries. In the event of an interruption in the supply from the power source, the batteries can energize the rail for a sufficient period of time to permit an orderly shutdown or even to maintain reduced operation for a limited period of time. Redundant rails may be provided, each of which is separately powered, either from a separate power source or from batteries. In the event of an interruption of the power supply on one rail, power can be drawn from the other rail. Finally, even in a single rail system, that rail may be provided with power from more than one source. Thus, that rail will remain energized even should one of the power sources fail.
Two fault tolerant power distribution systems for computer systems are particularly relevant here. These systems both employ two rails, with power provided by 1,500 watt, 58 volt DC bulk power supplies. The computer system requires approximately 3,000 watts of DC power, at between 52 and 58 volts. Hence, two bulk power supplies are used in parallel.
In the first system, referred to as "N+1," the first rail is powered by two bulk power supplies to provide the 3,000 watt system requirements, plus a third bulk power supply to provide fault tolerance. All three bulk power supplies, in turn, draw power from an AC power distribution unit ("PDU") connected to a conventional AC power source. The second rail is powered by three batteries. As with the bulk power supplies, two batteries would be sufficient to meet the power requirements of the system. The third battery merely provides additional fault tolerance.
In the event any one of the three bulk power supplies fails or is taken out of service, the remaining bulk power supplies can meet system requirements. Should two or more bulk power supplies be unavailable, or AC power to the bulk power supplies is interrupted, system components can draw power from the second, battery-powered rail without any interruption in operation.
In the second power distribution system, a pair of the same bulk power supplies provide 3,000 watts of power to the first rail. A second pair of bulk power supplies provides power to the second rail. Each pair of bulk power supplies draws power from a separate PDU. In addition, each rail is also associated with a pair of batteries. This power distribution system is sometimes referred to as a "2N" system.
The 2N power distribution system provides even greater fault tolerance than the N+1 system. Either PDU can fail or be taken out of service. Even if AC power is interrupted completely, both rails remain energized by their separate batteries. In addition, the redundant pairs of bulk power supplies provides great flexibility and fault tolerance.
It sometimes occurs, however, that customer demand or changing conditions dictate that an N+1 system should be upgraded to a 2N system or that the protections of a 2N system are no longer required. The current invention permits such conversion between power distribution systems of varying degrees of fault tolerance and operational availability quickly, easily, and cost-effectively.

Flexible implementation of distributed DC power


A method provides a demonstration capability for a plurality of network coupled users by which many users can watch a primary user interact with an application. The method includes providing an application to a primary user from an application server over a network and translating output from the application into a broadcast protocol. The broadcast protocol is then translated into a browser protocol transmitted over a network for rendering by browsers at a plurality of network attached computers.

In recent years, there have been dramatic improvements in technologies that make bandwidth available for data transmission. These improvements have resulted in ubiquitous networks, such as the Internet, and have brought about rapid change in the operation of numerous industries including the software industry.
Conventionally, the software industry has developed application software for proprietary operating systems. Application software was then conventionally hosted on mainframe computers with output from software applications provided to character based terminals pursuant to proprietary protocols.
With the advent of inexpensive personal computers, this mainframe application software delivery model changed to a client-server model in which application software developers distributed application software programs to end users. In the latter scenario, the end users loaded or downloaded the application software on their computer, a "fat client" machine, and ran the application software directly on a proprietary operating system such as Microsoft Windows or Unix.
Some of the application programs in a client-server model reside on a fat client and require interaction with network resources, such as programs and data resident on servers within the network. In other client-server models, the application programs reside on the server and are provided to the client system with the aid of emulation software on the client system.
With the advent of the Internet and the world-wide web, client systems have been implementing browser programs to present information received from a network to users. The browser programs include an application program interface (API) that programmers may use to create plug-ins that enable browsers to render previously unrecognized information, to recognize new communications protocols and to execute applications. Browser programs, supplemented with plug-ins as necessary, provide the flexibility to interact with software applications that are remotely executed on a network. Moreover, on the server side, an application program that was written for a proprietary operating system or display protocol may be web enabled and provided to browsers on remote client systems over a network. This entails translating the output from the application program into a protocol that is recognized by the browser program or an associated plug in.
The ability to web enable existing applications and remotely host them on a network provides advantages to application software vendors as well as end users of the software. Businesses called application service providers (ASPs) have arisen to facilitate providing application software to end users and their organizations over a network and, in some cases, to facilitate web enabling of software applications. ASP businesses allow users and their organizations the flexibility to rent, as opposed to purchase, software, to avoid time consuming installations of software on client systems and to order and use software on an as needed basis. For organizations, use of an ASP may effectively represent an outsourcing of maintenance operations and information services to the ASP. ASPs also allow software vendors additional software distribution channels from which to derive revenue from end users.
In order for ASP businesses to succeed in delivering software application service to end users, the ASP must be able to deliver reliable, high-performance, secure service that is convenient for organizations and users to configure. If any of these features is lacking, organizations and users may prefer local execution and control of the application software. ASP businesses must also confront problems of scalability, extensibility and integration. With respect to scalability, demand for application service for a particular ASP may exponentially increase several orders of magnitude over a short period of time. Therefore, scalability may be critical.
Accordingly, there is a need for an architecture and methods for providing application service that allow an ASP to commission new servers and equipment for delivering application service rapidly and without interrupting existing service. In addition, there is a need for robust architecture and methods that help prevent service disruption despite server and network link failures. There is a further need for an architecture and methods that make efficient use of server and other resources of the ASP in delivering service. There is still a further need for an architecture and methods that minimize administrative burdens associated with providing application service to organizations including, for example, burdens of providing users and organizations immediate and changeable access to applications and data associated with diverse proprietary operating systems, the ability to bill for service and to perform periodic data backups. There is still a further need for methods that maximize the value of the ASP architecture.
There is a further need for an architecture and technique that allow a primary user, such as a presenter of information, to demonstrate an application over the Internet to a plurality of users simultaneously in a way that is efficient and easy for users to access.

One to many mapping of application service provision


The invention relates to a control apparatus for a hybrid system that output engine drive force and electric motor drive force, and selectively performs an engine operation mode in which at least the engine is operated, and an engine operation stop mode in which engine operation is stopped. In cases where release of vaporized fuel captured in a vaporized-fuel capturing/releasing device is required, when the engine is being operated, release of vaporized fuel is started if there is no abnormality in the vaporized-fuel capturing/releasing device, and operation of the engine is continued to release the vaporized fuel until condition for terminating release of the vaporized fuel is satisfied; and in cases where release of the vaporized fuel is required, when the engine is not being operated, operation of the engine is started and release of the vaporized fuel is started if there is no abnormality in the vaporized-fuel capturing/releasing device.

1. Field of the Invention
The invention relates to a control apparatus and a control method for a hybrid system.
2. Description of Related Art
Japanese Patent Application Publication No. 2008-238837 (JP-2008-238837 A) discloses a hybrid system capable of outputting drive force output by an internal combustion engine and drive force output by an electric motor, wherein at least an engine operation mode in which the internal combustion engine is operated and an engine operation stop mode in which the internal combustion engine is not operated are performed selectively. Furthermore, an internal combustion engine is available which includes a vaporized-fuel capturing/releasing apparatus that captures vaporized fuel generated inside a fuel tank of the internal combustion engine and releases the captured vaporized fuel into an air intake passage of the internal combustion engine.
Here, if an internal combustion engine including a vaporized-fuel capturing/releasing apparatus is used in the hybrid system described above, vaporized fuel continues to flow into the vaporized-fuel capturing/releasing apparatus from the fuel tank, even while the engine operation stop mode is being implemented in the hybrid system. Consequently, the amount of vaporized fuel which is captured by the vaporized fuel capture and release apparatus becomes large when the engine operation stop mode is implemented over a long period of time. Hence, there are cases where it becomes necessary to release vaporized fuel from the vaporized-fuel capturing/releasing apparatus while the engine operation stop mode is being implemented.
However, when it has become necessary to release vaporized fuel from the vaporized-fuel capturing/releasing apparatus, if there is an abnormality in the vaporized-fuel capturing/releasing apparatus, then even if release of vaporized fuel is to be performed from the vaporized-fuel capturing/releasing apparatus (hereinafter, this release is simply called "release of vaporized fuel"), satisfactory release of vaporized fuel cannot be performed. Consequently, if the internal combustion engine is operated only in order to release vaporized fuel in spite of the fact that there is an abnormality in the vaporized-fuel capturing/releasing apparatus, fuel is consumed unnecessarily in the internal combustion engine and the fuel economy of the internal combustion engine is unnecessarily reduced.

Control apparatus and control method for hybrid system


1,2-dioxetane compounds bearing a proteolytic enzyme specific amino acid or peptide are provided, which amino acid or peptide can be removed by action of the corresponding protease. When the amino acid or peptide is removed, the 1,2-dioxetane decomposes with chemiluminescence, the generation of light providing a rapid, ultra-sensitive and convenient means for detecting the presence of the protease in the sample being inspected. The amount of light generated, or degree of chemiluminescence, can be correlated with the amount of protease present. Immunoassays, as well as DNA hybridization and DNA probe assays are provided.

Field of the Invention
This invention pertains to chemiluminescent compounds, their use in assays for the detection of proteases, and kits comprising the compounds and other elements used in protease detection assays. Specifically, dioxetane compounds bearing a proteolytic enzyme-specific amino acid or peptide which, when removed by enzymatic reaction, causes the dioxetane to decompose and chemiluminesce, is provided. These compounds, when added to a sample suspected of containing the protease, provide a rapid, ultrasensitive and convenient means for detecting the presence of the protease in the sample. The amount of light generated, or degree of chemiluminescence, can be correlated with the amount of protease present.

Dioxetane compounds for the chemiluminescent detection of proteases, methods of use and kits therefore


In certain embodiments, a method for bandwidth allocation includes receiving at least a first traffic flow and a second traffic flow, each traffic flow including at least committed information rate (CIR) and excess information rate (EIR) parameters. The CIR parameter in each traffic flow is associated with a corresponding guaranteed pass-through rate. The first traffic flow and the second traffic flow are stored in first and second queues, respectively. The first queue is associated with a first provisioned weight, and the second queue is associated with a second provisioned weight. The method further includes scheduling downstream transmission of the first traffic flow and second traffic flow stored in the first and second queues according to at least first and second implementation weights that are determined based on a bandwidth of a downstream communication link, a CIR parameter of the first queue, a CIR parameter of the second queue, and each of the first and second provisioned weights.

Communication networks may bottleneck at a point in the network that receives more traffic than it can pass. In other words, at that point in the network, there is not sufficient downstream bandwidth to pass all of the traffic at once. In such cases, a decision must be made as to the manner in which bandwidth will be allocated among various incoming traffic flows. Typical systems do not provide a robust bandwidth allocation solution for allocating bandwidth among the various incoming traffic flows.


A fuel gas generator for lean gas generation by gasification of organic, inorganic, or fossil fuel substances. The triple shell structure of the generator includes a frame casing, a shaft jacket, and a reactor shaft. A fuel feeder including a fuel feed container is located substantially at the top of the reactor shaft and has a gas-tight entry lock. Reaction gas feed and ash discharge are located substantially at the base of the reactor shaft. Preheating, degassing, oxidation, and reduction zones and lean gas take-off orifices having at least one lean gas removal pipe connected thereto are arranged one after another in the shaft. The reactor shaft is gas-tight except for the lean gas take-off orifices. A firebox defined by a conical constriction is located in a middle region of the reactor shaft substantially below the preheating and degassing zones. The constriction tapers downwardly towards the base of the firebox retaining and supports a bed, pile, or stack of degassed and partially oxidized fuel substrate. A circular or annular opening, passage, or slot acts as a grate or grid element located at the base of the constriction at the termination of the reduction zone and as an upper terminus of a gas-tight ash chamber. At least one lean gas take-off orifice is located in the reactor shaft below the grid element.

Between the main generator/gasifier systems, the generally preferred countercurrent gasifier and the cocurrent gasifier, the latter is preferred according to the invention for generating the lean gas. The generator gas obtained according to the principle of countercurrent gasification is of limited use since it can be used only for subsequent direct combustion because it has a high content of viscous pyrolysis products, such as tar, phenol and the like, which condense at temperatures below 400.degree. C.
The principle which is preferred according to the basic concept of the invention involves descending gasification, in which the dry zone and the pyrolysis zone are formed in the upper part of the reactor. According to preferred aspects of the present invention, in contrast to the countercurrent principle, air is fed in from above, directly after the pyrolysis zone. The combustion produces the necessary temperatures to cleave the descending low-temperature carbonization products from the pyrolysis zone into readily combustible gases. The remaining volatile substances are also gasified from the charcoal. Thus, no tar products enter the subsequent reduction zone.
Regarding the technological peculiarities of these gasification processes, reference is made to "Holzvergasung", Willy Bierter/Christian Gaegauf, Karlsruhe, 1982, page 52 et seq. Furthermore, the prior art in the area of gas generators includes German Patent 3,239,624, FIG. 1 to 3 and associated description, column 2, line 11 et seq and column 4, lines 41 to 7, page 10.
The stated patent describes five gasification principles, among which the cocurrent principle is most closely related to the invention. In order to carry out this gasification principle, the invention provides a generator whose elements and features have, in some cases been radically redesigned and in some cases, modified compared with the prior art, so that the generator process is based on a modified cocurrent principle.

Fuel gas generator for lean gas generation


.alpha.- Phosphonocarboxylate compounds are provided which inhibit the enzyme squalene synthetase and thereby inhibit cholesterol biosynthesis. These compounds have the formula ##STR1## wherein R.sup.1 is a lipophilic group which contains at least 7 carbons and is substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl or optionally substituted aryl;. Z is H, halogen, hydroxy, hydroxyalkyl or lower alkyl; PA1 R.sup.2 and R.sup.3 are independently H, metal ion or other pharmaceutically acceptable cation, or a prodrug ester; PA1 R.sup.4 is H, metal ion or other pharmaceutically acceptable cation, lower alkyl, lower alkenyl, arylalkyl, aryl or a prodrug ester.

Squalene synthetase is a microsomal enzyme which catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate (FPP) in the presence of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) to form squalene (Poulter, C.D.; Rilling, H.C., in "Biosynthesis of Isoprenoid Compounds", Vol. I, Chapter 8, pp. 413-441, J. Wiley and Sons, 1981, and references therein). This enzyme is the first committed step of the de novo cholesterol biosynthetic pathway. The selective inhibition of this step should allow the essential pathways to isopentenyl tRNA, ubiquinone, and dolichol to proceed unimpeded. Squalene synthetase along with HMG-CoA reductase have been shown to be down-regulated by receptor mediated LDL uptake (Faust, J.R.; Goldstein, .L.; Brown, M.S. Proc. Nat. Acad. Sci. U.S.A. 1979, 76, 5018-5022), lending credence to the proposal that inhibiting squalene synthetase will lead to an up-regulation of LDL receptor levels, as has been demonstrated for HMG-CoA reductase, and thus ultimately should be useful for the treatment and prevention of hypercholesterolemia and atherosclerosis.
U.S. Pat. No. 3,313,735 to McCune disclose shampoo compositions which include phosphono compounds of the formulae ##STR2## wherein R is an alkyl radical containing 6 to 18 carbons, X is H or methyl, Z is OH, COOM and PO.sub.3 M.sub.2, and M is H, Na, K, ammonium, and low molecular weight substituted ammonium.
B. Eriksson et al, Biochimica et Biophysica Acta 1982, 696, 115-123 and Proc. Int. Congr. Chemother. 13th 1982, 6, 114/29-114/32 disclose inhibitors of DNA polymerases of cytomegalovirus and herpes simplex virus having the formula ##STR3## wherein R is H, CH.sub.3, CH.sub.2 CH.sub.3, (CH.sub.2).sub.2 CH.sub.3, (CH.sub.2).sub.8 CH.sub.3, phenyl or OH.
B. Lofgren et al, Antiviral Research 1989, 12, 301-310 discloses inhibitors of the DNA polymerase of hepadnaviruses having the structure ##STR4## wherein R is OH, (CH.sub.2).sub.4 CH.sub.3, (CH.sub.2).sub.6 CH.sub.3, (CH.sub.2).sub.8 CH.sub.3, (CH.sub.2).sub.10 CH.sub.3, ##STR5##
A. Widell et al, Antiviral Research 1986, 6, 103-112, discloses inhibitors of hepatitis A virus having the structure ##STR6##
E.W. Maurer et al, J. Am. Oil Chemists' Soc., 1964, 41(3), 206-208, discloses .alpha.-phosphono fatty acids, esters and their salts having the structure ##STR7## wherein R is (CH.sub.2).sub.6 CH.sub.3 to (CH.sub.2).sub.15 CH.sub.3 and R.sup.a is H or methyl, isopropyl or aryl esters (containing 14 to 19 carbons in total).
B. Ackerman et al, J. Am. Chem. Soc. 1957, 79, 6524-6526 discloses triethyl esters of .alpha.-phosphono acid of the structure ##STR8## wherein R is C.sub.2 H.sub.5 to C.sub.16 H.sub.33.
Y. Okamoto et al, Kogyo Kagaku Zasshi 1966, 69(9), 1871-1875, disclose surface-active agents and detergents having the formula ##STR9## wherein n is 9, 11, 13 or 15.

.alpha.-phosphonocarboxylate squalene synthetase inhibitors


The present invention aims at the production of musical sounds by calculating motion data based on inputted image data using a simple technique without preliminarily preparing playing information or the like and by producing musical sounds based on the calculated data. A musical sound producing apparatus includes an operation part specifying means which extracts motion data indicative of motions from differentials of respective pixels corresponding to image data of a plurality of frames using image data for respective frames as an input; a musical sound producing means which produces musical sound data containing a sound source, a sound scale and a sound level in accordance with the motion data specified by the motion part specifying means; and an output means which outputs the musical sound data produced by the musical sound producing means, wherein an image database in which patterns are registered and an image matching means are provided, and a musical sound synthesizing means is provided to the musical sound producing means, in the musical sound producing means, so as to synthesize the musical sound data with other sound data, thereby producing the musical sound data.

1. Technical Field
The present invention relates to a musical sound producing apparatus, a musical sound producing method, a musical sound producing program, and recording medium for automatically producing musical sound data corresponding to image data.
2. Background Art
As a technique which controls playing corresponding to an image, for example, Japanese Patent 2629740 discloses a technique which controls tempo or the like by making use of a profile of an object to be photographed. In this technique, respective signals of R (red), G (green), B (blue) are separated from inputted video signals, and gray scale data indicative of gray scales are generated as digital data for respective colors. Then, the object to be photographed is specified based on the gray scale data of respective colors and preset threshold value data thus detecting the profile of the object to be photographed, and the playing is controlled corresponding to "the complexity of the detected profile".
Japanese Laid-open Patent Publication 2002-276138 discloses a technique which produces musical sound by detecting a position of a moving manipulation object, wherein the position of the specified manipulation object having a fixed shape is detected, and musical sounds are generated corresponding to both elements consisting of a traveling time from an arbitrary position to a current position of the manipulation object and the current position. To be more specific, when a position of a specified portion of the object to be photographed is detected, musical sound which is produced is allocated to a sound producing region set on an image display screen, and after a lapse of a predetermined time from the determination that the specified portion is not present in one region on the image display screen, it is determined that the specified portion exists in another region on the different image display screen, and the determined another region belongs to the sound producing region, the musical sound allocated to the sound producing region is generated.
On the other hand, as a technique which overcomes a problem which arises in the production of musical sound by catching the movement of an object, for example, Japanese Laid-open Patent Publication 2000-276139 discloses a technique in which a plurality of motion vectors is extracted from each block of a supplied image, one control vector is calculated from the plurality of motion vectors, and musical sound is produced based on the calculated control vector.
In the method which extracts the plurality of motion vectors from each block of the image, in respective blocks (16×16) corresponding to a specified image frame and an image frame which follows the specified image frame, pixels which exhibit the least color difference are picked up and the difference of positions of these pixels is set as the motion vector.
However, in the technique disclosed in Japanese Patent 2629740, it is necessary to determine the complexity of a profile of an object to be photographed by using a still image as an object, by decomposing color signals of the still image, specifying the object to be photographed by threshold inspections for respective colors, and by detecting a profile of the object to be photographed. Accordingly, this technique is an existing sound data modifying technique in view of a drawback that a load of processing is increased and the complexity of the profile. Accordingly, Japanese Patent 2629740 has a drawback that the patent has no idea of producing musical sound.
The technique disclosed in Japanese Laid-open Patent Publication 2000-276138 discloses the judgment on the movement which follows a registered specified operator and aims at the production of musical sound. However, this technique has a drawback that musical sound is not produced from an arbitrary motion picture frame.
The technique disclosed in Japanese Laid-open Patent Publication 2000-276139 copes with a task to produce musical sounds based on the analysis of the motion and also develops a method which detects motion vectors by performing the analysis in a limited specified region for reducing a load on the analysis. However, this technique is a technique which cannot avoid a fundamental drawback that a large load is applied to the calculation of the motion vectors.
It is an object of the present invention to provide a technique which, using continuous motion picture frames as objects, can take out motion data using a simple method and can produce musical sound data based on this taken-out motion data. It is also an object of the present invention to construct a unique application field by further combining the musical sound data produced in such a manner with an existing technique.
Accordingly, the present invention provides a musical sound producing apparatus, a musical sound producing method, a musical sound producing program and a recording medium for automatically producing musical sound data by calculating motion data based on inputted image data using a simple technique without preparing playing information or the like in advance.

Musical sounding producing apparatus, musical sound producing method, musical sound producing program, and recording medium