The present invention relates to novel anticancer agents, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. The present invention more particularly relates to novel derivatives of andrographolide, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. The novel derivatives of andrographolide have the general formula (I).

The present invention relates to novel anticancer agents, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. The present invention more particularly relates to novel derivatives of andrographolide, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. The novel derivatives of andrographolide have the general formula (I),
where R1, R2 and R3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl group or a group xe2x80x94(CO)xe2x80x94Wxe2x80x94R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR2 and OR3 together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms; R4 represents hydrogen, halogen or XR7 where X represents O, S, or NH and R7 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, alkenoyl, alkanoyl, aroyl, heteroaroyl, aralkenoyl, aralkanoyl, sulfonyl groups or a group xe2x80x94(CO)xe2x80x94NHxe2x80x94R8 where R8 represents substituted or unsubstituted groups selected from alkyl, aryl, or aralkyl; with provisos that (i) R1, R2 and R3 may be same except when they represent hydrogen or alkanoyl group and (ii) when R2 and R3 represent hydrogen, R1 does not represent unsubstituted alkanoyl.
The andrographolide derivatives represented by general formula (I) as defined above and general formulas (X) and (XI) as defined below of the present invention are useful for treating cancer and other proliferative diseases including but not limited to herpes simplex virus types I and II (HSV I and HSV II) and human immunodeficiency (HIV). The compounds of the present invention are also useful in the treatment of psoriasis, restenosis, atherosclerosis and other cardiovascular disorders. The compounds of the present invention are also useful as antiviral, antimalarial, antibacterial, hepatoprotective, immunomodulating agents and for the treatment of metabolic disorders. The anticancer activity exhibited may be through cytotoxic activity, antiproliferation, cell cycle kinase inhibition or may be through cell differentiation.
The novel compounds of this invention are also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, body weight reduction, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders.
The present invention also relates to pharmaceutical compositions containing compounds of general formula (I), formula (X), or formula (XI), or their stereoisomers, their polymorphs, their salts or their solvates or mixtures thereof.
The present invention also relates to a process for the preparation of the compounds of general formula (I), formula (X), and formula (XI), and their stereoisomers, their polymorphs, and their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates.
The plant andrographis paniculata is extensively used in medicine as a bitter tonic, febrifuge and in bowel complaints (Glossary of Indian Medicinal Plants., Ed. R. N. Chopra, S. L. Nayar, I. C. Chopra, p18, 1996. The useful plants of India, Ed. By S. B. Ambasta, p39, 1992). The plant is useful in the treatment of bacterial infections (Int. J. Crude Drug Res. 1990, 28(4), p273-283; Drugs of the Future. 1990, 15(8) p809-816). It is reported to possess antimalarial (Int. J. Pharmacognosy, 1992, 30(4), p263-274; J. Ethnopharmocol., 1999, 64(3), p249-254) and immunostimulant activity (J. Nat. Prod., 1993, 56(7), p995-999). The plant has also been shown to be antithrombotic (Chinese Medical Journal 1991, 104(9), p770-775) and inhibit stenosis and restenosis after angioplasty in the rat (Chinese Medical Journal, 1994, 107(6), p464-470). It is also known that the plant extract and its constituents exhibit promising hepatoprotective activity (Planta Medica, 1987, 53(2), p135-140). Significant attention has been paid by several research groups on A. paniculata in recent years due to its cytotoxic, antitumorogenic, cell differentiation inducing activities and anti-HIV activities.
Andrographolide having the formula (II),
the major constituent of the plant A. paniculata was first isolated by Gorter (Rec. trav. chim., 1911, 30, p151-160).
The extracts of the dried plant, which contains compounds of formula (III), have been assayed for the ability to decrease expression and phosphorylation of p34cdc2 kinase, cyclin B and c-Mos for treating or preventing pathogenecity of diseases such as AIDS, Alzheimer""s disease and hepatitis (WO 96/17605).
Cell cycle kinases are naturally occurring enzymes involved in regulation of the cell cycle (Progress in Cell Cycle Research, 1995, 1, p351-363). Typical enzymes include the cyclin-dependent kinases (cdk) cdk1, cdk2, cdk4, cdk5, cdk6 and wee-1 kinase. Increased activity or temporarily abnormal activation of these kinases has been shown to result in development of tumors and other proliferative disorders such as restenosis. Compounds that inhibit cdks, either by blocking the interaction between a cyclin and its kinase partner or by binding to and inactivating the kinase, cause inhibition of cell proliferation and are thus useful for treating tumors or other abnormally proliferating cells.
The extract of A. paniculata was found to show significant cytotoxic activity against KB and P388 cells. Interestingly, Andrographolide of the formula II, has been shown for the first time to have potent cytotoxic activity against KB as well as P388 lymphocytic leukemia, where as 14-deoxy-11,12-didehydroandrographolide and neoandrographolide having the formulae IV and V
where R represents xcex2-D-glucose moiety, have shown no cytotoxic activity in tumor cell lines (J. Sci. Soc. Thailand, 1992, 18, p187-194).
The methanolic extract of the aerial parts of A. paniculata Nees showed potent cell differentiation inducing activity on mouse myeloid leukemia (M1) cells (Chem. Pharm. Bull. 1994, 42(6) 1216-1225).
Japanese patent application JP 63-88124, discloses a mixture of at least two compounds of formula VIa, VIb,
where R1, R2, R3, R4 and R5 represent hydrogen or lower alkanoyl group and their activity as antitumorogenic agents.
DASM (dehydroandrographolide succinic acid monoester) prepared from andrographolide of the formula II is found to be inhibiting HIV virus and nontoxic to the H9 cell at the concentrations of 50-200 xcexcg/ml and was inhibitory to HIV-1 (EIB) at the minimal concentration of 1.6-3.1 xcexcg/ml (Proc. Soc. Exp. Biol. Med., 1991, 197, p59-66).
The plant Andrographis paniculata is also reported to inhibit proprotein convertases-1,-7 and furin possibly by suppressing the proteolytic cleavage of envelops glycoprotein gp 160 of HIV, which is known to be PC-mediated, particularly by furin and PC (Biochem. J, 1999, 338, 107-113)
In International patent application WO 91/01742, compositions containing one or more ingredients obtained from the plants Valeariana officinalis and/or A. paniculata were disclosed to have antiviral, antineoplastic, antibacterial and immunomodulatory activity.
Although several novel andrographolide derivatives have been prepared, screened and reported in the above said prior-art literature for their anticancer activity, they are not showing interesting activity.
With an objective of preparing novel andrographolide derivatives useful for treating cancer, infections and diseases caused by HSV, HIV, psoriasis, restenosis, atherosclerosis, cardiovascular disorders, also useful as antiviral, antimalarial, antibacterial, hepatoprotective, immunomodulating agents and for treatment of metabolic disorders, which are potent at lower doses and having better efficacy with lower toxicity, we focussed our research efforts in preparing the novel andrographolide derivatives of the formula (I) as defined above.
The main objective of the present invention is, therefore, to provide novel andrographolide derivatives of the formula (I), formula (X), formula (XI), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and compositions containing them or their mixtures.
Another objective of the present invention is to provide pharmaceutical compositions containing compounds of formula (I), formula (X), formula (XI), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of formula (I), formula (X), formula (XI), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates, or their mixtures in combination with one or more pharmaceutically acceptable active compounds with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
Still another objective of the present invention is to provide a process for the preparation of novel andrographolide derivatives of the formula (I), formula (X), formula (XI), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activity with little or no toxic effect or reduced toxic effect.
Accordingly, the novel derivatives of andrographolide of the present invention have the general formula (I)
where R1, R2 and R3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl group or a group xe2x80x94(CO)xe2x80x94Wxe2x80x94R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR2 and OR3 together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms; R4 represents hydrogen, halogen or XR7 where X represents O, S, or NH and R7 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, alkenoyl, alkanoyl, aroyl, heteroaroyl, aralkenoyl, aralkanoyl, sulfonyl groups or a group xe2x80x94(CO)xe2x80x94NHxe2x80x94R8 where R8 represents substituted or unsubstituted groups selected from alkyl, aryl, or aralkyl; with provisos that (i) R1, R2 and R3 may be same except when they represent hydrogen or alkanoyl group and (ii) when R2 and R3 represent hydrogen, R1 does not represent unsubstituted alkanoyl; their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.
Suitable groups represented by R1, R2 and R3 include hydrogen, substituted or unsubstituted, linear or branched (C1-C8) alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; heteroaryl group such as pyridyl, furyl, thiophenyl and the like, the heteroaryl group may be substituted; aralkyl such as benzyl, phenethyl and the like, the aralkyl group may be substituted; heteroaralkyl group such as pyridylmethyl, pyridylethyl, furanmethyl, furanethyl and the like, the heteroaralkyl group may be substituted; (C2-C8) alkanoyl group such as ethanoyl, propanoyl, butanoyl and the like, the (C2-C8) alkanoyl group may be substituted; (C3-C8) alkenoyl group such as propenoyl, butenoyl, pentenoyl and the like, (C3-C8) alkenoyl group may be substituted; aroyl group such as benzoyl and the like, the aroyl group may be substituted; heteroaroyl group such as pyridyl carbonyl, furyl carbonyl and the like; the heteroaroyl group may be substituted; aralkenoyl group such as phenylpropenoyl, phenylbutenoyl, phenylpentenoyl and the like, the aralkenoyl group may be substituted; aralkanoyl group such as phenylpropanoyl, phenylbutanoyl, phenylpentanoyl and the like, the aralkanoyl group may be substituted; heteroaralkanoyl group such as pyridylethanoyl, pyridylpropanoyl, thiopheneethanoyl, thiophenepropanoyl and the like, the heteroaralkanoyl group may be substituted; heteroaralkenoyl group such as pyridylethenoyl, pyridylpropenoyl, thiopheneethenoyl, thiophenepropenoyl and the like, the heteroaralkenoyl group may be substituted; sulfonyl group such as methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl and the like, the sulfonyl group may be substituted.
Suitable cyclic structures formed by OR2 and OR3 may be selected from xe2x80x94Oxe2x80x94(CR9R10)mxe2x80x94Oxe2x80x94 where R9 and R10 may be same or different and independently represent hydrogen, unsubstituted or substituted groups selected from (C1-C6) alkyl such as methyl, ethyl, n-propyl and the like; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; heteroaryl group such as pyridyl, furyl, thiophenyl, pyrrolyl and the like; the heteroaryl group may be substituted or R9 and R10 together represent Cxe2x95x90O; m represents an integer 1 or 2. The substituents on R9 and R10 include hydroxy, halogen such as fluorine, chlorine, bromine and the like; nitro, cyano or amino, (C1-C6)alkyl, (C1-C6)alkoxy, aryl or aroyl groups.
Suitable groups represented by R4 include hydrogen, halogen such as fluorine, chlorine, bromine and the like; or XR7 where R7 represents hydrogen or linear or branched (C1-C8) alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like, the alkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl such as benzyl, phenethyl and the like, the aralkyl group may be substituted; (C3-C8) alkenoyl group such as propenoyl, butenoyl, pentenoyl and the like, the alkenoyl group may be substituted; (C2-C8) alkanoyl group such as ethanoyl, propanoyl, butanoyl and the like, the alkanoyl group may be substituted; aroyl group such as benzoyl and the like, the aroyl group may be substituted; heteroaroyl group such as pyridyl carbonyl, furyl carbonyl and the like, the heteroaroyl group may be substituted; aralkenoyl group such as phenylpropenoyl, phenylbutenoyl, phenylpentenoyl and the like, the aralkenoyl group may be substituted; aralkanoyl group such as phenylpropanoyl, phenylbutanoyl, phenylpentanoyl and the like, the aralkanoyl group may be substituted; sulfonyl group such as methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl and the like, the sulfonyl group may be substituted or a group xe2x80x94(CO)xe2x80x94NHxe2x80x94R8 where R8 represents linear or branched (C1-C8) alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like, (C1-C8)alkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; or aralkyl such as benzyl, phenethyl and the like, the aralkyl group may be substituted.
Suitable groups represented by R5 include (C1-C6)alkyl such as methyl, ethyl, n-propyl and the like, the (C1-C6)alkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl such as benzyl, phenethyl and the like, the aralkyl group may be substituted; or aroyl group such as benzoyl and the like, the aroyl group may be substituted. The substituents on the alkyl group, aromatic moiety of the aryl group, aralkyl group or aroyl group include halogen atom such as fluorine, chlorine and bromine; amino group, cyano, hydroxy, nitro, trifluoroethyl, (C1-C6) alkyl, or (C1-C6) alkoxy.
Suitable groups represented by R6 include hydrogen, or substituted or unsubstituted (C1-C6) alkyl such as methyl, ethyl, n-propyl and the like. The substituents on the alkyl group include halogen atom such as fluorine, chlorine and bromine; amino group, cyano, hydroxy, nitro, trifluoroethyl, (C1-C6) alkyl, or (C1-C6) alkoxy.
The suitable substituents on R1, R2, R R7 and R8 may be selected from cyano, hydroxy, nitro, thio, halogen atom such as fluorine, chlorine, bromine and the like; or substituted or unsubstituted groups selected from linear or branched (C1-C8) alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like; amino, mono or disubstituted amino group; alkanoyl group such as ethanoyl, propanoyl, butanoyl and the like; thio(C1-C8)alkyl such as thiomethyl, thioethyl, thiopropyl and the like; (C1-C6)alkoxy group such as methoxy, ethoxy, propyloxy, butyloxy and the like; aroyl group such as benzoyl and the like; acyloxy group such as acetyloxy, propanoyloxy, butanoyloxy and the like; aryl group such as phenyl, naphthyl and the like, the aryl group may be mono or disubstituted; heteroaryl group such as pyridyl, furyl, thienyl and the like; acylamino groups such as CH3CONH, C2H5CONH, C3H7CONH, C4H9CONH and C6H5CONH; aralkylamino group such as C6H5CH2NH, C6H5CH2CH2NH, C6H5CH2NCH3 and the like; alkoxycarbonylamino group such as C4H9OCONH, C2H5OCONH, CH3OCONH and the like; aryloxycarbonylamino group such as C6H5OCONH, C6H5OCONCH3, C6H5OCONC2H5, C6H4(CH3)OCONH, C6H4(OCH3)OCONH, and the like; aralkoxycarbonylamino group such as C6H5CH2OCONH, C6H5CH2CH2OCONH, C6H5CH2OCON(CH3), C6H5CH2OCON(C2H5), C6H4(CH3)CH2OCONH, C6H4(OCH3)CH2OCONH and the like; (C1-C8)alkylthio group such as methylthio, ethylthio, propylthio and the like; heteroarylthio group such as pyridylthio, furylthio, thiophenylthio, benzothiazolethio, purinethio, benzimidazolethio, pyrimidinethio and the like; acylthio group such as acetylthio, propanoylthio, butanoylthio and the like; aralkylthio group such as benzylthio, phenylethylthio, phenylpropylthio and the like; arylthio group such as phenylthio, napthylthio and the like; (C1-C8)alkylseleno such as methylseleno, ethylseleno, propylseleno, iso-propylseleno and the like; acylseleno such as acetylseleno, propionylseleno and the like; aralkylseleno such as benzylseleno, phenylethylseleno, phenylpropylseleno and the like; arylseleno such as phenylseleno, napthylseleno and the like or COOR, where R represents hydrogen or (C1-C6) alkyl groups. The substituents are selected from halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, aryl or (C1-C6)alkoxy groups.
When the groups R1, R2, R3, R5, R7 and R8 represent disubstituted aryl, the two substituents on the adjacent carbon atoms form a linking group such as xe2x80x94Xxe2x80x94CH2xe2x80x94Yxe2x80x94, xe2x80x94Xxe2x80x94CH2xe2x80x94CH2xe2x80x94Yxe2x80x94, where X and Y may be same or different and independently represent O, NH, S or CH2.
When the groups represented by R1, R2, R3, R5, R7 and R8 are multi substituted, the substituents present on the two adjacent carbons may form a linking group xe2x80x94Xxe2x80x94(CR11R12)nxe2x80x94Yxe2x80x94 where R11 and R12 represent (C1-C8)alkyl such as methyl, ethyl and the like, X and Y may be same or different and independently represent CH2, O, S, NH; and n=1 or 2.
Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N,Nxe2x80x2-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N,Nxe2x80x2-diphenylethylenediamine, N,Nxe2x80x2-dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, omithine, lysine, arginine, serine, threonine, and phenylalanine; unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.
Particularly useful compounds according to present invention include:
3,19-Isopropylidene andrographolide;
3,19-Benzylidene andrographolide;
3,19-(1-Phenylethylidene)andrographolide;
3,19-Isopropylidene-14-(N-Boc methionyl)andrographolide;
14-Acetyl 3,19-methylenedioxy andrographolide;
14-Acetyl 3,19-O-cyclic carbonyl andrographolide;
14-Acetyl andrographolide;
14-Chloroacetyl andrographolide;
14-(Phenylcarbamoyl)andrographolide;
14-(N-Isopropyl carbamoyl)andrographolide;
14-Cinnamoyl andrographolide;
14-Isopropanoyl andrographolide;
14-Pivaloyl andrographolide;
14-Benzoyl andrographolide;
14-Benzyl andrographolide;
3,19-Diacetyl-14-(2xe2x80x2-acetyl-3xe2x80x2-acetamido 3xe2x80x2-phenyl)propionyl andrographolide;
3,19-Diacetyl-14-[4xe2x80x2S,5xe2x80x2R-(N-t-Butoxycarbonyl)-2xe2x80x2,2xe2x80x2-dimethyl-4xe2x80x2-phenyl-5xe2x80x2-oxazolidine]carbonyl andrographolide;
3,19-Diacetyl-14-(2xe2x80x2hydroxy-3xe2x80x2-benzoylamino 3xe2x80x2-phenyl) propionyl andrographolide;
3,19-Diacetyl-14-(2xe2x80x2hydroxy-3-N-Boc amino-3xe2x80x2-phenyl)propionyl andrographolide;
14-(N-Boc-glycinyl)-3,19-dipropionyl andrographolide;
14-(N-Boc-glycinyl)-3,19-diacetyl andrographolide;
14-(N-Acetylglycinyl)-3,19-diacetyl andrographolide;
14-(N-Benzoylglycinyl)-3,19-diacetyl andrographolide;
3,19-Diacetyl-14-O-ethyl andrographolide;
3,19-Diacetyl-14-O-methyl andrographolide;
3,19-Diacetyl-14-(3 ,4-dimethoxycinnamoyl)andrographolide;
14-(3,4-dimethoxy)cinnamoyl-3,19-dipropionyl-andrographolide;
3-Acetyl andrographolide;
3,14-Diacetyl andrographolide;
3,14,19,7-Tetra acetyl andrographolide;
3,19-Isopropylidene-14-acetyl andrographolide;
14-Chloroacetyl-3,19-isopropylidene andrographolide;. 14-Carbamoyl-3,19-isopropylidene andrographolide;
3,19-Isopropylidene-14-(N-isopropyl)carbamoyl andrographolide;
14-[4xe2x80x2S,5R-(N-t-butoxycarbonyl-2xe2x80x2,2xe2x80x2-dimethyl-4xe2x80x2-phenyl-5xe2x80x2-oxazolidine]carbonyl 3,19-isopropylidene andrographolide;
14-[4xe2x80x2S,5xe2x80x2R-(N-t-butoxycarbonyl-2xe2x80x2,2xe2x80x2-dimethyl-4xe2x80x2-phenyl-5xe2x80x2-oxazolidine]carbonyl andrographolide;
3,19-Isopropylidene-14-(N-Boc-glycinyl)andrographolide;
14-(N-Boc-glycinyl)andrographolide;
14-O-Ethyl-3,19-isopropylidene andrographolide;
14-O-Ethyl andrographolide;
14-O-Methyl-3,19-isopropylidene andrographolide;
14-O-Methyl andrographolide;
14-(3,4-Dimethoxy)cinnamoyl andrographolide;
19-Trityl andrographolide;
3-Acetyl-19-trityl andrographolide;
3,14-Diacetyl-19-trityl andrographolide and 7-Hydroxy-3,14,19-triacetyl andrographolide.
The present invention also provides a process for the preparation of novel andrographolide of the general formula (I), where R1, R2 and R3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroalkenoyl, sulfonyl group or a group xe2x80x94(CO)xe2x80x94Wxe2x80x94R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR2 and OR3 together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms and R4 represents hydrogen; with provisos that (i) R1, R2 and R3 may be same except when they represent hydrogen or alkanoyl group, (ii) when R2 and R3 represent hydrogen, R1 does not represent unsubstituted alkanoyl; their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises: reacting the compound of formula (VII)
with R1xe2x80x94L, R2xe2x80x94L and R3xe2x80x94L, where R1, R2 and R3 are as defined above and L represents hydroxy or a leaving group such as halogen atom like fluorine, chlorine, bromine or iodine; p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like; or an alkanoate such as acetate, propanoate, butanoate and the like, to produce a compound of formula (I), where all symbols are as defined earlier and R4 represents hydrogen.
The reaction of a compound of formula (VII) with R1xe2x80x94L, R2xe2x80x94L and R3xe2x80x94L, to produce a compound of formula (1) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like. The reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C6H6, dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 160xc2x0 C. and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
In another embodiment of the present invention the compounds of formula (I) may also be prepared by a process, which comprises:
(i) protecting the hydroxy groups present on carbons 3 or 19 or 3 and 19 together in the compound of formula (VII) with suitable protecting groups using conventional methods to produce a compound of formula (VIII),
where R4 represents hydrogen; P1 and P2 may be same or different and represent hydrogen, trityl, t-butyl dimethyl silyl, pivaloyl and the like or esters such as acetate, propionate, benzoate and the like or together may form methylene dioxy, isopropylidene, benzylidene, 1-phenyl ethylidene, carbonate and the like,
(ii) reacting the compound of formula (VIII) defined above with a compound of formula (IX)
R1xe2x80x94Lxe2x80x83xe2x80x83(IX)
where R1 and L have the meanings given above to produce a compound of formula (X),
where R1, R4, P1 and P2 are as defined above,
(iii) deprotecting the compound of formula (X) by conventional methods to produce a compound of formula (XI),
where R1 and R4 have the meanings given above,
(iv) reacting the compound of formula (XI) where R1 has the meaning given above with R2xe2x80x94L and/or R3xe2x80x94L, where R2 and R3 are as defined above to produce a compound of formula (I), and if desired,
(v) converting the compound of formula (I) into their stereoisomers, pharmaceutical salts by conventional methods.
The protection of a compound of formula (VII) may be carried out using trityl chloride, t-butyldimethylsilyl chloride, pivaloyl chloride, dimethylsulfoxide, acetone, 2,2-dimethoxy propane, trimethyl ortho acetate, benzaldehyde, p-methoxy benzaldehyde and the like. The reaction may be carried out in the presence of a suitable catalyst such as SOCl2, H2SO4, HClO4, pyridinium p-toluene sulphonate, pyridine, p-toluene sulfonic acid, dimethyl aminopyridine, and the like. The reaction may be carried out in the absence or presence of suitable solvent such as benzene, DMF, DMSO, acetonitrile, DCM, and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 60xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 40xc2x0 C. The reaction time may range from 2 to 6 h, preferably from 2 to 4 h.
The reaction of a compound of formula (VIII) with a compound of formula (IX) to produce a compound of formula (X) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DLAD) and the like. The reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C6H6, dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 160xc2x0 C. and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
The deprotection of a compound of formula (X) to produce a compound of formula (XI) may be carried out using deprotecting agent such as acetic acid, hydrochloric acid, formic acid, trifluoroacetic acid and the like. The reaction may be carried in the presence of a suitable solvent such as water, THF, dioxane, DCM, CHCl3, methanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 60xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 40xc2x0 C. The reaction time may range from 2 to 6 h, preferably from 2 to 4 h.
The reaction of compound of formula (XI) with R2xe2x80x94L and/or R3xe2x80x94L, to produce a compound of formula (I) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like. The reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C6H6, dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 160xc2x0 C. and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
In another embodiment of the invention there is provided a process for the preparation of the compound of formula (I) where R4 represents XR7 where R7 and other symbols are as defined earlier, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises:
(i) converting the compound of formula (I) where R4 represents hydrogen and all other symbols are as defined earlier to produce a compound of formula (XII),
where all the symbols are as defined above, the compound of formula (XII) represents a compound of formula (I) when X represents O,
(ii) reacting the compound of formula (XII) with R7xe2x80x94L where R7 is as defined earlier, to produce a compound of formula (I).
Conversion of the compound of formula (I) to produce a compound of formula (XII) may be carried out in the presence of reagents such as SeO2, t-BuO2H, H2O2 and the like. The reaction may be carried out in the presence of solvents such as DCM, CHCl3, benzene, THF, dioxane, DMF, methanol, ethanol and the like or mixtures thereof. The temperature and duration of the reaction may be maintained in the range of 0 to 30xc2x0 C. and 3 to 48 h respectively.
The reaction of compound of formula (XII) with R7xe2x80x94L to produce a compound of formula (I) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like. The reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C6H6, dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 160xc2x0 C. and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
In another embodiment of the invention there is provided a process for the preparation of the compound of formula (I) where R4 represents halogen and other symbols are as defined earlier, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises:
(i) converting the compound of formula (I) where R4 represents hydrogen and all other symbols are as defined earlier to produce a compound of formula (XII),
where all the symbols are as defined above, the compound of formula (XII) represents a compound of formula (I) when X represents O,
(ii) converting the compound of formula (XII) to a compound of formula (I), where R4 represents halogen atom such as fluorine, chlorine, bromine or iodine.
Conversion of the compound of formula (I) to produce a compound of formula (XII) may be carried out in the presence of reagents such as SeO2, t-BuO2H, H2O2 and the like. The reaction may be carried out in the presence of solvents such as DCM, CHCl3, benzene, THF, dioxane, DMF, methanol, ethanol and the like or mixtures thereof. The temperature and duration of the reaction may be maintained in the range of 0 to 30xc2x0 C. and 3 to 48 h respectively.
The conversion of compound of formula (XII) to compound of formula (I) may be carried out using halogenating agents such as thionyl chloride, thionyl bromide, phosphonyl chloride, PCl5, PBr3, bromine trifluoride, N-bromosuccinimide-hydrogen fluoride (NBS-HF), cobalt (III) fluoride, lithium fluoride, potassium fluoride, sodium fluoride, cesium fluoride, potassium iodide, sodium iodide, iodine, iodine cerium (IV) ammonium nitrate or R7xe2x80x94L where R7 and L are as defined above. The reaction may be carried out in the presence of solvents such as ether, dichloromethane, chloroform, DMF, DMSO and the like. The reaction may be carried out in the range of xe2x88x9240xc2x0 C. to 160xc2x0 C. The duration of the reaction may range from 1 to 6 h.
In another embodiment of the invention there is provided a process for the p reparation of the compound of formula (I) where R4 represents halogen and other symbols are as defined earlier, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises: reacting the compound of formula (I) where R4 represents hydrogen and all other symbols are as defined earlier with suitable halogenating agent to produce a compound of formula (I), where R4 represents halogen atom such as fluorine, chlorine, bromine or iodine.
The reaction of compound of formula (I) where R4 represents hydrogen with halogenating agents, to produce a compound of formula (I) where R4 represents halogen may be carried out in the presence of reagents such as bromine trifluoride, N-bromosuccinimide-hydrogen fluoride (NBS-HF), cobalt (III) fluoride, lithium fluoride, potassium fluoride, sodium fluoride, cesium fluoride, potassium iodide, sodium iodide, iodine, iodine cerium (IV) ammonium nitrate, N-bromosucinimide, (NBS), N-chlorosucinimide (NCS), N-iodosucinimide (NIS), bromine, chlorine, POCl3, PCl3, PBr3 or SOCl2. The reaction may be carried out in the presence of solvents such as DCM, CHCl3, benzene, THF, dioxane, DMF, methanol, ethanol and the like or mixtures thereof. The temperature and duration of the reaction may be maintained in the range of xe2x88x9280 to 32xc2x0 C. and 3 to 48 h respectively.
In another embodiment of the present invention there is provided a novel intermediate of formula (X)
where R1 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, aralkanoyl, aralkenoyl, heteroaroyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl groups or a group xe2x80x94(CO)xe2x80x94Wxe2x80x94R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl; R4 represents hydrogen; P1 and P2 may be same or different and independently represent trityl, t-butyldimethylsilyl, pivaloyl and the like, or esters such as acetate, propionate, benzoate and the like, or P1 and P2 together represent methylene dioxy, isopropylidene, benzylidene, 1-phenyl ethylidene, carbonate and the like.
The present invention also provides a process for the preparation of the compound of formula (X), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises:
(i) protecting the hydroxy groups present on carbons 3 or 19 or 3 and 19 together in the compound of formula (VII) with suitable protecting groups using conventional methods to produce a compound of formula (VIII),
where R4 represents hydrogen; P1 and P2 may be same or different and represent hydrogen, trityl, t-butyl dimethyl silyl, pivaloyl and the like or esters such as acetate, propionate, benzoate and the like or together may form methylene dioxy, isopropylidene, benzylidene, 1-phenyl ethylidene, carbonate and the like,
(ii) reacting the compound of formula (VIII) defined above with compound of formula (IX)
R1xe2x80x94Lxe2x80x83xe2x80x83(IX)
where R1 and L have the meanings given above to produce a compound of formula (X),
where R1, R4, P1 and P2 are as defined earlier.
The protection of a compound of formula (VII) may be carried out using trityl chloride, t-butyldimethylsilyl chloride, pivaloyl chloride, dimethylsulfoxide, acetone, 2,2-dimethoxy propane, trimethyl ortho acetate, benzaldehyde, p-methoxy benzaldehyde and the like. The reaction may be carried out in the presence of a suitable catalyst such as SOCl2, H2SO4, HClO4, pyridinium p-toluene sulphonate, pyridine, p-toluene sulfonic acid, dimethyl aminopyridine, and the like. The reaction may be carried out in the absence or presence of suitable solvent such as benzene, DMF, DMSO, acetonitrile, DCM, and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 60xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 40xc2x0 C. The reaction time may range from 2 to 6 h, preferably from 2 to 4 h. The reaction of a compound of formula (VIII) with a compound of formula (IX) to produce a compound of formula (X) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like. The reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C6H6, dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 160xc2x0 C. and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
In yet another embodiment of the present invention there is provided a novel intermediate of formula (XI)
where R1 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, aralkanoyl, aralkenoyl, heteroaroyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl groups or a group xe2x80x94(CO)xe2x80x94Wxe2x80x94R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl and R4 represents hydrogen.
The present invention also provides a process for the preparation of the compound of formula (XI), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises:
(i) protecting the hydroxy groups present on carbons 3 or 19 or 3 and 19 together in the compound of formula (VII) with suitable protecting groups using conventional methods to produce a compound of formula (VIII),
where R4 represents hydrogen; P1 and P2 may be same or different and represent hydrogen, trityl, t-butyl dimethyl silyl, pivaloyl and the like or esters such as acetate, propionate, benzoate and the like or together may form methylene dioxy, isopropylidene, benzylidene, 1-phenyl ethylidene, carbonate and the like,
(ii) reacting the compound of formula (VIII) defined above with compound of formula (IX)
R1xe2x80x94Lxe2x80x83xe2x80x83(IX)
where R1 and L have the meanings given above to produce a compound of formula (X),
where R1, R4, P1 and P2 are as defined earlier,
(iii) deprotecting the compound of formula (X) by conventional methods to produce a compound of formula (XI),
where R1 and R4 have the meanings given above.
The protection of a compound of formula (VII) may be carried out using trityl chloride, t-butyldimethylsilyl chloride, pivaloyl chloride, dimethylsulfoxide, acetone, 2,2-dimethoxy propane, trimethyl ortho acetate, benzaldehyde, p-methoxy benzaldehyde and the like. The reaction may be carried out in the presence of a suitable catalyst such as SOCl2, H2SO4, HClO4, pyridinium p-toluene sulphonate, pyridine, p-toluene sulfonic acid, dimethyl aminopyridine, and the like. The reaction may be carried out in the absence or presence of suitable solvent such as benzene, DMF, DMSO, acetonitrile, DCM, and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 60xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 40xc2x0 C. The reaction time may range from 2 to 6 h, preferably from 2 to 4 h. The reaction of a compound of formula (VIII) with a compound of formula (IX) to produce a compound of formula (X) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like. The reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C6H6, dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 200xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 160xc2x0 C. and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
The deprotection of a compound of formula (X) to produce a compound of formula (XI) may be carried out using deprotecting agent such as acetic acid, hydrochloric acid, formic acid, trifluoroacetic acid and the like. The reaction may be carried in the presence of suitable solvent such as water, THF, dioxane, DCM, CHCl3, methanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 0xc2x0 C. to 60xc2x0 C., preferably at a temperature in the range of 20xc2x0 C. to 40xc2x0 C. The reaction time may range from 2 to 6 h, preferably from 2 to 4 h.
It is appreciated that in any of the above-mentioned reactions, any reactive group in the substrate molecule may be protected according to conventional chemical practice. Suitable protecting groups in any of the above-mentioned reactions are those used conventionally in the art. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
The compound of formula (I) when produced through an intermediate compound, conventional functional group transformations such as hydrolysis, reduction or oxidation may be carried out.
For example, the compound of formula (I) where R1, R2 or R3 are multi substituted and the two substituents may form a linking group xe2x80x94Xxe2x80x94(CR11R12)nxe2x80x94Yxe2x80x94, which may be converted to a compound of formula (I), where R1, R2 or R3 are multisubstituted and the substituents are independent.
The pharmaceutically acceptable salts are prepared by reacting the compounds of formula (I), formula (X) or formula (XI) wherever applicable with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, tromethamine, guanidine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
The stereoisomers of the compounds of formula (I), formula (X) and formula (XI) forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al. in xe2x80x9cEnantiomers, Recemates and Resolutionxe2x80x9d (Wiley Interscience, 1981).
Various polymorphs of compound of general formula (I), formula (X) and formula (XI) forming part of this invention may be prepared by crystallization of compound of formula (I), formula (X) or formula (XI) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or slow cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray data or such other techniques.
Pharmaceutically acceptable solvates of compounds of formula (I), formula (X) and formula (XI) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of formula (I) in solvents such as water, methanol, ethanol etc., preferably water and recrystallizing by using different crystallization techniques.
The present invention also envisages pharmaceutical compositions containing compounds of the formula (I), formula (X), formula (XI), or their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their mixtures in combination with the usual pharmaceutically employed carriers, solvents, diluents and other media normally employed in preparing such compositions.
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active compound, the remainder of the composition may be pharmaceutically acceptable carriers, diluents or solvents and also contain other active ingredients.
The compounds of the formulae (I), (X) and (XI) as defined above are clinically administered to mammals, including man, via either oral or parenteral routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or absorption following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally. By either route, the dosage is in the range of about 0.01 to about 100 mg/kg body weight of the subject per day or preferably about 0.01 to about 30 mg/kg body weight per day administered singly or as a divided dose. However, the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans. The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Anticancer compounds: process for their preparation and pharmaceutical compositions containing them


A cooperative processing system includes a first data processing component, existing on a first computer, that generates an output containing object having a function of outputting data contained therein to a stream, a pipeline section that causes the output containing object to output the data contained in the output containing object to a stream addressed to a second computer, and causes the second computer to generate an input containing object that receives the stream and stores data transferred through the stream, and a second data processing component, existing on the second computer, that receives the input containing object to perform a data process.

1. Field of the Invention
The present invention relates to a distributed data processing technique for causing plural data processing components to perform a series of processes in a cooperative manner.
2. Description of the Related Art
A distributed data processing method for causing plural data processing components to cooperate and perform a series of processes is known. According to this method, information on a procedure of a cooperative process and information on an intermediate result are circulated as a transfer information unit through a network while each node for performing each partial process and holding the result acquires the transfer information unit from the network. Based on the procedure information of the transfer information unit, part of the cooperative process is performed using the result of the partial process held by the node and the acquired intermediate result, so that in accordance with the result the intermediate result information is updated, and sent together with the procedure information to the network.
A system for acquiring a result of complex processing by causing a process server operative on an HTTP server to process a material file on a web server and plural process servers to cooperate upon processing is also known. In this system, a web browser sends a request with a first virtual URL (Uniform Resource Locator) having the material file qualified with a procedure name, a parameter, a computer name, and the like. A composite process formed by a combination of plural partial processes is denoted by the first virtual URL. For forming a composite process, a partial process is expressed as a second virtual URL, which is described in the first virtual URL as an argument. Thus, using a virtual URL as an argument, another virtual URL expressing a composite process can be formed in a hierarchical manner, as if forming a functional composition. Each process server interprets a virtual URL addressed thereto, and extracts the unprocessable argument (virtual URL) included therein, and transfers it to a second process server capable of processing the argument as a request in HTTP (Hypertext Transfer Protocol). A first process server acquires the process result as a response, and uses it for its own process as input data. Thus, the input virtual URL is regarded as a multiple-nested computing process, so that the processes can be performed from the innermost one in sequence in a distributed manner. In this case, the components are connected in the HTTP protocol to communicate with each other to achieve distributed pipeline processing.
Also, a method of processing an externally applied HTTP request through cooperative processing by plural HTTP modules in an event-driven manner in a single application run on a single host computer is known. According to this method, an HTTP request from an external source is logically expressed to produce a context object for encapsulating at least one property related to the HTTP request. An event pipeline having plural request events, each having a corresponding event and corresponding to a context object, is formed. When an event corresponding to the request event occurs, and when at least one of an application and a module is registered in association with that request event, a callback is produced, and in response to the callback for processing the context object, each application and each module registered in association with the request event are initiated.
In the method for causing plural data processing components to cooperate and perform a series of processes described above, the data entity of the intermediate result is included in the transfer process unit circulated through the network, and therefore each process component must be programmed in view of communication for transmitting and receiving the data entity of the intermediate result. Consequently, this method is associated with a problem of complex programming of the process component.
This problem occurs also upon cooperation among plural data processing components in a single computer device. The pipeline processing function provided by an operating system (OS) such as UNIX (registered trademark) achieves cooperative processing by first using the OS to activate each program forming a pipeline in concurrent way, connecting a standard output stream of the program to a standard input stream of a next program in the pipeline. Such a method, however, requires each component to achieve data communication in a stream, and therefore cannot be adapted to simple programming for invoking a method using as an argument data or an object which is not in the form of a stream.
For cooperation among data processing components via a network, the data of the intermediate result is passed via the network using a network communication protocol, such as HTTP. In the network communication protocol of this kind, data transferred through the network is usually in the form of a stream. The function of transmitting and receiving a stream is generally hard to program. What is important about the data processing component is the content of the process to be performed, and input/output control for the process is a secondary matter. Using programming resources for such a secondary input/output control is not desirable. For example, a vendor developing a data processing component for implementing an individual business logic acting as an element of a work flow system usually focuses on programming of the business logic, and does not wish to allocate resources for programming of input/output control.
According to the method for acquiring a result of complex processing described above, each data processing component must be implemented to receive an HTTP request as input and transmit an HTTP response as output, and therefore the same problem arises.
The method of processing an externally applied HTTP request through cooperative processing by plural HTTP modules described above causes cooperation among HTTP modules in the same host computer, particularly in the same application, and therefore cannot be applied to cooperation among the processing components in different host computers via a network without modification. In other words, an object to be processed can be directly passed among the HTTP modules in the same host computer, but such a simple data passing method cannot be implemented for the communication through the network.

System, device, and method for cooperative processing


A mixing apparatus, comprising, a frame, a pair of handles secured to the frame with each handle having a proximal and a distal end thereto and a pair of downwardly depending support elements. A first wheel is secured to the distal ends of the pair of handles by frame elements and a rear set of wheels are secured to the proximal ends of the pair of handles by frame elements. A mounting element is secured to the frame for supporting a drive engine. A drive chain mechanism is linked to a toothed wheel and to the drive engine, the toothed wheel having an internal brake drum and internal brake shoes. The internal brake drum and internal brake shoes are connected to a brake cable having a tension reduction cam for tension reduction. A centrifugal clutch for engagement with the drive mechanism is linked to a throttle operably engaged to the to the drive engine. A mixing barrel is secured to the frame, the mixing barrel being linked to a hydraulic motor shaft connected to a hydraulic pump and a hydraulic pump motor which is engaged to a gear reduction box. The mixing barrel is equipped with a handle for control and dumping of the mixing barrel.

1. Field of Invention
This invention relates mixing apparatuses, and more particularly to mixing apparatuses which are equipped with wheels, an engine, and drive means for propelling the apparatus.
2. Description of the Related Art
The usefulness of mixing apparatuses are well known to those involved in construction, gardening, and other uses for mixing cement, gravel, dirt, and other particulates in a mix with water or other particulates. Prior mixers have been proposed and developed which are placed on various apparatuses such as truck beds, motorized frames, wheels and the like.
Such mixers are useful for particular applications, however, all suffer from significant disadvantages and limitations when used for small mixing jobs, construction, home repair, garden work and the like. For example, such mixers are bulky, cumbersome, and difficult and dangerous to use in many types situations such as home use, construction, landscaping and the like.
Accordingly, it is the primary object of this invention to provide a motorized mixer with a hydraulic driven pump which is lightweight, strong, balanced, and efficient at mixing a wide variety of different substances such as cement, gravel, dirt, and other particulates. The motorized mixer of the present invention has high performance capability and possesses sufficient power to drive the mixer at both slow speeds or at high speeds with small, medium or large loads. The mixer of the present invention is equipped with a front wheel and a rear set of wheels for balance and ease of movement.
Additional objects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and obtained by means of the instrumentality's and combinations particularly pointed out in the appended claims.


A method and system for measuring a flow profile in a portion of a flow path in a turbine engine is provided. The system includes a mass flow sensor assembly having a plurality of hot wire mass flow sensors, the mass flow sensor assembly disposed in the portion of the flow path at a location where the flow profile is to be measured. The system also includes a controller that converts signals from the temperature sensor, the pressure sensor and the plurality of hot wire mass flow sensors to flow profile measurements.

Control systems for modern turbine engines measure internal conditions at various positions within the air and the gas flow paths through the turbine engine. Air pressure and temperature measurements may be made through the use of Pitot tubes, thermocouples, and other devices positioned within the compressor and elsewhere. In the absence of suitable hardware, the sensors may be slotted into the compressor or other location on rakes. Rakes are generally mounted onto a machined surface within the compressor and elsewhere.
Currently, compressor inlet volumetric flow measurements are taken using static pressure together with differential pressure measurements in the inlet bellmouth of the turbine engine during continual operation. Compressor inlet mass flow calculation from a volumetric flow measurement additionally requires inlet air density derived from the inlet air temperature and relative humidity measurements combined. This method works reasonably well at full load, where the airflow rate is high and fairly stable, but the accuracy of this approach diminishes as the airflow rate is reduced. Below full speed no load, for example, the current method for measuring airflow is known to be inaccurate and is highly variable. In addition each measurement type has an associated measurement uncertainty, resulting in potentially higher uncertainty than a single measurement. Due to this high variability it is difficult to obtain an accurate understanding of compressor airflow and therefore the utilization of compressor inlet airflow for turbine engine control presents control and diagnostics issues.
Currently, exhaust velocity profiles are measured by utilizing exhaust temperature and total pressure rakes which traverse the exhaust duct. These measurements are then utilized to calculate the exhaust velocity profile utilizing physics based equations. This method works reasonably well for validation testing purposes and is currently applied for the validation of turbine aerodynamic design changes which impact the exhaust flow velocity profile. However, this method requires the installation of two separate sets of rakes increasing the probability of instrument failure during testing. In addition each measurement type has an associated measurement uncertainty, resulting in potentially higher uncertainty than a single measurement. Other than validation testing for the purpose of validating new turbine aerodynamic airfoil shapes the measurement of exhaust velocity and or mass flow profiles is currently not standard within the industry.
Compressor extraction flow measurements for non-modulated turbine engine systems are typically calculated by measuring the temperature and pressure drop across an orifice plate. This method works reasonably well at full load, where the airflow rate through the extraction system is high and fairly stable. However, the accuracy of this method diminishes at lower airflow rates, for which the orifice is over sized, resulting in increased inaccuracy at low loads or low flow levels. In addition the presence of a fixed orifice size in the extraction system limits the functionality of a modulated extraction flow system since at higher flow rates the simple orifice will be the flow limiting component in the extraction flow system.
Accordingly, there is a need for instrumentation for the measurement of exhaust gas velocity profiles to provide a means of validation and calibration of turbine aerodynamic models, and to validate the mixing of exhaust cooling mechanisms. Additionally there is a need for instrumentation for the measurement of turbine engine compressor inlet flow mass flow profiles to enable the validation of the mixing of inlet conditioning measures. There is also a need for instrumentation to accurately measure flow density through a compressor extraction conduit to provide the ability to actively control the level of compressor extraction mass flow rate.

Systems and methods for measuring a flow profile in a turbine engine flow path


To provide an etching method capable of forming a cavity portion having a large space portion or a complicated structure by etching a sacrifice layer through a very fine etching opening at favorable accuracy in configuration. An etching process of a object is carried out by exposing the object to a processing fluid containing etching reaction seed (the third step S3, the fourth step S4), and then, the pressure in the processing chamber is reduced to make a density of the processing fluid around the object lower than that in the fourth step S4 (the first step S1). While the first step S1 to the first step S4 are repeated, in the third step S3 and the fourth step S4 executed after the first step S1, the processing fluid containing etching reaction seed is newly supplied to the processing atmosphere in which the object is placed to make the density of the processing fluid around the object higher than that in the first step S1.

1. Field of the Invention
The present invention relates to an etching method and particularly to an etching method applicable to the case that a cavity portion to form is larger than a size of an etching opening or the case that a cavity portion having a complicated structure is formed when a microstructure having a cavity portion is formed in production of a semiconductor apparatus or a micromachine.
2. Related Art
With development of microstructure technologies, micromachines (Micro Electro Mechanical Systems: MEMS) and small devices including a micromachine have attracted attention. The micromachine is an element in which a movable portion comprising a three-dimensional structure formed on a substrate, such as a silicon substrate and a glass substrate, and a semiconductor integrated circuit or the like for control of driving the movable portion are electrically, mechanically combined.
Conventionally, as a technology for providing the three dimensional structure, in such a micromachine field, a three-dimensional structure having a cavity portion under a patterned structure layer is provided by previously forming a sacrifice layer on a substrate, forming a structural member layer on this sacrifice layer which is patterned, and then selectively removing the sacrifice layer. As the sacrifice layer, silicon dioxide (SiO2) or silicon (Si) is used.
If the sacrifice layer is formed with silicon dioxide, an etching liquid of Fluorine (F) type is used as an etchant and if the sacrifice layer is formed with silicon, an etching gas such as Xenon fluoride (XeF2), and bromine fluoride (BrF3) is used as an etchant, for example in Japanese laid-open patent application No. 2002-214548, particularly paragraphs 0002 and 0030.
For example, if a three-dimensional structure is formed having a structure as shown in FIG. 1, first, a sacrifice layer 2 is buried in a hollow portion 1a formed on the surface side of the substrate 1 and a structural member layer 3 is formed to cover the substrate 1 and the sacrifice layer 2. Next, the structural member layer 3 is patterned to have a required configuration as well as an etching opening 3a reachable the sacrifice layer 2 is formed in the structural member layer 3. After that, the sacrifice layer 2 is removed by etching through the etching opening 3a. This forms a cavity portion "a" under the structural member layer 3. This forms a cavity portion "a" under the structural member layer 3. Here in this etching, as described above, a suitable etchant is selected in accordance with the material forming the sacrifice layer.


The invention provides for a sideband signal for the USB that has real-time interrupt capabilities. A system and method for hardware detection of an interrupt signal provides for the ability to superimpose a high frequency interrupt signal on a USB power line for transmission to a controller. Alternatively, an overcurrent flow may be generated from a peripheral device and detected by an overflow current detector on the USB. In response, the overflow current detector may output an interrupt/overflow current detection signal to the controller.

The USB is an industry standardized bus architecture developed to provide efficient, cost effective connections of peripherals to gaming machine systems, consumer electronics, personal computers, and other electronic devices. USB is designed to efficiently integrate many various peripheral devices (e.g., up to 127 peripheral devices per USB port) to the gaming machine system. There are a wide variety of associated peripheral devices that can be connected to a gaming machine such as a slot machine or video poker machine. Some examples of these devices are lights, ticket printers, card readers, speakers, bill validators, ticket readers, coin acceptors, display panels, key pads, coin hoppers and button pads. Many of these devices are built into the gaming machine or components associated with the gaming machine such as a top box.
Typically, utilizing a master gaming controller, the gaming machine controls various combinations of devices that allow a player to play a game on the gaming machine and also encourage game play on the gaming machine. For example, a game played on a gaming machine usually requires a player to input money or indicia of credit into the gaming machine, indicate a wager amount, and initiate a game play. These steps require the gaming machine to control input devices, including bill validators and coin acceptors, to accept money into the gaming machine and recognize user inputs from devices, including key pads and button pads, to determine the wager amount and initiate game play. After game play has been initiated, the gaming machine determines a game outcome, presents the game outcome to the player and may dispense an award of some type depending on the outcome of the game. All of these functions may be performed via a USB.
USB differs from previous expansion bus systems. One difference is that USB connects peripheral devices to the gaming machine system without consuming the input output resources of the gaming machine system. Unlike previous expansion bus systems, peripheral devices designed to function with USB do not require memory or input output address space and do not require interrupt request lines from the gaming machine system. This increases the number of peripheral devices the gaming machine may reliably support. USB also provides a single connector type to connect peripheral devices designed to function with USB. Each peripheral device connects to a standard USB connector. Additionally, USB provides the ability to couple a number of peripheral devices to a single USB connector. USB also provides for automatic Peripheral device configuration and eliminates gaming machine system resource conflicts. These, and other, advantages allow USB to simplify and ease the process of adding peripheral devices to a gaming machine, providing a "plug and play" system.
Currently, a USB controller determines peripheral device states by periodically polling (i.e., querying) each peripheral device. Each connected peripheral device is polled in successive 1 ms intervals (e.g., frames). When a connected peripheral device requires service (e.g., a data transfer from an internal buffer to the master gaming controller), it waits until the next 1 ms interval, or frame, in which it is polled to communicate the required service to the USB controller or master gaming controller. In this manner, each connected peripheral device is polled in a round-robin manner to determine whether it requires service. It would be desirable to provide improvements over prior art methods.

Sideband signal for USB with interrupt capability


An object of the present invention is to provide a nucleic acid amplification method for amplifying a desired nucleic acid while suppressing amplification of byproducts in a PCR reaction, a reagent kit used for nucleic acid amplification, a method of detecting single nucleotide polymorphism to detect single nucleotide polymorphism by utilizing that amplification of byproducts is suppressed in a PCR reaction, and a reagent kit used for detecting single nucleotide polymorphism. The method of amplifying nucleic acids by PCR is characterized by admixing in a reaction solution, a homologous recombinant protein which contains at least one of a RecA protein derived from Thermus thermophilus, and a modified RecA protein obtained by modification of the RecA protein and having a function similar to that of the RecA protein, and carrying out PCR.

1. Field of the Invention
The present invention relates to a method of amplifying nucleic acids by PCR, a reagent kit for amplifying nucleic acids by PCR, a method of detecting single nucleotide polymorphism by PCR and a reagent kit for detecting single nucleotide polymorphism by PCR.
2. Description of Related Art
A method of amplifying nucleic acids by PCR is conventionally known. That is, PCR is a technique to obtain certain DNA by mixing a template DNA, primer DNAs, a DNA polymerase, etc. in a reaction solution, and specifically amplifying a region narrowed by two kinds of the primer DNAs in the template DNA.
As such a method of amplifying nucleic acids, a method using a RecA protein of E. coli is known (for example, Patent Document 1).
[Patent Document 1] Japanese Patent No. 3010738 (pages 1 to 4)
However, when PCR is carried out, there may be the cases in which not only a desired nucleic acid (a right specific PCR product), but also byproducts (non-specific PCR products) are amplified. Further, in such cases in the above-mentioned conventional methods, byproducts are amplified in a significant amount even if PCR conditions are changed appropriately.
In light of such circumstances, an object of the present invention is to provide a nucleic acid amplification method for amplifying a desired nucleic acid while suppressing amplification of byproducts in a PCR reaction, a reagent kit for nucleic acid amplification for amplifying the desired nucleic acid while suppressing amplification of the byproducts in the PCR reaction, a method for detecting single nucleotide polymorphism utilizing amplification of the desired nucleic acid while suppressing amplification of the byproducts in the PCR reaction, and a reagent kit for detecting single nucleotide polymorphism by detecting single nucleotide polymorphism utilizing amplification of the desired nucleic acid while suppressing amplification of the byproducts in the PCR reaction.

Method of amplifying nucleic acids, reagent kit for amplifying nucleic acids, method of detecting single nucleotide polymorphism, and reagent kit for detecting single nucleotide polymorphism


The present invention relates to humanized antibodies specific for HBV surface antigen pre-S1, which show binding affinity similar to mouse monoclonal antibody and which show remarkably reduced immunogenicity since they have less mouse-derived amino acid residues. Thus, the humanized antibodies of the present invention may be useful for the prevention of HBV infection and for the treatment of hepatitis B.

HBV (Hepatitis B Virus) is responsible for chronic or acute human hepatitis that may get worse to liver cirrhosis or cancer. It is estimated that about three hundred million people are suffering from hepatitis in the world (Tiollais and Buendia, Sci. Am. 264:48, 1991).
There are three kinds of HBV surface proteins containing different sets of surface antigens. Particularly, these surface antigen proteins includes the Major Protein containing S antigen, the Middle Protein containing S and pre-S2 antigens, and the Large Protein containing S, pre-S2 and pre-S1 antigens (Neurath and Kent, Adv. Virus Res., 34:65–142, 1988). All the surface antigen proteins can induce antibodies that neutralize HBV, and especially, antibodies against HBV pre-S antigen are associated with the elimination of the virus and the recovery from HBV infection, overcoming non-responsiveness to the S antigen (Iwarson et al., J. Med. Virol., 16:89–96, 1985; Itoh et al., Proc. Natl. Acad. Sci. USA, 85:9174–9178, 1986; Budkowska et al., J. Med. Virol., 20:111–125, 1986; Milich et al., Proc. Natl. Acad. Sci. USA, 82:8168–8172, 1985; Milich et al., J. Immunol., 137:315–322, 1986). Unlike pre-S2 or S antigen, pre-S1 antigen is exclusively present in infectious virus particles (Heerman et al., J. Virol., 52:396–402, 1984) and involved in the infection into human liver cells. Thus, it has been reported that monoclonal antibody specific for pre-S1 antigen may efficiently neutralize HBV (Neurath et al., Cell, 46:429, 1986; Pontisso et al., Virology, 173:533, 1989; Neurath et al., Vaccine, 7:234, 1989), and the monoclonal antibody is considered to be useful in the prevention of HBV infection and the treatment of chronic hepatitis B.
So far hepatitis B immunoglobulin has been employed as a preventive for HBV infection, which may protect, for example, a newborn baby from a HBV-positive mother, medical personnel exposed to HBV, and liver transplant patient with chronic HBV-related liver disease (Beasley et al., Lancet, 2:1099, 1983; Todo et al., Hepatology, 13:619, 1991). However, hepatitis B immunoglobulin has some shortcomings such as its limited availability, low specific activity and its possible contamination with infectious agents. Furthermore, it is another disadvantage of hepatitis B immunoglobulin that blood plasma should be continuously supplied.
As an alternative for the hepatitis B immunoglobulin, mouse monoclonal antibodies against HBV surface antigens have been developed. Although the mouse monoclonal antibodies show high affinity for the antigen and can be prepared on a large scale, they induce human anti-mouse antibody response in patients (Shawler et al., J. Immunol., 135:1530, 1985). There were attempts to prepare human monoclonal antibodies, but few of these antibodies showed a high level of affinity.
Instead, humanized antibodies have been developed. Humanized antibody has a high level of affinity and specificity similar to mouse antibodies, whereas its immunogenicity is minimized. Humanized antibody is a hybrid antibody in which CDRs (Complementarity Determining Regions) of a mouse antibody is grafted to a human antibody by genetic engineering technique. It can be easily prepared on a large scale, and hardly elicits immune responses in humans since most of the DNA sequences encoding the humanized antibodies are derived from a human DNA sequence (Riechman et al., Nature, 332:323, 1988; Nakatani et al., Protein Engineering, 7:435, 1994).
To overcome the aforementioned and other disadvantages of mouse or human HBV immunoglobulin, we, the inventors of the present invention, have attempted to prepare humanized antibodies which can be used to prevent HBV infection and to treat chronic hepatitis B. Prior to this invention, we prepared a mouse monoclonal antibody KR127 against HBV surface antigen pre-S1. Additionally, we isolated the genes encoding the heavy and light chain variable regions of KR127 antibody and determined the sequences of the genes (Korea Patent Application No. 1997-30696). The present invention is performed by selecting human immunoglobulin genes homologous to the sequences of KR127 antibody light chain and heavy chain variable regions; constructing the humanized antibody genes; inserting the genes into expression vectors; introducing the vectors into host cells; obtaining humanized antibodies from the culture of the transformed cells; and confirming that the humanized antibodies have high affinity to HBV pre-S1 antigen, similar to the mouse monoclonal antibody KR127.

Humanized antibody specific for surface antigen pre-S1 of HBV and preparation method thereof

Korea Institute of Science and Technology


A flip-flop circuit includes first and second logic gates, a first selection circuit and a latch circuit. The first logic gate executes a logic operation on a first data signal and a first control signal. The second logic gate executes a logic operation on a second data signal and the first control signal. The operation results of the first and second logic gates are forcibly fixed to a predetermined value irrespective of the first and second data signals, if the first control signal is asserted. A first selection circuit selects one of the operation results of the first and second logic gates, and outputs the selected operation result as a first selection signal. A latch circuit latches the first selection signal.

1. Field of the Invention
The present invention relates to a flip-flop circuit, and more particularly to a flip-flop circuit capable of preventing data signal propagation delays by reducing the number of stages of logic circuits located on a data signal input path.
2. Description of the Related Art
A CMOS flip-flop circuit, provided with three functions for a test operation, clear operation and output feedback operation in addition to data input operation, is widely used in a semiconductor integrated circuit. Referring to FIG. 1A, a CMOS flip-flop circuit will be described. FIG. 1A is a circuit diagram illustrating a CMOS flip-flop circuit.
As shown, the CMOS flip-flop circuit 1 mainly comprises an input signal selection section 2 and a latch circuit 3. The input signal selecting section 2 includes selection circuits 2-1–2-3 and inverters 2-4 and 2-5. The selection circuit 2-1 is a multiplexer, for example. This circuit selects either the inverted output signal QN of the CMOS flip-flop or an input data signal DI inverted by the inverter 2-4. The selection circuit 2-2 is a NAND gate, for example. This circuit selects either the signal selected by the selection circuit 2-1 or a reset signal RN inverted by the inverter 2-5. The selection circuit 2-3 is a multiplexer, for example. This circuit selects either the signal selected by the selection circuit 2-2 or a test signal TI. The latch circuit 3 is of a master-slave type, for example. This circuit latches the signal selected by the selection circuit 2-3.
The usual operation of the CMOS flip-flop circuit 1 constructed as above is the data input operation. When executing the data input operation, an enable signal Enb for controlling the selection circuit 2-1 is asserted. As a result, the selection circuit 2-1 selects the input data signal DI inverted by the inverter 2-4. The input data signal DI is latched by the latch circuit 3 via the selection circuits 2-2 and 2-3.
When executing the clear operation, the reset signal RN is asserted. As a result, the output of the selection circuit 2-2 is forcibly fixed. The output signal of the selection circuit 2-2 is latched by the latch circuit 3 via the selection circuit 2-3. Thus, the data latched by the latch circuit 3 is reset.
When executing the test operation, a test enable signal TE input to the selection circuit 2-3 is asserted. As a result, the selection circuit 2-3 selects the test signal TI, and the latch circuit 3 latches the test signal TI.
Further, the CMOS flip-flop circuit 1 executes an output feedback operation in addition to the aforementioned three operations. The output feedback operation is executed to secure an output state even if there is no input signal. When there is no input signal, the selection circuit 2-1 selects the inverted output signal QN of the latch circuit 3. The latch circuit 3 again latches the inverted output signal QN via the selection circuits 2-2 and 2-3.
The order of priority of the four above-mentioned operations is test operation, clear operation and enable/data-input operations. In other words, even if the reset signal RN or input data signal DI is input, the test operation is executed unconditionally as long as the test enable signal TE is asserted. If, on the other hand, the test enable signal is not asserted, the reset operation is executed in preference to the output feedback operation or data input operation.
More specifically, as shown in FIG. 1B, when fixing an order of priority to signals input to the flip-flop circuit, a selection circuit MUX1 is used to select one of two signals IN(1) and IN(2), which have the lowest priority. After that, a selection circuit MUX2 is used to select one of the elected signal and a signal IN(3) having the second lowest priority. Similarly, selection circuits MUX3–MUX(n−2) execute signal selection. The selection circuit MUX(n−1) of the last stage selects either a signal IN(n) of the highest priority or the output signal of the selection circuit MUX(n−2). By virtue of this structure, it can be determined, in accordance with a control signal Cnt(n−1) for the selection circuit MUX(n−1) of the last stage, whether or not the signal IN(n) of the highest priority should be selected, irrespective of the states of the selection circuits MUX1–MUX(n−2).
FIG. 1C is a timing chart illustrating the waveforms of a clock CP and the input data signal DI. The input data signal DI is normally captured by the flip-flop circuit in synchronism with the clock CP. As shown, when the input data signal DI is captured in synchronism with the leading edge of each pulse of the clock CP, it is necessary to input the input data signal DI to the flip-flop circuit before the rise of each pulse of the clock CP. The time required from the input of the input data signal DI to the rise of each pulse of the clock CP is called a "setup time". The reason why the setup time is provided is that determined time is required until the input data signal DI is actually captured by the flip-flop circuit after it is input. Therefore, the longer the input path of the input data signal, the longer the setup time should be.
In the case of the flip-flop circuits shown in FIGS. 1A and 1B, the input path of a signal selected by a selection circuit of a later stage is very long. For example, in the flip-flop circuit shown in FIG. 1A, the input data signal DI must pass through the selection circuits 2-2 and 2-3 before it reaches the latch circuit. Thus, the input path of the input data signal DI is long and hence the setup time should be set long. Where the setup time is long, it may impede an increase in the operation speed of the flip-flop circuit. Furthermore, it requires a large operational margin and hence may make the circuit design complicated.
FIG. 1D is a block diagram illustrating a semiconductor integrated circuit. As shown, the semiconductor integrated circuit comprises flip-flop circuits 1-1–1-4, and logic circuits 4-1–4-2 to be controlled by the outputs of the flip-flop circuits. When executing a test operation, the test signal TI is input to each flip-flop 1-1–1-4, and the test operation is executed in synchronism with the clock CP.
Usually, the propagation speed of the test signal TI is very high since the signal propagates through a test signal path wired by a dedicated wiring method. On the other hand, the clock CP has a skew, which may involve a problem during the operation of each flip-flop. Specifically, there is a case where the test signal TI reaches a flip-flop circuit earlier than the clock CP. For example, in the case of FIG. 1D, the test signal TI reaches each flip-flop 1-1–1-4 circuit earlier than the clock CP. Therefore, it is possible that the reliability of the test operation will be significantly degraded.
This clock skew problem can be solved by inserting a delay cell only in the test signal path. In this case, however, the whole circuit size will be inevitably large, and further, it is necessary to review the design of the entire flip-flop structure so as to insert a delay cell. Therefore, the insertion of a delay cell is not a preferable solution.

Flip-flop circuit for capturing input signals in priority order


An SiC film having an excellent strength and thermal characteristics. The SiC film is prepared by a CVD process (i.e. CVD-SiC fabrication) and has a thermal conductivity along the direction of the SiC crystal growth between 100 and 300 W/m.multidot.K, and an average grain diameter of the internal structure between 4 to 12 .mu.m. It is preferred that the ratio of the thermal conductivity along the direction of the SiC crystal growth to the thermal conductivity in the perpendicular direction is in a range of 1.10 to 1.40.

Silicon carbide (hereinafter referred to as "SiC") has excellent material characteristics such as thermal resistance, wear resistance, and corrosion resistance, which makes it useful a material for various industrial applications. In particular, an SiC fabrication (CVD-SiC fabrication) manufactured by utilizing a chemical vapor deposition (CVD) method is widely used in a variety of materials suitable for manufacturing semiconductors because of its compactness and high purity.
Such a CVD-SiC fabrication is prepared by having SiC crystal grains deposited on a substrate surface by a gas phase reaction of gaseous raw materials, and, after forming a solid coating by growing the crystal grains, removing the substrate body. The material, therefore, is characterized by its high compactness, high purity, and high degree of uniformity in structure.
As a CVD-SiC fabrication, for example, a CVD self-supported film structure is disclosed in Japanese Patent Application Laid-Open No. 188927/1995, wherein the CVD self-supported film structure comprising a heat resistant ceramic material such as SiC, Si.sub.3 N.sub.4, and the like is characterized by having randomly orientated crystal grains. In this invention, the crystal grain orientation is randomized by an additional heat treatment at a temperature higher than the recrystallization temperature, for example between 1,700 to 2,200.degree. C., so that anisotropy in the mechanical strength of the CVD self-supported film structure is reduced. Such an additional step, however, makes the manufacturing process more complicated.
Additionally, in Japanese Patent Application Laid-Open No. 188408/1996, there are disclosed methods for manufacturing a CVD-SiC fabrication by building an SiC coating on either side of an SiC substrate prepared by a CVD process, and also by forming an SiC coating on a substrate, turning it to an SiC substrate by removing said substrate, and building an additional SiC coating on both sides of the SiC substrate.
Furthermore, in Japanese Patent Application Laid-Open No. 188468/1996, there is disclosed a method for manufacturing a CVD-SiC fabrication comprising a lamination of three or more of SiC layers each having a thickness of 100 .mu.m or less, and also a method for manufacturing a CVD-SiC fabrication employing a technique whereby an SiC coating is formed on a substrate and then made into an SiC fabrication by removing said substrate. In the latter method, a process of building an SiC layer with a CVD method and subsequently leveling the surface of said SiC layer is repeated several times to build a lamination of SiC layers, each having a thickness of 100 .mu.m or less, to a desired total thickness prior to removing the substrate.
The above-mentioned inventions in the Japanese Patent Application Laid-Open Nos. 188408/1996 and 188468/1996 employ, for the purpose of preventing cracks or warp occurring on an SiC fabrication, methods wherein (a) the growth of an SiC coating is interrupted without bringing it to the desired thickness in one process, thereby minimizing accumulation of internal stress in the coating, to prepare an SiC coating made up with uniform crystal grains and reduced surface roughness, and thereafter an SiC coating is built on both top and back sides of said SiC coating used as a substrate (Japanese Patent Application Laid-Open No. 188408/1996); or (b) a process of interrupting the formation of an SiC layer at an earlier stage of growth and leveling the layer surface is repeated several times (Japanese Patent Application Laid-Open No. 188468/1966).
The above-mentioned inventions in the Japanese Patent Application Laid-Open Nos. 188408/1996 and 188468/1996, therefore, have such shortcomings as complicating the manufacturing process by requiring the CVD growth of an SiC coating to be interrupted without bringing it to the desired thickness in one process, or otherwise requiring leveling treatment of the surface, both adversely affecting the manufacturing efficiency. Moreover, the strength characteristics or thermal shock resistance of the product of these inventions still leaves much to be desired.


A Datacenter Management Service (DMS) is provided as a platform designed to automate datacenter management tasks that are performed across multiple technology silos and datacenter servers or collections of servers. The infrastructure to perform the automation is provided by integrating heterogeneous task providers and implementations into a set of standardized adapters through dependency inversion. A platform automating datacenter management tasks may include three main components: integration of adapters into an interface allowing a common interface for datacenter task execution, an execution platform that works against the adapters, and implementation of the adapters for a given type of datacenter management task.

With the proliferation of networked computing, many computing tasks are increasingly being handled at remote computing resources such as cloud-based services. Datacenters housing a multitude of servers and other specialized computing devices provide businesses with a range of solutions for systems deployment and operation. New technologies and practices are designed to handle the scale and the operational requirements of such large-scale operations. These practices eventually migrate toward private data centers, and are adopted largely because of their practical results.
Managing a datacenter depends on performing datacenter management tasks across multiple technologies across multiple datacenter servers. Challenges with datacenter management include the fact that high number of technologies employed in a typical datacenter may require resources knowledgeable about each technology and the high number of servers employed in a typical datacenter may require that management tasks be employed against many servers. A task that is trivial to perform against one server may quickly become non-trivial when it must be performed against multiple servers at a time. Management tasks often cross technology silos, resulting in even greater complexity as organizational boundaries necessitate that multiple participants be employed in the completion of the task.
Furthermore, a resource that performs a task across one or more technologies may often require broad permissions to perform the task, making the principle of least privilege difficult to employ without requiring that a task involve multiple participants—each with their own limited scope of access per datacenter technology, resource, or server. Moreover, datacenter tasks are not necessarily evenly distributed per technology or server, making resource allocation difficult while minimizing scope of access. In addition, resources with the knowledge to perform tasks across multiple technologies are typically more expensive and difficult to acquire.

This patent is subject to a terminal disclaimer.

Optimized datacenter management by centralized task execution through dependency inversion