The invention concerns compounds of formula (I),

This is a U.S. National Stage filing under 35 U.S.C. 371 of International Patent Application No. PCT/GB98/03496, filed Nov. 24, 1998, which is based on British Patent Application No. 9725244.9, filed Nov. 29, 1997.
The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing an oxazolidinone ring. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention are regarded primarily as effective against Gram-positive pathogens because of their particularly good activity against such pathogens.
Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus (MRSA), methicillin resistant coaguiase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium.
The major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens.
The present inventors have discovered a class of antibiotic compounds containing an oxazolidinone ring which has useful activity against Gram-positive pathogens including MRSA and MRCNS and, in particular, against various strains exhibiting resistance to vancomycin and against E. faecium strains resistant to both aminoglycosides and clinically used xcex2-lactams.
We have now discovered a range of compounds which have good activity against a broad range of Gram-positive pathogens including organisms known to be resistant to most commonly used antibiotics. In comparison with compounds described in the art (Walter A. Gregory et al in J.Med.Chem. 1990, 33, 2569-2578 and Chung-Ho Park et al in J.Med.Chem. 1992, 35, 1156-1165) the compounds also possess a favourable toxicological profile.
Accordingly the present invention provides a compound of the formula (I):
wherein R1 is hydroxy, amino, chloro, fluoro, (1-4C)alkanesulfonyloxy, azido, (1-4C)alkoxy, or of the formula xe2x80x94NHC(xe2x95x90O)Ra wherein Ra is hydrogen, (1-4C)alkoxy, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl or (1-4C)alkyl;
R2 and R3 are independently hydrogen or fluoro;
R5 and R6 are independently selected from hydrogen, (1-4C)alkyl, halo and trifluoromethyl;
R4 is xe2x80x94Xxe2x80x94Yxe2x80x94Het.;
wherein X is a direct bond or xe2x80x94CH(OH)xe2x80x94 and
Y is xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(CH2)mxe2x80x94, xe2x80x94COxe2x80x94(CH2)mxe2x80x94, xe2x80x94CONHxe2x80x94(CH2)mxe2x80x94, xe2x80x94C(xe2x95x90S)NHxe2x80x94(CH2)mxe2x80x94 or xe2x80x94C(xe2x95x90O)Oxe2x80x94(CH2)mxe2x80x94;
or wherein X is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94CH(Me)xe2x80x94(CH2)mxe2x80x94 and Y is xe2x80x94(CH2)mxe2x80x94NHxe2x80x94(CH2)mxe2x80x94, xe2x80x94COxe2x80x94(CH2)mxe2x80x94, xe2x80x94CONHxe2x80x94(CH2)mxe2x80x94, C(xe2x95x90S)NHxe2x80x94(CH2)mxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94(CH2)mxe2x80x94 or xe2x80x94S(O)pxe2x80x94(CH2)mxe2x80x94;
or wherein X is xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2NHxe2x80x94 or xe2x80x94CH2N(R)xe2x80x94 [wherein R is (1-4C)alkyl] and Y is xe2x80x94COxe2x80x94(CH2)mxe2x80x94, xe2x80x94CONHxe2x80x94(CH2)mxe2x80x94 or xe2x80x94C(xe2x95x90S)NHxe2x80x94(CH2)mxe2x80x94; and additionally Y is xe2x80x94SO2xe2x80x94 when X is xe2x80x94CH2NHxe2x80x94 or xe2x80x94CH2N(R)xe2x80x94 [wherein R (1-4C)alkyl], and Y is xe2x80x94(CH2)mxe2x80x94 when X is xe2x80x94CH2Oxe2x80x94 or xe2x80x94CH2N(R)xe2x80x94;
wherein n is 1, 2 or 3; m is 0, 1, 2 or 3 and p is 0, 1 or 2; and when Y is xe2x80x94(CH2)mxe2x80x94NHxe2x80x94(CH2)mxe2x80x94 each m is independently selected from 0, 1, 2 or 3;
wherein Het. is a heterocyclic ring [which heterocyclic ring may be unsaturated (linked via either a ring carbon or ring nitrogen atom to xe2x80x94Xxe2x80x94Yxe2x80x94) or saturated (linked via a ring nitrogen atom to xe2x80x94Xxe2x80x94Yxe2x80x94), with the proviso that when it is unsaturated and linked via nitrogen to xe2x80x94Xxe2x80x94Yxe2x80x94 the ring is not quaternised] which heterocyclic ring is optionally substituted on an available carbon atom by up to three substituents independently selected from (1-4C)alkyl [optionally substituted by trifluoromethyl, (1-4C)alkyl S(O)pxe2x80x94 (wherein p is 0, 1 or 2), carbamoyl, N-(1-4C)alkyicarbamoyl, di(N-(1-4C)alkyl)carbamoyl, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, cyano, nitro, amino, N-(1-4C)alkylamino, di(N-(1-4C)alkyl)amino or (1-4C)alkanoylamino], halo, trifluoromethyl, (1-4C)alkyl S(O)p(wherein p is 0, 1 or 2), carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, di(N-(1-4C)alkyl)carbamoyl, (2-4C)alkenyl, cyano, nitro, amino, (2-4C)alkanoylamino, (1-4C)alkoxy, di(N-(1-4C)alkyl)aminomethylimino, hydroxy, oxo or thioxo (xe2x95x90S); and optionally substituted on an available nitrogen atom (if the ring will not thereby be quaternised) by (1-4C)alkyl [optionally substituted by trifluoromethyl, (1-4C)alkyl S(O)pxe2x80x94 (wherein p is 0, 1 or 2), (1-4C)alkoxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, di(N-(1-4C)alkyl)carbamoyl, cyano, nitro, amino, N-(1-4C)alkylamino, di(N-(1-4C)alkyl)amino or (1-4C)alkanoylamino] or oxo (to form an N-oxide); and pharmaceutically acceptable salts thereof.
In a further aspect of the invention there is provided a compound of the formula (I) as described hereinabove, wherein when X is a direct bond, Y is additionally xe2x80x94CON(R)xe2x80x94 (CH2)mxe2x80x94 [wherein R is (1-4C)alkyl], and the optional substituents on an available carbon atom in the Het. heterocyclic ring additionally include amino.
The term xe2x80x98alkylxe2x80x99 includes straight chained and branched structures. For example, (1-4C)alkyl includes propyl, isopropyl and t-butyl.
Examples of (1-4C)alkyl include methyl, ethyl, propyl, isopropyl and t-butyl; examples of N-(1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl; examples of di(N-(1-4C)alkyl)carbamoyl include di(methyl)carbamoyl and di(ethyl)carbamoyl; examples of (1-4C)alkylS(O)pxe2x80x94 include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; examples of (2-4C)alkenyl include allyl and vinyl; examples of (1-4C)alkoxy include methoxy, ethoxy and propoxy; examples of (2-4C)alkanoylamino include acetamido and propionylamino; examples of N-(1-4C)alkylamino include methylamino and ethylamino; example of di-(N-(1-4C)alkyl)amino include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino; examples of (1-4C)alkoxycarbonyl include methoxycarbonyl and ethoxycarbonyl; examples of halo include fluoro, chloro and bromo; examples of di-(N-(1-4C)alkyl)aminomethylimino include dimethylaminomethylimino and diethylaminomethylimino and examples of (1-4C)alkanesulfonyloxy include methylsulfonyloxy and ethylsulfonyloxy.
A heterocyclic ring means a 5- or 6-membered monocyclic ring or a 5/6 or 6/6 bicyclic ring (linked via either, or any, of the rings) containing up to four heteroatoms selected independently from O, S and N. An unsaturated ring means a fully unsaturated (aromatic) ring and partially unsaturated ring systems (such as, for example, tetrahydropyridine). Preferred examples of unsaturated 5- or 6-membered heterocyclic groups with up to four heteroatoms selected independently from O, S and N are furan, pyrrole, thiophene, those containing one, two or three N atoms (for example, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3- and 1,2,4-triazole), two N atoms and one S atom (for example 1,2,4- and 1,3,4-thiadiazole, ), one N and one O atom (for example oxazole, isoxazole and oxazine) and one N and one S atom (for example thiazole and isothiazole). Unsaturated 5-membered heterocyclic groups are preferred. Thiazole is particularly preferred. Links via a ring carbon atom are preferred.
Preferred examples of a 5/6 or 6/6 bicyclic ring (linked via either of the rings) containing up to four heteroatoms selected independently from O, S and N are, for example, indole, quinoline, isoquinoline, benzpyrrole, benzpyrazole, benzimidazole, quinoxaline, benzthiazole, benzoxazole, benzthiadiazole, benztriazole and 1,4-benzodioxan. Preferred are 5/6 bicyclic rings, particularly those containing up to two heteroatoms only, such as benzthiazole and benzoxazole, especially benzthiazole. Links via a ring carbon atom are preferred.
It is to be understood that when a value for xe2x80x94Xxe2x80x94 is a two-atom link and is written, for example., as xe2x80x94CONHxe2x80x94 it is the left hand part (xe2x80x94COxe2x80x94 here) which is bonded to the imidazole ring in formula (I) and the right hand part (xe2x80x94NHxe2x80x94 here) which is bonded to xe2x80x94Yxe2x80x94 in the definition of R4. Similarly, when xe2x80x94Yxe2x80x94 is a two-atom link and is written, for example, as xe2x80x94CONHxe2x80x94 it is the left hand part of xe2x80x94Yxe2x80x94(xe2x80x94COxe2x80x94 here) which is bonded to the right hand part of xe2x80x94Xxe2x80x94, and the right hand part of xe2x80x94Yxe2x80x94(xe2x80x94NHxe2x80x94 here) which is bonded to the Het. moiety in the definition of R4.
Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethyiamine or amino acids for example lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically-acceptable salt is the sodium salt.
However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
The compounds of the formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I). Examples of pro-drugs include in-vivo hydrolysable (in-vivo cleavable) esters of a compound of the formula (I).
An in-vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include (1-6C)alkoxymethyl esters for example methoxymethyl, (1-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and (1-6C)alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
An in-vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and xcex1-acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of xcex1-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
The compounds of the present invention have a chiral centre at the C-5 position. The pharmaceutically active enantiomer is of the formula (IA):
The present invention includes the pure enantiomer depicted above or mixtures of the 5(R) and 5(S) enantiomers, for example a racemic mixture. If a mixture of 5(R) and 5(S) is used, a larger amount (depending up on the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer. Furthermore, some compounds of the formula (I) may have other chiral centres, for example when X is xe2x80x94CH(Me)xe2x80x94.
It will be appreciated that when the Het. moiety in R4 is optionally substituted by hydroxy, oxo or thioxo the phenomenon of tautomerism may be present depending upon the nature of the Het. moiety. Thus, for example, in fully unsaturated (aromatic) systems a hydroxy substituent may represent one tautomeric form, and an oxo substituent the other tautomeric form. The invention includes all tautomeric forms which possess antibacterial activity.
Preferably R1 is of the formula xe2x80x94NHC(xe2x95x90O)Ra wherein Ra is hydrogen, methoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl or (1-4C)alkyl.
Yet more preferably R1 is of the formula xe2x80x94NHC(xe2x95x90O)(1-4C)alkyl.
Most preferably R1 is acetamido.
Preferably one of R2 and R3 is hydrogen and the other is fluoro.
Preferably R5 and R6 are hydrogen.
Preferably the Het. moiety in R4 is unsaturated, ie. fully unsaturated (aromatic) ring or partially unsaturated ring systems. Preferably the Het. moiety in R4 ring is linked via a ring carbon atom.
Preferred values for the Het. moiety in R4 are furan, thiophene, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3- and 1,2,4-triazole, 1,2,4- and 1,3,4-thiadiazole, oxazole, isoxazole, thiazole, isothiazole, indole, quinoline, isoquinoline, benzpyrazole, benzimidazole, quinoxaline, benzthiazole, benzoxazole, benzthiadiazole, benztriazole and 1,4-benzodioxan.
Preferred values for xe2x80x94Xxe2x80x94Yxe2x80x94 links are xe2x80x94CH2Sxe2x80x94, xe2x80x94CH2Oxe2x80x94COxe2x80x94, xe2x80x94CH2NHxe2x80x94, xe2x80x94CH2NHCOxe2x80x94 and xe2x80x94CONHxe2x80x94.
Other preferred values for xe2x80x94Xxe2x80x94Yxe2x80x94 links are a direct link, xe2x80x94CH2SO2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2NHSO2xe2x80x94, xe2x80x94CH2Oxe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CONHxe2x80x94CH2xe2x80x94, xe2x80x94CONHxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94 and xe2x80x94CON(Me)xe2x80x94.
Preferred optional substituents (preferably, zero, one or two) on an available carbon atom of the Het. moiety of R4 are (1-4C)alkyl, halo, cyano, nitro. amino, (2-4C)alkanoylamino, (1-4C)alkoxy, hydroxy, oxo and thioxo (xe2x95x90S).
Preferred optional substituents (preferably, zero or one) on an available nitrogen atom of the Het. moiety of R4 are (1-4C)alkyl, especially methyl, and oxo (to form an N-oxide).
Accordingly, in a particular aspect of the present invention there is provided a compound of the formula (I) in which R1 is acetamido; one of R2 and R3 is hydrogen and the other is fluoro; R5 and R6are hydrogen; the xe2x80x94Xxe2x80x94Yxe2x80x94 link is xe2x80x94CH2Sxe2x80x94, xe2x80x94CH2Oxe2x80x94COxe2x80x94, xe2x80x94CH2NHxe2x80x94, xe2x80x94CH2NHCOxe2x80x94 or xe2x80x94CONHxe2x80x94; the Het. moiety in R4 is a fully unsaturated (aromatic) ring linked via a ring carbon atom and selected from furan, thiophene, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3- and 1,2,4-triazole, 1,2,4- and 1,3,4-thiadiazole, oxazole, isoxazole, thiazole, isothiazole, indole, quinoline, isoquinoline, benzpyrazole, benzimidazole, quinoxaline, benzthiazole, benzoxazole, benzthiadiazole, benztriazole and 1,4-benzodioxan; wherein the Het moiety is optionally substituted by up to two substituents on an available carbon atom selected from (1-4C)alkyl, halo, cyano, nitro, amino, (2-4C)alkanoylamino, (1-4C)alkoxy, hydroxy, oxo and thioxo (xe2x95x90S), and optionally substituted by a substituent on an available nitrogen atom selected from (1-4C)alkyl and oxo; and pharmaceutically-acceptable salts thereof.
Of the compounds in the above particular aspect, those in which the Het. moiety is a monocyclic ring are preferred.
An especially preferred compound of the invention is selected from the group consisting of:
N-[(5S)-3-(3-Fluoro-4-(4-pyrimidin-2-ylthiomethylimidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;
N-[(5S)-3-(3-Fluoro-4-(4-(2-furoyloxymethyl)imidazol-1-yl)phenyl)-2-oxooxazolidin-5-yl-methyl]acetamide;
N-[(5S)-3-(3-Fluoro-4-(4-(5-nitropyridin-2-ylaminomethyl)imidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;
N-[(5S)-3-(3-Fluoro-4-(4-(quinoxalin-2-ylcarbonylaminomethyl)imidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;
N-[(5S)-3-(3-Fluoro-4-(4-(thiazol-2-ylaminocarbonyl)imidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide; and pharmnaceutically-acceptable salts thereof.
Of the above, N-[(5S)-3-(3-Fluoro-4-(4-(thiazol-2-ylaminocarbonyl)imidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide is especially preferred.
A further especially preferred compound of the invention is N-[(5S)-3-(3-Fluoro-4-(thiazol-2-ylimidazol-1-yl)phenyl)-2-oxooxazolidin-5-yl-methyl]acetamide; and pharmaceutically-acceptable salts thereof.
In a further aspect the present invention provides a process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The compounds of the formula (I) may be prepared by deprotecting a compound of the formula (II):
wherein R2, R3, R5 and R6 are as hereinabove defined, R9 is R4 or protected R4 and R10 is R1 or protected R1, and thereafter if necessary forming a pharmaceutically acceptable salt.
Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the sake of convenience, in which xe2x80x9clowerxe2x80x9d signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
A carboxy protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
Examples of carboxy protecting groups include straight or branched chain (1-12C)alkyl groups (eg isopropyl, t-butyl); lower alkoxy lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl; lower aliphatic acyloxy lower alkyl groups, (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (eg trimethylsilylethyl); and (2-6C)alkenyl groups (eg allyl and vinylethyl).
Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, metal- or enzymically-catalysed hydrolysis.
Examples of hydroxy protecting groups include lower alkenyl groups (eg allyl); lower alkanoyl groups (eg acetyl); lower alkoxycarbonyl groups (eg t-butoxycarbonyl); lower alkenyloxycarbonyl groups (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, pmethoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, pnitrobenzyloxycarbonyl); tri lower alkyl/arylsilyl groups (eg trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl); aryl lower alkyl groups (eg benzyl) groups; and triaryl lower alkyl groups (eg triphenylmethyl).
Examples of amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg t-butoxycarbonyl); lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups.
Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, metal- or enzymically-catalysed hydrolysis, for groups such as o-nitrobenzyloxycarbonyl, photolytically and for groups such as silyl groups, fluoride.
Examples of protecting groups for amide groups include aralkoxymethyl (eg. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (eg. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (eg. trimethylsilyl, t-butyldimethylsily, t-butyldiphenylsilyl); tri alkyl/arylsilyloxymethyl (eg. t-butyldimethylsilyloxymethyl, t-butyldiphenylsilyloxymethyl); 4-alkoxyphenyl (eg. 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (eg. 2,4-dimethoxyphenyl); 4-alkoxybenzyl (eg. 4-methoxybenzyl); 2,4-di(alkoxy)benzyl (eg. 2,4-di(methoxy)benzyl); and alk-1-enyl (eg. allyl, but-1-enyl and substituted vinyl eg. 2-phenylvinyl).
Aralkoxymethyl, groups may be introduced onto the amide group by reacting the latter group with the appropriate aralkoxymethyl chloride, and removed by catalytic hydrogenation. Alkoxymethyl, tri alkyl/arylsilyl and tri alkyl/silyl groups may be introduced by reacting the amide with the appropriate chloride and removing with acid, or in the case of the silyl containing groups fluoride ions. The alkoxyphenyl and alkoxybenzyl groups are conveniently introduced by arylation or alkylation with an appropriate halide and removed by oxidation with ceric ammonium nitrate. Finally alk-1-enyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid.
For further examples of protecting groups see one of the many general texts on the subject, for example, xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by Theodora Green (publisher: John Wiley and Sons).
In another aspect of the present invention the compounds of the formulae (I) and (II) and pharmaceutically acceptable salts thereof can be prepared:
(a) by modifying a substituent in or introducing a substituent into another compound of the formula (I) or (II), or modifying a linking group in another compound of the formula (I) or (II);
(b) by reaction of a compound of the formula (III) with a compound of the formula Hetxe2x80x94Yxe2x80x94L1 [wherein L1 and L2 are independently hydrogen or a leaving group], or with a compound capable of forming a Het. moiety [wherein L2 may form part of the final Het. moiety], or with a Hetxe2x80x94Yxe2x80x94L1 compound such that xe2x80x94Yxe2x80x94L1 or L2xe2x80x94Xxe2x80x94 (or a part thereof) may form part of the final xe2x80x94Xxe2x80x94Yxe2x80x94 link:
(c) when R1 or R10 is of the formula xe2x80x94NHC(xe2x95x90O)Ra, by introducing xe2x80x94C(xe2x95x90O)Ra into a compound of the formula (I) or (II) wherein R1 or R10 is amino;
(d) when R1 or R10 is amino, by reducing a compound of the formula (I) or (II) wherein R1 or R10 is azido;
(e) when R1 or R10 is azido, by reacting a compound of the formula (IV) [wherein R12 is mesyloxy, tosyloxy or a phosphate ester] with a source of azide:
(f) when R1 or R10 is hydroxy, by reacting a compound of the formula (V) with a compound of the formula (VI) [wherein R13 is (1-6C)alkyl or benzyl, and R14 is (1-5 6C)alkyl]:
(g) when R10 is of the formula xe2x80x94N(CO2R15)CO(1-4C)alkyl [wherein R15 is (1-4C)alkyl or benzyl], from a compound of the formula (I) or (II) wherein R1 or R10 is hydroxy;
(h) when R5 or R10 is chloro, fluoro, (1-4C)alkanesulfonyloxy or (1-4C)alkylaminocarbonyloxy, from a compound of the formula (I) or (II) wherein R1 or R10is hydroxy;
(i) when R1 or R10 is chloro, (1-4C)alkylthio or (1-4C)alkoxy, from a compound of the formula (IV);
wherein L2, L1, X, Y, R2, R3, R5, R6 and R9 are as hereinabove or hereinafter defined, and thereafter if necessary:
i) removing any protecting groups;
ii) forming a pharmaceutically acceptable salt,
iii) forming a suitable N-oxide.
The processes (a) and (c) to (i) may be performed using compounds of the formula (I) or (II) as defined hereinbefore with compounds of the formula (II) in which R9 is xe2x80x94Xxe2x80x94L2 (or a protected version thereofxe2x80x94see hereinbefore and Examples for suitable protecting groups). The process (b) may then be performed using the compound in which xe2x80x94Xxe2x80x94L2 is unprotected. Certain values of assembled xe2x80x94Xxe2x80x94Yxe2x80x94 links in compounds of formula (I) and (II) (wherein R9 is R4 or protected R4) are unsuitable for use with processes (a) and (c) to (i); the skilled organic chemist will recognise when this is so, and, for example, the oxazolidinone ring should be assembled before the xe2x80x94Xxe2x80x94Yxe2x80x94 link is assembled.
Certain intermediate compounds described hereinbefore and hereinafter, for example those in which xe2x80x94Xxe2x80x94L2 in a compound of formula (II) is azidomethyl are novel and are provided as a further feature of the invention.
Process (a)
Methods for converting substituents into other substituents are known in the art. For example a cyano group reduced to an amino group, a nitro group reduced to an amino group, a hydroxy group alkylated to a methoxy group, a bromo group to a cyano group, a thio group oxidised to a sulfinyl or sulfonyl group, a (1-4C)alkoxycarbonyl group converted to a carbamoyl group (see Example 27, for example) or an amino group converted to a (2-4C)alkanoylamino group (see Example 48, for example).
A linking group in one compound of the formula (I) or (II) may be converted into another linking group, for example, a xe2x80x94COxe2x80x94 link may be converted into a xe2x80x94CH(OH) link.
Process (b)
It will be appreciated that process (b) provides means for assembling the xe2x80x94Xxe2x80x94Yxe2x80x94 link in compounds of the formula (I). In describing the reactions suitable for this assembly the terms L2xe2x80x94Xxe2x80x94 and xe2x80x94Yxe2x80x94L1 have been used to define certain intermediate compounds, but the terms L2, X, Y and L1 are not necessarily strictly limited to those defined hereinbefore. Thus, for example, amide links may be established by reaction of a compound of formula (III) in which L2xe2x80x94Xxe2x80x94 is a carboxy group (i.e. L2 is xe2x80x94OH and X is xe2x80x94COxe2x80x94) with a Het.xe2x80x94Yxe2x80x94L1 compound wherein Y is xe2x80x94NHxe2x80x94 and L1 is H. The xe2x80x94Xxe2x80x94Yxe2x80x94 link in this case (xe2x80x94CONHxe2x80x94) is provided for in the definition of compounds of formula (I) hereinbefore by X as a direct bond and Y as xe2x80x94CONHxe2x80x94 (CH2)mxe2x80x94 with m is 0. Thus, process (b) includes those processes in which compounds of formula (III) and Het.xe2x80x94Yxe2x80x94L1 are such that L2xe2x80x94Xxe2x80x94 and xe2x80x94Yxe2x80x94L1 (or a part thereof) are suitable to give an assembled xe2x80x94Xxe2x80x94Yxe2x80x94 link as defined hereinbefore. The skilled organic chemist will recognise from the range of assembled xe2x80x94Xxe2x80x94Yxe2x80x94 links and the description for process (b) given hereinbefore and hereinafter how such xe2x80x94Xxe2x80x94Yxe2x80x94 links may be assembled.
The coupling reaction between a compound of the formula (III) and a compound of the formula Hetxe2x80x94Yxe2x80x94L1 is conveniently performed in an inert solvent such as acetonitrile, dichloromethane, N,N-dimethylformamide or N,N-dimethylacetamide, at a temperature in the range 0xc2x0 C. to the reflux temperature of the solvent, preferably in the range ambient to 70xc2x0 C. The precise reaction conditions and the nature of the starting materials will depend upon the nature of the xe2x80x94Xxe2x80x94Yxe2x80x94 bond that is to be formed between the imidazole ring in the compound of formula (III) and the Het. group in R4 or R9. The skilled organic chemist will be able to select suitable starting materials and conditions to produce the range of xe2x80x94Xxe2x80x94Yxe2x80x94 bonds detailed in this specification, and non-limiting representative examples are provided in the Examples contained herein. Suitable values for the leaving groups L1 and L2 are provided below. For example:
Methylthio linkages (X is xe2x80x94CH2xe2x80x94, Y is xe2x80x94Sxe2x80x94) may be prepared by the reaction of an (activated) methylhydroxy compound (X is xe2x80x94CH2xe2x80x94, L2 is xe2x80x94OH or another suitable leaving group prepared from xe2x80x94OH) with a thioxo or thiol compound (xe2x80x94Yxe2x80x94L1 is =S, or Y is xe2x80x94Sxe2x80x94and L1 is xe2x80x94H) in the presence of an agent such as N,N-dimethylformarnmide dineopentylacetal (DMFDMPA) which activates the xe2x80x94OH group for displacement and also generates an in-situ base for generating the required nucleophile.
Methylamino linkages (X is xe2x80x94CH2NHxe2x80x94, Y is a direct bond) may be prepared by the reaction of a methylamino compound (X is xe2x80x94CH2NHxe2x80x94, L2 is xe2x80x94H) with, for example, a halo compound (xe2x80x94Yxe2x80x94L1 isxe2x80x94halo, Y is a direct bond, L1 is halo).
Amide (for example methylaminocarbonyl) linkages (X is xe2x80x94CH2NHxe2x80x94, Y is xe2x80x94COxe2x80x94) may be prepared by the reaction of a methylamino compound (X is xe2x80x94CH2NHxe2x80x94, L2 is xe2x80x94H) with an acid chloride compound (xe2x80x94Yxe2x80x94L1 is xe2x80x94COCl, Y is xe2x80x94COxe2x80x94, L1 is chloro). Other amide linkages (for example carbonylamino(1-4C)alkyl and carbonylamino; X is xe2x80x94CONHxe2x80x94, Y is xe2x80x94(CH2)nxe2x80x94 wherein n is 0, 1, 2 or 3) may be prepared by the reaction of an activated carboxy compound (Xxe2x80x94L2 is xe2x80x94CO2H, L2 is xe2x80x94OH) with an amine (xe2x80x94Yxe2x80x94L1 is xe2x80x94(CH2)nNH2, L1 is xe2x80x94H), optionally in the presence of a coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide. Suitable activated carboxy compounds are, for example, the esters formed from the reaction of the carboxy compound with 4-nitrophenol, or 1-hydroxybenzotriazole.
Amide linkages in which the nitrogen atom of the amide bond is provided by a ring nitrogen atom in a non-aromatic Het. moiety can be prepared from a carboxy compound (X is xe2x80x94COxe2x80x94, Y is xe2x80x94(CH2)nxe2x80x94 wherein n is 0, ie. a direct bond) may be prepared by the reaction of an activated carboxy compound (Xxe2x80x94L2 is xe2x80x94CO2H, L2 is xe2x80x94OH) with a non-aromatic nitrogen containing Het. compound (optionally with functionalities protected, xe2x80x94Yxe2x80x94 is a direct bond, xe2x80x94L1 is xe2x80x94H), optionally in the presence of a coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide.
Amide (urea or thiourea) linkages in which xe2x80x94Yxe2x80x94L1 or L2xe2x80x94Xxe2x80x94 may form part of the final xe2x80x94Xxe2x80x94Yxe2x80x94 link may be prepared from the reaction of a compound of the formula (III) in which L2xe2x80x94Xxe2x80x94 is an isocyanate or isothiocyanate group with a Het.xe2x80x94(CH2)m-amine (wherein m is 0 to 3). Alternatively, Het.xe2x80x94(CH2)mxe2x80x94NCO or Het.xe2x80x94(CH2)mxe2x80x94NCS may be reacted with a compound of the formula (III) in which L2xe2x80x94Xxe2x80x94 is an amine group (wherein m is 0 to 3). These reactions illustrate cases in which xe2x80x94Yxe2x80x94L1 or L2xe2x80x94Xxe2x80x94 is xe2x80x94(CH2)m-amine, or xe2x80x94(CH2)mxe2x80x94NCO or xe2x80x94(CH2)mxe2x80x94NCS.
Similarly, sulfonamide (for example methylaminosulfonyl) linkages (X is xe2x80x94CH2NHxe2x80x94, Y is xe2x80x94SO2xe2x80x94) may be prepared by the reaction of a methylamino compound (X is xe2x80x94CH2NHxe2x80x94, L2 is xe2x80x94H) with a sulfonyl chloride compound (xe2x80x94Yxe2x80x94L1 is xe2x80x94SO2Cl, Y is xe2x80x94SO2xe2x80x94, L1 is chloro).
Ester linkages (for example methoxycarbonyl) linkages (X is xe2x80x94CH2Oxe2x80x94, Y is xe2x80x94COxe2x80x94) may be prepared by the reaction of a methylhydroxy compound (X is xe2x80x94CH2Oxe2x80x94, L2 is xe2x80x94H) with carboxy compound (xe2x80x94Yxe2x80x94L1 is xe2x80x94CO2H, L1 is xe2x80x94OH) in the presence of a coupling agent such as DMFDMPA which activates the xe2x80x94OH group for displacement and also generates an in-situ base for generating the required nucleophile. Other ester linkages (for example carbonyloxymethyl; X is a direct bond, Y is xe2x80x94C(xe2x95x90O)Oxe2x80x94CH2xe2x80x94) may be prepared by the reaction of a carboxy compound (Xxe2x80x94L2 is xe2x80x94CO2Hxe2x80x94, L2 is xe2x80x94OH) with a methylhydroxy compound (xe2x80x94Yxe2x80x94L1 is xe2x80x94CH2OH, L1 is xe2x80x94H) in the presence of a coupling agent such as dimethylarninopyridine and dicyclohexylcarbodiimide.
Alkylene chain linkages (for example X is methylene, xe2x80x94CH2xe2x80x94) to a ring nitrogen atom in a non-aromatic Het. moiety can be prepared, for example, by reaction of a methylhydroxy compound (X is xe2x80x94CH2xe2x80x94, L2 is xe2x80x94OH) with a non-aromatic Het. compound (optionally with functionalities protected, xe2x80x94Yxe2x80x94 is a direct bond, xe2x80x94L1 is xe2x80x94H), optionally in the presence of a coupling agent such as N,N-dimethylformamide dineopentylacetal (DMFDMPA) which activates the xe2x80x94OH group for displacement and also generates an in-situ base for generating the required nucleophile.
Direct bond linkages (in which the Het. moiety of R4 is linked directly to the imidazole ring in the compound of formula (III)) may be formed, for example by reaction of a compound of formula (III) in which L2xe2x80x94Xxe2x80x94 is formyl (L2 is xe2x95x90O here) with a compound capable of forming a Het. moiety incorporating the formyl carbon atom as part of the Het. ring. Thus, as illustrated in Examples 81 and 82, a diamine (such as 2-aminoaniline) may be reacted with the formyl compound (to give a benzimidazole moiety as Het., directly C-linked to the imidazole ring of the product compound).
The reaction between a compound of the formula (III) and a compound capable of forming a Het. moiety may be performed, for example, using a compound of the formula (III) in which L2xe2x80x94Xxe2x80x94 is azidomethyl to form a 1,2,3-triazole ring upon reaction with ethyl propiolate. In this case L2 is not a leaving group as all three nitrogen atoms of the azido group are incorporated in the 1,2,3-triazole ring.
Compounds of the formula (III) may be prepared by using the processes described in this specification, and as, for example, illustrated in the accompanying Examples. Thus, for example, a compound of the formula (III) in which L2xe2x80x94Xxe2x80x94 is hydroxymethyl may be prepared using process (f), ie. from a compound of the formula (V) in which R9 is hydroxymethyl (or protected hydroxymethyl). This hydroxymethyl group may be modified to a azidomethyl group, which may then be reduced to an aminomethyl group (see, for example, Example 19 preparation of intermediate). Such modifications are known in the art. The hydroxymethyl group may also be oxidised to an alkanoyl (eg. formyl) group, and further oxidised to a carboxy group, using known oxidising techniques and reagents.
The preparation of compounds of the formula Het.xe2x80x94Yxe2x80x94L1, Het.xe2x80x94(CH2)m-amine, Het.xe2x80x94(CH2)mxe2x80x94NCO or Het.xe2x80x94(CH2)mxe2x80x94NCS (wherein m is 0 to 3) and of compounds capable of forming a Het. moiety, is within the skill of the skilled organic chemist, or are cornmercially available.
Process (c)
When Ra is (1-4C)alkyl, the group xe2x80x94C(xe2x95x90O)(1-4C)alkyl may be introduced into a compound of the formula (I) or (II) wherein R1 or R10 is amino by standard acetylation procedures. For example, the amino group may be acetylated to give an acetamido group using the Schotten-Baumann procedure i.e. reacting the compound of the formula (I) or (II) wherein R1 or R10 is amino with acetic anhydride in aqueous sodium hydroxide and THF in a temperature range of 0xc2x0 C. to 60xc2x0 C. , preferably between 0xc2x0 C. and ambient temperature. The acylation may be carried out in situ following the catalytic hydrogenation of a compound of the formula (I) or (II) wherein R1 or R10 is azido, by performing the hydrogenation in the presence of acetic anhydride (for example using similar methods to those used in example 4).
When Ra is hydrogen, the xe2x80x94CHO group may be introduced into the compound of the formula (I) or (II) wherein R1 or R10 is amino (amino compound) by reacting the latter compound in formic acetic anhydride, in an inert organic solvent such as THF, in a temperature range of 0xc2x0 C. to ambient temperature, or by reacting it with ethyl formate in an inert organic solvent in the temperature range of 50-100xc2x0 C.
When Ra is (1-4C)alkoxy, the xe2x80x94COO(1-4C)alkyl group may be introduced into the amino compound by reacting the latter compound with (1-4C)alkyl chloroformate, in the presence of an organic base such as triethylamine, in an organic solvent such as dichloromethane and in a temperature range of 0xc2x0 C. to ambient temperature.
When Ra is chloromethyl, dichloromethyl, cyanomethyl or methoxymethyl, the xe2x80x94C(xe2x95x90O)Ra group may be introduced into the amino compound by reacting the latter compound with the appropriate acid chloride under standard conditions. The acid chloride may be prepared from the appropriate acid. When Ra is acetyimethyl, the xe2x80x94C(xe2x95x90O)Ra group may be introduced into the amino compound by reacting the latter compound with diketene, in an inert organic solvent such as THF, in a temperature range of 0xc2x0 C. to ambient temperature.
Alternatively, the amino compound may be reacted with the appropriate acid anhydride, in dichloromethane or THF, in the presence of an organic base such as triethylamine and in a temperature range of 0xc2x0 C. to ambient temperature, or the amino compound may be reacted with the appropriate acid in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an organic base such as triethylamine, in an organic solvent such as dichloromethane, in a temperature range of 0xc2x0 C. to ambient temperature.
Process (d)
Suitable reducing agents for reducing azido to amino in a compound of the formula (I) or (II) include triethylamine/hydrogen sulfide, triphenylphosphine or phosphate ester, or hydrogen in the presence of a catalyst. More specifically the reduction of the azido group may be carried out by heating it in an aprotic solvent, such as 1,2-dimethoxyethane, in the presence of P(OMe)3 and subsequently heating in 6N aqueous hydrochloric acid, or reacting it with hydrogen in the presence of palladium on carbon in a protic such as DMF or ethyl acetate. For further details on the reduction of azides to amines see U.S. Pat. No. 4,705,799. The azido compound may be reduced and converted to a compound of the formula (I) or (II), wherein R1 or R10 is acetamido, in situ using acetic anhydride in DMF.
Process (e)
A compound of the formula (I) or (II) wherein R1 or R10 is azido may be prepared, for example, by reacting a compound of the formula (IV) with sodium azide in an inert solvent such as DMF in a temperature range of ambient to 100xc2x0 C., normally in the region of 75xc2x0 C.-85xc2x0 C., A compound of the formula (IV) may be prepared by converting the hydroxy group in a compound of the formula (I) or (II) wherein R1 or R10 is hydroxy into a tosyloxy or mesyloxy group by standard methods known in the art. For example, by reacting a compound of the formula (I) or (II) wherein R1 or R10 is hydroxy with tosyl chloride, mesyl chloride or a chlorophosphate ester in the presence of a mild base such as triethylamine, or pyridine.
Process (f)
Compounds of the formulae (V) and (VI) are conveniently reacted together in the presence of a strong base such as butyl lithium, lithium bistrimethylsilylamide, sodium hydride, or lithium diisopropylamnide. The reaction is conveniently carried out in an inert solvent such as tetrahydrofuran (THF), dimethylformamide (DMF), N,N1-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone in a temperature range of xe2x88x9278xc2x0 C. to xe2x88x9250xc2x0 C. for the deprotonation and cyclisation. Suitable values for R13 include ethyl and benzyl and suitable values for R14 include ethyl and n-propyl, preferably n-propyl.
A compound of the formula (V) is conveniently prepared by reacting a chloroformate of the formula (ClCOOR13) with a compound of the formula (VA):
wherein R2, R3, R5, R6 and R9 are as hereinabove defined. The reaction is conveniently carried out in the presence of an inorganic or organic base such as sodium bicarbonate or an amine base such as dimethylaniline, the former in a solvent such as acetone/water and the latter in an organic solvent such as TRF, toluene, DMF or acetonitrile.
A compound of the formula (VA) may be prepared by reducing a compound of the formula (VB):
wherein R2, R3, R5, R6 and R9 are as hereinabove defined.
Many reduction methods suitable for the reduction of a nitro to an amino group are known in the art, for example catalytic hydrogenation, metal reductions or with reducing agents such as sodium hydrosulfite. Suitable catalysts in catalytic hydrogenation include Raney nickel, platinum metal and its oxide, rhodium, palladium-on-charcoal and Wilkinson""s catalyst RhCl (Ph3P)3. Catalyst hydrogenation is conveniently carried out in the temperature range 0xc2x0 C.-50xc2x0 C., but preferably at ambient temperature at slightly above atmospheric pressure.
A compound of the formula (VB) is conveniently prepared by reacting together compounds of the formulae (VC) and (VD):
wherein R2, R3, R5, R6 and R9 are as hereinabove defined and L3 is a leaving group, preferably halo and in particular fluoro.
The reaction between compounds of the formulae (VC) and (VD) is carried out in the presence of an organic or inorganic base such as sodium bicarbonate, potassium carbonate or an amine base such as diisopropylethylamine, in an inert solvent such as acetonitrile, DMF, DMPU or N-methylpyrrolidone, in a temperature range of 50xc2x0 C.-150xc2x0 C.
Compounds of the formula (VC) may be prepared by introducing substituents into or modifying substituents in a known optionally substituted imidazole ring. Such conversions are well known to the skilled chemist, for example a cyano group may be hydrolysed to a carboxy group which in turn may be converted to a carbamoyl or alkoxycarbonyl group or reduced to a hydroxymethyl group; an amino group may be acylated to an alkanoylamino group; a thio group may be alkylated to an alkylthio group which in turn may be oxidised to an alkylsulfinyl or alkylsulfonyl group and a hydroxyalkyl group may be alkylated to an alkoxyalkyl group.
Alternatively compounds of the formula (VC) may be prepared using the methods described in Houben-Weyl, Methoden der organischen Chemie, Heterarene III Teil 3, ed E Schaumann (1994), or The Chemistry of Heterocyclic Compounds, Vol 6, Part 1 xe2x80x9cImidazole and its Derivativesxe2x80x9d (1953).
Process (g)
A compound of the formula (II) wherein R10 is of the formula xe2x80x94N(CO2R15)CO(1-4C)alkyl is conveniently prepared by reacting a compound of the formula (I) and (II) wherein R1 or R10 is hydroxy with an amide of the formula HN(CO2R15)CO(1-4C)alkyl under Mitsunobu conditions. For example, in the presence of tri-n-butylphosphine and 1,1xe2x80x2-(azodicarbonyl)dipiperndine in an organic solvent such as THF, and in the temperature range 0xc2x0 C.-60xc2x0 C., but preferably at ambient temperature. Details of analogous Mitsunobu reactions are contained in Tsunoda et al., Tet. Letts., 34, 1639, (1993). Amides of the formula HN(CO2R15)CO(1-4C)alkyl may be prepared by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist.
Process (h)
A compound of the formula (I) or (II) wherein R1 or R10 is fluoro may be prepared by reacting a compound of the formula (I) or (II) wherein R1 or R10 is hydroxy (hydroxy compound) with a fluorinating agent such as diethylaminosulfur trifluoride in an organic solvent such as dichloromethane in the temperature range of 0xc2x0 C. to ambient temperature.
When R1 or R10 is chloro, the compound of the formula (I) or (II) may be formed by reacting the hydroxy compound with a chlorinating agent. For example, by reacting the hydroxy compound with sulfinyl chloride in a temperature range of ambient temperature to reflux, optionally in a chlorinated solvent such as dichloromethane or by reacting the hydroxy compound with carbon tetrachloride/triphenyl phosphine in dichloromethane, in a temperature range of 0xc2x0 C. to ambient temperature.
The (1-4C)alkanesulfonyloxy compound may be prepared by reacting the hydroxy compound with (1-4C)alkanesulfonyl chloride in the presence of a mild base such as triethylamine or pyridine.
The (1-4C)alkylaminocarbonyloxy compound may be prepared by reacting the hydroxy compound with (1-4C)alkyl cyanate in an organic solvent such as THF or acetonitrile, in the presence of triethylamine, in a temperature range of 0xc2x0 C. to 50xc2x0 C.
Process (i)
A compound of the formula (I) or (II) wherein R1 or R10 is chloro may also be prepared from a compound of the formula (IV), by reacting the latter compound with lithium chloride and crown ether, in a suitable organic solvent such as THF, in a temperature range of ambient temperature to reflux. A compound of the formula (I) or (II) wherein R1 or R10 is (1-4C)alkylthio or (1-4C)alkoxy may be prepared by reacting the compound of the formula (IV) with sodium thio(1-4C)alkoxide or sodium (1-4C)alkoxide respectively, in an alcohol or THF, in a temperature range of 0xc2x0 C. to reflux.
Suitable N-oxides of compounds of the formula (I) or (II) may be prepared directly from a corresponding parent compound of the formula (I) or (II) using techniques well known to the ordinary skilled organic chemist, such as, for example, using a peracid (such as m-chloroperbenzoic acid) or perphthalic acid in a suitable solvent (such as dioxan or a mixture of water and THF) at a suitable temperature (such as ambient temperature). The preparation of suitable N-oxides by assembly from suitable N-oxide starting materials and the use of the processes described in this specification is within the skill of the ordinary skilled organic chemist, and is illustrated by, for example, Example 5.
When an optically active form of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using an optically active starting material or by resolution of a racemic form of the compound or intermediate using a standard procedure.
According to a further feature of the invention there is provided a compound of the formula (I), or a pharmnaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy,
According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt thereof.
The invention also provides the use of a compound of the present invention, or a pharmaceutically-acceptable salt thereof, for use as a medicament; and the use of a compound of the present invention, or a pharmaceutically-acceptable salt thereof, in the manufacture of a novel medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.
In order to use a compound of the formula (I) or a pharmaceutically-acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmnaceutically-acceptable salt thereof and a pharmaceutically-acceptable diluent or carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents (for example xcex2-lactams or aminoglycosides). These may include penicillins, for example oxacillin or flucloxacillin, carbapenems (for example meropenem or imipenem) and monobactams (for example aztreonam) to broaden the therapeutic effectiveness. Compounds of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein product (BPI) or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg and 1 g of the compound of this invention.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of 5 mgkg-1 to 20 mgkg-1 of the compound of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
Antibacterial Activity
The pharmaceutically acceptable compounds of the present invention are useful antibacterial agents having a good spectrum of activity in vitro against standard Gram-positive organisms, which are used to screen for activity against pathogenic bacteria. Notably, the pharmaceutically acceptable compounds of the present invention show activity against enterococci, pneumococci and methicillin resistant strains of S. aureus and coagulase negative staphylococci. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system.
The antibacterial properties of the compounds of the invention may also be demonstrated in vivo in conventional tests.
The following results were obtained on a standard in vitro test system. The activity is described in terms of the minimum inhibitory concentration (MIC) determined by the agar-dilution technique with an inoculum size of 104 CFU/spot.
The organisms were tested on a standard semi-defined susceptability test medium (IsoSensitest agar), using an inoculum of 104 CFU/spot and an incubation temperature of 37xc2x0 C. for 24 hours.
Novb. Res=Novobiocin resistant
MRQR=methicillin resistant quinolone resistant
MR=methicillin resistant

Substituted phenyloxazolidinones and their use as antibiotics

Abstract: wherein, for example,

Abstract: R1 is of the formula xe2x80x94NHC(xe2x95x90O)Ra wherein Ra is (1-4C)alkyl;

Abstract: R5 and R6 are, for example, hydrogen;

Abstract: wherein, for example,

Abstract: X is a direct bond and Y is xe2x80x94(CH2)mxe2x80x94 or xe2x80x94CONHxe2x80x94(CH2)mxe2x80x94;

Abstract: or X is xe2x80x94(CH2)nxe2x80x94 and Y is xe2x80x94S(O)pxe2x80x94(CH2)mxe2x80x94;

Abstract: or X is xe2x80x94CH2Oxe2x80x94or xe2x80x94CH2NHxe2x80x94 and Y is xe2x80x94COxe2x80x94(CH2)mxe2x80x94;

Abstract: wherein Het. is a heterocyclic ring, unsaturated or saturated, optionally substituted by, for example, (1-4C)alkyl, halo, cyano, nitro or amino; pharmaceutically acceptable salts and in vivo hydrolysable ester thereof; processes for their preparation; pharmaceutical compositions containing them and their use as antibacterial agents.


An apparatus for manipulating a printable medium for the use in a printer is described. The apparatus comprises a drag device, a feed device and a lock device. The drag device conveys the printable medium to a printing area. The feed device feeds the printable medium to the drag device. The lock device is disposed between the feed device and the drag device. The lock device temporarily fixes a first portion of the printable medium so as to cause a second portion of the printable medium being in contact with the drag device to slip along the drag device.

Some printers comprise a printhead having nozzles connected to ink containers. The printhead may move along a direction that is transverse to a feed direction of a printable medium, such as paper. A feed mechanism may feed the printable medium towards a printing zone in which the printhead ejects ink drops onto the printable medium according to the image to be printed.
In some printers, the printhead and the array of nozzles disposed at the printhead is as wide as the page to be printed on the printable medium. The printhead may comprise thousands or tens of thousands of nozzles that are arranged in a pagewide array. This configuration allows for printing on the printable medium without moving the printhead.

Temporary fixation of a portion of a printable medium

Hewlett-Packard Development Company, L.P.


Provided is a method for increasing proliferation of mesenchymal stem cells. The method entails contacting the cells with 6-bromoindirubin-3′-oxime (BIO). This results in robust proliferation and “stemness” in a dose-dependent fashion, as indicated by the gene expression of two stem cell genes: Sox2 and Nanog.

Bone marrow derived mesenchymal stem cells (MSCs) have been shown capable of differentiating down several tissue lineages, including bone, cartilage, fat, and tendon. For this reason these cells have been demonstrated as effective contributors in tissue-engineered applications for regenerative therapeutics, particularly in the areas of musculoskeletal repair. Using marrow aspirate MSCs can be easily isolated from a patient, expanded ex vivo, and reintroduced for therapeutic purposes. The use of MSCs in such tissue-engineering strategies relies heavily on both successful MSC proliferation as well as maintaining the ability for these proliferative cells to differentiate down mesenchymal lineages. Moreover, inducing controllable MSC proliferation in vivo proves advantageous in mimicking native healing cascades while ensuring the presence of an ample cell population to effectively contribute to injury remodeling. Such strategies enable tissue-engineering therapeutics to be achieved in regenerative medicine applications.
Currently MSCs can be expanded in vitro, using serum supplements (fetal bovine serum, autologous serum, platelet lysate, feeder-cells) but these approaches are transient in nature, require continual application in vitro, and often yield a highly heterogeneous MSC population. Furthermore, during extended culture, required to attain a therapeutically relevant cell number due to limited MSC numbers in bone marrow, cells exhibit an increasingly senescent phenotype, reduced proliferation, impaired homing capacity, and diminished differentiation potential. Reduced proliferative capacity in particular equates to a diminished long-term regenerative potential once these cells are transplanted for therapeutic purposes.

Methods and compositions for mesenchymal stem cell proliferation


A heat exchanger, typically a cooling radiator for an internal combustion engine of a motor vehicle, has a water header with an integral expansion chamber. The header comprises a header body or casing having an elongated open bottom face closed by a header plate, which is fixed to the header body. Liquid flows in the header between a first end and a second end of the latter, so as to cover the header plate. The header body has a set of transverse, integral baffles spaced apart along the header body between its two ends. Each baffle has a free edge close to the header plate and an opening defining a flow cross section through the baffle. The area of this opening decreases in successive baffles in the direction of flow.

It is already known, from the specification of French published Patent Application FR2443657A, to provide a water header of this type which has an elongated open face and which is adapted to be assembled over a header plate or collector which is arranged in a substantially horizontal position, such that a liquid can flow in the header between a first end and second end of the latter, with the liquid covering the header plate.
Such a water header is adapted to be sealingly connected to the upper end of a heat exchanger body, which typically consists of a bundle comprising a multiplicity of heat exchange tubes arranged so as to extend generally vertically. The open face of the header body is then assembled on the header plate (or perforated plate), in which the upper ends of the tubes in the bundle are sealingly received. The lower ends of the tubes are generally joined to another water header, through a header plate of the latter.
In the header described in the above mentioned French Patent Specification, removable transverse grids are provided, these being spaced apart between the two ends of the header, so that air which is entrained by the liquid flowing in the heat exchanger can become separated from the liquid in the chambers which are defined between these grids. In this way, such a header enables the liquids flowing in the heat exchanger to be de-gassed, this liquid commonly being the cooling liquid for an internal combustion engine. The gases separated from the liquid then accumulate in the upper part of the fluid header, which also serves as an expansion vessel or chamber.
However, this known type of water header has a certain number of drawbacks. First of all, it is expensive to make, because it requires the provision of the grids which have to be fitted into the header body before the latter is assembled onto the header plate of the heat exchanger. In addition, because each of these grids is in the form of a mesh having a large number of holes, it tends to encourage the formation of bubbles which are detrimental to proper functioning of the heat exchanger. Furthermore, these grids give rise to energy losses in the flow of the liquid in the heat exchanger.

Fluid header with an integral expansion chamber for a heat exchanger, in particular for a motor vehicle


Spin controller that can enable an autonomous vehicle (AV) to spin in place. A model predictive controller (MPC) can trigger the spin controller any time the MPC determines that a spin in place is required. In some configurations, the spin controller can move the AV to within 5° of the destination point. Spin controller can determine spin method based on the configuration of the AV, calculate an optimum turning path based at least on device mode and obstacles, and can enable the AV to spin in place.

The present teachings relate generally to autonomous vehicle navigation, and in particular to reaching a destination requiring a sharp turn of the autonomous vehicle.
Autonomous vehicles can experience both automatic and manual control, and when it comes to turning sharply, autonomous vehicles typically rely on an operator to navigate such a complicated move. Autonomous recognition of possible sharp turns typically takes the form of map annotations for a possible purpose of discerning how an operator navigates the pre-mapped sharp turn.
What is needed is a system and method for responding to a dynamically-determined need to, for example, avoid an obstacle by spinning the autonomous vehicle in place before proceeding on an alternate path that does not encounter the obstacle.

System and method for navigating a turn by an autonomous vehicle


A planar inertial sensor includes a first region and a second region of semiconductor material. The second region is capacitively coupled, and mobile with respect to the first region. The second region extends in a plane and has second portions, which face respective first portions of the first region. Movement of the second region, relative to the first region, in any direction belonging to the plane modifies the distance between the second portions and the first portions, which in turn modifies a value of the capacitive coupling.

1. Field of the Invention
The present invention relates to a planar inertial sensor, in particular for portable devices having a stand-by function, of micro-electro-mechanical-system (MEMS) type.
In particular, the subject matter of the present invention is an inertial sensor for detecting movement that is able to generate a capacitive variation signal, as a function of an input acceleration having any direction parallel to the plane of the sensor.
2. Description of the Related Art
Inertial devices for detecting movement are known and are able to detect acceleration in one or more directions. They generally comprise a moving element and a fixed body, the moving element being able to move with respect to the fixed body in response to an acceleration. The movement of the moving element brings about the variation of an electrical signal, which can be used by an appropriate control circuit.
Most known devices for detection of movement are currently formed by objects of large dimensions.
For example, inertial devices are known consisting of a glass bulb filled with mercury or other conductive liquids and accommodating a plurality of electrodes that enable detection of an electrical conductivity variation in the case of contact between the electrodes and the liquid following upon a displacement of the device.
Also known (see for example the U.S. Pat. No. 4,337,402) are switches for detecting movement, formed by a non-conductive cylindrical body accommodating a plurality of electrical contacts forming parallel tracks arranged along the circumference thereof, and a conductive bail, suspended in proximity of the electrical contacts via two conductive springs. When moving in a horizontal or vertical direction, the ball comes into contact with the conductive tracks, generating an activation signal.
More recently, the use of MEMS technology has been proposed for inertial movement-detection sensors. These sensors comprise a mobile part and a fixed part, both of conductive material (silicon and/or metal), capacitively coupled to one another. The movement of the mobile part with respect to the fixed one in presence of an acceleration brings about a capacitance variation detectable by an associated control circuit.
In particular, when the mobile part is formed by a suspended moving element, in case of an acceleration acting on the device, the suspended moving element moves with respect to the fixed part according to the translation, or rotation, degrees of freedom allowed to the suspended moving element according to the specific suspension type. The degrees of freedom correspond to the preferential axes of detection of the sensor in so far as the displacement of the moving element is maximum when the acceleration has a direction parallel to one of these axes and is considerably smaller otherwise.
Currently, inertial sensors perform detection of the movement in one or at the most two preferential directions of detection, for example ones parallel to the plane of the suspended moving element. When it is desired to detect the movement with a number of preferential directions of detection it is therefore necessary to replicate the sensor an appropriate number of times within the same device, with obvious problems of increase in dimensions and circuit complexity.
In the specific case of inertial switches, their operation envisages generation of a movement detection pulse as soon as the acceleration component in one of the preferential detection directions exceeds a certain threshold. Usually, an appropriate value is attributed to this threshold so as to prevent false detection due to disturbance of various nature; in general the detection threshold is the same for all the directions of movement.
The drawback of these inertial devices is due to the fact that, in case of movements in a plane direction different from the preferential detection axes, the acceleration necessary for exceeding the threshold is higher than in case of movements made in the preferential detection directions. Consequently, an acceleration, albeit having an intensity higher than the preset threshold, cannot be detected if its direction departs significantly from the preferential detection axes and its components along the preferential detection axes are smaller than the preset threshold.
In order to overcome this problem, commonly known as threshold error, it is possible to lower the detection threshold; this solution is not, however, satisfactory in so far as it causes the detection of disturbance even of modest intensity.
In U.S. patent application Ser. No. 10/788,962, filed on Feb. 27, 2004 in the name of the present applicant, the use is proposed of an inertial device comprising two movement sensors, each having a respective preferential detection direction (orthogonal to one another), and two detection thresholds having different values. In particular, a first threshold, of higher value, relates to accelerations directed in one of the preferential detection directions, and a second threshold, of lower value, relates to accelerations directed in different directions. Basically, the device detects a movement when at least one of the two components of the acceleration signal along the detection axes is greater than the first upper threshold, or else when both the components are simultaneously greater than the second lower threshold.
In this way, the threshold errors are sensibly reduced but the reading electronics must be doubled since it must comprise twice as many threshold comparators and an additional logics for controlling the logic relations between the signals at output from the comparators.
The same technique can moreover be extended so as to reduce further the threshold error by including a larger number of preferential detection directions and hence of threshold comparators and additional thresholds, with the obvious disadvantage, however, of increasing further the complexity of the reading electronics.

Planar inertial sensor, in particular for portable devices having a stand-by function


An aspirated smoke detector includes at least one ambient atmosphere inflow collection pipe with a plurality of inflow ports arranged along the pipe. The ports of the pipe are defined at least in part by temperature sensitive materials which alter the area of the respective inflow port in response to physical and/or chemical changes. As the temperature increases the area increases, thereby drawing more of the local ambient air and airborne particulate matter into the flow pipe, and then onto the smoke sensing chamber. This increased flow off-sets the dilution present due to other air in the respective pipe from other inflow ports which might not be near the developing fire condition.

Various types of aspirated smoke detectors are known. One example is disclosed in U.S. Pat. No. 7,493,816 entitled, "Smoke Detectors" which issued Feb. 24, 2009. Another is disclosed in published US Patent Application 2009/0025453 entitled "Apparatus and Method of Smoke Detection" published Jan. 29, 2009. Both the '816 patent and the published '453 application are assigned to the assignee hereof and incorporated herein by reference.
Aspirated smoke detectors usually need a careful balance between sensitivity and nuisance rejection. Such detectors usually supervise a pretty wide area: in case of a fire, only a few holes in the aspirating pipe will be exposed to smoke/gas whilst most of the pipe still sucks clean air. So a large and unpredictable dilution effect will occur. Since the system must take in account the high dilution effect, high sensitivity—usually laser based—optical systems, are employed to maintain early fire detection in such conditions. This tends to limit the suitability of aspirated systems to clean environments such as computer rooms, telecommunication rooms or the like.
There is a need for aspirated detectors which might be usable in a broader range of environments.

Environmental parameter responsive, aspirated fire detector


Functionality is disclosed for automated deployment of applications. A network-based deployment service provides functionality for deploying software components to physical or virtual hosts in a service provider network and/or to hosts in other types of networks external to the service provider network. A user of the deployment service creates an application revision that includes deployable content and an application specification defining how the application is to be deployed and one or more lifecycle events. The application revision is then uploaded to a storage service, source code repository, or other location. A deployment configuration is also created that defines the location of the application revision, a deployment group, and a schedule for the deployment. A deployment agent executing on hosts in the deployment group obtains the application revision from the specified location, deploys the deployable content according to the schedule, and performs the lifecycle events.

Deployment of software to a large number of network hosts ("hosts") in a fleet can be a complex and time consuming process. For example, a fleet containing a large number of physical or virtual machine hosts might be utilized to provide a network-accessible service or application, such as a Web site. In order to deploy the software for providing the service or application to the hosts in the fleet, or an update to the software, it may be necessary for a system administrator to perform many complex manual tasks and/or to utilize many different types of software components. In addition, it might be difficult for a system administrator to coordinate the deployment of the software to the hosts in a fleet in a way that does not negatively impact the performance of the service or application provided by the hosts. Deployment of software to hosts in a fleet efficiently, and in a way that does not negatively impact application performance, can be complicated and time consuming, even for skilled system administrators.
The disclosure made herein is presented with respect to these and other considerations.


Built-in self test techniques for testing circuit blocks on integrated circuits are provided. A BIST controller is provided on-chip to test two or more circuit blocks. High routing congestion is avoided by loading test data into the circuit blocks through scan chain segments that run continuously along the inputs and outputs of the circuit blocks. The BIST controller takes control of the scan chain segments during test and has the ability to partition the scan chains at specified intervals.

The present invention relates to built-in self tests for on-chip circuit blocks, and more particularly, to configurations for built-in self tests for on-chip circuit blocks that reduce routing and die area.
Programmable logic devices (PLDs) are integrated circuits that can be configured to perform a variety of user functions. PLDs typically have numerous logic blocks that can be configured to implement various combinatorial and sequential functions. The logic blocks have access to a programmable interconnect structure. The programmable interconnect structure can be programmed to interconnect the logic blocks in almost any desired configuration.
PLDs usually have on-chip memory blocks. Each of the memory blocks contains an array of memory cells. The memory cells can be, for example, SRAM, DRAM, EPROM, EEPROM, or Flash EEPROM cells. The memory blocks are dispersed throughout the chip in between the logic blocks.
After a PLD is manufactured, the memory cells in the memory blocks must be tested to ensure that they are operating properly. In recent years, the number of memory cells in PLD chips has grown considerably. As the number of on-chip memory blocks in PLDs increases, it becomes increasingly difficult to test the memory blocks in a cost effective manner.
Usually on-chip memory is tested using build-in self test (BIST) controllers. BIST is a preferred technique for memory blocks that have a large number of memory cells. PLDs often have a huge number of small memory blocks that have 512 bits to 64K bits each. As a result, it is not cost effective to have separate on-chip BIST controllers for each memory block.
Another option is to place one BIST controller on the PLD and route test signals from the single BIST controller directly to all of the memory blocks. However, this techniques places a large demand on the PLD's interconnect structure. The same set of signals has to be routed to numerous on-chip memory blocks from one BIST controller along dedicated routing wires.
Another option is to program soft BIST controllers in programmable logic on a PLD. The BIST controllers are used for testing the memory blocks and then erased after testing is completed. There is no hardware overhead, and the existing programmable routing structure is programmed to route signals from the BIST controller to the memory blocks.
Once a particular design for a PLD has been successfully implemented and tested, the design may not need to be changed again. At that point, it may be desirable to reduce production costs by implementing the design in a lower cost mask-programmable PLD (MPLD). Altera's Hardcopy device is an example of a MPLD.
An MPLD is a device that is configured or "hard-wired" during the fabrication of the device. For example, the PLD manufacturer fabricates a MPLD design by using a specific mask corresponding to a user's design. The specific mask is chosen so that logic blocks and the interconnect structure are pre-programmed to perform the design.
Soft BIST controllers cannot be programmed into MPLDs to test on-chip memory blocks, because the functionality of the on-chip logic is fixed during manufacture. Therefore, additional hardware is required to implement BIST for memory blocks in MPLDs.
It is generally more efficient to have a dedicated BIST controller for a large memory block, because the relative hardware overhead is small. However, it is very expensive in terms of tester time and memory to run all the memory vectors from the tester. Also, getting enough pins to access all the memory blocks may be difficult to come by.
It is not cost effective to have an individual BIST controller for every memory block on an integrated circuit (IC) that has a large number of small memory blocks. On other hand, using one BIST controller that routes test signals directly it to hundreds of memory blocks all over an IC along dedicated routing wires causes routing congestion.
Therefore, it would be desirable to provide techniques for testing memory blocks and other circuit blocks on MPLDs and ASICs that minimize the amount of on-chip circuitry and dedicated routing resources needed to implement the tests.

Method and apparatus for routing efficient built-in self test for on-chip circuit blocks


A lens is obtained by injection molding. The lens includes a plurality of projections arranged on a surface at a pitch smaller than or equal to a predetermined value to reduce reflection of light with a wavelength equal to or greater than the pitch, and a gate mark formed on an outer periphery of the optical element in the injection molding. A peripheral portion of the surface includes a first region whose circumferential position corresponds to the gate mark, and a second region being adjacent to the first region. Axes of first projections in the first region are inclined more outward than axes of second projections in the second region.

The present disclosure relates to optical elements having on their surface, an antireflection structure for reducing reflection of incident light.
In recent years, various types of optical elements having an antireflection structure for reducing reflection of light on their surface have been suggested.
In one suggested antireflection structure, fine structure units (e.g., a fine structure having groove or ridge projections or recesses, a fine structure having cone, pyramid, or column projections or recesses, etc.) are formed on the surface of an optical member at a pitch equal to or smaller than the wavelength of incident light.
For example, Japanese Patent Publication No. 2006-053220 shows an optical element having an antireflection structure on a real or virtual curved surface. The antireflection structure includes fine structure units arranged at a pitch equal to or smaller than the wavelength of light whose reflection is to be reduced.

Optical element, imaging apparatus including the element, and method of manufacturing the optical element

Panasonic Intellectual Property Management Co., Ltd.


The invention relates to the production of plants with reduced development and a mutant gene of the GRAS family.

The use of dwarf plants in the context of agricultural production has many advantages; for example, in cereals, the use of short-straw mutant plants has made it possible to produce crops which tolerate considerable amounts of nitrogen-containing fertilizers, which are less affected by weather conditions and, in particular, more resistant to torrential rain than the plants which are normal in size. In addition, the small size of the plants facilitates the maintenance of the crops, in particular the application of plant-protection treatments, and also the harvesting thereof.
Dwarf mutants of plants other than cereals have also been described in the literature. Mention will in particular be made below of mutants which have characteristics similar to those induced by a deficiency in gibberellins and which are insensitive to the providing of exogenous gibberellins. Such mutants have in particular been described in Arabidopsis [Koornneef et al., Physiol. Plant., 65, 33-39, (1985)]. These mutants, named gai (for gibberellic acid insensitive) are smaller in size and do not respond to exogenous applications of gibberellins. The gai mutation is a semi-dominant mutation of the "gain of function" type. GAI/gai heterozygous mutants have an intermediate phenotype between that of gai/gai dwarf mutants and GAI/gai wild-type plants.
Mutants having the same characteristics as the gai mutants of Arabidopsis have been described by Zanewich et al. [J. Plant Growth Regul., 10, 121-127, (1991)], in Brassica napus (dwf1 mutation) and Brassica rapa (mutations named dwf1 and dwf2).
The team of the inventors has obtained a dwarf mutant of B. rapa [Foisset et al., Theor. Appl. Genet., 91, 756-761, (1995)]. The mutation, named bzh, has characteristics of "semi-dominance" and of insensitivity to gibberellins, which are similar to those of the gai mutation.
A rapeseed line, named ISN1770, homozygous for the bzh mutant allele, has been the subject of a Certificat d'Obtention Végétale [Plant Variety Protection Certificate] filed on May 18, 1998, with the CPOV [French Plant Variety Protection Office] (11 rue Jean Nicaud, 75007 Paris) under the reference 10751. A rapeseed hybrid, named "Lutin" (B017), comprising in its genome the bzh mutant allele in heterozygous form was proposed for listing in the Catalogue Français des Obtentions Végétales [French Catalogue of Plant Varieties] on Jul. 31, 1999, under the reference 072426.
The GAI gene of Arabidopsis has recently been cloned and sequenced [Peng et al., Genes and development, 11, 3194-3205 (1997); PCT application WO 97/29123 in the name of John Innes Centre Innovations Ltd.]. This gene-encodes a 532 aa protein (GAI). The gai allele, which is responsible for dwarfism, contains a deletion of 51 base pairs in frame with the reading frame, which leads to the absence of 17 aas located close to the N-terminal end of the GAI protein. The GAI protein is involved in the perception of and response to gibberellins, and is thought to act, in wild-type plants, as a negative regulator of cellular elongation in the absence of gibberellins.
Comparison of the GAI sequence with that of the translation products of other known genes has made it possible to place it in the family named GRAS [Pysh et al., The Plant Journal, 18(1), 11-119, (1999)] or VHIID [Schumacher et al., P.N.A.S., 96, 1, 290-295, (1999)].
This family encompasses, besides GAI, the RGA [Silvestrone et al., Genetics, 146, 1087-1099, (1998)] and SCARECROW [Di Laurenzio et al., Cell, 86, 423-433, (1996)] genes of Arabidopsis, and also the tomato LS (lateral suppressor) gene [Shumacher et al., P.N.A.S., 96, 1, 290-295, (1999)]. At the current time, about twenty genes belonging to the GRAS family have been identified in Arabidopsis.
The proteins which make the GRAS family have a very variable N-terminal portion and a very conserved C-terminal portion with five recognizable motifs, in particular the VHIID motif.
The biological functions of most of these proteins are not yet precisely known, but their role as transcription factors is strongly presumed. The investigations carried out on the 4 most thoroughly studied genes at the current time (SCR, GAI, RGA and LS), show that these genes encode transcription factors involved in controlling the perception of and the response to gibberellins, and indicate the probable importance of this family in controlling the morphogenesis and the development of higher plants.

Mutant gene of the GRAS family and plants with reduced development containing said mutant gene

Institut National de la Recherche Agronomique (INRA)


A method of printing user data on a preprinted form comprising: scanning a preprinted form into a computer, and storing pixel data representing the form in a memory, indicating and storing the coordinates of data entry spaces of the scanned form, entering data into the computer at displayed locations within at least one of the indicated data entry spaces, and storing said data, inserting said preprinted form into a printer, and printing the entered data on the preprinted form within locations indicated by said coordinates.

In the past, information to be added to a preprinted form was required to be printed on the form by hand or typed into spaces provided on the form. Since personal computers came into widespread use, some forms have been provided in software. An example of this is income tax software, which allows a user to bring up forms which emulate preprinted government forms on a computer display, and then to enter the required information in designated spaces. The forms with the data which has been entered can then be printed on a computer printer.
However, the design of such form is required to be programmed, and it has been a tedious and sometimes difficult task to design the forms in software to exactly mimic the officially printed forms on the display, when printed.

Method of printing user input data on preprinted forms


By using a piercing mill that includes a pusher on the entrance side, a plug on the exit side along a pass line, and a plurality of angled rolls as being provided around the plug so as face to each other, in the case where the maximum diameter of an unsound region consisting of center segregation and porosity in a cross section of a billet is d [mm], piercing-rolling is performed under the condition that the plug nose rolling reduction ratio (TDF) expressed by Formula (1) satisfies Formula (2).TDF=(Bd−D1)/Bd  (1)TDF≦−0.50×(d/Bd)+0.06  (2)In Formulae (1) and (2), Bd is the billet diameter [mm], and D1 is the opening [mm] between the angled rolls at the plug nose position. Thereby, when piercing-rolling is performed, the occurrence of an inner surface flaw attributable to the center segregation and porosity in the billet can be prevented reliably.

A seamless tube/pipe can be produced by the Mannesmann tube-making process. This tube-making process consists of the following steps:
(1) A round billet heated to a predetermined temperature is subjected to a piercing-rolling process by using a piercing mill (piercer) to form a hollow blank (hollow shell).
(2) The hollow blank is subjected to an elongation-rolling process by using an elongation-rolling mill (for example, a mandrel mill).
(3) The hollow shell thus elongated is sized so as to have a predetermined outside diameter and wall thickness by using a sizing mill (for example, a stretch reducer).
The piercing mill used in the piercing-rolling step among these steps includes a plurality of angled rolls, a plug, and a pusher as principal components. The pusher is provided on the entrance side along the pass line. The plug is disposed on the exit side along the pass line. The angled rolls are provided around the plug so as to face to each other in a state of having a predetermined crossing angle with respect to the pass line and inclination angle to the horizontal.
In the piercing-rolling using the piercing mill, a billet heated in a heating furnace is supplied along the pass line, and the rear end thereof is pushed by the pusher. Thereby, the billet is conveyed along the pass line toward the angled rolls and the plug, and the front end thereof is engaged into the angled rolls. Thereafter, the billet engaged into the angled rolls advances along the pass line while being rotated by action of the angled rolls. At this time, by the rotary forging effect, Mannesmann fracture is generated successively in the central portion of the billet until the billet reaches the plug nose, and thereby the core part of billet becomes torn off in a brittle manner. Successively, the billet is subjected to a wall-thickness rolling work process by the plug contacting with the central portion thereof and the angled rolls contacting with the outer circumference thereof, and thereby the hollow blank is formed.
The piercing-rolling is performed on an as-continuously-cast billet, which is cast to have a circular cross section, or a billet which is rolled to have a circular cross section by subjecting a cast slab to hot working such as blooming. In the core portion of such a billet, center segregation and porosity more or less occur, and especially for an alloy such as a stainless steel, they occur remarkably. Therefore, on account of the center segregation and porosity in the billet, a leaf-like, fin-like, or lap-like flaw (hereinafter, referred to as an "inner surface flaw") is generated on the inner surface of the pierced hollow blank by the rotary forging effect at the time of piercing-rolling and by the additional shearing deformation caused by the wall-thickness rolling work.
The prior art for preventing the occurrence of inner surface flaw at the time of piercing-rolling is disclosed in the Patent Literatures described below.
Patent Literature 1 discloses a method for producing a seamless tube/pipe, in which the rotational speed of the angled rolls is restricted to less than 4.5 m per second in circumferential speed, and a back pressure is applied to the billet by the pusher until the billet is securely engaged into the angled rolls. Further, in the technique disclosed in this Literature, piercing-rolling is performed under the condition that a plug nose draft "d/D" is 97% or more, the plug nose draft being defined as the ratio of the angled rolls opening "d" at the plug nose position to the billet diameter "D".
Patent Literature 2 discloses a pusher which applies a back pressure to the billet until the billet is securely engaged into the angled rolls, and the pushing speed and back pressure of which are variable. Also, this Literature describes that it is necessary to increase the back pressure generated by the pusher with the increase in a draft in terms of the ratio of "roll opening at plug nose position to billet diameter", which is defined in the same way as a plug nose draft described in Patent Literature 1, and gives 98%, 98.5%, 98.9%, and 99.1% as the draft.
Patent Literature 3 discloses a method for producing a seamless tube/pipe, in which during the time period between when the billet is engaged into the angled rolls and comes into contact with the plug and when the piercing-rolling becomes in a steady state, the billet is pushed by the pusher so that the traveling speed of billet is not less than the traveling speed in a steady state. Further, in the technique disclosed in this Literature, piercing-rolling is performed under the condition that the ratio "Dg/d" of the gorge portion diameter "Dg" of the angled roll to the billet diameter "d" is not less than 4.5, and the gorge draft ratio "Rg/d", which is defined by the ratio of the gorge portion roll opening "Rg" to the billet diameter "d", satisfies the specified range in accordance with the piercing-rolling ratio "L1/L0", which is defined by the ratio of the pierced hollow blank length "L1" to the billet length "L0".
Patent Literature 4 discloses a method for producing a seamless tube/pipe, in which piercing-rolling is performed under the conditions that the plug nose rolling reduction ratio (TDF) defined by Formula (a) is not more than 0.04, and/or the square root "(TDF×N)0.5" of the product of the plug nose rolling reduction ratio (TDF) and the billet rotational speed "N" is not more than 0.4, and the gorge rolling reduction ratio, which is defined in the same way as the gorge draft ratio described in Patent Literature 3, satisfies the specified range in accordance with the piercing-rolling ratio that is the same as that of Patent Literature 3:TDF=1−(d1/Bd)  (a)where, in Formula (a),
Bd: billet diameter [mm], and
d1: angled roll opening [mm] at plug nose position.
Further, in the technique disclosed in this Literature, piercing-rolling is performed by using a plug having such a geometry that the ratio "L2/d2", given that "L2" is the length of the rolling portion of the plug, and "d2" is the outside diameter of the reeling start point of the plug, satisfies the specified range in accordance with the square root "(TDF×N)0.5" of the product of the plug nose rolling reduction ratio (TDF) and the billet rotational speed "N". At this time, the billet is pushed by the pusher at least until the piercing-rolling reaches a steady state from an unsteady state.

NIPPON STEEL & SUMITOMO METAL CORPORATION


A tunable laser for providing a laser beam with a selectable wavelength. In one example, the tunable laser includes a gain medium for generating the laser beam; a waveguide for processing the laser beam, the waveguide having liquid crystal material or other electro-optic material disposed therein; an optical path length control element disposed within said waveguide for controlling an effective optical path length of the laser cavity; and a wavelength selective element for controlling the wavelength of the laser beam. The tunable laser may be designed without any moving mechanical parts if desired.

Tunable lasers are lasers in which the frequency or color of the lasing light can be controllably altered. Tunable lasers have utility in a number of diverse applications, including but not limited to telecommunications, open air remote sensing for environmental monitors, distributed fiber sensors, holographic data storage, spectroscopy, atomic frequency and time standards, optical coherence tomography for medical imaging, laser cooling, lidar, and many more. As a specific example, the ability to control the wavelength of the laser light has enabled wavelength division multiplexing in telecommunications, thereby increasing the bandwidth of optical fibers. As a second specific example, common embodiments of distributed fiber sensors require a tunable laser interrogator, through which temperature, pressure, chemical analysis, or other measurable quantities can be probed in diverse environments such as along power lines, embedded inside oil wells, along bridges and tunnels, and many more. In a third example, tunable laser light can be passed through suspect regions of air and then the intensity measured. Wavelength specific absorption features can signify the presence of certain chemicals, contaminants, or other pollutants. As another specific example, in the emerging market of holographic data storage, tunable lasers can be utilized to compensate for temperature changes in the storage medium.
There are various types of conventional tunable lasers. Prominent examples include distributed Bragg reflector (DBR) lasers, distributed feedback (DFB) lasers, and external cavity diode lasers (ECDL). Multi-section DBR lasers can provide significant wavelength tuning (up to 100 nm), but not in a continuous fashion. Specifically, after the DFB laser tunes a small amount, the frequency may jump (mode-hop) in an often-uncontrollable way. DBR lasers can typically only change the laser wavelength a small amount (a few nanometers). Furthermore, both DBR and DFB lasers are difficult to construct at arbitrary wavelengths. Conventional external cavity diode lasers provide wavelength versatility and large continuous mode-hop free tuning ranges.
Conventional external cavity diode lasers, however, typically utilize various moving mechanical parts for electromechanically tuning the laser. For instance, a conventional tunable laser includes a cavity whose length may be mechanically adjusted so that the phase of the laser output signal can be electromechanically controlled for particular applications. Furthermore, intricate mechanical systems have been devised for controlling the frequency of the laser output. For instance, some conventional mechanically tunable lasers include a reflection grating which, depending upon the angle at which light strikes the grating, retro-reflects back only certain frequencies of light. In order to provide for large, continuous mode-hop free tuning, both the phase (total optical path length) and the frequency of the laser must be tuned in a synchronous and often complex mechanical fashion.
Conventionally, a frequency selective grating may be connected to one end of a pivot arm, which at its opposing end is fixed to a pivot point. The pivot arm and grating are then mechanically rotated in a highly precise and often complex manner so that only certain desired frequencies of light are reflected within the mechanically tunable laser cavity as desired. Furthermore, by appropriate choice of the pivot point, rotation of the grating about that pivot point results in the desired synchronous tuning of both the frequency and total optical path length of the laser. This can provide extended mode-hop free tuning. One such example of a mechanically tunable laser is described in U.S. Pat. No. 5,319,668 incorporated herein by reference.
These mechanical laser designs can utilize a wide array of laser diodes as the gain medium, thereby providing wavelength versatility. Furthermore, within the laser diodes gain profile, the mechanical external cavity diode laser can provide extended continuous tunability.
However, as recognized by the present inventors, mechanically tunable lasers have various limitations. First, it is difficult to make such mechanical devices compact. Second, such devices have limited lifetimes due to mechanical wear and failure issues. Third, mechanical devices are inherently vibration sensitive, which limits the type of environment in which they can be used. Finally, mechanical devices necessitate a level of design complexity including gears, bearings, and other mechanical components, which add to the cost, expense, and maintenance of such designs.
Accordingly, as recognized by the present inventors, what is needed is a tunable laser, with the desirable attributes of mechanically tuned external cavity lasers, which may be implemented without the need for any mechanically movable parts.
It is against this background that various embodiments of the present invention were developed.

Tunable laser having liquid crystal waveguide