Phenylalanine derivatives of formula (1) are described:

This invention relates to a series of phenylalanine derivatives, to compositions containing them, to processes for their preparation, and to their use in medicine.
Over the last few years it has become increasingly clear that the physical interaction of inflammatory leukocytes with each other and other cells of the body plays an important role in regulating immune and inflammatory responses [Springer, T A. Nature, 346, 425, (1990); Springer, T. A. Cell 76, 301, (1994)]. Many of these interactions are mediated by specific cell surface molecules collectively referred to as cell adhesion molecules.
The adhesion molecules have been sub-divided into different groups on the basis of their structure. One family of adhesion molecules which is believed to play a particularly important role in regulating immune and inflammatory responses is the integrin family. This family of cell surface glycoproteins has a typical non-covalently linked heterodimer structure. At least 14 different integrin alpha chains and 8 different integrin beta chains have been identified [Sonnenberg, A. Current Topics in Microbiology and Immunology, 184, 7, (1993)]. The members of the family are typically named according to their heterodimer composition although trivial nomenclature is widespread in this field. Thus the integrin termed xcex14xcex21 consists of the integrin alpha 4 chain associated with the integrin beta 1 chain, but is also widely referred to as Very Late Antigen 4 or VLA4. Not all of the potential pairings of integrin alpha and beta chains have yet been observed in nature and the integrin family has been subdivided into a number of subgroups based on the pairings that have been recognised [Sonnenberg, A. ibid].
The importance of cell adhesion molecules in human leukocyte function has been further highlighted by a genetic deficiency disease called Leukocyte Adhesion Deficiency (LAD) in which one of the families of leukocyte integrins is not expressed [Marlin, S. D. et al J. Exp. Med. 164, 855 (1986)]. Patients with this disease have a reduced ability to recruit leukocytes to inflammatory sites and suffer recurrent infections which in extreme cases may be fatal.
The potential to modify adhesion molecule function in such a way as to beneficially modulate immune and inflammatory responses has been extensively investigated in animal models using specific monoclonal antibodies that block various functions of these molecules [e.g. Issekutz, T. B. J. Immunol. 3394, (1992); Li, Z. et al Am. J. Physiol. 263, L723, (1992); Binns, R. M. et al J. Immunol. 157, 4094, (1996)]. A number of monoclonal antibodies which block adhesion molecule function are currently being investigated for their therapeutic potential in human disease.
One particular integrin subgroup of interest involves the xcex14 chain which can pair with two different beta chains xcex21 and xcex27 [Sonnenberg, A. ibid]. The xcex14xcex21 pairing occurs on many circulating leukocytes (for example lymphocytes, monocytes and eosinophils) although it is absent or only present at low levels on circulating neutrophils. xcex14xcex21 binds to an adhesion molecule (Vascular Cell Adhesion Molecule-1 also known as VCAM-1) frequently up-regulated on endothelial cells at sites of inflammation [Osborne, L. Cell, 62, 3, (1990)]. The molecule has also been shown to bind to at least three sites in the matrix molecule fibronectin [Humphries, M. J. et al. Ciba Foundation Symposium, 189, 177, (1995)]. Based on data obtained with monoclonal antibodies in animal models it is believed that the interaction between xcex14xcex21 and ligands on other cells and the extracellular matrix plays an important role in leukocyte migration and activation [Yednock, T. A. et al, Nature, 356, 63, (1992); Podolsky, D. K. et al. J. Clin. Invest. 92, 373, (1993); Abraham, W. M. et al. J. Clin. Invest. 93, 776, (1994)].
The integrin generated by the pairing of xcex14 and xcex27 has been termed LPAM-1 [Holzmann, B and Weissman, I. EMBO J. 8, 1735, (1989)] and like xcex14xcex21, binds to VCAM-1 and fibronectin. In addition, xcex14xcex27 binds to an adhesion molecule believed to be involved in the homing of leukocytes to mucosal tissue termed MAdCAM-1 [Berlin, C. et al, Cell: 74, 185, (1993)]. The interaction between xcex14xcex27 and MAdCAM-1 may also be important at sites of inflammation outside of mucosal tissue [Yang, X-D. et al, PNAS, 91, 12604 (1994)].
Regions of the peptide sequence recognised by xcex14xcex21 and xcex14xcex27 when they bind to their ligands have been identified. xcex14xcex21 seems to recognise LDV, IDA or REDV peptide sequences in fibronectin and a QIDSP sequence in VCAM-1 [Humphries, M. J. et al, ibid] whilst xcex14xcex27 recognises a LDT sequence in MAdCAM-1 [Briskin, M. J. et al, J. Immunol. 156, 719, (1996)]. There have been several reports of inhibitors of these interactions being designed from modifications of these short peptide sequences [Cardarelli, P. M. et al J. Biol. Chem. 269, 18668, (1994); Shroff, H. N. Bioorganic. Med. Chem. Lett. 6, 2495, (1996); Vanderslice, P. J. Immunol. 158, 1710, (1997)]. It has also been reported that a short peptide sequence derived from the xcex14xcex21 binding site in fibronectin can inhibit a contact hypersensitivity reaction in a trinitrochlorobenzene sensitised mouse [Ferguson, T. A. et al, PNAS 88, 8072, (1991)].
Since the alpha 4 subgroup of integrins are predominantly expressed on leukocytes their inhibition can be expected to be beneficial in a number of immune or inflammatory disease states. However, because of the ubiquitous distribution and wide range of functions performed by other members of the integrin family it is very important to be able to identify selective inhibitors of the alpha 4 subgroup.
We have now found a group of compounds which are potent and selective inhibitors of xcex14 integrins. Members of the group are able to inhibit xcex14 integrins such as xcex14xcex21 and/or xcex14xcex27 at concentrations at which they generally have no or minimal inhibitory action on a integrins of other subgroups. The compounds are thus of use in medicine, for example in the prophylaxis and treatment of immune or inflammatory disorders as described hereinafter.
Thus according to one aspect of the invention we provide a compound of formula (1)
wherein
R is a carboxylic acid or a derivative thereof;
R1 is a hydrogen atom or a hydroxyl, straight or branched alkoxy or optionally substituted cycloaliphatic, polycycloaliphatic, hetero-cycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group;
Alk1 is an optionally substituted aliphatic or heteroaliphatic chain;
L1 is a linker atom or group;
r and s, which may be the same or different, is each zero or an integer 1 provided that when r is zero R1 is an optionally substituted cycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group;
Ra and Rb, which may be the same or different is each an atom or group xe2x80x94L2(CH2)pL3(Rc)q in which L2 and L3 is each a covalent bond or a linker atom or group, p is zero or the integer 1, q is an integer 1, 2 or 3 and Rc is a hydrogen or halogen atom or a group selected from straight or branched alkyl, xe2x80x94ORd [where Rd is a hydrogen atom or an optionally substituted straight or branched alkyl group], xe2x80x94SRd, xe2x80x94NRdRe, [where Re is as just defined for Rd and may be the same or different], xe2x80x94NO2,xe2x80x94CN, xe2x80x94CO2Rd, xe2x80x94SO3H, xe2x80x94SO2Rd, xe2x80x94OCO2Rd, xe2x80x94CONRdRe, xe2x80x94OCONRdRe, xe2x80x94CSNRdRe, xe2x80x94CORd, xe2x80x94N(Rd)CORe, N(Rd)CSRe, xe2x80x94SO2N(Rd)(Re), xe2x80x94N(Rd)SO2Re, xe2x80x94N(Rd)CONReRf [where Rf is a hydrogen atom or an optionally substituted straight or branched alkyl group], xe2x80x94N(Rd)CSNReRf or xe2x80x94N(Rd)SO2NReRf;
Alk2 is a straight or branched alkylene chain;
m is zero or an integer 1;
R2 is a hydrogen atom or a methyl group;
R3 is a hydrogen atom or a straight or branched alkyl group;
Ar is an optionally substituted aromatic group;
and the salts, solvates, hydrates and N-oxides thereof, for use in modulating cell adhesion.
The compounds of formula (1) are potent and selective inhibitors of xcex14 integrins. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter. In particular compounds of the invention are advantageously selective xcex14xcex21 inhibitors
The compounds of formula (1) are thus of use in modulating cell adhesion and in particular are of use in the prophylaxis and treatment of diseases or disorders involving inflammation in which the extravasation of leukocytes plays a role. The invention extends to such a use and to the use of compounds of formula (1) for the manufacture of a medicament for treating such diseases or disorders. Diseases or disorders of this type include inflammatory arthritis such as rheumatoid arthritis vasculitis or polydermatomyositis, multiple sclerosis, allograft rejection, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
For the prophylaxis or treatment of disease the compounds of formula (1) may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents, for use in modulating cell adhesion, particularly in the prophylaxis and treatment of diseases or disorders involving inflammation as just described.
Pharmaceutical compositions for use according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation and the invention extends to the use of a compound of formula (1) in the manufacture of such formulations.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of formula (1) required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, effective daily dosages may range from around 100 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration and around 0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for nasal administration or administration by inhalation or insufflation.
Particular compounds of formula (1) form a further feature of the invention and in a further aspect we therefore provide a compound of formula (1a):
wherein
R is a carboxylic acid or a derivative thereof;
R1 is an optionally substituted cycloaliphatic, polycycloaliphatic, heterocycloaliphatic. polyheterocyclialiphatic, aromatic or heteroaromatic group;
Alk1 is an optionally substituted aliphatic or heteroaliphatic chain;
L1 is a linker atom or group;
r and s, which may be the same or different, is each zero or an integer 1; Ra and Rb, which may be the same or different is each an atom or group xe2x80x94L2(CH2)pL3(Rc)q in which L2 and L3 is each a covalent bond or a linker atom or group, p is zero or the integer 1, q is an integer 1, 2 or 3 and Rc is a hydrogen or halogen atom or a group selected from straight or branched alkyl, ORd [where Rd is a hydrogen atom or an optionally substituted straight or branched alkyl group], xe2x80x94SRd, xe2x80x94NRdRe, [where Reis as just defined for Rd and may be the same or different], xe2x80x94NO2,xe2x80x94CN, xe2x80x94CO2Rd, xe2x80x94SO3H, xe2x80x94SO2Rd, xe2x80x94OCO2Rd, xe2x80x94CONRdRe, xe2x80x94OCONRdRe, xe2x80x94CSNRdRe, xe2x80x94CORd, xe2x80x94N(Rd)CORe, N(Rd)CSRe, xe2x80x94SO2N(Rd)(Re), xe2x80x94N(Rd)SO2Re, xe2x80x94N(Rd)CONReRf [where Rf is a hydrogen atom or an optionally substituted straight or branched alkyl group], xe2x80x94N(Rd)CSNReRf or xe2x80x94N(Rd)SO2NReRf;
Alk2 is a straight or branched alkylene chain;
m is zero or an integer 1;
R2 is a hydrogen atom or a methyl group;
R3 is a hydrogen atom or a straight or branched alkyl group;
Ar is an optionally substituted aromatic group;
and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that compounds of formulae (1) and (1a) may have one or more chiral centres. Where one or more chiral centres is present, enantiomers or diastereomers may exist, and the invention is to be understood to extend to all such enantiomers, diasteromers and mixtures thereof, including racemates. Formulae (1) and (1a) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
In the compounds of formulae (1) and (1a), derivatives of the carboxylic acid group R include carboxylic acid esters and amides. Particular esters and amides include xe2x80x94CO2Alk4 and xe2x80x94CON(R4)2 groups as described herein.
When in the compounds of formulae (1) and (1a) L1 is present as a linker atom or group it may be any divalent linking atom or group. Particular examples include xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(R4)xe2x80x94 [where R4 is a hydrogen atom or a straight or branched alkyl group], xe2x80x94CON(R4)xe2x80x94, xe2x80x94OC(O)N(R4)xe2x80x94, xe2x80x94CSN(R4)xe2x80x94, xe2x80x94N(R4)COxe2x80x94, xe2x80x94N(R4)C(O)Oxe2x80x94, xe2x80x94N(R4)CSxe2x80x94, xe2x80x94S(O)N(R4)xe2x80x94, xe2x80x94S(O)2N(R4)xe2x80x94, xe2x80x94N(R4)S(O)xe2x80x94, xe2x80x94N(R4)S(O)2xe2x80x94, xe2x80x94N(R4)CON(R4)xe2x80x94, xe2x80x94N(R4)CSN(R4)xe2x80x94, xe2x80x94N(R4)SON(R4)xe2x80x94 or xe2x80x94N(R4)SO2N(R4)xe2x80x94 groups. Where the linker group contains two R4 substituents, these may be the same or different.
Alk2 in the compounds of formulae (1) and (1a) may be for example a straight or branched C1-3alkylene chain. Particular examples include xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94C(CH3)2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94.
When R3 and/or R4 in the compounds of formula (1) is a straight or branched alkyl group it may be a straight or branched C1-6 alkyl group, e.g. a C1-3 alkyl group such as a methyl or ethyl group.
When Alk1 in compounds of formula (1) is an optionally substituted aliphatic chain it may be an optionally substituted C1-10 aliphatic chain. Particular examples include optionally substituted straight or branched C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene chains.
Heteroaliphatic chains represented by Alk1 include the aliphatic chains just described but with each chain additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups L4 where L4 is as defined above for L1 when L1 is a linker atom or group. Each L4 atom or group may interrupt the aliphatic chain, or may be positioned at its terminal carbon atom to connect the chain to the atom or group R1.
Particular examples of aliphatic chains represented by Alk1 include optionally substituted xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94(CH2)2CH2xe2x80x94, xe2x80x94CH(CH3 )CH2xe2x80x94, xe2x80x94(CH2)3CH2xe2x80x94, xe2x80x94CH(CH3 )CH2CH2xe2x80x94, xe2x80x94CH2CH(CH3)CH2xe2x80x94, xe2x80x94C(CH3)2CH2xe2x80x94, xe2x80x94(CH2)4CH2xe2x80x94, xe2x80x94(CH2)5CH2xe2x80x94, xe2x80x94CHCHxe2x80x94, xe2x80x94CHCHCH2xe2x80x94, xe2x80x94CH2CHCHxe2x80x94, xe2x80x94CHCHCH2CH2xe2x80x94, xe2x80x94CH2CHCHCH2xe2x80x94, xe2x80x94(CH2)2CHCHxe2x80x94, xe2x80x94CCxe2x80x94, xe2x80x94CCCH2xe2x80x94, xe2x80x94CH2CCxe2x80x94, xe2x80x94CCCH2CH2xe2x80x94, xe2x80x94CH2CCCH2xe2x80x94, or xe2x80x94(CH2)2CCxe2x80x94 chains. Where appropriate each of said chains may be optionally interrupted by one or two atoms and/or groups L4 to form an optionally substituted heteroaliphatic chain. Particular examples include optionally substituted xe2x80x94L4CH2xe2x80x94, xe2x80x94CH2L4CH2xe2x80x94, xe2x80x94L4(CH2)2xe2x80x94, xe2x80x94CH2L4(CH2)2xe2x80x94, xe2x80x94(CH2)2L4CH2xe2x80x94, xe2x80x94L4(CH2)3xe2x80x94 and xe2x80x94(CH2)2L4(CH2)2xe2x80x94 chains.
The optional substituents which may be present on aliphatic or heteroaliphatic chains represented by Alk1 include one, two, three or more substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxyl, C1-6alkoxy, e.g. methoxy or ethoxy, thiol, C1-6alkylthio e.g. methylthio or ethylthio, amino or substituted amino groups. Substituted amino groups include xe2x80x94NHR4 and xe2x80x94N(R4)2 groups where R4 is a straight or branched alkyl group as defined above. Where two R4 groups are present these may be the same or different. Particular examples of substituted chains represented by Alk1 include those specific chains just described substituted by one, two, or three halogen atoms such as fluorine atoms, for example chains of the type xe2x80x94CH(CF3)xe2x80x94, xe2x80x94C(CF3)2xe2x80x94CH2CH(CF3)xe2x80x94, xe2x80x94CH2C(CF3)2xe2x80x94, xe2x80x94CH(CF3)xe2x80x94 and xe2x80x94C(CF3)2CH2.
Alkoxy groups represented by R1 in compounds of formula (1) include straight of branched C1-6alkoxy groups such as methoxy and ethoxy groups.
When R1 is present in compounds of formulae (1) and (1a) as an optionally substituted cycloaliphatic group it may be an optionally substituted C3-10 cycloaliphatic group. Particular examples include optionally substituted C3-10 cycloalkyl, e.g. C3-7cycloalkyl, C3-10 cycloalkenyl e.g. C3-7cycloalkenyl or C3-10cycloalkynyl e.g. C3-7cycloalkynyl groups.
Optionally substituted heterocycloaliphatic groups represented by R1 include the optionally substituted cycloaliphatic groups just described for R1 but with each group additionally containing one, two, three or four heteroatoms or heteroatom-containing groups L2 as just defined.
Optionally substituted polycycloaliphatic groups represented by R1 include optionally substitued C7-10 bi- or tricycloalkyl or C7-10bi- or tricycloalkenyl groups. Optionally substituted polyheterocycloaliphatic groups represented by R1 include the optionally substituted polycycloalkyl groups just described, but with each group additionally containing one, two, three or four L2 atoms or groups.
Particular examples of R1 cycloaliphatic, polycycloaliphatic, heterocyclo-aliphatic and polyheterocycloaliphatic groups include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, adamantyl, norbornyl, norbornenyl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinone, oxazolidinyl, oxazolidinone, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, piperidinone, 1,4-dioxanyl, morpholinyl, morpholinone, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or 4H-1,4- oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl, e.g. o- or p-isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or oxadiazinyl e.g. 1,3,5-oxodiazinyl groups.
The optional substituents which may be present on the R1 cycloaliphatic, polycycloaliphatic, heterocycloaliphatic or polyheterocycloaliphatic groups include one, two, three or more substituents represented by R5 in which R5 is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl or ethyl, haloC1-6alkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, hydroxyl, C1-6alkoxy, e.g. methoxy or ethoxy, haloC1-6alkoxy, e.g. halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, thiol, C1-6alkylthio e.g. methylthio or ethylthio, xe2x80x94N(R4)2, xe2x80x94CN, xe2x80x94CO2R4, xe2x80x94NO2, xe2x80x94CON(R4)2, xe2x80x94CSN(R4)2, xe2x80x94COR4, xe2x80x94CSN(R4)2, xe2x80x94N(R4)COR4, xe2x80x94N(R4)CSR4, xe2x80x94SO2N(R4)2, xe2x80x94N(R4)SO2R4, xe2x80x94N(R4)CON(R4)2, xe2x80x94N(R4)CSN(R4) and xe2x80x94N(R4)SO2N(R4)2, groups. In these substituents the group R4 when present is a hydrogen atom or a straight or branched alkyl group as defined above. Where more than one R4 group is present in a substituent each group may be the same or different. The substituent may be present on any available carbon atom or where appropriate any nitrogen atom, in the R1 group.
In the compounds of formulae (1) and (1a), optionally substituted aromatic groups represented by the group R1 include for example monocyclic or bicyclic fused ring C6-12 aromatic groups, such as phenyl, 1- or 2- naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl groups, optionally substituted by one, two, three or more L2(CH2)pL3(Rc)q atoms or groups, where L2, L3, p and q are as previously defined and Rc is as previously defined but is other than a hydrogen atom when L2 and L3 is each a covalent bond and p is zero.
Optionally substituted heteroaromatic groups, represented by the group R1 in compounds of formulae (1) and (1a) include for example optionally substituted C1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example nine- to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of heteroaromatic groups of these types include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-C1-6aimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, (2,3-dihydro]-benzofuryl, benzothienyl, benzotriazolyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1,2-alpyridyl, benzothiazolyl, benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, and imidyl, e.g. succinimidyl, phthalimidyl, or naphthalimidyl such as 1,8-naphthalimidyl.
Optional substituents which may be present on R1 heteroaromatic groups include one, two, three or more xe2x80x94L2(CH2)pL3(Rc)q atoms or groups as just defined.
Examples of the substituents represented by Ra and Rb in compounds of formula (1) and which may be present on aromatic or heteroaromatic groups represented by R1 include atoms or groups xe2x80x94L2(CH2)pLRc, xe2x80x94L2(CH2)pRc, xe2x80x94L2Rc, xe2x80x94(CH2)pRc and Rc wherein L2, (CH2)p, L and Rc are as defined above. Particular examples of such substituents include xe2x80x94L2CH2L2Rc, xe2x80x94L2CH(CH3)L3Rc, xe2x80x94L2(CH2)2L3Rc, xe2x80x94L2CH2Rc, xe2x80x94L2xe2x80x94L2(CH2)2Rc, xe2x80x94CH2Rc, xe2x80x94CH(CH3)Rc and xe2x80x94(CH2)2Rc groups.
Thus each of Ra and Rb and, where present, substituents on R1 and aromatic or heteroaromatic groups in compounds of the invention may be for example selected from a hydrogen atom, a halogen atom, e.g. a fluorine, chlorine, bromine or iodine atom, or a C1-6alkyl, e.g. methyl, ethyl, n-propyl, i- propyl, n-butyl or t-butyl, C1-6alkylamino, e.g. methylamino or ethylamino, C1-6hydroxyalkyl, e.g. hydroxymethyl, hydroxyethyl or xe2x80x94C(OH)(CF3)2, carboxyC1-6alkyl, e.g. carboxyethyl, C1-6alkylthio e.g. methylthio or ethylthio, carboxyC1-6alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC1-6alkoxy, e.g. 2-hydroxyethoxy, haloC1-6alkyl, e.g. xe2x80x94CF3, xe2x80x94CHF2, CH2F, haloC1-6alkoxy, e.g. xe2x80x94OCF3,xe2x80x94OCHF2,xe2x80x94OCH2F, C1-6alkylamino, e.g. methylamino or ethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylaminoethyl, C1-6dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, isopropylaminoethoxy, or dimethylaminopropoxy, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl (HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2R12, C1-6alkanoyl e.g. acetyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, sulphonyl (xe2x80x94SO3H), C1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoC1-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6dialkylaminoC1-6alkylaminocarbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino. C1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylamino-carbonylamino or diethylaminocarbonylamino, C1-6alkylaminocabonylC1-6alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonyl-amino, C1-6alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1-6alkylaminothiocarbonylC1-6alkylamino, e.g. ethylaminothiocarbonylmethylamino, C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonyl-amino or diethylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, aminoC1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkylaminoC1-6alkanoylamino, e.g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino group.
Aromatic groups represented by the group Ar in compounds of formulae (1) and (1a) include optionally substituted monocyclic of bicyclic fused ring C1-6 aromatic groups. Particular examples include optionally substituted phenyl, 1- or 2-naphthyl, 1- or 2- tetrahydronaphthyl, indanyl or indenyl groups.
Optional substituents present on the aromatic groups represented by Ar include one, two, three or more substituents, each selected from an atom or group R6 in which R6 is xe2x80x94R6a or xe2x80x94Alk3(R6a)m, where R6a is a halogen atom, or an amino (xe2x80x94NH2), substituted amino, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), substituted hydroxyl, formyl, carboxyl (xe2x80x94CO2H), esterified carboxyl, thiol (xe2x80x94SH), substituted thiol, xe2x80x94COR7 [where R7 is an xe2x80x94Alk3(R6a)m, aryl or heteroaryl group], xe2x80x94CSR7, xe2x80x94SO3H, xe2x80x94SO2R7 xe2x80x94SO2NH2, xe2x80x94SO2NHR7 SO2N(R7)2, xe2x80x94CONH2, xe2x80x94CSNH2, xe2x80x94CONHR7, xe2x80x94CSNHR7, xe2x80x94CON[R7]2, xe2x80x94CSN(R7)2, xe2x80x94N(R4)SO2R7, xe2x80x94N(SO2R7)2, xe2x80x94NH(R4)SO2NH2, xe2x80x94N(R4)SO2NHR7, xe2x80x94N(R4)SO2N(R7)2, xe2x80x94N(R4)COR7, xe2x80x94N(R4)CON(R7)2, xe2x80x94N(R4)CSN(R7)2, xe2x80x94N(R4)CSR7, xe2x80x94N(R4)C(O)OR7, xe2x80x94SO2NHet1 [where xe2x80x94NHet1 is an optionally substituted C5-7cyclicamino group optionally containing one or more other xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94 groups], xe2x80x94CONHet1, xe2x80x94CSNHet1, xe2x80x94N(R4)SO2NHet1, xe2x80x94N(R4)CONHet1, xe2x80x94N(R4)CSNHet1, xe2x80x94SO2N(R4)Het2 [where Het2 is an optionally substituted monocyclic C5-7carbocyclic group optionally containing one or more xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94 groups], xe2x80x94CON(R4)Het2, xe2x80x94CSN(R4)Het2, xe2x80x94N(R4)CON(R4)Het2,xe2x80x94N(R4)CSN(R4)Het2, aryl or heteroaryl group; Alk3 is a straight or branched C1-6alkylene, C2-6alkenylene or C2-6alkynylene chain, optionally interrupted by one, two or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94S(O)n [where n is an integer 1 or 2] or xe2x80x94N(R8)xe2x80x94groups [where R8 is a hydrogen atom or C1-6alkyl, e.g. methyl or ethyl group]; and m is zero or an integer 1, 2 or 3. It will be appreciated that when two R4 or R7 groups are present in one of the above substituents, the R4 or R7 groups may be the same or different.
When in the group xe2x80x94Alk3(R6a)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R6a may be present on any suitable carbon atom in xe2x80x94Alk3. Where more than one R6a substituent is present these may be the same or different and may be present on the same or different atom in xe2x80x94Alk3. Clearly, when m is zero and no substituent R6a is present the alkylene, alkenylene or alkynylene chain represented by Alk3 becomes an alkyl, alkenyl or alkynyl group.
When R6a is a substituted amino group it may be for example a group xe2x80x94NHR7 [where R7 is as defined above] or a group xe2x80x94N(R7)2 wherein each R7 group is the same or different.
When R6a is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R6a is a substituted hydroxyl or substituted thiol group it may be for example a group xe2x80x94OR7 or a xe2x80x94SR7 or xe2x80x94SC(xe2x95x90NH)NH2 group respectively.
Esterified carboxyl groups represented by the group R6a include groups of formula xe2x80x94CO2Alk4 wherein Alk4 is a straight or branched, optionally substituted C1-8alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C6-12arylC1-8alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6-12aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6-12aryloxyC1-8 alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyl-oxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C1-8alkanoyloxyC1-8alkyl group, such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a C6-12aroyloxyC1-8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group. Optional substituents present on the Alk4 group include R6a substituents described above.
When Alk3 is present in or as a substituent it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, atoms or xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R8)xe2x80x94 groups.
Aryl or heteroaryl groups represented by the groups R6a or R7 include mono- or bicyclic optionally substituted C6-12 aromatic or C1-9 heteroaromatic groups as described above for the groups R1 and Het. The aromatic and heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e.g. nitrogen atom as appropriate.
When xe2x80x94NHet1 or xe2x80x94Het2 forms part of a substituent R6 each may be for example an optionally substituted pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinyl group. Additionally Het2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on -NHet1 or xe2x80x94Het2 include those R5 substituents described above.
Particularly useful atoms or groups represented by R6 include fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrrolyl, furyl, thiazolyl, or thienyl, C1-6alkylamino, e.g. methylamino or ethylamino, C1-6hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC1-6alkyl, e.g. carboxyethyl, C1-6alkylthio e.g. methylthio or ethylthio, carboxyC1-6alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxyxe2x80x94propylthio, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC1-6alkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C5-7cycloalkoxy, e.g. cyclopentyloxy, haloC1-6alkyl, e.g. trifluoromethyl, haloC1-6alkoxy, e.g. trifluoromethoxy, C1-6alkylamino, e.g. methylamino or ethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylamino ethyl, C1-6dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, isopropylaminoethoxy, or dimethylaminopropoxy, imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk4 [where Alk4 is as defined above], C1-6 alkanoyl e.g. acetyl, optionally substituted benzoyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, xe2x80x94SC(xe2x95x90NH)NH2, sulphonyl (xe2x80x94SO3H), C1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoC1-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6dialkylaminoC1-6alkylaminoxe2x80x94carbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, C1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, C1-6alkylaminocabonylC1-6alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonylamino, C1-6alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1-6alkylaminothiocarbonylC1-6alkylamino, e.g. ethylaminothiocarbonylmethylamino, xe2x80x94CONHC(xe2x95x90NH)NH2, C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, optionally substituted phenylsulphonylamino, aminosulphonylamino (xe2x80x94NHSQ2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonyl-amino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonylC1-6alkylamino, optionally substituted phenylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, aminoC1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkylaminoC1-6alkanoyl-amino, e.g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino. ethoxycarbonylamino or t-butoxycarbonylamino or optionally substituted benzyloxy, pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino, benzyloxycarbonylaminoC1-6alkyl e.g. benzyloxycarbonylaminoethyl benzothio: pyridylmethylthio or thiazolylmethylthio groups.
Where desired, two R6 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C1-6alkylenedioxy group such as methylenedioxy or ethylenedioxy.
It will be appreciated that where two or more R6 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the heteroaromatic group represented by Het.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates. fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth met al salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
R in compounds of the invention is preferably a xe2x80x94CO2H group.
When present, the aliphatic chain represented by Alk1 in compounds of the invention is preferably a xe2x80x94CH2xe2x80x94 chain.
Alk2 in compounds of formula (1) is preferably a xe2x80x94CH2xe2x80x94 chain and m is preferably an integer 1. In compounds of this type, the carbon atom to which Alk2 and R are attached forms a chiral centre and is preferably in the L configuration.
R2 in compounds of formula (1) is preferably a hydrogen atom.
R3 in compounds of the invention is preferably a hydrogen atom.
In general in compounds of the invention xe2x80x94(Alk1)n(L1)sxe2x80x94 is preferably CH2Oxe2x80x94, xe2x80x94SO2NH, xe2x80x94C(O)Oxe2x80x94 or xe2x80x94CON(R4)xe2x80x94 and is especially xe2x80x94CONHxe2x80x94.
In general in compounds of the invention the group R1 is preferably an optionally substituted aromatic or heteroaromatic group. Particularly useful groups of these types include optionally substituted phenyl, pyridyl or pyrimidinyl groups, particularly those in which the substituent when present is an atom or group xe2x80x94L2(CH2)pL3(Rc)q as described above. Each substituent may be present on any available ring carbon or nitrogen atom.
The aromatic group represented by Ar in compounds of formulae (1) and (1a) is preferably on optionally substituted phenyl group. Each optional substituent when present is preferably an atom or group R6 as defined above.
A particularly useful class of compounds according to the invention has the formula (1b)
wherein xe2x80x94Wxe2x95x90 is xe2x80x94CHxe2x95x90 or xe2x80x94Nxe2x95x90, R9 and R10, which may be the same or different, is each a xe2x80x94L2(CH2)pL3(Rc)q atom or group as generally and particularly defined above, and Alk1, r, L1, s, Ra, Rb, R and Ar are as generally and particularly defined above, and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that the various preferences stated above in relation to groups present in compounds of formulae (1) and (1a) apply equally to the same groups when present in compounds of formula (1b).
Additionally, in compounds of formula (1b) xe2x80x94(Alk1)r(L1)rxe2x80x94 is preferably a xe2x80x94CH2O or xe2x80x94CON(R4)xe2x80x94 group and is especially a xe2x80x94CONHxe2x80x94 group.
Ar is preferably an optionally substituted phenyl group. Particularly useful compounds of formula (1b) are those wherein Ar is a 2- , 3- or 4-monosubstituted or a 2,6-disubstituted phenyl group.
One of R9 or R10 in compounds of formula (1a) may be for example a hydrogen atom and the other a substituent L2(CH2)pL3(Rc)q in which Rc is not a covalent bond and p is zero, but preferably each of R9 and R10 is a substituent xe2x80x94L(2CH2)pL3(Rc)q where Rc is as just defined. Particularly useful R9 or R10 substituents include a hydrogen atom or halogen atom, especially fluorine or chlorine atoms, or a methyl, ethyl, methoxy, ethoxy, xe2x80x94CF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94COCH3, xe2x80x94SCH3, xe2x80x94CO2H or xe2x80x94CO2CH3 group.
Particularly useful compounds according to the invention include the following:
(N-2,6-Dimethoxybenzoyl)-[O-(3,5-dichloro-4-pyridinyl)methyl]-L-tyrosine; 2-Carboxybenzoyl-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;
(N-2,6-Dimethoxybenzoyl)-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;
(N-3-Carboxybenzoyl)-(Nxe2x80x2-3,5-dichloroisonicotoninoyl)-L-4-aminophenyalanine;
(N-4-Carboxybenzoyl)-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;
(N-2-t-Butoxycarbonylbenzoyl)-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;
(N-3-Cyanobenzoyl)-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;
[N-3-(1-H-Tetrazol-5-yl)benzoyl]-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;
[N-(3-Methoxycarbonylbenzoyl)]-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalnine;
and the salts, solvates, hydrates and N-oxides thereof.
The compounds of formulae (1), (1a) and (1b) may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols R1-R3, L1, Alk1, Ra, Rb, Alk2, m, r, s and Ar when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, 1991]. In some instances, deprotection may be the final step in the synthesis of the desired compound and the processes described hereinafter are to be understood to extend to such removal of protecting groups. For convenience, the processes described below all refer to the preparation of a compound of formula (1) but clearly the description applies equally to the preparation of compounds of formulae (1a) and (1b).
Thus a compound of formula (1) may be obtained by hydrolysis of an ester of formula (2):
where R11 is an alkyl group.
The hydrolysis may be performed using either an acid or a base depending on the nature of R9, for example an organic acid such as trifluoracetic acid or an inorganic base such as lithium hydroxide optionally in an aqueous organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran or dioxane or an alcohol, e.g. methanol at around ambient temperature. Where desired, mixtures of such solvents may be used.
Esters of formula (2) may be prepared by coupling an amine of formula 3):
(where R11 is as just described) or a salt thereof with an acid of formula (4):
ArCO2Hxe2x80x83xe2x80x83(4)
or an active derivative thereof.
Active derivatives of acids of formula (4) include anhydrides, esters and halides. Particular esters include pentafluorophenyl or succinyl esters.
The coupling reaction may be performed using standard conditions for reactions of this type. Thus for example the reaction may be carried out in a solvent, for example an inert organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran, or a halogenated hydrocarbon, such as dichloromethane, at a low temperature, e.g. around xe2x88x9230xc2x0 C. to around ambient temperature, optionally in the presence of a base, e.g. an organic base such as an amine, e.g. triethylamine, pyridine, or dimethylaminopyridine, or a cyclic amine, such as N-methylmorpholine.
Where an acid of formula (4) is used, the reaction may additionally be performed in the presence of a condensing agent, for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,Nxe2x80x2-dicyclohexylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxybenzotriazole. Alternatively, the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to reaction with the amine of formula (3).
Intermediates of formulae (2), (3) and (4), or compounds of formula (1), may be manipulated to introduce substituents to aromatic or heteroaromatic groups or modify existing substituents in groups of these types. Typically, such manipulation may involve standard substitution approaches employing for example alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation or coupling reactions. Alternatively, exisitng substituents may be modified for example by oxidation, reduction or cleavage reactions. Particular examples of such reactions are given below. Where these are paticularly described in relation to the generation of the group R1(Alk1)r(L1l)sxe2x80x94, it will be appreciated that each reaction may also be used to introduce or modify R5 and/or R6 substituents in for example Ar groups as appropriate.
Thus in one example, a compound wherein R1(Alk1)r(L1)sxe2x80x94 is a xe2x80x94L1H group may be alkylated, arylated or heteroaryiated using a reagent R1(Alk1)rX in which R1 is other than a hydrogen atom and X is a leaving atom or group such as a halogen atom, e.g. a fluorine, bromine, iodine or chlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g. trifluoromethylsulphonyloxy or arylsulphonyloxy, e.g. p-toluenesulphonyloxy group,
The reaction may be carried out in the presence of a base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran.
In another example, a compound where R1(Alk1)r(L1)s is a xe2x80x94L1H group is a hydrogen atom may be functionalised by acylation or thioacylation, for example by reaction with a reagent R1(Alk1)rL1X [wherein L1 is a xe2x80x94C(O)xe2x80x94, C(S)xe2x80x94, xe2x80x94N(R4)C(O)xe2x80x94 or N(R4)C(S)xe2x80x94 group], in the presence of a base, such as a hydride, e.g. sodium hydride or an amine, e.g. triethylamine or N-methylmorpholine, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or carbon tetrachloride or an amide, e.g. dimethylformamide, at for example ambient temperature, or by reaction with R1(Alk1)rCO2H, R1(Alk)4COSH or an activated derivative thereof, for example as described above for the preparation of esters of formula (2).
In a further example a compound may be obtained by sulphonylation of a compound where R1(Alk1)r(L1)s is an xe2x80x94OH group by reaction with a reagent R1(Alk1)rL1Hal [in which L1 is xe2x80x94S(O)xe2x80x94 or xe2x80x94SO2xe2x80x94and Hal is a halogen atom such as chlorine atom] in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
In another example, a compound where R1(Alk1)r(L1)s is a xe2x80x94L1H group, may be coupled with a reagent R1 OH (where R1 is other than a hydrogen atom) or R1Alk1 OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl, diisopropyl- or dimethylazodicarboxylate to yield a compound containing a R1(Alk1)rOxe2x80x94 group.
In a further example, ester groups xe2x80x94CO2R4 or xe2x80x94CO2Alk4 in compounds of formula (1) may be converted to the corresponding acid [xe2x80x94CO2H] by acid- or base-catalysed hydrolysis depending on the nature of the grousp R4 or Alk4. Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxane or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
In a second example, xe2x80x94OR7 [where R7 represents an alkyl group such as methyl group] groups in compounds of formula (1) may be cleaved to the corresponding alcohol xe2x80x94OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around xe2x88x9278xc2x0 C.
Alcohol [xe2x80x94OH] groups may also be obtained by hydrogenation of a corresponding xe2x80x94OCH2R7 group (where R7 is an aryl group) using a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature. In another example, xe2x80x94OH groups may be generated from the corresponding ester [xe2x80x94CO2Alk4 or CO2R4] or aldehyde [xe2x80x94CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
In another example, alcohol xe2x80x94OH groups in compounds of formula (1) may be converted to a corresponding xe2x80x94OR3 group by coupling with a reagent R7OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
Aminosulphonylamino [xe2x80x94NHSO2NH2] groups in compounds of formula (1) may be obtained, in another example, by reaction of a corresponding amine [xe2x80x94NH2] with sulphamide in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In a further example amine (xe2x80x94NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
In a further example, amine [xe2x80x94NH2] groups in compounds of formula (1) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [xe2x80x94NO2] group may be reduced to an amine [xe2x80x94NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
Aromatic halogen substituents in compounds of the invention may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around xe2x88x9278xc2x0 C., in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using dimethylformamide as the electrophile; a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
In another example, sulphur atoms in compounds of the invention, for example when present in the linker group L1 may be oxidised to the corresponding sulphoxide using an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature. Intermediates of formulae (3) and (4), R1(Alk1)rX, R1(Alk1)rL1X, R1(Alk1)rCO2H, R1OH and R1Alk1OH for use in the above processes are either known compounds or may be prepared from known starting materials by use of analogous processes to those used for the preparation of the known compounds and/or by treating known compounds by one or more of the alkylation, acylation and other manipulations described herein, such as particularly described for the preparation of the Intermediates in the exemplification section hereinafter.
N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70xc2x0 C. to 80xc2x0 C., or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1) with an appropriate base in a suit able solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
Where it is desired to obtain a particular enantiomer of a compound of formula (1) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
Thus for example diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
In another resolution process a racem ate of formula (1) may be separated using chiral High Performance Liquid Chromatography. Alternatively. if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.

Abstract: wherein

Abstract: L1 is a linker atom or group;

Abstract: The compounds are able to inhibit the binding of alpha4 integrins to their ligands and are of use in the prophylaxis and treatment of immune or inflammatory disorders.


A computer system, program product and method implement a time delay in an in-focus switch operation to minimize inadvertent switching between user interface components such as windows and the like. More specifically, in response to user input to move a pointer from the display region of a first user interface component to the display region of a second user interface component, the second user interface component is promoted to a higher layer than the first user interface component so long as no user input to move the pointer back to the display region of the first user interface component is received within a predetermined period of time. As a result, when a user inadvertently moves the pointer from the display region of the first user interface component to that of the second user interface component, the in-focus switch operation is delayed to permit the user to cancel the in-focus switch operation if so desired by moving the pointer back within the display region of the first user interface component prior to expiration of the predetermined time period.

Many computer systems utilize graphical user interfaces (GUIs) to permit user interaction with data stored in such systems. In a GUI environment, users are typically able to interact with a computer system through intuitive operations such as "pointing and clicking" on graphical user interface components displayed on a computer display with a graphical pointer controlled by a mouse or other user interface device.
Data is often presented to a user in a GUI environment using a graphical user interface component known as a window. A computer application may use one or more windows, and moreover, multiple computer applications may operate at the same time in a computer system, resulting in multiple windows being displayed at once on a computer display.
Due to limited space on a computer display, windows are typically arranged in layers, giving the visual impression that a window displayed in a relatively higher layer overlaps a window displayed in a relatively lower layer. The window displayed at the top layer is also often referred to as being in the "foreground", while windows that are displayed in layers other than the top layer are referred to being in the "background".
A window assigned to the foreground is also often referred to as being in "focus", as the computer application associated with the window typically interacts with a user by processing the non-pointer input received from a user (e.g., from a keyboard). When a user wishes to interact with a window other than the current "in-focus" window, the user must bring that window into focus, typically by "pointing and clicking" on that window while the pointer is located over the window. In response to such an operation, the clicked-on window is assigned to the top layer to become the new "in-focus" window, while the previous in-focus window is assigned to a relatively lower layer. Put another way, the clicked-on window is often said to be "promoted" to the foreground, with the previous in-focus window "demoted" to the background.
In many computer systems, an automatic in-focus window switch feature is provided to permit windows to be automatically brought into focus immediately whenever the pointer is moved over such windows by a user. Thus, whenever a pointer moves from the display region for the current in-focus window to the display region of another window, that other window is promoted to the foreground to become the new in-focus window.
Automatic in-focus window switching often improves user productivity when working with multiple windows since a user need not perform the separate action of depressing a button to bring a window into focus. However, eliminating the need to depress a button increases the risk that a user will inadvertently switch to another window. As one example, many windows are implemented with controls such as buttons, resizing handles, and/or scroll bars that are located along the outer boundaries of the windows. Performing operations with such controls requires that the pointer be moved by a user close to the boundary of the display region of a window. Should the user accidently move the pointer beyond the boundary of an in-focus window and over the display region of another window when attempting to operate a control, the other window is automatically selected, resulting in the original in-focus window being demoted to the background.
In many circumstances, inadvertent switching to another window can significantly impact user productivity. A noticeable amount of processing by a computer system is often required to promote a particular window to the foreground, often resulting in a delay of as much as one or more seconds before the operation is complete. As a result, inadvertently switching to another window and then attempting to switch back to the original in-focus window may lead to a substantial user delay.
In addition, inadvertently switching to another window may result in the original in-focus window being completely occluded by the new in-focus window--with all traces of the original window completely removed from the display. As a result, even more productivity is lost since a user often must perform more user-intensive operations to bring the original window back into focus--e.g., closing, moving, resizing or minimizing the new in-focus window, toggling between tasks, etc.
Consequently, while in-focus window switching can provide productivity gains when interacting with windows in a graphical user interface environment, the adverse impact of inadvertent switching between user interface components such as windows can often negate these potential gains for many users. Therefore, a significant need exists for a manner of improving in-focus switching operations to minimize inadvertent switching.

Computer system, program product and method utilizing in-focus switch delay for user interface components

International Business Machines Corporation


An impulse ring centered on a central axis, for a sensor-bearing unit including a bearing is provided. The impulse ring includes a magnetized target that generates a magnetic fields adapted to be sensed by a sensor, and an annular target holder. The target holder provides an inner axial tubular portion adapted to be fixed to a rotatable inner ring of the bearing, an outer axial tubular portion holding the magnetized target that is positioned radially beyond an outer ring of bearing, and an intermediate portion that radially extends between the inner axial tubular portion and outer axial tubular portion. The intermediate portion provides a radial part, an inclined part and a plurality of stiffening ribs.

Today, sensor-bearing units are commonly used in a wide range of technical fields, for example in automotive industry and aeronautics. These units provide high quality signals and transmissions, while allowing integration in simpler and more compact apparatus.
Such a sensor-bearing unit generally provides a bearing, an impulse ring, typically a magnetic impulse ring, and detection means facing the impulse ring. The impulse ring provides a target holder and a magnetized target including alternating North and South poles, whose number depends on bearing size, detection precision and particular application. With a bearing having suitable dimensions, the target holder may be fixed to a rotating ring of this bearing, while the detection means may be fixed to a non-rotating ring of this bearing or to a fixed casing.
The magnetized target is made from a magnetized material and is attached to a tubular portion of the target holder. Such a design is known from FR-A-2 884 367, in which the target holder provides an inner portion, which is attached to the inner ring of a bearing, a radial portion, and an outer tubular portion, which holds the magnetic target. The radial portion and the outer tubular portion form a right angle, which can be damaged in case of high rotation speeds, for example above 20 000 rotations per minute (rpm) and vibrations during operation of the impulse ring. In addition, the radial portion of the target holder provides a portion axially offset to avoid interferences with outer ring, but the specific shape increases the necessary space to integrate the sensor-bearing unit.

Impulse ring and a sensor-bearing unit comprising such impulse ring


A balancing device for firearms having at least one barrel and one stock, a front support and a rear support respectively mounted in a region adjacent to the muzzle and in the region of the stock of the firearm; the front support and the rear support are configured to support one or more weight members which are modular and mutually analogous.

The present invention relates to a balancing device for firearms.
It has long been known to modify the balance of a firearm by applying weights in various positions on the body of the firearm.
Balancing systems of the known type are numerous and disparate. For example, balancing systems are known which are constituted by weights which can be applied to the barrel or barrels of a gun or to the rib.
The weights are normally fixed by means of screws in discrete positions or along guides that allow a continuous adjustment of the position of the weight or weights with respect to the extension of the barrel.
U.S. Pat. No. 3,726,037 discloses a system of the type described above.
Balancing devices are also known which provide for the application of one or more weights at the stock or grip of the firearm.
US 2010/0285720 discloses a marching band rifle which includes a recess in the stock for accommodating a series of weights, constituted by metallic discs, so as to adjust the balance of the rifle.
Italian patent application ITBS2009A218 discloses a balancing systems for hunting guns and target shooting guns which provides for one or more rear balancing masses which are inserted and retained transversely in the stock of the gun and one or more front balancing weights applied to the barrels. The stock of the gun is provided, in the region of the grip, with a cavity that is extended vertically and the rear balancing masses are accommodated and enclosed within the cavity.
DE19825951 discloses a lightweight frame for a gun made of carbon fiber laminate. The single piece frame includes the barrel support and the stock and has shaped recesses into which balance masses can be fitted to adjust the balance of the weapon. The ballast masses are secured by screw fasteners into threaded sleeves bonded into the laminate.
Balancing systems of the prior art have drawbacks of a functional nature, especially as regards the ease of application of the heavy masses.
In order to obtain the desired balance, the user must in fact mount and remove the weights several times before achieving the desired combination.
Since balancing systems of the known type have different weights and fastening systems for the barrels or for the stock, it is furthermore necessary to be equipped with several components having different shapes and weights.
The balancing system disclosed in DE19825951 cannot be adapted to different rifles and shotguns because it is not provided with a support for the masses. The weight of the masses cannot be finely adjusted and the masses cannot be mounted close to the muzzle.
Other prior art balancing systems do not allow for an independent balancing of the right or left hand side of the weapon.


Methods and compositions for producing 1-butanol are described herein. In some examples, the methods can comprise, contacting a reactant comprising ethanol with a catalyst system, thereby producing a product comprising 1-butanol. The catalyst system can comprise, for example, an iridium catalyst and a nickel, copper, and/or zinc catalyst. The nickel, copper, and zinc catalysts can comprise nickel, copper, and/or zinc and a sterically bulky ligand.

Butanol represents an alternative to gasoline as a transportation fuel with certain advantages over ethanol. For example, butanol can be blended into gasoline at higher concentrations (16%) than ethanol, which can provide more renewable content in every gallon. Butanol can be used in existing vehicles and infrastructure (e.g., a drop-in fuel). Butanol does not mix with water as does ethanol, meaning it can be transported via existing infrastructure. Butanol has a low vapor pressure, so there will be lower evaporative losses associated with butanol compared to ethanol.
In addition, 1-butanol can be used as an entry level chemical in the synthetic commodity chemical industry. Butanol can be used in the chemical industry for different purposes, such as the manufacture of butyl acrylate, butyl acetate, glycols, plasticizers and solvents. Butanol can be used in the manufacture of pharmaceuticals, polymers, pyroxylin plastics, herbicide esters, and butyl xanthate. Butanol can also be used as a solvent for the extraction of essential oils or as an ingredient in perfumes; as an extractant in the manufacture of antibiotics, hormones, and vitamins; as a solvent for paints, coatings, natural resins, gums, synthetic resins, alkaloids, and camphor. Other applications of butanol include, for example, as a swelling agent in textiles; as a component of brake fluids, cleaning formulations, degreasers, and repellents; and as a component of ore floatation agents and of wood-treating systems.
Production of multi-carbon alcohols, such as butanol, using most conventional processes has been limited by economic and environmental constrains. The compositions and methods disclosed herein address these and other needs.


Electrical impedance tomography (EIT) data processing system, for acquiring and processing data from two-phase flows, comprising a dual-plane sensor, a plurality of digital signal processing modules configured in a data pipeline processing arrangement and a plurality of data acquisition subsystems in communication with a first one of said digital signal processing modules.

There are many industrial two-component flow applications where it is required to monitor the flow rate of one, or both, of the flowing components. In a two component flow where the continuous component is electrically conductive, and where there is a conductivity contrast between the continuous and discontinuous components, a technique known as dual-plane Electrical Impedance Tomography (EIT) has the potential to be used on-line to obtain accurate estimates of the local disperse phase volumetric flow rate, the mean disperse and continuous phase volume fractions and the distributions of the local axial, radial and angular velocity components of the disperse phase.
The invention is concerned with online data acquisition and processing of measurements from two-phase flows, whose axial velocities can be up to 10 ms−1, with ±5% precision. To be able to measure two-phase flows at these velocities requires data acquisition and processing speeds of 1000 frames per second per dual-plane in order to generate flow velocity maps and this has not been possible to date, using conventional techniques.
The following prior art documents are incorporated herein by reference.
DICKIN F, WANG M, Electrical resistance tomography for process applications, Meas. Sci. Technol. 7 (1996), 247-260
WANG M, DICKIN F J, BECK M S, Improved electrical impedance tomography data collection system and measurement protocols, Tomography Technique and Process Design and Operation ISBN1813122467
TII, (2000), TMA320C6202/B Fixed-Point Digital Signal Processors, Texas Instruments Incorporated
WANG M., (1994), Electrical impedance tomography on conducting walled process vessels, PhD thesis, UMIST


Endoscopes and wands, useful for near infrared imaging, particularly for medical purposes, have transmitting members that transmit between about 95% and 99.5% of the energy at a wavelength within the infrared spectrum. The wands and endoscopes have at least one channel for transmitting and receiving light in the visible spectrum and at least one channel for transmitting and receiving light in the infrared spectrum.

An endoscope or wand viewing apparatus is usually configured in a way that is well suited for illumination and imaging in visible light.
In this background section endoscopes and wand like devices shall be described in terms of their internal working components. In the second portion of the background section the shortcomings of these predicate devices shall be described with respect to their use for laser induced fluorescence imaging.
An endoscope is an opto-mechanical imaging device characterized by the following: an objective lens assembly containing an optional deviating prism assembly, a relay system forming a plurality of intermediate images for the case of a rigid endoscope, an ocular, a camera system containing multiple detectors with a prism assembly directing sections of the electromagnetic spectrum to dedicated sensors, or in the case of chip-on-a-stick endoscope where there are no intermediate images; an objective lens assembly coupled directly to the camera detector which is embedded in the distal most portion of the device. In either case the optical elements are contained in an inner most tube member which is surrounded by other tube members which may include fiber optics for illumination in the annulus formed by two or more of the tubes and may contain other tubes for the passage of instruments and or irrigation.
An objective lens assembly in the distal most portion of the device forms a real image of the scene coincident with the plane of the detector in the case of a chip-on-a-stick endoscope or intraoral camera, or distal most plane of a relay system that is contained within the shaft portion of the endoscope.
In an endoscope with a relay system (the second case above), there are 2 basic forms of relays, those of lenses and those using coherent imaging fibers.
In both examples the role of the relay is to reform the image produced by the objective lens through the length of the shaft by producing intermediate images in the case of a rigid endoscope to a new position where the ocular, in the case of a visual endoscope or camera lens group in the case of a digital or electronic imaging device, may then reform the image originally produced by the objective lens group for the eye or to a camera detector.
The shaft portions of all endoscopes are made to facilitate the insertion of the device into a body cavity or body lumen, that is to say diameter is the dimension being minimized. In the case of a body cavity insertion, the shaft is often rigid and comprised of thin walled stainless steel tubes. This tube within tube construction allows for an innermost tube to contain the optical train and then surrounding tubes can contain fiber optics to transmit illumination to the scene in the form of an annulus. Additional tubes can be contained within the assembly for the introduction of surgical instruments for various purposes.
For the case of an endoscope that utilizes coherent imaging fibers for the relay system the functional concept being optimized in the device is flexibility, and to some degree what is being compromised is resolution, particularly when the diameter of the tip is small. However, large diameter flexible endoscopes often use detectors directly behind the objective lens assembly and are therefore considered "chip-on-a-stick" configurations. These flexible endoscopes often have internal channels, instrument and irrigation channels, to pass forceps, etc. and have internal guide wires and steering mechanisms at the tip controlled by levers at the proximal end of the device.
There is a class of smaller diameter endoscopes utilizing coherent imaging fibers as relays whose shafts have a limited amount of flexibility, and these devices are commonly called semi-flexible. Often configured with a working channel, called a forceps channel, used for instruments and are often used in Urology.
Whether rigid, flexible, or semi-flexible, endoscopes have a proximal eyepiece section for viewing and or coupling to a camera system. An eyepiece is not present on chip-on-a-stick endoscopes or intraoral cameras, often called dental cameras, as the camera is imbedded into the distal portion of the device.
Where eyepieces are used, manufacturers have almost universally adopted a nominal 32 mm eye cup for blocking room light from the physician's view, and this eye cup serves to support the coupling mechanism to the camera. There are some commercial applications of directly coupling the camera and optical assemblies included in the shaft mechanism and or coupling mechanism but this has not found wide acceptance, except in Orthopedics for Arthroscopy. The fear among users has been that if the electronics of the camera fail for some reason then the doctor is left with no means to view within the patient, hence the continuing presence of endoscopes with eyepieces.
The class of endoscopes not utilizing eyepieces is commonly called chip-on-a-stick. The intraoral dental camera shares the lack of eyepiece or ocular, as well. Both instruments send a video signal to a monitor or computer for viewing.
Endoscopes are most commonly fixed focus imaging devices. There is a broad distance from the tip of the device to the subject that is in focus due to the relatively small aperture of the optical system. A small aperture allows only a small amount of light to be imagined for any point in the scene. Should focusing be required it is accomplished by repositioning the optics in the camera module proximal to the endoscope, or in some cases the detector itself is moved.
Such low levels of return signal in the visible spectrum require endoscopes to have large light sources such as xenon, halogen, and metal halide.
In the case of an endoscope, commonly called a chip-on-a-stick which contain a distal most detector (CCD, CMOS, or other sensor), the change in image plane position for a near object of interest versus a far object of interest is usually ameliorated by installing a very small aperture in the objective lens assembly to increase depth of field at the expense of a bright field or higher potential resolution.
This is a distinction between endoscopes and chip-on-a-stick endoscopes regarding focus. Endoscopes with proximal cameras do provide a means for focus even if they themselves are fixed focus. Chip-on-a-stick endoscopes usually do not provide a focus means. However, large diameter flexible endoscopes used in gastroenterology do often have moveable detectors or lenses providing focus.
For smaller chip-on-a-stick endoscopes, all of the optical elements in the objective lens assembly are optimized for the small aperture which allows great depth of field. It is not the case that the aperture could be removed for increased brightness. The advantage is that no motion (focus) is required and when provided with powerful illumination systems in the visible light the overall system can perform well given the constraint of illumination.
A focus means becomes an area of distinction between a chip-on-a-stick endoscope and a wand imaging device, referred to as an intraoral or dental camera, as well. Both chip-on-a-stick endoscope and a wand imaging devices contain the detector plane in the distal or forward portion of the device directly behind the objective lens assembly. The intraoral or dental camera is often required to be used in stand off mode, a distance that is greater than endoscopy requires. The distinction results from the use; endoscopy is done in closed surgical or diagnostic sites, the intraoral devices are used external to the body or inserted in natural cavities such as the mouth. In such stand off modes, not the mouth but full face views, great amounts of illumination would be required to satisfy the large change in s and s′ (the optical path length on either side of the objective lens) in the intraoral or dental camera where to be fixed focus. Therefore, intraoral or wand like dental cameras frequently contain a means to move the detector plane, or focus the device. Using a faster F number, with inherently less depth of field but higher sensitivity, and by moving the detector plane a lower powered illumination system is required. This allows a wand with near IR capabilities to accommodate large changes in distances to the object of interest, thereby allowing a faster optical system to be designed, a characteristic that requires variable focus, but provides higher inherent resolution, and more conservative illumination sources.
Endoscopes and wands are generally designed to visualize in the visible spectrum. However, fluorescent dyes, such as indocyanine green (ICG) (Akorn, Inc., Buffalo Grove, Ill.) are commonly being used to image anatomy in the infra red spectrum. Use of ICG is described in, for example, U.S. Pat. No. 6,915,154, which is incorporated herein by reference in its entirety. Once excited, ICG emits in the infra red spectrum at about 825 to about 835 nm. FIG. 1 shows the excitation and emission spectrum of the ICG composition sold by Akorn, Inc. There is therefore a need for endoscope and wand devices that are capable of imaging and visualizing in the infrared spectrum.


The motion signal detecting circuit is adapted to an image reproducing system having a frequency unfolding circuit for generating an unfolded luminance signal by unfolding a high frequency component folded into low frequency component into the original frequency band in order to reproduce a full bandwidth image signal in which the high frequency component folded into the low frequency component and recorded on a recording medium having a limited bandwidth. The detecting circuit comprises a prefilter for eliminating the folding carrier contained in the unfolded luminance signal and sidebands thereof and a comb filter for detecting a motion signal which is the differential component between frames in the unfolded luminance signal by filtering the output of the prefilter.

The present invention relates to a system for smoothing of spreading transitions between image regions included in television signals to be transmitted which are processed in a still picture signal processing method and a motion picture signal processing method, and particularly to a circuit for accurately detecting a motion signal which represents a moving image, so as to control the transitions between image regions of a frequency-unfolded image signal.
Standard television system such as an NTSC or a PAL system, which represent images, processes a television signal adaptively in accordance with an amount of motions of the signal. This adaptive processing of the signal may result in quasi-motion picture regions between image regions being processed in a still picture signal processing method and other image regions being processed in a motion picture signal processing method. If differences in the processing methods are perceived and, the different regions and the transition between them are discerned by a viewer, image quality is degraded.
For example, for the purpose of separating chrominance and luminance components from a composite video signal, a frame comb filter or a line comb filter may be used. As long as there is no change in the image signal at frame time intervals, when separating chrominance and luminance components from the composite video signal using the frame comb filter, the luminance and chrominance components can be completely separated. If the scene changes, however, over the frame time intervals, then some color information will be present in the separated luminance component and some brightness information will be present in the chrominance component.
A line comb filter also used to separate the luminance and chrominance components from the composite video signal does not produce significantly degraded component signals in the presence of image motion. However, the line comb filter reduces the vertical resolution of the reproduced image in comparison with the frame comb filter. In addition, in locations where a vertical transition occurs, an image processed by the line comb filter may be degraded due to both color information introduced into the luminance component, producing an image artifact known as hanging dots and brightness information introduced into the chrominance, producing incorrect colors in the neighborhood of the transition.
Therefore the television signal is adaptively processed by detecting the presence or absence of image motion. In the regions in which the image is stationary, the frame comb filter is used, and in the regions in which the image is moving, the line comb filter is used.
Another example of such adaptive processing is an adaptive double-scanned, non-interlaced scan converter. In such a converter, interstitial lines are displayed between lines of the current field. However, the interstitial lines may be those transferred from the preceding field, in the presence of image changes producing visible artifacts such as serrated contours. The interstitial lines may also be interpolated from lines within the current field, but the vertical resolution is reduced and line flicker may occur. In regions in which image changes are detected, intrafield interpolated interstitial lines are displayed and field-delayed interstitial lines are displayed in other way.
Yet another example is an adaptive peaking circuitry in which regions having relatively high noise are processed with a relatively low peaking factor and regions having relatively low noise are processed with a relatively high peaking factor.
In all of the above examples, the television signals are processed adaptively in response to the values of estimated parameters of the image. The parameters are a motion in the case of luminance/chrominance separation and double scanning non-interlaced conversion, and a relative level of noise in the case of the peaking. Differently processed regions, and noticeable boundaries between regions where the parameter is present and those where it is absent are undesirable artifacts introduced by the above types of adaptive processing types.
U.S. Pat. No. 5,113,262 issued May 12, 1992, to Strolle et alii, entitled "AN IMPROVED VIDEO SIGNAL RECORDING SYSTEM" and assigned to Samsung Electronic Co., Ltd., describes a recording system for recording and reproducing a full bandwidth video signal on and from a recording medium having a limited bandwidth by folding the high frequency component of a luminance signal into the low frequency component of the luminance signal.
In U.S. Pat. No. 5,113,262 a motion signal which represents a moving image is recorded together with the folded luminance signal and the chrominance signal on the recording medium. The motion signal is used to control the transition between regions of the full bandwidth luminance signal which is unfolded into the original frequency bands when reproducing.
That is, in the previous work of the inventor and his co-workers, the high frequency component of the luminance signal is folded into the low frequency component of the luminance signal in recording. At this time, the high frequency component of the luminance signal is modulated by a folding carrier, so that the folded luminance signal has a phase difference of 180 degrees between frames, between scanning lines, and between pixels.
Accordingly, in reproducing, the high frequency component folded into the low frequency component of the folded luminance signal is demodulated by the unfolding carrier having the same phase and frequency as those of the folding carrier, so that the high frequency component of the luminance signal is unfolded to the original frequency band.
However, the folding carrier and the sideband thereof will be present in the unfolded luminance signal. The resultant luminance signal unfolded by the folding carrier and the sidebands thereof has a phase difference of 180 degrees between frames.
As a result, the conventional motion signal detecting circuit for detecting the level difference of pixels between fames as the motion signal, has difficulty in detecting accurately the motion signal from the unfolded luminance signal due to the phase off-set between frames.
More particularly, the unfolding procedure involves the heterodyning, or multiplicative mixing, of the folded-spectrum signal (or the folded-down portion thereof separated by comb filtering) with an unfolding carrier, the horizontal spatial frequency of which is located above the folded spectrum. This unfolding carrier acquires lower and upper sidebands from this multiplicative mixing procedure. The original high-frequency subspectrum, which appears in the folded-spectrum signal as a reversed-in-frequency subspectrum that occupies the same band as the original low-frequency subspectrum, mixes with the unfolding carrier to generate a lower sideband component that reproduces the original high-frequency subspectrum without spectrum reversal. There is also a higher sideband component which reproduces the reversed-in-frequency subspectrum as translated up in frequency, which product of the unfolding procedure can be suppressed by lowpass filtering or bandreject filtering.
In practice, since the folded-spectrum signal is descriptive of both image portions that change from frame to frame and image portions that do not change from frame to frame, separating the folded-down portion of the folded-spectrum signal by comb filtering cannot be done without previously generating a motion signal indicative of frame-to-frame change in the signal prior to its having been folded. As noted previously, such a motion signal cannot be determined from the folded-spectrum signal using highpass frame comb filtering, because in the folded-spectrum signal the frame-to-frame reversal of phase in the folded-down high frequency subspectrum is indistinguishable from frame-to-frame change in the signal prior to its having been folded. U.S. patent application Ser. No. 07/569,029 describes an unfolding procedure in which the complete folded-spectrum signal is mixed with the (un)folding carrier. Then, the resulting product is vertically lowpass filtered to generate an unfolded high-frequency subspectrum that is added back to the complete folded-spectrum signal. In the unfolded signal that results from this additive combining, the low-frequency subspectrum is still accompanied by an overlapping folded-high-frequency subspectrum. Since it is an in-band artifact of unfolding, removal of this undesirable reversed-in-frequency subspectrum cannot be done by the lowpass filtering or bandreject filtering of the prior art.
When the complete folded-spectrum signal is mixed with the (un)folding carrier to generate an unfolded high-frequency subspectrum, there are other undesirable products of the unfolding procedure that arise from the original low-frequency subspectrum multiplicatively mixing with the unfolding carrier. These products exhibit frame-to-frame anti-correlation, so they must be suppressed in signal supplied to a motion detector, or they will be detected to give spurious indications of frame-to-frame image motion. There is an additional upper sideband component of the unfolding carrier, which reproduces the original low-frequency subspectrum as translated up in frequency, and this undesirable product of the unfolding procedure can also be suppressed by lowpass filtering or bandreject filtering. Another undesirable product of the unfolding procedure is an additional lower sideband component of the unfolding carrier which is a reversed-in-frequency subspectrum generated as the difference between the original low-frequency subspectrum and the unfolding carrier. When the horizontal spatial frequency of the folding and unfolding carriers is not much above the uppermost frequency in the original high-frequency subspectrum, this reversed-in-frequency subspectrum occupies the same horizontal-spatial-frequency band as the reproduction of the original high-frequency subspectrum without spectrum reversal. Since it is an in-band artifact of unfolding, removal of this undesirable reversed-in-frequency subspectrum cannot be done by the lowpass filtering or bandreject filtering of the prior art.
The problem of removing the reversed-in-frequency subspectra that are undesirable in-band artifacts of unfolding is solved by applicant and his co-inventors in their U.S. patent application Ser. No. 07/562,907 filed Aug. 6, 1990; entitled "APPARATUS FOR ELIMINATING THE FOLDING CARRIER AND SIDEBANDS FROM THE UNFOLDED VIDEO SIGNAL" and assigned to Samsung Electronics Co., Ltd., which U.S. application corresponds to Korean patent application 90-17610.


The most important data in a first memory of a data processing system are stored in a limited second data memory given upon a transfer thereof. The demarcation between important (and still storable) data on the one hand and less important (and therefore no longer storable) data is made dependent on the available storage volume (SV) of the target data memory. This achieves that an optimal amount of the most important data can be stored on the target data memory.

1. Field of the Invention
The present invention concerns a method for digital storage of data in at least one data memory of a data processing system in a second data memory with limited available storage space.
2. Description of the Prior Art
Although the size of the available storage volumes of modern data memories continues to increase further due to the rapidly progressing technical development of storage media technologies, the limitation of the available storage space in many applications of information technology remains a challenge for the developers of methods and applications of information technology. This is due to the steadily increasing data flood, i.e. in the steadily increasing size of the files in modern applications (multimedia, medical technology etc.), which is often caused by the likewise increasing processor power or improved acquisition methods with higher resolution. Moreover, the importance of portable storage media is increasing, the storage volume of which is primarily limited by requirements of size, weight and production costs.
Important examples are memory cards and chip cards (with or without their own processors) that today are used in multimedia applications or, for example, in a similar form in medical telematics in the form of patient cards ("electronic health insurance cards"). The storage volumes of such storage media are limited and normally cannot be subsequently expanded due to their portability or for cost reasons. Precisely in applications in medical telematics should be expected that a large amount of data (patient data, findings, prescriptions, image data etc.), the total volume of which could quickly exceed the available storage volume, will be stored on such portable storage media in the future.

Method for digital storage of data on a data memory with limited available storage space