The present invention relates to new heterocyclic derivatives having an inhibitory activity on calpains and/or a trapping activity on reactive oxygen species, of formula

The present invention relates to new heterocyclic derivatives having an:,inhibitory activity on calpains and/or a trapping activity on reactive oxygen species (ROS""s). The invention also relates to methods for their preparation, pharmaceutical preparations containing them and their use for therapeutic purposes, in particular as inhibitors of calpains and selective or non-selective ROS traps.
Given the potential role of calpains and ROS""s in physiopathology, the new derivatives according to the invention can produce beneficial or favourable effects in the treatment of pathologies involving these enzymes and/or these radicular species, and in particular:
inflammatory and immunological diseases such as for example rheumatoid arthritis, pancreatitis, multiple sclerosis, inflammation of the gastro-intestinal tract (ulcerative or non-ulcerative colitis, Crohn""s disease),
cardiovascular and cerebrovascular diseases including for example arterial hypertension, septic shock, cardiac or cerebral infarctions of ischemnic or hemorrhagic origin, ischemia as well as disorders linked to platelet aggregation,
disorders of the central or peripheral nervous system such as for example neurodegenerative diseases where there can in particular be mentioned trauma to the brain or spinal cord, sub-arachnoid haemorrhages, epilepsy, ageing, senile dementia, including Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, peripheral neuropathies,
osteoporosis,
muscular dystrophies,
proliferative diseases such as for example atherosclerosis or recurrence of stenosis,
cataracts,
organ transplants,
auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes and its complications, multiple sclerosis,
cancer,
all the pathologies characterized by an excessive production of ROS""s and/or activation of calpains.
In all these pathologies, there is experimental evidence demonstrating the involvement of ROS""s (Free Radic. Biol. Med. (1996) 20, 675-705; Antioxid. Health. Dis. (1997) 4 (Handbook of Synthetic Antioxidants), 1-52) as well as the involvement of calpains (Trends Pharmacol. Sci. (1994) 15, 412419; Drug News Perspect (1999) 12, 73-82). For example, cerebral lesions associated with cerebral infarction or experimental cranial trauma are reduced by antioxidants (Acta Physiol. Scand. (1994) 152, 349-350; 1. Cereb. Blood Flow Metabol. (1995) 15, 948-952; J Pharmacol Exp Ther (1997) 2, 895-904) as well as by inhibitors of calpains (Proc Natl Acad Sci USA (1996) 93, 3428-33; Stroke, (1998) 29, 152-158; Stroke (1994) 25, 2265-2270).
A subject of the present invention is therefore compounds of general formula (I)
in which
R1 represents a hydrogen atom, an xe2x80x94OR3, xe2x80x94SR3, oxo or cyclic acetal radical,
in which R3 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
R4 and R5 represent, independently, a hydrogen atom or an alkyl radical, or R4 and R5 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R2 represents a hydrogen atom, an alkyl, aryl or aralkyl radical, the aryl group being optionally substituted by one or more identical or different radicals chosen from: xe2x80x94OR6, xe2x80x94NR7R8, halogen, cyano, nitro or alkyl,
in which R6, R7 and R8 represent, independently, a hydrogen atom, an alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical;
A represents
either an A1 or Axe2x80x21 radical
xe2x80x83in which R9, R10, R11, R12, R13 represent, independently, a hydrogen atom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitro or xe2x80x94NR15R16 radical,
R15 and R16 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR17 group, or R15 and R16 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R17 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR18R19 radical,
R18 and R19 represent, independently, a hydrogen atom or an alkyl radical, or R18 and R19 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R14 represents a hydrogen atom, an alkyl radical or a xe2x80x94COR20 group,
R20 represents a hydrogen atom, an alkyl, alkoxy, aryl, aralkyl, heterocycloalkyl or xe2x80x94NR21R22 radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
R21 and R22 represent, independently, a hydrogen atom or an alkyl radical, or R21 and R22 together with the nitrogen atom to which they are, attached form an optionally substituted heterocycle,
W represents a bond, O or S or also an xe2x80x94NR23 radical, in which R23 represents a hydrogen atom or an alkyl radical;
or an A2 radical
xe2x80x83in which
R24, R25 and R26 represent, independently, a hydrogen, a halogen, the OH or SR27 group, an alkyl, alkenyl, alkoxy radical or an xe2x80x94NR28R29 radical,
R27 represents a hydrogen atom or an alkyl radical,
R28 and R29 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR30 group, or R28 and R29 form together with the nitrogen atom to which they are attached an optionally substituted heterocycle,
R30 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR31R32 radical,
R31 and R32 represent, independently, a hydrogen atom or an alkyl radical, or R31 and R32 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
Q represents xe2x80x94OR33, xe2x80x94SR33, xe2x80x94NR34R35 or an aryl radical substituted by one or more identical or different substituents chosen from: halogen, the OH group, an alkyl, alkoxy, cyano, nitro or xe2x80x94NR15R16 radical,
R33 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
R34 and R35 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COxe2x80x94R36 radical, or together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R36 representing an alkyl radical;
or an A3 radical
xe2x80x83in which R37 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
T represents a xe2x80x94(CH2)mxe2x80x94 radical with m=1 or 2;
or an A4 radical
in which R38 represents a hydrogen atom, an alkyl, xe2x80x94(CH2)qxe2x80x94NR39R40 or aralkyl radical, the aryl group being optionally substituted by one or more identical or different substituents chosen from: OH, alkyl, halogen, nitro, alkoxy or xe2x80x94NR39R40,
q being an integer comprised between 2 and 6;
or an A5 radical
xe2x80x83in which Rxe2x80x238 and Rxe2x80x338 represent independently a hydrogen atom, nitro, xe2x80x94NRxe2x80x239Rxe2x80x240, an alkyl or arylalkyl radical, the aryl group being optionally substituted by one or more identical or different substituents chosen from: OH, the alkyl, halogen, nitro, alkoxy or xe2x80x94NR39R40 radicals,
Rxe2x80x239, Rxe2x80x240, R39 and R40 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR41 group, or R39 and R40 or Rxe2x80x239 and Rxe2x80x240 together with the nitrogen atom form an optionally substituted heterocycle,
R41 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR42R43 radical,
R42 and R43 represent, independently, a hydrogen atom or an alkyl radical, or R42 and R43 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
T representing a xe2x80x94(CH2)mxe2x80x94 radical with m=1 or 2,
or finally an A6 radical
in which R44 represents a hydrogen atom, the OH group or an alkyl or alkoxy radical;
X represents xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94(CHn)2xe2x80x94COxe2x80x94, xe2x80x94N(45)xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94NHxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94Sxe2x80x94(CH2)n,xe2x80x94COxe2x80x94 or xe2x80x94Zxe2x80x94COxe2x80x94;
D represents a phenylene radical optionally substituted by one or more identical or different radicals chosen from alkyl, alkoxy, OH, nitro, halogen, cyano, or carboxyl optionally esterified by an alkyl radical;
Z represents a heterocycle,
R45 represents a hydrogen atom or an alkyl radical,
R46 and R47 represent, independently, a hydrogen atom, an alkyl, aryl or aralkyl radical the alkyl and aryl groups of which are optionally substituted by one or more identical or different substituents chosen from: the OH, xe2x80x94SH, halogen, nitro, alkyl, alkoxy, alkylthio, aralkoxy, aryl-alkylthio, xe2x80x94NR48R49 and carboxyl group optionally esterified by an alkyl radical;
R48 and R49 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR50 group, or R48 and R49 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R50 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR51R52 radical,
R51 and R52 represent, independently, a hydrogen atom or an alkyl radical, or R51 and R52 together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle;
n being an integer comprised between 0 and 6;
Y represents xe2x80x94(CH2)pxe2x80x94, xe2x80x94C(R53R54)xe2x80x94(CH2)pxe2x80x94, xe2x80x94C(R53R54)xe2x80x94COxe2x80x94;
R53 and R54 represent, independently, a hydrogen atom, an alkyl radical, an aralkyl radical the aryl group of which is optionally substituted by one or more identical or different substituents chosen from: the OH, halogen, nitro, alkyl, alkoxy, xe2x80x94NR55R56 group,
R55 and R56 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR57 group, or R55 and R56 together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle,
R57 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR58R59 radical,
R58 and R59 represent, independently, a hydrogen atom or an alkyl radical, or R58 and R59 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle;
p being an integer comprised between 0 and 6;
Het represents a heterocycle,
as well as the addition salts with mineral and organic acids or with mineral and organic bases of said compounds of general formula (I),
with the exception of the compounds of formula (I) in which when Het represents tetrahydrofuran or tetrahydropyran, R1 represents the OR3 radical with R3 representing a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl radical the heterocycloalkyl radical of which is connected by a carbon atom, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical, R2 represents a hydrogen and Y represents the xe2x80x94(CH2)pxe2x80x94radical with p=0, then X does not represent xe2x80x94COxe2x80x94N(R45)xe2x80x94C(R46R47)xe2x80x94COxe2x80x94 with R45=R46=H.
In certain cases, the compounds according to the present invention can comprise asymmetrical carbon atoms (of xe2x80x9cRxe2x80x9d or xe2x80x9cSxe2x80x9d configuration). As a result, the present invention includes the enantiomeric, diastereoisomeric forms and all combinations of these forms, including the xe2x80x9cRSxe2x80x9d racemic mixtures. In an effort to simplify matters, when no specific configuration is indicated in the structural formulae, it should be understood that the two enantiomeric (or diastereoisomeric) forms and their mixtures are represented.
By alkyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms such as, for example, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. The alkoxy radicals can correspond to the alkyl radicals indicated above such as for example the methoxy, ethoxy, propyloxy or isopropyloxy radicals but also linear, secondary or tertiary butoxy. Similarly the alkylthio radicals can correspond to the alkyl radicals indicated above such as for example methylthio or ethylthio.
By alkenyl, unless otherwise specified, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one unsaturation (double bond). By halogen, is meant the fluorine, chlorine, bromine or iodine atoms.
By aryl, is meant a carbocyclic or heterocyclic system comprising at least one aromatic ring, a system being called heterocyclic when at least one of the rings composing it comprises a heteroatom (O, N or S). As an example of a carbocyclic aryl radical, there can be mentioned phenyl or naphthyl. As an example of a heterocyclic aryl radical (or heteroaryl), there can be mentioned thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidyl, benzothienyl, benzofuryl and indolyl.
The term heterocycle (or heterocycloalkyl), represented for example by the Het or Z radicals, preferably represents a saturated or unsaturated, mono or bicyclic heterocycle, comprising 1 to 5 heteroatoms chosen from O, S, N. The nitrogen atom can optionally be substituted by a radical chosen from: alkyl, aryl, aralkyl and alkylcarbonyl. As an example of a saturated heterocycle, there can be mentioned tetrahydrofuran, tetrahydropyran, oxetane, oxepane, tetrahydrothiophene, tetrahydrothiopyran, thietane, pyrrolidine, piperidine, azetidine, 1,3-dioxane, 1,3-dioxolane, 1,3-dithiolane, 1,3-dithiane, 1,3-oxathiolane, 1,3-oxazolidine, 1,3-imidazolidine or 1,3-thiazolidine. As an example of an unsaturated heterocycle, there can be mentioned: thiophene, furan, pyrrol, imidazole, pyrazole, isothiazole, thiazole, isoxazole, oxazole, pyridine, pyrazine, pyrimidine, benzimidazole, benzofun, benzopyran, 1,3-benzothiazole, benzoxazole, quinoline.
The arylalkyl (or aralkyl) radicals designate the radicals in which the aryl and alkyl radicals respectively are as defined above such as for example benzyl, phenylethyl or naphthylmethyl. The aralkoxy (aryl-alkoxy) radicals designate the radicals in which the aryl and alkoxy radicals respectively are as defined above such as for example benzyloxy or phenylethoxy. The arylalkylthio radicals designate the radicals in which the aryl and alkylthio radicals respectively are as defined above such as for example benzylthio.
The alkylcarbonyl, heterocycloalkylcarbonyl, arylcarbonyl or aralkylcarbonyl radicals designate the radicals in which the alkyl, heterocycloalkyl, aryl and aralkyl radicals respectively have the meaning indicated previously.
In the case of radicals of formula xe2x80x94NRiRj where Ri and Rj together with the nitrogen atom to which they are attached form an optionally substituted heterocycle, the heterocycle is preferably saturated and comprises 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms. Said heterocycle can be, for example, the azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine ring. Said heterocycle can be substituted by one or more identical or different substituents chosen from the hydroxy group, an alkyl, aryl, aralkyl or alkoxy radical or a halogen atom.
A more particular subject of the invention is the compounds of formula (I) as defined above, in which Het represents a monocyclic radical containing 1 to 2 heteroatoms chosen from O and N, and preferably a radical corresponding to the tetrahydrofuran, dioxolane, pyrrolidine, 1,3-oxazolidine ring, and R1 represents the hydrogen atom, the xe2x80x94OR3 or oxo radical.
A more particular subject of the invention is the compounds of formula (I) as defined above, in which X represents xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94NHxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94C(R46R47)xe2x80x94COxe2x80x94 or xe2x80x94Zxe2x80x94COxe2x80x94,
and preferentially when R45 and R47 represent the hydrogen atom, R46 represents the hydrogen atom, an alkyl or phenyl radical, D represents the phenylene radical and Z represents the thiazole radical.
A more particular subject of the invention is also compounds of formula (I) as defined above, in which R2 represents a hydrogen atom or an aralkyl radical, and preferably the benzyl radical.
A more particular subject of the invention is also compounds of formula (I) as defined above, in which A represents
either A1 with W representing the sulphur atom,
or Axe2x80x21
or A2 with R24, R25 and R26 which represent, independently, a hydrogen or an alkyl radical and Q which represents xe2x80x94OR33,
or A3 with T representing the xe2x80x94(CH2)2xe2x80x94radical;
or A4 with T representing the xe2x80x94(CH2)xe2x80x94radical,
and preferably the radicals of formula
A more particular subject of the invention is also the compounds described hereafter in the examples and preferably the products corresponding to the following formulae:
(2R)-6-hydroxy-N-[(3S)-2-hydroxytetrahydro-3-furayl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;
N-1-(4-anilinophenyl)-N-4-[(3S)-2-hydroxytetrahydro-3-furanyl]succinamide;
(3S)-3-{[4-(4-anilinoanilino)-4-oxobutanoyl]amino}tetrahydro-2-furanyl acetate;
N-1-(4-anilinophenyl)-N-4-[(1S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl]succinamide;
N-1-(4-anilinophenyl)-N-3-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenylmalonamide;
3-(4-anilinoanilino)tetrahydro-2-furanol;
N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)-amino]pentanoyl}amino)tetrahydro-2-furanyl acetate;
N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;
N-[4-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;
N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl pivalate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)-tetrahydro-2-furanyl3,3dimethylbutanoate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl benzoate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl phenylacetate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl (2S)-2-(dimethylamino)-3-phenylpropanoate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl 4-morpholinecarboxylate;
N-{(1S)-3-methyl-1-[(3-oxo-1-pyrrolidinyl)carbonyl]butyl}-10H-phenothiazine-2-carboxanmide;
2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-hydroxytetrahydro-3-furanyl]acetamide;
N1-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenyl-N3-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide;
N-(2-anilinophenyl)-Nxe2x80x2-[(3S)-2-hydroxytetrahydro-3-furanyl]urea;
Nxe2x80x2-[(3S)-2-hydroxytetrahydro-3-furanyl]-N2-(1-propyl-2,3-dihydro-1H-indol-5-yl)ethanediamnide;
(2R)-N-[(1S)-1-(1,3-dioxolan-2-yl)-2-phenylethyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;
N-[(3S)-2-hydroxytetrahydro-3-furanyl]-5-indolinecarboxamide.
The compounds of formula I according to the invention can be prepared via several synthesis routes according to the definition of the variable groups.
The compounds of general formula (I) in which Het represents the tetrahydrofuran ring and Y represents the xe2x80x94(CH2)p radical, can be prepared according to the following diagram:
in which A, X, R2 and R3 are as described above, by condensation of the acids of general formula (II) on the amines of general formula(III), under standard conditions for peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1xe2x80x2-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)) in order to produce the intermediate carboxamides of general formula (IV). The lactonic ring of the intermediates of general formula (IV) is then reduced using a reducing agent such as, for example, diisobutylaluminium hydride (DIBAL), in an inert solvent such as, for example, THF or CH2Cl2, at a temperature varying from 0 to xe2x88x9278xc2x0 C. The lactol derivative of general formula (Ixe2x80x2) obtained in this 1 s way can be acylated using, for example, an acid chloride (R3xe2x80x94Cl) or an acid anhydride (acetic anhydride, benzoyl chloride, etc.) in the presence of a base such as, for example, triethylamine, in an inert solvent such as for example CH2Cl2 in order to produce the compound of general formula (I).
The compounds of formula (I) in which Het represents the pyrrolidinyl radical and Y represents xe2x80x94C(R53R54)xe2x80x94COxe2x80x94, R53 and R54 being as defined above, can be prepared according to the following diagram:
in which A, X and R2 are as described above, by condensation of the acids of general formula (V) on the amines of general formula (VI) (J. Med. Chem. (1992) 35 (8), 1392-1398) under standard conditions for peptide synthesis, as described previously, in order to produce the compounds of general formula (Ixe2x80x2). The optional deprotection of the ketone function is then carried out according to the methods described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)), in order to produce the compounds of general formula (I).
The compounds of formula (I) in which Het represents the 1,3-dioxolane, 1,3-dioxane, 1,3-dithiane, 1,3-dithiolane, 1,3-oxathiolane, 1,3-oxazolidine, 1,3-imidazolidine or 1,3-thiazolidine ring, and Y represents xe2x80x94C(R53R54)xe2x80x94COxe2x80x94, R53 and R54 being as defined above, can be prepared according to the following diagram:
in which A, X and R2 are as described above and V and Vxe2x80x2 represent independently N, O or S, by condensation of the acids of general formula (II) described previously, on the commercial amino-esters of general formula (VII), under the standard conditions for peptide synthesis described previously, in order to produce the intermediates of general formula (VIII). Reduction of the carboxylic ester using a reducing agent such as, for example, DIBAL, in an inert solvent such as, for example, THF or CH2Cl2, at a temperature varying from 0 to xe2x88x9278xc2x0 C., leads to the aldehydes of general formula (IX). Conversion of the aldehyde to a heterocycle is carried out according to the methods in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)).
The compounds of formula (I) in which Het represents the oxazolidine ring can be prepared according to the following diagram:
in which A, X, Y, R2 and R3 are as described above, by condensation of the acids of general formula (V) described previously, with the commercial amino-esters of general formula (X) under the peptide synthesis conditions described previously. The esters of general formula (XI) obtained intermediately are then saponified in order to produce carboxylic acids of general formula (XII), which by heating in the presence of paraformaldehyde and of an acid such as, for example, PTSA, while continually trapping the water formed during the reaction using a device of Dean-Stark type, lead to the oxazolidinones of general formula (XIlI). These are then reduced using a reducing agent such as, for example, DIBAL, in an inert solvent such as, for example, THF or CH2Cl2, at a temperature varying from 0 to xe2x88x9278xc2x0 C. in order to produce oxazolidine derivatives of general formula (Ixe2x80x2). The compounds of general formula (Ixe2x80x2) obtained in this way can be acylated using, for example, an acid chloride (R3xe2x80x94Cl) or an acid anhydride (acetic anhydride, benzoyl chloride, etc.) in the presence of a base such as, for example, triethylamine, in an inert solvent such as for example CH2Cl2 in order to produce the compounds of formula (I).
The compounds of general formula (I) in which Het represents the tetrahydrofuran ring, X represents the xe2x80x94(CH2)nxe2x80x94 radical (n=0) and Y represents the xe2x80x94(CH2)pxe2x80x94 radical (p=0), can also be prepared according to the following diagram:
in which A, R2 and R3 are as described above, by nucleophilic substitution of the halogen of the lactones of general formula (XV) using the amines of general formula (II.1), while heating the reaction mixture to a temperature varying from 50 to 110xc2x0 C. in an inert solvent such as for example, acetonitrile or DMF, for a duration varying from 30 minutes to 5 hours, in order to produce the intermediates of general formula (XV). Reduction of the lactone function followed by acylation of the lactol of general formula (Ixe2x80x2) are carried out under the conditions described previously.
The compounds of general formula (I) in which Het represents the tetrahydrofuran ring, X represents the xe2x80x94N(R45)xe2x80x94(CH2)nxe2x80x94COxe2x80x94 radical (n=0) and Y represents the xe2x80x94CH2)pxe2x80x94 radical (p=0) are ureas which can be prepared according to the following synthesis diagram:
in which A, R2 and R3 are as described above, by condensation of the amines of general formula (II.1) with the amines of general formula (III) in the presence of triphosgene and of a base such, as, for example, diisopropylethylamine in an inert solvent such as dichloromethane according to an experimental protocol described in J. Org. Chem. (1994) 59 (7), 1937-1938. The lactonic ring of the ureas of general formula (XVI) is then reduced and modified under the experimental conditions described previously in order to produce the compounds of general formula (I).
The compounds of the present invention have useful pharmacological properties: they have an inhibitory activity on calpains and/or a trapping activity on reactive oxygen species.
The compounds of the present invention can thus be used for different therapeutic applications. They can produce beneficial or favourable effects in the treatment of pathologies where these enzymes and/or these radicular species occur.
These properties render the products of formula I suitable for pharmaceutical use. A subject of the present Application is also, as medicaments, the products of formula I as defined above, as well as the addition salts with pharmaceutically acceptable mineral or organic acids or mineral or organic bases of said products of formula I, as well as the pharmaceutical compositions containing, as active ingredient, at least one of the medicaments as defined above.
The invention therefore relates to pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable addition salt of the latter, in combination with a pharmaceutically acceptable support. The pharmaceutical composition can be in the form of a solid, for example, powders, granules, tablets, gelatin capsules or suppositories. The appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water, added to pharmaceutically acceptable oils or greases. Sterile liquid compositions can be used for intramuscular, intraperitoneal or sub-cutaneous injections and sterile compositions can also be administered intravenously.
Certain compounds of general formula I described previously are covered by the Application EP 641800. The compounds of this Application have an inhibitory activity on cathepsine L which is different from the inhibitory activity on calpains and/or the trapping activity on reactive oxygen species.
A subject of the invention is therefore also the use of compounds of formula (Ia) as defined above,
in racemic, enantiomeric, diastereoisomeric form or all combinations of these forms, in which
Ra1 represents a hydrogen atom, an xe2x80x94OR3, xe2x80x94SR3, oxo or cyclic acetal radical,
in which R3 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
R4 and R5 represent, independently, a hydrogen atom or an alkyl radical, or R4 and R5 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
Ra2 represents a hydrogen atom, an alkyl, aryl or aralkyl radical, the aryl group being optionally substituted by one or more identical or different radicals chosen from: xe2x80x94OR6, xe2x80x94NR7R8, halogen, cyano, nitro or alkyl,
in which R6, R7 and R8 represent, independently, a hydrogen atom, an alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical;
Aa represents
either an A1 or Axe2x80x21 radical
in which R9, R10, R11, R12, R13 represent, independently, a hydrogen atom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitro or xe2x80x94NR15R16 radical,
R15 and R16 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR17 group, or R15 and R16 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R17 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR18R19 radical,
R18 and R19 represent, independently, a hydrogen atom or an alkyl radical, or R18 and R19 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R14 represents a hydrogen atom, an alkyl radical or a xe2x80x94COR20 group,
R20 represents a hydrogen atom, an alkyl, alkoxy, aryl, aralkyl, heterocycloalkyl or xe2x80x94NR21R22 radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
R21 and R22 represent, independently, a hydrogen atom or an alkyl radical, or R21 and R22 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
W represents a bond, O or S or also an xe2x80x94NR23 radical, in which R23 represents a hydrogen atom or an alkyl radical;
or an A2 radical
xe2x80x83in which
R24, R25 and R26 represent, independently, a hydrogen, a halogen, the OH or SR27 group, an alkyl, alkenyl, alkoxy radical or an xe2x80x94NR28R29 radical,
R27 represents a hydrogen atom or an alkyl radical,
R28 and R29 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR30 group, or R28 and R29 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R30represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR31R32 radical,
R31 and R32 represent, independently, a hydrogen atom or an alkyl radical, or R31 and R32 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
Q represents xe2x80x94OR33, xe2x80x94SR33, xe2x80x94NR34R35 or an aryl radical substituted by one or more identical or different substituents chosen from: halogen, the OH group, an alkyl, alkoxy, cyano, nitro or xe2x80x94NR15R16 radical,
R33 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
R34 and R35 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COxe2x80x94R36 radical, or together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R36 representing an alkyl radical;
or an A3 radical
in which R37 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
T represents a xe2x80x94(CH2)mxe2x80x94 radical with m=1 or 2;
or an A4 radical
in which R38 represents a hydrogen atom, an alkyl, xe2x80x94(CH2)qxe2x80x94NR39R40 or aralkyl radical, the aryl group being optionally substituted by one or more identical or different substituents chosen from: OH, alkyl, halogen, nitro, alkoxy or xe2x80x94NR39R40,
q being an integer comprised between 2 and 6;
or an A5 radical
in which Rxe2x80x238 and Rxe2x80x338 represent independently a hydrogen atom, nitro, xe2x80x94NRxe2x80x239Rxe2x80x240, an alkyl or arylalkyl radical, the aryl group being optionally substituted by one or more identical or different substituents chosen from: OH, the alkyl, halogen, nitro, alkoxy or xe2x80x94NR39R40 radicals,
Rxe2x80x239, Rxe2x80x240, R39 and R40 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR41 group, or R39 and R40 or Rxe2x80x239 and Rxe2x80x240 together with the nitrogen atom form an optionally substituted heterocycle,
R41 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR42R43 radical,
R42 and R43 represent, independently, a hydrogen atom or an alkyl radical, or R42 and R43 together with the nitrogen atom to which they are .attached form an optionally substituted heterocycle,
T representing a xe2x80x94(CH2)mxe2x80x94 radical with m=1 or 2,
or finally an A6 radical
in which R44 represents a hydrogen atom, the OH group or an alkyl or alkoxy radical;
Xa represents xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94(CH2)nxe2x80x94COxe2x80x94,xe2x80x94N(R45)xe2x80x94COxe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94NHxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94Sxe2x80x94(CH2)n,xe2x80x94COxe2x80x94 or xe2x80x94Zxe2x80x94COxe2x80x94;
D represents a phenylene radical optionally substituted by one or more identical or different radicals chosen from alkyl, alkoxy, OH, nitro, halogen, cyano, or carboxyl to optionally esterified by an alkyl radical;
Z represents a heterocycle,
R45 represents a hydrogen atom or an alkyl radical,
R46 and R47 represent, independently, a hydrogen atom, an alkyl, aryl or aralkyl radical the alkyl and aryl groups of which are optionally substituted by one or more identical or different substituents chosen from: the OH, xe2x80x94SH, halogen, nitro, alkyl, alkoxy, alkylthio, aralkoxy, aryl-alkylthio, xe2x80x94NR48R49 and carboxyl group optionally esterified by an alkyl radical;
R48 and R49 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR50 group, or R48 and R49 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R50 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR51R52 radical,
R51 and R52 represent, independently, a hydrogen atom or an alkyl radical, or R51 and R52 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle;
n being an integer comprised between 0 and 6;
Ya represents xe2x80x94(CH2)pxe2x80x94, xe2x80x94C(R53R54)xe2x80x94(CH2)pxe2x80x94, xe2x80x94C(R53R54)xe2x80x94COxe2x80x94;
R53 and R54 represent, independently, a hydrogen atom, an alkyl radical, an aralkyl radical the aryl group of which is optionally substituted by one or,more identical or different substituents chosen from: the OH group, halogen, nitro, alkyl, alkoxy, xe2x80x94NR55R56,
R55 and R56 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR57 group, or R55 and R56 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R57 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR58R59 radical,
R58 and R59 represent, independently, a hydrogen atom or an alkyl radical, or R58 and R59 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle;
p being an integer comprised between 0 and 6;
Heta represents a heterocycle,
as well as addition salts with mineral and organic acids or with mineral and organic bases of said compounds of general formula (I),
for the preparation of medicaments for the treatment of pathologies where calpains and/or reactive oxygen species are involved.
A more particular subject of the invention is the use of compounds of formula (Ia) as defined above, for the preparation of medicaments for the treatment of pathologies involving reactive oxygen species. A more particular subject of the invention is also the use of compounds of formula (Ia) as defined above, for the preparation of medicaments for the treatment of pathologies involving reactive oxygen species and calpains. The invention therefore relates to the use of compounds of formula (Ia) as defined above, for the preparation of medicaments for the treatment of pathologies such as inflammatory and immunological diseases, cardiovascular and cerebrovascular diseases, disorders of the central or peripheral nervous system, osteoporosis, muscular dystrophy, proliferative diseases, cataracts, organ transplants, auto-immune and viral diseases, cancer, and all pathologies characterized by an excessive production of ROS""s and/or the activation of calpains.
A more particular subject of the invention is the use of compounds of formula (Ia) as defined above, characterized in that Het represents a monocyclic radical containing 1 to 2 heteroatoms chosen from O and N. Preferentially, Het represents tetrahydrofuran, dioxolane, pyrrolidine, 1,3-oxazolidine, and R1 represents the hydrogen atom, the xe2x80x94OR3 or oxo radical.
A more particular subject of the invention is the use of compounds of formula (Ia) as defined above, characterized in that X represents xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94Zxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94NHxe2x80x94C(R46R47)xe2x80x94COxe2x80x94 or xe2x80x94COxe2x80x94N(R45)xe2x80x94C(R46R47)xe2x80x94CO and preferentially when R45 and R47 represent the hydrogen atom, R46 represents the hydrogen atom, an alkyl or phenyl radical, D represents the phenylene radical and Z represents the thiazole radical.
A more particular subject of the invention is the use of compounds of formula (Ia) as defined above characterized in that R2 represents a hydrogen atom or an aralkyl radical, and preferably the benzyl radical.
A more particular subject of the invention is the use of compounds of formula (Ia) as defined above characterized in that A represents either A1 with W representing the sulphur atom; or Axe2x80x21; or A2 together with R24, R25 and R26 which represent, independently, a hydrogen or an alkyl radical and Q which represents xe2x80x94OR33; or A3 together with T representing the xe2x80x94(CH2)2xe2x80x94 radical; or A4 together with T representing the xe2x80x94(CH2)xe2x80x94 radical. Preferably, A represents a radical chosen from
A more particular subject of the invention is also the use as defined above, of compounds of formula (Ia) as described in the examples and preferentially the compounds which correspond to one of the following formulae:
(2R)-6-hydroxy-N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;
N-1-(4-anilinophenyl)-N-4-[(3S)-2-hydroxytetrahydro-3-furanyl]succinamide;
(3S)-3-{[4-(4-anilinoanilino)-4-oxobutanoyl]amino}tetrahydro-2-furanyl acetate;
N-1-(4-anilinophenyl)-N-4-[(1S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl]succinamide;
N-1-(4-anilinophenyl)-N-3-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenylmalonamide;
3-(4-anilinoanilino)tetrahydro-2-furanol;
N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl acetate;
N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;
N-[4-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;
N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl pivalate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl 3,3-dimethylbutanoate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl benzoate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl phenylacetate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl (2S)-2-(dimethylamino)-3-phenylpropanoate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl 4-morpholinecarboxylate;
N-{(1S)-3-methyl-1-[(3-oxo-1-pyrrolidinyl)carbonyl]butyl}-10H-phenothiazine-2-carboxamide;
2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-hydroxytetrahydro-3-furanyl]acetamide;
N1-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenyl-N3-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide;
N-(2-anilinophenyl)-Nxe2x80x2-[(3S)-2-hydroxytetrahydro-3-furanyl]urea;
N1-[(3S)-2-hydroxytetrahydro-3-furanyl]-N2-(1-propyl-2,3-dihydro-1H-indol-5-yl)ethanediamide;
(2R)-N-[(1S)-1-(1,3-dioxolan-2-yl)-2-phenylethyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;
N-[(3S)-2-hydroxytetrahydro-3-furanyl]-5-indolinecarboxamide.
The non-commercial synthesis intermediates of formula (II), (III) and (V) can be prepared according to the different synthesis routes below:
1) Synthesis of Intermediates (II)
The carboxylic acids of general formula (II), in which A, X, D, n, R45, R46 and R47 are as described above, are accessible from the following synthetic diagrams:
1.1) Starting from A-NH(R45)
The preparation of carboxylic acids of general formula (II) can be carried out, in this case, from 3 different acid-ester derivatives (II.2), (II.4) and (II.6):
The condensation of the anilines of general formula (II.1) with commercial acid-esters (Alk=Alkyl) of general formula (II.2), Diagram 1.1, is carried out by standard peptide condensation. The carboxarnide obtained intermediately (II.3) is then saponified in order to produce the carboxylic acids of general formula (II). The synthesis of the intermediates of general formula (II.1) is described below.
The synthesis of the carboxylic acids of general formula (II) can also be carried out by condensation of the anilines of general formula (II.1) with the acid-ester derivatives of general formula (II.4) under the conditions described previously. This condensation is followed by standard saponification in order to produce acids of general formula (II). The synthesis of intermediates of general formula (II.4) is described below.
The condensation of the amines of general formula (II.1) with the commercial aromatic acids of general formula (II.6), under standard peptide synthesis conditions described already, after saponification of the intermediates of general formula (II.7) also leads to carboxylic acids of general formula (II).
Alternatively, the carboxylic acids of general formula (II) are also accessible by opening cyclic anhydrides such as for example succinic anhydride, using the amines of general formula (II.1) according to an experimental protocol described in the literature (J. Amer. Chem. Soc. (1951) 73, 4007).
1.1.1) Preparation of Intermediates (II.1)
The non-commercial anilines of general formula (II.1), derivatives of indoline or 1,2,3,4-tetrahydroquinoline, Diagram 1.1.1, in which T and R38 are as defined above, can be prepared from the corresponding nitro derivatives of general formula (II.1.1). 6-nitro-1,2,3,4-tetrahydroquinoline is described in Can. J. Chem. (1952), 30, 720-722. Alkylation of the amine is carried out in a standard fashion using a strong base such as, for example, NaH, in a polar aprotic solvent such as, for example, DMF in the presence of a halogenated derivative R38-Hal, such as for example 3-dimethylaminopropanol chloride or benzyl bromide. The nitro derivative of general formula (II.1.2) obtained intermediately is then reduced, for example, by Raney Nickel in the presence of hydrazine hydrate in order to produce the anilines of general formula (II.1).
Moreover, certain non-commercial derivatives of phenylenediamines of general formula (II.1) can be prepared according to Farmaco (1951) 6,713-717.
In the particular case where A is a phenolic derivative (A=A2), the anilines of general formula (II.1) are obtained by hydrogenation, in the presence of Pd/C, of the nitrophenol derivative precursors. The nitrated derivatives of di-alkyl phenols are accessible according to the methods described in J. Org. Chem. (1968) 33 (1), 223-226 or J. Med. Chem. (1998), 41, 1846-1854.
The intermediates of general formula (II.1) in which Axe2x80x21 is a diphenylamine are accessible via the methods described in the literature (Synthesis (1990) 430; Indian J. Chem. (1981) 20B, 611-613; J. Med. Chem. (1975) 18 (4), 386-391) which involve the reduction of a nitrodiphenylamine intermediate. Reduction of the nitro function is carried out in a standard fashion by hydrogenation in the presence of a catalytic quantity of Pd/C in order to access the aminodiphenylamines of general formula (II.1).
When A is a carbazole derivative (W then represents a direct bond), the methods for preparing the aminocarbazoles of general formula (II.1) involve the synthesis of a nitrocarbazole intermediate. These methods are described in Pharmazie (1993) 48 (11), 817-820; Synth. Commun. (1994) 24(1), 1-10; J. Org. Chem. (1980),45, 1493-1496; J. Org. Chem. (1964) 29 (8), 2474-2476; Org. Prep. Proced. Int. (1981) 13 (6), 419-421 or J. Org. Chem. (1963) 28, 884. Reduction of the nitro function of the nitrocarbazole intermediates is, in this case, preferably carried out using hydrazine hydrate in the presence of Raney Nickel.
The intermediates of general formula (II.1) in which A is a phenothiazine derivative (W represents a sulphur atom), are accessible via methods in the literatures which involve the synthesis of a nitrophenothiazine derivative. In particular 3-nitrophenothiazine is described in J. Org. Chem. (1972) 37, 2691. The reduction of the nitro function in order to access the aminophenothiazines of general formula (II.1) is carried out in a standard fashion by hydrogenation in the presence of a catalytic quantity of Pd/C in a solvent such as ethanol.
1.1.2) Preparation of Intermediates (II.4)
The acid-esters of general formula (II.4), Diagram 1.1.2, can be prepared from the commercial diesters of general formula (II.4.1) according to a method described in the literature (Tetrahedron Asymmetry (1997) 8(11), 1821-1823).
1.2) Starting from A-CO2H
The carboxylic acid intermediates of general formula (II) are also accessible via the condensation of the carboxylic acids of general formula (II.8) with the commercial amino-esters of general formula (II.9A) or (II.9B), Diagram 1.2, during a peptide synthesis stage described previously. The carboxamides obtained intermediately (II.10A) and (II.10B) are then saponified in order to produce the carboxylic acids of general formula (II).
1.2.1) Preparation of Intermediates (II.8)
The carboxylic derivatives of general formula (II.8), which are not commercially accessible, can be prepared from the literature (e.g.: J. Org. Chem. (1961) 26, 1221-1223; Acta Chem. Scandinavica (1973) 27, 888-890; Can. J. Chem. (1972),50, 1276-1282; J. Med. Chem. (1992) 35(4), 716-724; J. Org. Chem. (1989) 54, 560-569; J. Med. Chem. (1998) 41(2), 148-156; Bull. Soc. Chim. Fr. (1960), 1049-1066)).
1.3) Starting from A-OH or A-SH
The acids of general formula (II) (Diagram 1.3) in which X represents xe2x80x94Oxe2x80x94(CH2)nxe2x80x94COxe2x80x94, are prepared from the hydroquinones of general formula (II.11) obtained according to the literature (J. Chem. Soc. Perkin 1 (1981) 303-306). The condensation on commercial halogen esters of general formula (II.12) is carried out in the presence of a base such as, for example K2CO3, by heating in a polar solvent such as, for example, THF for at least 5 hours. The esters of general formula (II.13) intermediately obtained are then deprotected (in an acid medium in the case of tert-butyl esters) in order to produce acids of general formula (II).
The acids of general formula (II) in which X represents xe2x80x94Sxe2x80x94(CH2)nxe2x80x94COxe2x80x94, are prepared according to a method in the literature (J. Med. Chem. (1997) 40(12), 1906-1918).
1.4) Starting from A-CO2H, when Z represents a heterocycle with V=S or O
1.4.a) In the case where Z represents an unsaturated heterocycle, the carboxylic acids of general formula (II), Diagram 1.4a, can be prepared from carboxylic acids of general formula (II.8).
The formation of the primary carboxamide of general formula (II.14) is carried out according to an experimental protocol described in the literature (Synthesis (1989), 1, 37). By heating, between 50xc2x0 C. and reflux of the solvent, for a time comprised between 1 and 15 hours, intermediate (II.14) in the presence of an alkyl bromopyruvate, the oxazoles (V xe2x95x90O) of general formula (II.16) are obtained. Alternatively, the thiazoles (Vxe2x95x90S) of general formula (II.16), are accessible in two stages from the carboxamides of general formula (II.14). These, in the presence of Lawesson""s reagent in a solvent such as, for example, 1,4-dioxane, lead in a standard fashion to the thiocarboxamides of general formula (II.15). The cyclization stage is then carried out in the presence of alkyl bromopyruvate as described previously. The carboxylic acids of general formula (II) are finally obtained by deprotection of the acid function under standard conditions.
1.4.b) In the case where Z represents a saturated heterocycle, and in particular a thiazolidine, the carboxylic acids of general formula (II), Diagram 1.4b, are also accessible from the carboxylic acids of general formula (II.8).
The preparation of the aldehydes of general formula (II.17) is carried out in a standard fashion after activation of the acid function of the intermediates of general formula (II.8) in the form of an ester or an alkylhydroxamate, in the presence of DIBAL or of LiAlH4, according to the experimental protocols in the literature (e.g. J. Med. :Chem. (1990) 33, 11-13). The reaction of these aldehydes with cysteine in the presence of acetate salts leads directly to the thiazolidines of general formula (II.18) according to an experimental protocol described in J. Org. Chem. (1957) 22, 943-946. The amine of the thiazolidine ring is then protected in the form of a carbamate (e.g. Boc) under standard conditions in the literature in order to produce the carboxylic acids of general formula (II).
1.5) Starting from A-N(R45)xe2x80x94COxe2x80x94
The carboxylic acids of general formula (II), in which X=xe2x80x94N(R45)xe2x80x94(CH2)nxe2x80x94COxe2x80x94 with n=0, are constituted by a chain functionalized by a urea, Diagram 1.5.
The synthesis of these ureas is carried out by condensation of the amines of general formula (II.1) with the aminoesters of general formula (II.9) in the presence of triphosgene and a tertiary amine according to an experimental protocol described in the literature (J. Org. Chem. (1994), 59(7), 1937-1938) in order to produce the intermediates of general formula (II.19). The carboxylic acid of general formula (II) is then obtained in a standard fashion by deprotection of the intermediate ester.
2) Synthesis of Intermediates (III)
The preparation of intermediates of general formula (III), Diagram 1.4, in which R2 is as defined above and Y=xe2x80x94(CH2)pxe2x80x94, with p=0, is carried out from derivatives of N-Cbz aspartic acid of general formula (III.1) access to which is described in the literature (J. Med. Chem. (1973) 16(11), 1277-1280). By heating these intermediates in the presence of trioxane and a catalytic quantity of PTSA under reflux of a solvent such as, for example, toluene, (Synthesis (1989) 7, 542-544) the oxazolidinone derivatives of general formula (III.2) are obtained. Reduction of the acid function is then carried out using B2H6.THF in THF as described in Chem. Pharm. Bull. (1995) 43 (10), 1683-1691 and leads to alcohols of general formula (III.3). These are then treated in a basic medium, and intermediate (III.4) generated in this way is cyclized using a standard dehydration agent such as, for example, dicyclohexylcarbodiimide in order to obtain the substituted lactone of general formula (III.5). The intermediate of general formula (III) is obtained after cleavage of the benzyl carbamate using Pd/C under a hydrogen atmosphere.
3) Synthesis of Intermediates (V)
The intermediates of general formula (V) (Diagram 2.1), in which A, X, Y, R53 and R54 are as described above, are prepared in a standard fashion by peptide condensation of the acids of general formula (II), described previously, with commercial amino-esters of general formula (V.1). Carboxylic acids of general formula (V) are obtained after saponification of the intermediate esters of general formula (V.2).
A subject of the invention is also, as new industrial products, and in particular as new industrial products intended for the preparation of products of formula I, the products corresponding to one of the following formulae:
N-1-(4-anilinophenyl)-N-4-[(3S)-2-oxotetrahydro-3-furanyl]succinamide;
methyl (2S)-2-{([4-(4-anilinoanilino)-4-oxobutanoyl]amino}-4-methylpentanoate;
N1-(4-anilinophenyl)-N4-[(1S)-1-formyl-3-methylbutyl]succinamide;
benzyl 3-(4-anilinoanilino)-3-oxo-2-phenylpropanoate;
3-(4-anilinoanilino)-3-oxo-2-phenylpropanoic acid;
N-1-(4-anilinophenyl)-N-3-[(3S)-2-oxotetrahydro-3-furanyl]-2-phenylmalonamide;
3-(4-anilinoanilino)dihydro-2(3H)-furanone;
methyl (2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoate;
(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoic acid;
N-[(1S)-3-methyl-1-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)butyl]-10H-phenothiazine-2-carboxamide;
ethyl 2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxylate;
2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxylic acid;
N-[(3S)-2-oxotetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;
methyl 4-[(10H-phenothiazin-2-ylcarbonyl)amino]benzoate;
4-[(10H-phenothiazin-2-ylcarbonyl)amino]benzoic acid;
N-[4-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;
methyl (2S)-4-methyl-2-[(10H-phenothiazin-1-ylcarbonyl)amino]pentanoate;
(2S)-4-methyl-2-[(10H-phenothiazin-1-ylcarbonyl)amino]pentanoic acid;
N-[(1S)-1-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;
N-[(1S)-1-(1,4-dioxa-7-azaspiro[4.4]non-7-ylcarbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;
2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-oxotetrahydro-3-furanyl]acetamide
5-nitro-1-propylindoline;
1-propyl-2,3-dihydro-1H-indol-5-ylamine;
3-oxo-2-phenyl-N-(1-propyl-2,3-dihydro-1H-indol-5-yl)-beta-alanine;
N1-[(3S)-2-oxotetrahydro-3-furanyl]-2-phenyl-N3-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide;
N-(2-anilinophenyl)-Nxe2x80x2-[(3S)-2-oxotetrahydro-3-furanyl]urea;
ethyl oxo[(1-propyl-2,3-dihydro-1H-indol-5-yl)amino]acetate;
oxo[(1-propyl-2,3-dihydro-1H-indol-5-yl)amino]acetic acid;
methyl (2S)-2-({[(2R)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]carbonyl}amino)-3-phenylpropanoate;
(2R)-N-[(1S)-1-benzyl-2-oxoethyl]-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;
tert-butyl5-methyl 1,5-indolinedicarboxylate;
1-(tert-butoxycarbonyl)-5-indolinecarboxylic acid;
tert-butyl 5-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)-1-indolinecarboxylate;
tert-butyl 5-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-1-indolinecarboxylate.
Experimental Part
The following examples are presented in order to illustrate the above procedures and should in no event be considered as a limit to the scope of the invention.

Heterocyclic compounds and their use as medicines

Abstract: in which A, X, Y, R1, R2 and Het represent variable groups.

Abstract: The invention also relates to their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular as inhibitors of calpains and/or traps of reactive oxygen species, selectively or non-selectively.

Societe de Conseils de Recherches et d""Applications Scientifiques (S.C.R.A.S.)


The disclosure provides a method for dynamically loading a relocatable file, comprising: analyzing the relocatable file; searching for a relocation section according to the information obtained through the analysis; obtaining a relocation target address after the relocation section is found and calculating an address to be relocated and a skipping distance; determining whether the skipping distance exceeds a range of a short skipping, and if the skipping distance does not exceed the range of the short skipping, then writing the relocation target address into the address to be relocated to perform relocation loading; if the skipping distance exceeds the range of the short skipping, then adding a veneer code segment and making the skipping whose distance exceeds the range of the short skipping indirectly skip to the relocation target address to perform relocation loading. Accordingly, the disclosure provides a device for dynamically loading a relocatable file, comprising: an analyzing module, a calculating module, a searching module, a determining module, and a relocation dynamic loading module. With the solution, dynamically loading a relocatable file can be realized when the calling distance of a function exceeds the range of the short skipping.

With the development of science and technology, mobile phones show a personal computerized development trend, which requires more and more dynamic application files. Mobile phones are generally divided into smart phones and feather phones. Smart phones, such as wince operating system and ulinux operating system, etc, basically realize dynamic loading technology, such as a dynamic link library of a Windows operating system or a dynamically shared file of a linux operating system which can be dynamically loaded on a Personal Computer (PC); while most of the feather phones are developed based on the embedded microkernel operating system, and dynamic loading technology has not yet been implemented on most of the embedded operating systems.
So far, the market share of feather phones is still high, and there are generally two application development modes for feather phones: one mode is to use JAVA language, and the other mode is statically linked to a version. Wherein JAVA is an explanatory language and slow in operating speed, and meanwhile requires support from JAVA virtual machine; while for compiling and generating an executable file by static link between a traditional application and a mobile phone version, the larger the file, the larger the required capacity of the hardware resource, such as the Random Access Memory (RAM) or the nonvolatile or NOR FLASH, and since the code will be frequently modified in the debugging process, the overall mobile phone version has to be re-linked, burned and loaded each time that the code is modified, thus modifying the code takes even more time than debugging the code, which seriously affects the efficiency of application development and debugging. In addition, when the code is directly run on a mobile phone having NOR FLASH, the above phenomenon is even more serious since the burning time is long, and the efficiencies of application development and debugging are particularly low. Meanwhile, the telecom operators have demand on dynamically upgrading an application, while the statically linked application cannot be dynamically upgraded.
Presently, the dynamic linking technology is implemented in the microkernel operating system, which improves the software development efficiency, the loading is performed as required in order to save hardware resources, and new functions can be added to a mobile phone at any time. Wherein the dynamic loading process mainly comprises three processes: calculating and allocating memory required for loading the code, symbol analyzing and code relocating. However, in the prior art, during the relocation process, when the address distance between a function caller and a callee is too far and exceeds a range of the short skipping, it will cause failure in dynamic loading, or error in dynamic loading of the dynamic application file.

Method and device for dynamically loading relocatable file


A training sequence for a radio communications system is provided. According to one aspect of the present invention, the invention includes a core sequence of symbols, a successive repetition of the core sequence, and a marker sequence having a sequence of symbols different from the core sequence.

1. Field of the Invention
The present invention applies to the field of training sequences for radio communications systems and, in particular, to a training sequence having a unique periodic structure.
2. Description of the Prior Art
Mobile radio communications systems such as cellular voice and data radio systems typically have several base stations in different locations available for use by mobile or fixed user terminals, such as cellular telephones or wireless web devices. Each base station typically is assigned a set of frequencies or channels to use for communications with the user terminals. The channels are different from those of neighboring base stations in order to avoid interference between neighboring base stations. As a result, the user terminals can easily distinguish the transmissions received from one base station from the signals received from another. In addition, each base station can act independently in allocating and using the channel resources assigned to it.
Such radio communications systems typically include a broadcast channel (BCH). The BCH is broadcast to all user terminals whether they are registered on the network or not and informs the user terminals about the network. In order to access the network, a user terminal normally tunes to and listens to the BCH before accessing the network. It will then use the information in the BCH to request access to the network. Such a request typically results in an exchange of information about the network using separate control and access channels and ends in the user terminal receiving an assignment to a particular base station.
While frequency and timing offset can sometimes be determined by a user terminal based on the BCH, the initial request for access is typically received at the base station with an unknown amount of delay and unknown spatial parameters. In a spatial diversity multiple access system, the base station can enhance the capacity of the system by determining the position and range to the user terminal as well as any other spatial parameters. The delay in the arrival time of such request messages are proportional to the round trip delay encountered by messages traveling between the base station and the mobile terminal. For systems with a high coverage area per base station, this range and therefore the delay uncertainty may be very large. For example, a range of fifteen km results in a roundtrip delay time of around 100 microseconds.
In order to accurately resolve the access request and determine spatial parameters, a training sequence is typically transmitted with the request. Resolving the received signal using the training sequence can consume great computational resources and create delays in the base station""s response to the request. The greater the uncertainty of the received signal, the greater the computational resources that may be required.
A training sequence for a radio communications system is provided. According to one aspect of the present invention, the invention includes a core sequence of symbols, a successive repetition of the core sequence, and a marker sequence having a sequence of symbols different from the core sequence.

Training sequence for a radio communications system


A strong, high density foam glass tile having a small pore size which can be used as a facade on both exterior and interior building walls. The foam glass tile of the present invention is strong enough that it can also be used as a structural member for a building. The foam glass tiles are very strong, and have a compression strength of 6000 psi (lb./sq. in.) or greater, and more particularly of 8000 lb./sq. in. or greater, and even more particularly of 10,000 lb./sq. in. or greater, and even more particularly of 12,000 lb./sq. in. or greater, and even more particularly of 14,000 lb./sq. in. or greater. These foam glass tiles will absorb more energy from an explosion, withstand higher heat and wind loading and other mechanical forces. The tiles of the present invention may have an average pore size of 1.0 mm or less, and preferably 0.7 mm or less, and more preferably 0.6 mm or less, and even more preferably 0.5 mm or less, and even more preferably 0.4 mm or less, and even more preferably 0.3 mm or less.

Over the past decades, there have been a significant number of terrorists attacks on government buildings owned by the United States and other countries both outside of the United States and within. For example, in 1993, terrorists exploded a car bomb inside the garage of the World Trade Center located in New York City, resulting in loss of life and significant property damage. Since then, in 1995, other extremists exploded a truck outside of the Federal Building located in Oklahoma City, Okla. also resulting in significant loss of life and property damage. In 1998, the United States embassies in Nairobi and Dar Es Salaam were also subject to terrorists attacks by car bombs, each of which resulted in significant loss of life and property damages. More recently, the tragic events at the World Trade Center in New York City and the Pentagon in Virginia has further emphasize the long felt need to develop and manufacture building materials which are able to withstand the shock wave from car bomb explosions and other similar terrorist attacks.
Traditionally, the internal and external tiling of buildings, industrial and residential areas, government and private sector, etc., is commonly made of natural and artificial construction materials, the most used materials being cement, marble and granite, as well as ceramic tiles of various kind. In addition to be decorative, the construction materials used should be functional, exhibiting the following characteristics: long durability, resistance to weather effects; resistance to corrosion; inert behavior to chemicals; thermal insulation properties; resistance to abrasion; and at the same time it should also be economical in both production and installation costs.
While the concept of using foam glass as a construction material is well known in the prior art, generally such foam glass has been used as a high temperature insulator and thus seeks to minimize its density and weight and is not suitable for absorbing sufficient energy from a shock wave from unexpected explosions or to resist an earthquake and/or wind and heat loading. The shortcomings in such conventional foam glass as relevant to this long standing problem is now described.
For example, Pittsburgh Corning Corporation ("PCC") of Pittsburgh, Pa. has developed and marketed a product known as Foam Glas® Insulation Systems, which is described in U.S. Pat. Nos. 3,959,541, 4,119,422, 4,198,224, 4,571,321 and 4,623,585. Because the focus of these developments are directed to making a foam insulating material, the Foam Glas® Insulation Systems tile commercially sold by PCC is relatively light, weighing 9.5 lb./cu. ft. Furthermore, since the purpose of this tile is to be used as thermal insulation, it lacks surface strength, and can be dented very easily. Because the Foam Glas® Insulation Systems tile is of relatively low density, e.g., 9.5 lb./cu. ft., such tiles will easily break when exerted to forces typically asserted on exterior walls to a building or other structure. Thus, such tiles are not suitable to be used as tiling for an exterior wall. Similarly, this foam, when exposed to a shock wave from an explosion will absorb very little of the shock waves energy when it implodes. A shock wave is a measure associated with explosions which is easily understood by those skilled in the art as being a pressure front resulting from an explosion.
Others have also attempted to use foam glass tiles as the outer skin-surface of buildings. For example, U.S. Pat. No. 5,069,960 discloses a thermally insulating foam glass tile that is coated with an outside surface to make a hard skin to protect the outside of a building. The tiles disclosed are fabricated in extremely small sizes, i.e., 18 cm×18 cm×6 cm, and the interior foam material which makes up the bulk of the material is generally of a low density. Significantly, there is no indication that the strength of the material disclosed is capable of absorbing sufficient energy from an explosion, and indeed the size of the disclosed tiles would not be ideally suitable for absorbing such energy. Furthermore, there is no indication that small size pores are being used.
Prior work by the inventors and others have developed methods for making foam glass tiles of a wide a variety of densities as described in U.S. Pat. No. 4,430,108 that can be used for building materials. While the techniques and methods disclosed were useful to manufacture then-standard size tiles of 4.25 in.×4.25 in.×0.25 in., this disclosure does not teach how to manufacture tiles of a larger size, for example 2 ft.×2 ft.×3 in. Likewise the tiles manufactured under these methods were relatively light, e.g., less than 10 lbs., and were not manufactured to withstand the effects of an explosion. To the contrary, these methods sought to optimize the thermal insulation properties of the material, and thus made smaller, lighter and weaker tiles.
While still others have worked on trying to make some large-size porous shaped bodies, these have been smaller in critical dimensions and of lower density than the present invention and not suitable to absorb a substantial amount of a shock wave which impacts the bodies associated with an explosion or earthquake. For example, U.S. Pat. No. 5,151,228 describes a process for manufacturing large-size porous shaped bodies of low density by swelling, in order to manufacture large-size cellular ceramic structural elements, e.g., multi-story high wall elements having a low weight. In the example, it discloses a tile 8.2 ft.×1.64 ft.×2 in., with a density of 26 lb./cu. ft. and a mass of 60 lbs. It also teaches to obtain a low density in order to optimize thermal insulation. Thus, this foam when exposed to a shock wave from an explosion or earthquake or heat or wind loading or stress of any kind will absorb very little of the shock waves energy when it implodes.
Further, others, such as Central Glass Co. Ltd., of Ube, Japan, have attempted to make foam glass using densities in the range of 0.3 to 0.6 g/cu. cm (or 18.7 to 37.4 lb./cu. ft.) as disclosed in U.S. Pat. No. 4,798,758. The '758 Patent explains that in order to make the foam glass stronger, an outer layer is also added which has a density in the range of 0.8 to 1.7 g/cu. cm and a thickness of 1.5 to 20 mm. In the examples shown, all the samples which are over 30 lbs. in weight were found to be unacceptable from a cutability and impact resistance perspective, for among other reasons that the surface had appreciable breaking and sometimes cracking, thus not providing a closed pore surface. Further, U.S. Pat. No. 4,833,015, a later patent by Central Glass Co. Ltd., explains the tensile strength perpendicular to the surface of the tile described in the '758 Patent was very poor, i.e., below 150 lb./sq. in., thus making it unsuitable for purposes of the present invention. Even after putting a third layer to improve the strength of the product as described in the '015 Patent, the best tensile strength achieved was below 200 lb./sq. in., and making it unsuitable for purposes of the present invention.
Other efforts by Central Glass Co., Ltd. attempt to make higher density glass tiles, such as U.S. Pat. No. 4,992,321. However, these tiles do not appear to be a closed pore structure and there is no indication as to their strength. Indeed, filler materials are used in an attempt to increase the strength with no reporting data. Further, the tiles disclosed were also very thin,33 mm (or 1.3 in.).
Still others have attempted to make foam glass tiles with smaller pore size. For example, in U.S. Pat. No. 5,516,351, the relationship of pore size to thermal resistivity is shown in which the best pore size is always greater than 1.0 mm. Similarly, the density is always less than 12 lb./cu. ft. Other efforts to use small pore size and larger densities, such as U.S. Pat. Nos. 3,951,632 and 4,758,538, failed to achieve comparable strengths and does not disclose achieving a closed pore outer skin as disclosed by the present invention.
Unlike the prior art discussed above, the tiles of the present invention are designed and constructed of various materials so that such tiles have properties which are ideal for withstanding the shock wave associated with large explosions or make a building or other structure resistant to earthquakes.
Thus, while the prior art is of interest, the known methods and apparatus of the prior art present several limitations which the present invention seeks to overcome. In particular, it is an object of the present invention to provide a strong, high density foam glass tile with small average pore sizes which can be used as a building material.
It is another object of the present invention to increase from the commercially recommended density of 9.5 lb./cu. ft. to have a higher density of between 30-100 lb./cu. ft., and more particularly over 40 lb./cu. ft., and even more particularly over 60 lb./cu. ft.
It is another object of the present invention to make a foam glass tile with an average pore size of 1.0 mm or less, and more preferably of 0.6 mm or less, and even more preferably of 0.4 mm or less, and even more preferably of 0.3 mm or less.
It is a further object of the present invention to increase the weight of the foam glass tile to be greater than 30 lbs., and more particularly over 65 lbs. and even more particularly over 100 lbs.
It is a further object of the present invention to provide a strong, high density foam glass tile which can be used on the critical surfaces of buildings at high risk for terrorist attacks, in combination with cement, steel or other building materials.
It is also an object of the present invention to provide a glass foam tile that can be used in surfaces of typical buildings and has the advantage of having a rigid structure that when exposed to shock waves having blast energy, the tile can absorb a substantial portion of that blast energy. It also has the advantage of being more resistant to earthquakes and/or wind and heat loading.
These and other objects will become apparent from the foregoing description.

This patent is subject to a terminal disclaimer.

Strong, high density foam glass tile having a small pore size


Provided is a document reading apparatus capable of surely detecting the document cover open/closed state and the open/close operation, without being affected by the external environment. This document reading apparatus includes a light source, a linear reading device and a document cover. In this document reading apparatus, the light amount value of the light received by the linear reading section while the light source is turned on, and the light amount value of the light received by the linear reading section when the light source is turned off are used to detect the open/closed state and the open/close operation of the document cover, wherein the preparation for printing starts when the document cover has shifted from the open state to the closed state.

A document reading apparatus such as the scanner of a photocopier is generally equipped with a platen glass on which a document to be read is placed, and a document cover for bringing the mounted document in close contact with the platen glass.
In the field of document reading apparatuses, many proposals have been disclosed on the art of detecting an open/close operation of the document cover. They are disclosed, for example, in Japanese Unexamined Patent Application Publication No. H 06-309449, Japanese Unexamined Patent Application Publication No. 2004-357007, and Japanese Unexamined Patent Application Publication No. 2009-239929.
According to the technique described in Japanese Unexamined Patent Application Publication No. H 06-309449, the output value of a CCD sensor is monitored. The open/close operation of the document cover is detected by detecting the output of the CCD sensor to be increased by the light inside the room when the document cover is opened.
According to the technique disclosed in Japanese Unexamined Patent Application Publication No. 2004-357007, a control section inside the scanner determines, based on the detection signal value from the external light sensor, whether the intensity of the detected external light has been increased or not, and decreased or not, so that the open/close operation of document cover is detected.
Further, according to the technique introduced in Japanese Unexamined Patent Application Publication No. 2009-239929, a control section determines whether the document platen is being exposed to the external light or not, and the open/close operation of the document cover is thus detected.
However, with the method for detecting the open/close operation of the document cover disclosed in Japanese Unexamined Patent Application Publication No. H 06-309449, Japanese Unexamined Patent Application Publication No. 2004-357007, and Japanese Unexamined Patent Application Publication No. 2009-239929, the detection accuracy depends on the external environment, as exemplified by the case where detection accuracy deteriorates when the amount of external light is limited. Thus, the open/close operation of the document cover cannot be detected accurately.


There is provided a solution for simultaneous reception of dual channel transmission. The solution is based on applying a first and a second oscillating signals, mixing and adding in order to separate the in-phase and quadrature components of first and second signals from a combined radio frequency signal received as input.

It is an ongoing challenge to enhance the data rate in a mobile communication network. This may be pursued by developing completely new systems. An example of this type of evolution is the change in network architectures from a Global System for Mobile Communications (GSM) to a Universal Mobile Telecommunications System (UMTS) applying Wideband Code Division Multiple Access (WCDMA) and further to Long Term Evolution (LTE). Alternatively, the increase of the data rate may be obtained by developing the existing architectures. For example, a general packet radio service (GPRS) and enhanced data rates for global evolution (EDGE) were developed on top of the existing GSM network. Further, high-speed downlink packet access (HSDPA) was developed to coexist with the UMTS network.
One possible way to increase the data rate is to enable the dual channel reception in the mobile communication network. This technique is called a dual cell (DC) HSDPA. According to possible solutions for DC-HSDPA, a mobile terminal would require two separate receivers. Both of the receivers could separate the in-phase (I) and the quadrature (Q) branch from the received signal. The use of two receivers is, however, a highly space- and money-consuming solution. Alternatively, a diversity receiver of the mobile terminal could be applied together with the original receiver (such as a direct conversion receiver) for receiving two data channels simultaneously.


Automated testing of versioned information handling system applications is performed by automatically compiling currently available versions at regular time intervals throughout a development cycle and then automatically testing each compiled version on test information handling systems to detect errors associated with each compiled version of the application. For instance, production operating systems used to configure manufactured information handling systems are automatically tested at regular intervals during development so that versions of a complete operating system and application environment are properly integrated. Testing of the complete operating system and application environment of a production operating system is accomplished by interrupting power to test information handling systems and loading the production operating system with a PXE agent. Periodic compilation and testing of versions provides simplified identification and tracking of development errors.

1. Field of the Invention
The present invention relates in general to the field of information handling system application development, and more particularly to a method and system for automated testing of versioned information handling system applications, such as production operating system applications.
2. Description of the Related Art
As the value and use of information continues to increase, individuals and businesses seek additional ways to process and store information. One option available to users is information handling systems. An information handling system generally processes, compiles, stores, and/or communicates information or data for business, personal, or other purposes thereby allowing users to take advantage of the value of the information. Because technology and information handling needs and requirements vary between different users or applications, information handling systems may also vary regarding what information is handled, how the information is handled, how much information is processed, stored, or communicated, and how quickly and efficiently the information may be processed, stored, or communicated. The variations in information handling systems allow for information handling systems to be general or configured for a specific user or specific use such as financial transaction processing, airline reservations, enterprise data storage, or global communications. In addition, information handling systems may include a variety of hardware and software components that may be configured to process, store, and communicate information and may include one or more computer systems, data storage systems, and networking systems.
The wide variety of information handling system hardware and software configurations presents difficulty to efficient manufacture of information handling systems. One solution to address the problem of manufacturing different information handling system hardware and software configurations is to use a factory process operating system to configure manufactured information handling systems with their commercial operating system and applications. For instance, once the hardware for an ordered information handling system is assembled, power is applied to the assembled hardware and the information handling system is booted up with a production operating system. The production operating system then guides the configuration of the information handling system with desired software. As an example, a production operating system includes a Linux kernel and production applications which perform the loading and configuration of the MICROSOFT WINDOWS operating system and OFFICE application suite, such as with an image download.
The creation of a production operating system to configure the software of manufactured information handling systems generally requires close coordination from a disparate group of developers preparing software code to address various aspects of manufacturing a wide variety of information handling systems. One difficulty with developing a production operating system is that testing of the production operating system calls for more than running an application on an information handling system; rather, the production operating system is itself a complete operating system and application environment that generally cannot be completely tested unless it is tested from power up of a test information handling system. During a production operating system development cycle, a number of versions of a production operating system may be completed, compiled and run on basic test units and still end up failing in a production environment. Such production environment failures are often difficult to debug since often the time between when an error is introduced and checked in as a new version and when the error arises is lengthy so that developers have to search through a number of version changes to locate the error. Development teams have difficulty ensuring that numerous developed versions of a production operating system will interact properly in a production environment that includes a wide variety of information handling system configurations.

Method and system for automated testing of versioned information handling system applications


A device for providing vestibular and somatosensory stimulation through bone conduction of sound waves to skeletal bones is provided in the form of a pad that is applied to or wrapped around the individual in treatment, which is comfortable in use and may contain particulate filler material capable of providing bone conduction stimulation adjacent to the location of a bone conduction transducer and expand the sound conduction site over a larger area. The device may be located beneath a pillow or mattress.

The connection between what is heard and listened to by the ear of a subject and the subject's spoken voice is well recognized. Additionally, it is well recognized that hearing occurs through two distinct pathways: air conduction, which stimulates the cochlear system, and bone conduction (vibration of sound carried by the skeletal frame). Bone conduction delivery of sound occurs when the sound vibration is transmitted to the inner ear through the bones of the skeletal framework. This process stimulates the vestibular/cochlear and somatosensory systems as well as the central nervous system. Stimulating these physiological systems with the low frequencies carried by bone conduction tends to have a relaxing, stabilizing effect; it also influences the ability for spatial equilibrium and balance, as well as the ability to modulate sensory input and to process information. Many devices and methods, including those utilizing bone conduction have been directed toward assisting those with cochlear hearing and vestibular ear difficulties to hear better with an accompanying improvement in speech. Evidence of devices and methods can be found in U.S. Pat. Nos. 3,101,081, 3,043,913, 4,021,611, 4,212,119, 4,327,252 and 4,615,680 to Tomatis, U.S. Pat. No. 1,969,559 to Kelly and U.S. Pat. No. 3,101,390 to Maille, all of which are incorporated herein by reference.
In addition to providing the sense of hearing, the vestibular system is the primary organ of equilibrium and plays a major role in the sensation of motion and spatial orientation; it also provides input to the nervous system, adjusting muscle activity, body posture, and stabilizes the eyes during head movements. It is known that vestibular stimulation through air and bone conducted sound can enhance neurological development, and can be used in the treatment of autism, Asperger's, sensory processing disorder, and ADHD. It is widely recognized that the early detection of autism in children is fundamental to effective treatment. However, with very young children, because of the prior art device configurations, effective vestibular stimulation through sound is difficult.
Vestibular stimulation therapy of the prior art has consisted of the delivery of sound through headphones and the delivery of sound through headphones in conjunction with bone conduction delivery through a device attached to the headphones or the person's head. Although effective, the use of the headphones and bone conduction devices attached to a person's head may be uncomfortable and impractical in certain settings. Clearly with infants and small children such headphones and bone conduction devices are not practical; and in any application, such headphones and bone conduction devices can become unintentionally displaced, and therefore ineffective, through the movement of the individual. Further, such headphones and bone conduction devices cannot be applied to provide vestibular stimulation to a fetus in-utero.
Dr. Alfred A. Tomatis postulated and it is well recognized by others that: 1. The voice only contains that which the ear can hear; if you can't hear it, you won't be able to speak it; 2. the ear is like a battery to the brain, with a primary function of converting sound waves to electrical pulses to charge the cortex of the brain; 3. hearing is passive, listening is active and conscious, like the difference between seeing and looking; listening and looking are active focusing processes; 4. the quality of one's listening affects spoken and written language development, alertness, creativity, and the ability to focus; listening also influences communication and shapes social skills, confidence, and self-image; 5. communication begins in utero; an unborn child hears from the 4th month after conception; sound literally helps the brain and nervous system of the fetus to develop. Dr. Tomatis further mapped out and postulated that certain filtered frequencies corresponded to stimulation of certain body and mind properties: frequencies between 0 and 750 Hz corresponded to balance, coordination, motor skills, muscle tone, body awareness, and rhythm; frequencies between 750-3,000 Hz corresponded to memory, concentration, attention, receptive and expressive language; and frequencies greater than 3,000 Hz corresponded to integrating emotion, creativity, and higher cognitive thinking.
Auditory therapy, including bone conduction, treatment and filtering of music and sounds, and gating are well known in the prior art. Such therapy methods are premised upon the concept of neuroplasticity which holds that throughout the life of the subject new neural connections can be established through stimulation and training. Prior to the present disclosure, such auditory therapy has been limited to air conduction and bone conduction listening of music, speech, sounds, and the subject's own spoken voice. No attempt had been made to simultaneously utilize visual tracking stimuli, movement stimuli, and auditory stimuli in such therapy to integrate and refine the cochlear and vestibular signal with that of the other senses.
It is therefore an object of the present disclosure to provide a method of training that systematically integrates auditory, visual, vestibular, and movement sensory inputs.
It is another object of the present disclosure to provide a wirelessly transmitted program of treated music and sounds to wireless bone conduction headphones having a streamlined open ear fit allowing for participation in group exercise/therapy classes, group activities, and socialization. Air conduction signals, if desired, are then outputted via loud speakers to each user in the group setting. Such a program is primarily targeted at seniors who wish to maintain and improve balance during daily activities, but is contemplated as useful in such settings as aerobics classes, sports team training, and schools, etc.
It is another objective of the present disclosure to provide a bone conduction device for stimulation of the vestibular and somatosensory systems that may be utilized with young children and infants including pre-mature infants.
It is another object of the present disclosure to provide a bone conduction device for stimulation of the vestibular and somatosensory systems of a fetus in utero.
It is another object of the present disclosure to provide a bone conduction device for stimulation of the vestibular systems in individuals who receive little or no intrinsic vestibular stimulation as a result of their own limited or lack of movement.
It is another objective of the present disclosure to provide a bone conduction device for stimulation of the vestibular and somatosensory systems that remains effective even when the position of the transducer is displaced by the motion of the individual.
It is another objective of the present disclosure to provide a bone conduction device for stimulation of the vestibular and somatosensory systems that does not require head phones or attachment to the individuals head.
It is another objective of the present disclosure to provide a bone conduction device for stimulation of the vestibular and somatosensory systems that may be comfortably worn and provides stimulation during periods of physical activity and inactivity, including sleep.
It is another objective of the present disclosure to provide a bone conduction device for stimulation of the vestibular and somatosensory systems that includes one or more multi-sensory experiences including but not limited to temperature control, aroma therapy, and/or light therapy.
It is another objective of the present disclosure to provide a bone conduction device for stimulation of the vestibular and somatosensory systems that improves the sound resonance and reduces harmonics.


A device for emission of high frequency signals is provided. The emission device is capable of emission of signals in the Gigahertz (GHz) and Terahertz (THz) range. The device may utilize, for example, a cantilever comprising a material that is capable of altering its electrical properties when flexed.

The Gigahertz (GHz) and Terahertz (THz) regions of the microwave spectrum have been identified as an area where macro molecule resonances may be detected without destructive ionization of the original molecules. Of particular interest is the ability to stimulate the molecular vibration of large molecules in applications ranging from medical sensing to bio-terrorism warning sensors. Schemes for generating signals in these regions have primarily relied on the use of standard or exotic semiconductor materials or RF emissions generated by laser induced resonance in specific crystals. For high frequencies these devices require the formation of quantum wells and/or dots or require that the resonant crystal be machined in a specific shape. These approaches provide a narrow frequency response per device or, for the laser pumped crystal devices, they can be tuned over a narrow bandwidth via frequency shifting of the lasers used to stimulate the crystal.
Therefore a need exists for an emitter capable of operating over a broadband and able to provide the frequency tuning required for spectral analysis. Further, a device design capable of being used in communication and networking is also needed.

Device for emission of high frequency signals