The present invention provides a compound of formula I

1. Field of the Invention
The present invention provides heterocycle carboxamide derivatives. These compounds are useful as antiviral agents, in particular, as agents against viruses of the herpes family.
2. Technology Description
The herpesviruses comprise a large family of double stranded DNA viruses. They are also a source of the most common viral illnesses in man. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been shown to infect humans. HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals, respectively. They also occasionally cause infections of the eye and encephalitis. HCMV causes birth defects in infants and a variety of diseases in immunocompromised patients such as retinitis, pneumonia, and gastrointestinal disease. VZV is the causative agent of chicken pox and shingles. EBV causes infectious mononucleosis. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt""s lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. HHV-6 is the causative agent of roseola and may be associated with multiple sclerosis and chronic fatigue syndrome. HHV-7 disease association is unclear, but it may be involved in some cases of roseola. HHV-8 has been associated with Karposi""s sarcoma, body cavity based lymphomas, and multiple myeloma.
U.S. Pat. Nos. 5,753,666 and 5,891,878 and WO 97/04775 disclose specific 1-alkyl-substituted-quinolone-3-carboxamides that are alleged to have therapeutic utility via inhibition of Phosphodiesterase IV esterase and/or Tumor Necrosis factor activity.
Commonly assigned WO 00/40561 discloses quinolinecarboxamides as antiviral agents.
Commonly assigned WO 00/40563 discloses specific quinolinecarboxamides as antiviral agents.
Commonly assigned WO 00/53610 discloses 4-Oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamides as antiviral agents.
Commonly assigned WO99/32450, discloses specific 4-hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents.
U.S. Pat. No. 5,945,431 discloses specific naphthyridine heterocyclic compounds having antiviral activity that are useful in the therapy and prophylaxis of cytomegalovirus (CMV) infection in mammals.
WO99/10347 discloses specific substituted 4-oxo-naphthyridine-3-carboxamides as brain receptor ligands having potential use in the treatment of central nervous system diseases and/or disorders.
WO98/19673 discloses specific heterocyclic agents for the treatment of diseases caused by viruses.
JP08301849 discloses specific heterocyclic agents useful as tachykinin receptor antagonists.
JP07033729 discloses specific N-cyano-Nxe2x80x2-substituted-arylcarboxyimidamide compounds exhibiting K+ channel opening effects and having hypotensive action and coronary vasodilating action.
WO 00/40562 discloses novel 2-oxoquinolines as selective peripheral cannabinoid receptor modulators).
WO 97/34894 dosloses Naphthyridine derivatives and their analogues inhibiting cytomegalovirus.
Despite the above teachings, there still exists a need in the art for novel compounds that demonstrate desirable antiviral activity.
In accordance with the present invention, novel compounds which demonstrate antiviral activity are provided. More specifically, the compounds are specific heterocycle carboxamide derivatives which are useful as antiviral agents, particularly against herpes viruses.
Even more specifically, the present invention provides a compound of formula I,
wherein,
X is Cl, Br, F, CN or NO2;
G is
(a) C1-7alkyl which is partially unsaturated and is substituted by hydroxy, or
(b) C1-4alkyl substituted by NR1R2 or 4tetrahydropyran;
R1 is C2-7alkyl substituted by hydroxy, C1-4alkoxy, aryl, or heteroaryl;
R2 is hydrogen or C1-7alkyl;
or R1 and R2 together with the nitrogen to which they are attached form morpholine which may be optionally substituted by aryl or C1-7alkyl;
W is a heterocycle of formula W1, W3, or W4;
A is CR4 or nitrogen;
B is CR5 or nitrogen;
C is CR6 or nitrogen;
E and F are such that
(a) one is oxygen and the other is C(xe2x95x90O); or
(b) E is C(xe2x95x90O) and F is NR7;
J and K are such that
(a) J is nitrogen and K is CR8; or
(b) J is CR6 and K is nitrogen;
with the provisos that when W is of formula W3 and J is nitrogen, then at least one of A and B is nitrogen;
R4 is H, halogen, or C1-4alkyl optionally substituted by one to three halogens;
R5is
(a) H,
(b) halo,
(c) OR12,
(d) SR12,
(e) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR12, SR12, NR10R11, or halo,
(f) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR12, SR12, or NR10R11,
(g) (Cxe2x95x90O)R9,
(h) S(O)mR9,
(i) (Cxe2x95x90O)OR2,
(j) NHSO2R9,
(k) nitro, or
(l) cyano;
R6 is
(a) H,
(b) halo,
(c) aryl,
(d) het,
(e) OR12,
(f) SR12,
(g) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR12, SR12, NR10R11, aryl, halo, C3-8cycloalkyl optionally substituted by OR12, or het attached through a carbon atom,
(h) NR10R11,
(i) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR12, SR12, or NR10R11,
(j) (Cxe2x95x90O)R9,
(k) S(O)mR9,
(l) (Cxe2x95x90O)OR2,
(m) NHSO2R9,
(n) nitro, or
(o) cyano;
R7is
(a) H,
(b) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR12, SR12, NR10R11, or halo,
(c) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR12, SR12, or NR10R11,
(d) aryl, or
(e) het;
R8 is
(a) H,
(b) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR12, SR12, NR10R11, or halo,
(c) OR12, or
(d) SR12;
R9 is
(a) C1-7alkyl,
(b) NR10R11,
(c) aryl, or
(d) het, wherein said het is bound through a carbon atom;
R10 and R11 are independently
(a) H,
(b) aryl,
(c) C1-7alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from CONR2R2, CO2R2, het, aryl, cyano, or halo,
(d) C2-7alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR2R2, OR2, or SR2,
(e) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR2, SR2, or NR2R2, or
(f) R10 and R11 together with the nitrogen to which they are attached form a het;
R12 is
(a) H,
(b) aryl,
(c) het
(d) C1-7alkyl optionally substituted by aryl, het, or halogen,
(e) C2-7alkyl substituted by OR2, SR2, or NR2R2, or
(f) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR2, SR2, or NR2R2;
each m is independently 1 or 2;
aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl maybe optionally substituted with one or more substituents selected from halo, OH, cyano, NR2R2, CO2R2, CF3, C1-6alkoxy, and C1-6 alkyl which maybe further substituted by one to three SR2, NR2R2, OR2, or CO2R2 groups;
het is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and het may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO2R2, CF3, C1-6alkoxy, oxo, oxime, and C1-6 alkyl which may be further substituted by one to three SR2, NR2R2, OR2, or CO2R2 groups;
halo or halogen is F, Cl, Br, I;
1 represents the point of attachment between W and G;
2 represents the point of attachment between W and the carbonyl group of Formula (I);
and pharmaceutically acceptable salts thereof.
In particularly preferred embodiments, X is Cl and G is 4-morpholinylmethyl.
Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In preferred embodiments, the composition preferably comprises a therapeutically effective amount of the compound or salt.
Still another embodiment of the present invention provides a method for treating a disease or condition in a mammal caused by a viral infection, particularly a herpes viral infection, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For this embodiment, in addition to the compounds encompassed by formula (I), G can also represent C1-7alkyl which is fully saturated and is substituted by hydroxy.
A further embodiment of the present invention comprises the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating or preventing diseases or disorders caused by a viral infection, and particularly a herpes viral infection.
A final embodiment of the present invention comprises a method for inhibiting a viral DNA polymerase, comprising contacting (in vitro or in vivo) the polymerase with an effective inhibitory amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
An object of the present invention is to provide novel compounds having biological activity.
A further object of the present invention is to provide novel pharmaceutical compositions.
Still another object of the present invention is to provide a method for treating a disease or condition in a mammal caused by a viral infection, particularly a herpes virus infection.
Another object of the present invention is to provide a method for inhibiting a viral DNA polymerase.
These, and other objects, will readily be apparent to those skilled in the art as reference is made to the detailed description of the preferred embodiment.
In describing the preferred embodiment, certain terminology will be utilized for the sake of clarity. Such terminology is intended to encompass the recited embodiment, as well as all technical equivalents which operate in a similar manner for a similar purpose to achieve a similar result.
1. Terminology Definitions
The following definitions are used, unless otherwise described: halo is fluoro, chloro, bromo, or iodo. Alkyl denotes both straight and branched groups; but reference to an individual radical such as xe2x80x9cpropylxe2x80x9d embraces only the straight chain radical, a branched chain isomer such as xe2x80x9cisopropylxe2x80x9d being specifically referred to. When alkyl can be partially unsaturated, the alkyl chain may comprise one or more (e.g., 1, 2, 3, or 4) double or triple bonds in the chain.
Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic. Het is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated ring containing 1, 2 or 3 heteroatoms selected from the group consisting of non-peroxide oxygen, sulfur, and nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocyclic group. Het includes xe2x80x9cheteroarylxe2x80x9d, which encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, C1-4alkyl, phenyl or benzyl.
It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine antiviral activity using the standard tests described herein, or using other similar tests which are well known in the art.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating a lower and upper number of carbon atoms in the moiety, i.e., the prefix Ci-j indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, C1-7alkyl refers to alkyl of one to seven carbon atoms, inclusive.
The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, xe2x80x9cEtxe2x80x9d for ethyl, xe2x80x9chxe2x80x9d for hour or hours and xe2x80x9crtxe2x80x9d for room temperature).
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. The compounds of the invention include compounds of formula (I) having any combination of the values, specific values, more specific values, and preferred values described herein.
Mammal denotes human and animals, specifically including food animals and companion animals.
2. The Invention
The present invention comprises compounds of formula (I) as defined above, and their pharmaceutically acceptable salts.
For the compounds of formula (I), alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, etc.; C3-8cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, hexyloxy, 1-methylhexyloxy, or heptyloxy; het can be azetidinyl, 3,3-dihydroxy-1-azetinyl, pyrrolidino, piperidino, morpholino, thiomorpholino, or heteroaryl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
When alkyl is partially unsaturated, it can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-hexene-1-ynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl.
Specific examples of W1 include,
Specific examples of W3 include,
Particularly preferred compounds are those where X is Cl and G is 4-morpholinylmethyl.
Examples of the present invention include, but are not limited to the following:
N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-2-oxo-2H-pyrano[2,3-c]pyridine-3-carboxamide;
N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-1-oxo-1H-isochromene-3-carboxamide;
N-(4-chlorobenzyl)-4-hydroxy-1-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1H-isochromene-3-carboxamide;
N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-1-oxo-1H-isochromene-3-carboxamide;
N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxy-1-propynyl)-8-oxo-7,8-dihydro[1,7]-naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxamide;
N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxamide;
N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)[1,7]naphthyridine-3-carboxamide;
N-(4-chlorobenzyl)-8-ethoxy-4-hydroxy-6-(3-hydroxy-1-propynyl)[1,7]-naphthyridine-3-carboxamide;
N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)[1,7]naphthyridine-3-carboxamide;
N-(4-chlorobenzyl)-8-ethoxy-4-hydroxy-6-(4-morpholinylmethyl)[1,7]naphthyridine-3-carboxamide;
N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)[1,5]naphthyridine-3-carboxamide;
N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)[1,5]naphthyridine-3-carboxamide;
N-(4-chlorobenzyl)-4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)[1,5]-naphthyridine-3-carboxamide;
N-(4-chlorobenzyl)-8-hydroxy-2-(3-hydroxy-1-propynyl)pyrido[3,2-d]pyrimidine-7-carboxamide;
N-(4-chlorobenzyl)-8-hydroxy-2-(4-morpholinylmethyl)pyrido [3,2-d]pyrimidine-7-carboxamide;
N-(4-chlorobenzyl)-5-hydroxy-3-(4-morpholinylmethyl)[1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxy-1-propynyl)[1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-5-hydroxy-3-(tetrahydro-2H-pyran4-ylmethyl)[1,7]-naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-isoquinolinecarboxamide;
N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-isoquinolinecarboxamide;
N-(4-chlorobenzyl)-4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-isoquinolinecarboxamide; and
pharmaceutically acceptable salts thereof.
Representative examples of the synthesis of compounds falling within the scope of formulas W1, W3, or W4 are as follows.
The following Charts A-S describe the preparation of the compounds of the present invention. All of the starting materials are prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the variables used in the charts are as defined below or as in the claims.
W1.3. 4-Hydroxy-2-oxo-2H-pyrano[2,3-c]pyridine-3-carboxamides. Preparation of specific examples of heterocycle W1.3 follows an established precedent for the corresponding ring synthesis (Bull. Soc. Chim. Fr. 1979, 289), Chart A. 3-Hydroxy-6-methyl-4-pyridinecarboxylic acid A.1 (JP 45016705) is reacted with ethyl chloroformate followed by ethoxymagnesium diethylmalonate and potassium carbonate to afford the pyranopyridine A.2. Benzylic halogenation mediated by N-bromosuccinimide and AIBN affords the halide A.3 which undergoes displacement with a substituted amine (e.g. morpholine) to afford A.4. The resulting ester A.4 is then saponified to afford the corresponding carboxylic acid A.5 which is then coupled with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) mediated by 1,1xe2x80x2-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to provide amides of the general formula A.6.
W1.9. 4-Hydroxy-1-oxo-1H-isochromene-3-carboxamides. Preparation of specific examples of heterocycle W1.9 follows established precedent for 1-oxo-1H-isochromene ring synthesis (Indian J. Chem., B. 1983, 22, 349-351; Indian J. Chem., B. 1986, 25, 189-190.), Chart B. Benzolactones of the formula B.1 are prepared as described in Chart C (Y=morpholinylmethyl or 4-tetrahydropyranylmethyl), or are prepared according to literature procedures (Y=iodo; J. Chem. Soc. 1931, 867-871.). B.1 is condensed with oxalic acid diethyl ester in the presence of sodium ethoxide to afford isochromene B.2. The resulting ester B.2 is then saponified to afford the corresponding carboxylic acid B.3 which is then coupled with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) mediated by 1,1xe2x80x2-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to provide amides of the general formula B.4. B.1 (Y=morpholinylmethyl) is prepared according to Chart C. Reductive amination of C.1 (J. Chem. Soc. 1925, 2275-2295) with morpholine, acetic acid, and sodium triacetoxyborohydride provides the morpholine derivative B.1 (Y=morpholinylmethyl). Similarly, B.1 (Y=4-tetrahydropyranylmethyl) is prepared according to Chart C. Wittig olefination between C.1 and 4-tetrahydropyranylphosphonium bromide (Bestmann, H. J.; Stransky, W.; Vostrowsky, O. Chem. Ber. 1979, 109, 1694-1700.) employing sodium hexamethyldisilazide as base provides the olefin C.2. Hydrogenation of C.2 catalyzed by palladium on carbon provides B.1 (Y=4-tetrahydropyranylmethyl).
Where Y=iodo, the products of Chart B (B.4, Y=iodo) may be further elaborated as described in Chart D. Sonogashira coupling of B.4 (Y=iodo) with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the corresponding alkynyl derivatives of formula D.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula D.2 (Z=CH2OH).
W1.17. 5-Hydroxy-8-oxo-7,8-dihydro[1,7]naphthyridine-6-carboxamides. Preparation of specific examples of heterocycle W1.17 follows an established literature precedent described in Chart E (J. Heterocyclic Chem. 1996, 33, 361.). Cyclic anhydride E.1 prepared as described in the literature (J. Org. Chem. 1961, 26, 808.) is reacted with acetamide and acetic anhydride (J. Med. Chem. 1989, 32, 2116.) to afford succinimide derivative E.2. Coupling of E.2 with a substituted N-benzyl-2-chloroacetamide (e.g. N-(4-chlorobenzyl)-chloroacetamide prepared as described in U.S. Pat. No. 5,834,514) in the presence of an appropriate base affords the substituted imide derivative of the formula E.3. Compounds of the formula E.3 undergo rearrangement when treated with ethoxide to afford naphthyridines of the formula E.4. Sonogashira coupling of E.4 with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the corresponding alkynyl derivatives of formula E.5 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula E.6 (Z=CH2OH).
W1.21. 4-Hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxamides. Preparation of specific examples of heterocycle W1.21 follows an established literature precedent set forth in J. Heterocyclic Chem. 1985, 22, 577. and elaborated on in Charts F and G below. Examples in which G=3-hydroxypropyl or 3-hydroxy-1-propynyl are prepared as described in Chart F. Cyclic anhydride F.1 is reacted with acetamide and acetic anhydride as described in the literature (Bull. Chem. Soc. Japan 1957, 30, 958.) to afford succinimide derivative F.2. Coupling of F.2 with a substituted N-benzyl-2-chloroacetamide (e.g. N-(4-chlorobenzyl)-chloroacetamide prepared as described in U.S. Pat. No. 5,834,514) in the presence of an appropriate base affords the substituted imide derivative of the formula F.3. Compounds of the formula F.3 undergo rearrangement when treated with ethoxide to afford naphthyridines of the formula F.4. Sonogashira coupling of F.4 with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the corresponding alkynyl derivatives of formula F.5 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula F.6 (Z=CH2OH).
Compounds such as those in which G=morpholinylmethyl are prepared as described in Chart G. Diester G.1 (J. Am. Chem. Soc. 1996, 118, 8847) undergoes displacement with morpholine to afford morpholinylmethyl derivative G.2. Saponification of G.2 to afford the corresponding diacid followed by cyclic anhydride formation by heating with acetic anhydride (Org. Syn. Coll. 1941, 1, 410) affords G.4. Succinimide G.5 is then formed by reacting G.4 with ammonium carbonate in aq. ammonium hydroxide (Org. Syn. Coll. 1941, 1, 457). Coupling of G.5 with a substituted N-benzyl-2-chloroacetamide (e.g. N-(4-chlorobenzyl)-chloroacetamide) in the presence of an appropriate base affords the substituted imide derivative of the formula G.6. Compounds of the formula G.6 undergo rearrangement when treated with ethoxide to afford derivatives of the formula G.7.
W3.1. 4-Oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamides. The preparation of representative examples of heterocycle W3.1 is described in Chart H. Condensation of 3-aminopyridine-N-oxide H.1 with diethyl ethoxymethylenemalonate followed by cyclization provides 1,7-naphthyridine-3-carboxylate H.2 (J. Org. Chem. 1954, 2008). Condensation of the resulting ester with 4-chlorobenzylamine at elevated temperatures provides the corresponding benzyl amide H.3. Reduction of the N-oxide followed by treatment with POBr3 affords 6-bromo-1,7-naphthyridine H.4. Sonogashira coupling of H.4 with an electron-rich acetylene (e.g. propargyl alcohol) affords the alkynyl derivatives such as H.5. Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives such as H.6.
Specific examples of heterocycle W3.1 in which R6=OCH2CH3 are prepared as described in Chart I. 3-Amino-6-bromo-2-ethoxypyridine I.1 is condensed with diethyl ethoxymethylenemalonate, and the resulting enamine is cyclized thermally to provide naphthyridine ester I.2. Saponification of the ester followed by coupling of the resulting carboxylic acid with a benzylamine (e.g. 4-chlorobenzylamine) mediated by 1,1xe2x80x2-carbonyldiimidazole (or other suitable carboxylic acid activating agent) provides amides of the general formula I.3. Sonogashira coupling of I.3 with an electron-rich acetylene (e.g. propargyl alcohol) provides alkynyl-derivatives of the formula I.4. Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of the formula I.5.
Specific examples of heterocycle W3.1 in which G=CH2NR1R2 are prepared as described in Chart J. The aryl bromides prepared above in Charts H and I (H.4 and I.3) undergo palladium catalyzed carbonylation in the presence of tributyltin hydride to give the corresponding aldehydes of the formula J.1. Reductive amination with a primary or secondary amine (e.g. morpholine) and sodium cyanoborohydride affords derivatives of the formula J.2.
W3.2. 4-Oxo-1,4-dihydro[1,5]naphthyridine-3-carboxamides. Preparation of specific examples of heterocycle W3.2 follows established precedent for [1,5]naphthyridine ring synthesis (U.S. Pat. No. 3,225,055; Eur. J. Med. Chem. 1977, 12, 549; J. Chem. Soc., C. 1954, 2357-2361.), Chart K. 3-Aminopyridines K.1 (Y=morpholinylmethyl or tetrahydropyranylmethyl) prepared as described in Chart P are condensed with diethyl ethoxymethylenemalonate to afford enamines of the formula K.2. Thermal cyclization in refluxing diphenyl ether provides the 1,4-dihydro[1,5]naphthyridine-3-esters K.3. The resulting ester is then treated with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at high temperature to afford the corresponding amides of the general formula K.4 or, alternatively, ester K.3 may be saponified to afford the corresponding acid which is then coupled with a benzylamine mediated by 1,1xe2x80x2-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to likewise provide amides of the general formula K.4 or, alternatively, ester K.3 may be treated with an above benzylamine and trimethylaluminum in an appropriate solvent to provide amides of the general formula K.4.
K.1 (Y=morpholinylmethyl) is prepared according to Chart L. Reductive amination of 5-nitro-2-pyridine carboxaldehyde (L.1) with morpholine, acetic acid, and sodium triacetoxyborohydride provides the pyridylmethylmorpholine L.2. Reduction of the nitro group in L.2 employing hydrogenation catalyzed by palladium on carbon provides K.1 (Y=morpholinylmethyl). Similarly, K.1 (Y=4-tetrahydropyranylmethyl) is prepared according to Chart L. Wittig olefination between L.1 and 4-tetrahydropyranylphosphonium bromide (Bestmann, H. J.; Stransky, W.; Vostrowsky, O. Chem. Ber. 1979, 109, 1694-1700.) employing sodium hexamethyldisilazide as base provides the olefin L.3. Hydrogenation of L.3 catalyzed by palladium on carbon provides K.1 (Y=4-tetrahydropyranylmethyl).
As further described in Chart K for the case where Y=chloro, the enamine K.2 is prepared as described in the literature (J. Heindl et al., Eur. J. Med. Chem. Chim. Ther. 1977, 12, 549-555). Thermal cyclization in refluxing diphenyl ether provides the 1,4-dihydro[1,5]naphthyridine-3-ester K.3. The product K.3 (Y=chloro) may be further elaborated as described in Chart M. Sonogashira coupling of K.3 (Y=chloro) with an electron-rich acetylene (e.g. propargyl alcohol) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the corresponding alkynyl derivatives of formula M.1 (Z=CH2OH). The resulting ester is then treated with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) and trimethylaluminum in an appropriate solvent to provide amides of the general formula M.2. Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula M.3 (Z=CH2OH).
W3.4. 8-Hydroxypyrido[3,2-d]pyrimidine-7-carboxamides. Preparation of specific examples of heterocycle W3.4 follows an established literature precedent described in Chart N (U.S. Pat. No. 3,320,257 and J. Chem. Soc. C. 1967, 1745.). Heteroarylamine N.1 (Coll. Czech. Chem. Commun. 1975, 40, 1396-1402.) is condensed with diethyl ethoxymethylenemalonate to afford the enamine N.2. Cyclization of N.2 is effected by heating the enamine in diethylphthalate to provide bicycle N.3. The resulting ester N.3 is then saponified to afford the corresponding carboxylic acid N.4 which is then coupled with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) mediated by 1,1xe2x80x2-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to provide amides of the general formula N.5. Sonogashira coupling of N.5 with an electron-rich acetylene (e.g. propargyl alcohol) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the corresponding alkynyl derivatives of formula N.6 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula N.7 (Z=CH2OH).
Alternatively, derivatives where G=CH2NR1R2 (e.g. 4-morpholinomethyl) are prepared from N.5 as described in Chart O. Compounds of the formula N.5 undergo palladium catalyzed carbon monoxide insertion and trapping with methanol to afford methyl esters of the formula O.1. The resulting esters are reduced with lithium aluminum hydride or other suitable reducing agent to provide the corresponding alcohols of the formula O.2. Activation of the alcohol as the mesylate by reaction with methanesulfonyl chloride in the presence of an amine base (e.g. collidine) followed by displacement with a primary or secondary amine (HNR1R2 such as morpholine) provides compounds of the formula O.3.
W3.6. 5-Hydroxy-[1,7]naphthyridine-6-carboxamides. Preparation of specific examples of heterocycle W3.6 follows established precedent for 5-hydroxy--[1,7]naphthyridine ring synthesis (Just. Liebigs. 1979, 443-445.), Chart P. 5-Iodo-2-methylpyridine-3-carboxylic acid (P.1) (J. Am. Chem. Soc. 1953, 75, 737) is brominated under radical conditions (e.g. NBS, benzoylperoxide) to afford pyridine P.2. P.2 is treated with ethyl 2-N-toluenesulfonylaminoacetate to provide P.3. Upon treatment of P.3 with ethoxide in ethanol, ring cyclization and elimination occurs to afford naphthyridine P.4. The resulting ester is then treated with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at high temperature to afford the corresponding amides of the general formula P.5 or, alternatively, ester P.4 is saponified to afford the corresponding acid which is then coupled with a benzylamine employing standard amide coupling protocols (e.g. HOBT/EDC or other suitable carboxylic acid activating agent) to likewise provide amides of the general formula P.5.
Intermediate P.5 may be further elaborated as described in Chart Q to prepare derivatives where according to formula (I) G=3-hydroxy-1-propynyl and 3-hydroxypropyl. Sonogashira coupling of halide P.5 with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the corresponding alkynyl derivatives of formula Q.1 (A=N, Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula Q.2 (A=N, Z=CH2OH).
Intermediate P.5 may be further elaborated as described in Chart R to prepare derivatives where G=morpholinylmethyl. Carbon monoxide insertion under reductive conditions (J. K. Stille J. Am. Chem. Soc. 1986, 108, 452-461.) catalyzed by a palladium catalyst (e.g. Pd(OAc)2, PdCl2(PPh3)2) provides carboxaldehyde R.1. Reductive amination of R.1 with morpholine, acetic acid, and sodium triacetoxyborohydride provides the pyridylmethylmorpholine R.2. The intermediate R.1 may also be further elaborated as described in Chart R to prepare derivatives where G=4-tetrahydropyranylmethyl. Wittig olefination between R.1 and 4-tetrahydropyranylphosphonium bromide (Bestmann, H. J.; Stransky, W.; Vostrowsky, O. Chem. Ber. 1979, 109, 1694-1700.) employing sodium hexamethyldisilazide as base provides the olefin R.3. Hydrogenation of R.3 catalyzed by palladium on carbon provides R.4.
W3.7. 4-Hydroxy-3-isoquinolinecarboxamides. Preparation of specific examples of heterocycle W3.7 follows established precedent for 4-hydroxy-3-isoquinoline ring synthesis (Tetrahedron 1985, 41, 6063.), Chart S. 3-Bromobenzoic acid-6-carboxaldehyde (S.1) (U.S. Pat. No. 3,465,003) is reacted with 2-aminoacetic acid diethyl boronate to afford imine S.2. S.2 is treated with potassium tert-butoxide and dimethylsulfate followed by additional potassium tert-butoxide and the resulting product is acidified to afford isoquinoline S.3. The resulting carboxylic acid is then coupled with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) employing standard amide coupling protocols (e.g. HOBT, EDC) to afford the corresponding amides of the general formula S.4.
As described in Chart Q, Sonogashira coupling of halide S.4 with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the corresponding alkynyl derivatives of formula Q.1 (A=CH, Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula Q.2 (A=CH, Z=CH2OH). Intermediate S.4 may be further elaborated as described in Chart R to prepare derivatives where G=morpholinylmethyl. Carbon monoxide insertion under reductive conditions (J. K. Stille J. Am. Chem. Soc. 1986, 108, 452-461.) catalyzed by a palladium catalyst (e.g. Pd(OAc)2, PdCl2(PPh3)2) provides carboxaldehyde R.1 (A=CH). Reductive amination of R.1 (A=CH) with morpholine, acetic acid, and sodium triacetoxyborohydride provides the pyridylmethylmorpholine R.2 (A=CH). The intermediate R.1 may also be further elaborated to prepare derivatives where G=4-tetrahydropyranylmethyl. Wittig olefination between R.1 (A=CH) and 4-tetrahydropyranylphosphonium bromide (Bestmann, H. J.; Stransky, W.; Vostrowsky, O. Chem. Ber. 1979, 109, 1694-1700.) employing sodium hexamethyldisilazide as base provides the olefin R.3 (A=CH). Hydrogenation of R.3 (A=CH) catalyzed by palladium on carbon provides R.4 (A=CH).
The inventive compounds may be used in their native form or as salts. In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, etoglutarate, and glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
Compounds of the present invention can conveniently be administered in a pharmaceutical composition containing the compound in combination with a suitable excipient, the composition being useful in combating viral infections. Pharmaceutical compositions containing a compound appropriate for antiviral use are prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington""s Pharmaceutical Sciences by E. W. Martin (Mark Publ. Co., 15th Ed., 1975). The compounds and compositions of the present invention can be administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically (including but not limited to surface treatment, transdermal application, and nasal application), intravaginally, orally, or rectally, depending on whether the preparation is used to treat internal or external viral infections.
For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices such as the osmotic release type devices developed by the Alza Corporation under the OROS trademark.
The compounds or compositions can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
The compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
For internal infections, the compositions can be administered orally or parenterally at dose levels, calculated as the free base, of about 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal body weight, and can be used in man in a unit dosage form, administered one to four times daily in the amount of 1 to 1000 mg per unit dose.
For parenteral administration or for administration as drops, as for eye infections, the compounds are presented in aqueous solution in a concentration of from about 0.1 to about 10%, more preferably about 0.1 to about 7%. The solution may contain other ingredients, such as emulsifiers, antioxidants or buffers.
Generally, the concentration of the compound(s) of formula I in a liquid composition, such as a lotion, will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%. The concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
The exact regimen for administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment and, of course, the judgment of the attending practitioner. The compounds of the present invention can be administered to an animal in need of treatment. In most instances, this will be a human being, but the treatment of livestock and companion animals is also specifically contemplated as falling within the scope of the instant invention.
The compounds of formula (I) and pharmaceutically acceptable salts thereof are useful as antiviral agents. Thus, they are useful to combat viral infections in animals, including man. The compounds are generally active against herpes viruses, and are particularly useful against the varicella zoster virus, the Epstein-Barr Virus, the herpes simplex virus types 1 and 2 (HSV-1 and 2), the human herpes virus types 6, 7 and 8 (HHV-6, 7and 8) and the human cytomegalovirus (HCMV).
The invention will be further described by the following non-limiting examples.
A solution of diethyl 2-(((6-chloro-3-pyridinyl)amino)methylene)malonate (J. Heindl et al., Eur. J. Med. Chem. Chim. Ther. 1977, 12, 549-555) (1.00 g) in diphenyl ether (110 mL) is degassed by three cycles of evacuation and nitrogen purging at room temperature. The solution is heated rapidly to reflux and stirred for 15 minutes. After cooling, the mixture is diluted with diethyl ether (150 mL), stirred vigorously for 5 minutes, and then filtered. The collected solid is washed repeatedly with ether and then dried under vacuum, affording 0.711 g (84%) of the title compound as a beige powder. Physical characteristics: 1H NMR (DMSO-d6) xcex48.61, 8.12, 7.79, 4.23, 1.29; HRMS (FAB) calcd for C11H9ClN2O3+H m/z 253.0380, found 253.0387. Anal. Calcd for C11H9ClN2O3: C, 52.29; H, 3.59; N, 11.09; Cl, 14.03. Found: C, 52.25; H, 3.53; N 11.23
Triethylamine (10 mL) is added to dry cuprous iodide (52 mg) under nitrogen. The mixture is stirred for 5 minutes. Propargyl alcohol (50 xcexcL) is added. After stirring another 5 minutes, dichlorobis(triphenylphosphine)palladium(II) (48 mg) is added. The mixture is again stirred for 5 minutes before the addition of ethyl 6-chloro-4-hydroxy[1,5]naphthyridine-3-carboxylate (Preparation 1, 348 mg) and DMF (10 mL). After stirring another 5 minutes, the remaining propargyl alcohol (660 xcexcL) is added, and the reaction is tightly capped and stirred at 70xc2x0 C. for 11 hours. After cooling, the mixture is diluted with ether (75 mL), sonicated to break up any solids, and filtered. The collected solid is washed with ether, dried under vacuum and recrystallized from ethanol.

Heterocycle carboxamides as antiviral agents

Abstract: which is useful as antiviral agents, in particular, as agents against viruses of the herpes family.


A drainer basket assembling structure of a stepping wringer bucket includes a bucket body, having a containing space concavely formed at the bottom of a front side, a shaft base formed at the top of the containing space; a base, having two support stands installed in the containing space; a driving mechanism installed between the two support stands for producing a driving force; a transmission shaft installed in the containing space and whose bottom is driven by the driving mechanism; and a drainer basket driven by the transmission shaft. An upper end of the transmission shaft is protruded out from the shaft base, and a protruding end is provided for sheathing the coupling base of the drainer basket and form a sheathing and linking structure with the protruding end of the transmission shaft, such that the drainer basket can be assembled from the top of the bucket body.

1. Field of the Invention
The present invention relates to a drainer basket assembling structure of a stepping wringer bucket, and more particularly to a structure having a drainer basket that can be assembled from the top of the wringer bucket.
2. Description of the Related Art
Mop is a common tool for cleaning a floor, and it is necessary to clean and wash away the dirt attached onto cotton cloths of a mop head after the mop has been used, and then dry the mop for the next use. Since dirty water will be attached onto a user's hands during the process of drying the cotton cloths, it is troublesome for using such conventional mop.
Therefore, some manufacturers developed a wringer bucket for spinning of the dirty water of the mop, so that the dirty water will not be attached onto the hands of users, and such wringer bucket has been disclosed in R.O.C. Pat. No. M338634. With reference to FIGS. 1 and 2 for the structure of such wringer bucket 10A, the wringer bucket 10A comprises: a bucket body 11, having a containing space 110 concavely disposed at the bottom of a front side of the bucket body 11, and a shaft base 111 disposed at the top of the bucket body 11; a base 12, having two support stands 121, installed in the containing space 110; a driving mechanism 13, installed between the two support stands 121, for producing a rotational driving force; a drainer basket 14, having a transmission shaft 15 installed at the bottom of the drainer basket 14, and extended into the containing space 110 from top to bottom through the shaft base 111, and coupled to a transmission element 131 of the driving mechanism 13, so that a user can use the driving mechanism 13 to drive the drainer basket 14 to rotate in the bucket body 11 to remove water.
However, the whole transmission shaft 15 of the aforementioned conventional wringer bucket 10A is fixed with the drainer basket 14. After the transmission shaft 15 is entered from top to bottom in to the containing space 110 during an assembling process, the transmission shaft 15 and the driving mechanism 13 are fixed onto the base 12, and thus making the assembling and removal very inconvenient.
With reference to FIG. 3 for a cross-sectional view of another conventional stepping wringer bucket 10B, this wringer bucket 10B is substantially the same as the aforementioned wringer bucket 10A, and the difference resides on that the transmission shaft 16 is shorter, such that after the transmission shaft 16 is passed from top to bottom through the shaft base 111 and coupled to the transmission element 131, the transmission shaft 16 is fixed by a positioning element such as a screw from the bottom, such that the drainer basket 14 will not fall off during the rotation and water removal processes.
Since the transmission shaft 16 of the wringer bucket 10B is locked, therefore the transmission shaft 16 cannot be removed from the opening at the top of the bucket body 11, and thus making the assembling, removal, maintenance, repair and transportation inconvenient. Obviously, the prior art requires improvements.

Drainer basket assembling structure of stepping wringer bucket


The present invention provides a display system for displaying image data. The display system comprises a light source; a spatial light modulator including a plurality of controllable reflective elements; a light source controller, configured to control the light source to emit, in each of a plurality of time intervals, light with a different illumination power level, wherein the time intervals have the same length; and a spatial light modulator controller, configured to activate, based on received image data, the plurality of controllable elements for at least one of the time intervals for directing the light from the light source for display the image data. Accordingly, the frame rate and bandwidth of the display system are increased significantly so as to be suitable for the light filed applications.

With the development of light field display technology, less display latency and higher bandwidth of display are desired for a projection display system as compared with before. In particular, for Augmented Reality/Virtual Reality (AR/VR) applications, high frame rate of the projection display system is desired to reduce the display latency. In addition, light field displays should be capable of displaying a number of depth (focal) layers, in particular 6 or more depth (focal) layers, in order to allow a comfortable user experience. In order to meet the desired attributes, the device could have a bandwidth capable of supporting the desired frame rate taking into account the number of depth layers and image resolution. As an example, in systems with a frame rate of 90 fps (frames per second), with a resolution of 1920×1080, 6 depth layers and a color depth of 8 bits, the required bandwidth would be 2.7×1010 bits/s or 27 G bits/s (90 fps×1920×1080 (resolution)×6 (depth layers)×3(RGB)×8 (colour depth)).
Typically, conventional projection display systems use light reflected or transmitted by individual elements of a spatial light modulator (SLM) to generate a display image. One type of spatial light modulator is a digital micro-mirror device (DMD). Conventional DMD devices realize grey levels by reflecting light with constant predefined power from a light source for different time durations. As an example, in the case of a 4 bits color depth (=24 grey levels), the illumination power corresponding to the least significant bit will be obtained or accumulated by reflecting light for 1×Δt seconds, while the illumination power corresponding to the most significant bit will be obtained or accumulated by reflecting light for 8×Δt seconds, where Δt is a predefined time interval.
However, conventional projection display systems (as described above) only support 60 fps or less and have a bandwidth of the order of 109 bits/s (for 6 depth layers and a color depth of 8 bits). Therefore, it is difficult for such projection display systems to meet the requirements of new applications, such as 3D projection of AR/VR applications. Accordingly, there is a challenge for improving the design of projection display systems for the light field applications, such as AR/VR applications.

System, apparatus and method for displaying image data


Examples of golf club heads and methods to manufacture golf club heads are generally described herein. In one example, a body portion of a golf club head may include a cavity having an opening and an interior structure defined by a wall portion and a base portion. A hosel portion may include an insert portion and a neck portion extending therefrom. The hosel portion may be attached to the body portion by an interference fit between the neck portion and the opening of the cavity. The insert portion may be received inside the cavity and may be spaced apart from the interior structure of the cavity. A space between the insert portion and the interior structure of the cavity may be partially or entirely filled with an adhesive to hold the hosel portion in place. Other examples may be described and claimed.

Golf club heads may be manufactured using various materials and processes. By manufacturing golf club heads with removable interchangeable parts, more customization options may become available.
For simplicity and clarity of illustration, the drawing figures illustrate the general manner of construction, and descriptions and details of well-known features and techniques may be omitted to avoid unnecessarily obscuring the present disclosure. Additionally, elements in the drawing figures may not be depicted to scale. For example, the dimensions of some of the elements in the figures may be exaggerated relative to other elements to help improve understanding of examples of the present disclosure.

Golf club heads and methods to manufacture golf club heads


The invention discloses a three-dimensional cage-like hyperbranched monomer and preparation method and application thereof. The three-dimensional cage-like hyperbranched monomer has the structural formula I:

With the development of the petroleum industry, especially in recent years, our dependence on foreign oil and gas has become greater and greater. In order to ensure national energy security and vigorously improve the level of oil and gas exploration, higher requirements have been placed on oil and gas field extraction technologies. Especially the development of rock oil and gas fields is difficult, the working environment is complex, and the performance requirements of wellbore working fluids (including drilling fluids, completion fluids, and fracturing fluids) are higher. Due to the limitation of structure and group, the traditional wellbore working fluid can no longer meet the increasing performance requirements, which requires continuous design of new wellbore working fluid. In this process, molecular design has gradually gained attention, providing a more effective solution to these problems, which can not only improve the performance of the wellbore working fluid, but also meet the requirements of environmental protection.
At present, domestic and foreign wellbore working fluids can be divided into natural modified polymers, synthetic resins, and synthetic polymers according to their structure. Naturally modified polymer-type wellbore working fluids, mainly including modified starch, cellulose, lignin, humic acid, lignite, and tannin. They have a wide range of sources and low prices, but they generally have the weakness of low temperature and salt resistance. Synthetic resin type fluid loss reducer, such as the most commonly used sulfomethyl phenolic resin, is prepared by sulfonation reaction using phenolic resin as the precursor. Although it has good temperature resistance, salt resistance and filtration loss reduction properties, it is easy to cause environmental pollution during preparation and use. Therefore, the synthesis of new high temperature resistant, salt resistant and anti-calcium-magnesium fluid loss reducers is an issue we need to solve urgently. The key to solving the problem lies in the monomer with special structure and its synthesis method. Based on the concept of molecular design, a three-dimensional cage-like hyperbranched polymer with different groups and structures from traditional wellbore working fluids was designed to achieve the best results. Facts have proved that hyperbranched polymers can effectively improve the salt and temperature resistance of wellbore working fluids. However, the existing hyperbranched polymers have many synthetic steps, complicated synthetic processes, and insufficient performance. Therefore, the development of new three-dimensional cage-like hyperbranched monomers and new synthetic methods through organic synthesis reactions are very important to improve the performance of wellbore working fluids.

Three-dimensional cage-like hyperbranched monomer, and preparation method and application thereof

Abstract: wherein in the structural formula I: X is any one of —O, —S, —NH; y is any integer from 2 to 8; R is —H or —CH3. The beneficial effect of the technical scheme proposed in the present invention is: by introducing easily polymerizable olefin groups, the carboxyl group and amide group are combined in the three-dimensional cage-like hyperbranched monomer to make the water solubility good, and it can be copolymerized with many other monomers to obtain the three-dimensional cage-like hyperbranched polymer; when used as an additive for wellbore working fluids, due to the hyperbranched structure of the polymer, it has good salt and temperature resistance, and also has viscosity increasing, filtration loss, and flocculation properties; meanwhile, the synthesis method is simple and the cost is low.


As an apparatus which provides a high-quality service that reduces the service usage load of users, there is disclosed an information processing apparatus accessed from a communication terminal to browse images, which includes an issuing unit that assigns a session identification to a communication terminal, a storage unit that stores the session identification and the communication terminal user's personal information, a receiving unit that receives a session identification and a printing request of images, a determination unit that determines if the session identification is stored in the storage unit, a transmission unit that transmits the personal information to the communication terminal if the determination unit determines that the session identification is stored with the personal information in the storage unit, and an obtaining unit that obtains the user's personal information if the determination unit determines that the session identification is not stored in the storage unit.

Along with the recent improvement of communication infrastructure and development of information communication technology, information providing services using the Internet are becoming available.
For example, there are generated systems which offer information providing services, i.e., systems which offer services (image browsing services) in which image service sites (to be referred to as photo sites hereinafter) keep image data which users have taken by using image input devices in the storage areas of servers on the Internet and allow customers to browse again the image data at a desired time. There are also providers that provide such services.
In such a system which acquire input information input from a communication terminal and provides a service on the basis of the input information, a memory area called a cookie is ensured in the communication terminal to hold the input information. With this structure, the user need not repeatedly input the same information from the communication terminal.
That is, the input information input from the communication terminal is temporarily held in the cookie and then transmitted to an information processing apparatus. For this reason, when the system requires the same information again, the user need not input the same information.
However, there are some communication terminals which cannot ensure cookies because of a lack of sufficient memory areas. In this case, the user must input the same information many times. In addition, many portable terminals are inconvenient for character input, resulting in excess load on the user.
A photo site which provides an image browsing service manages a series of session information containing an access time, albums to be browsed, album image information, and the like for each access from a terminal. The photo site must also simultaneously manage actual album images.
The photo site which provides the image browsing service uses a session ID when accessed by a user. When a predetermined time has elapsed from the final access, session timeout occurs. From this time point, access with the previous session ID is refused.
Furthermore, since the number of pixels of a digital camera is increasing in recent years, the number of pixels of an original image also tends to increase. In a portable terminal, when an original image is to be browsed directly, the entire image may not be displayed in a window, or data transfer may be time-consuming. To prevent this, the photo site generates and manages browsing display images, i.e., images whose sizes or data amounts are decreased on the basis of uploaded original images.
At the time of providing the browsing service, the photo site makes a copy of a browsing display image file in the display area of the photo site server. At the end of the service, the photo site erases the browsing display image file that exists in the display area.
However, if the managed session information or the browsing display image file that is copied in the display area should be erased every time session timeout occurs during the image browsing service, a timeout time must be set and managed for each session.
In addition, the browsing display image is copied in the area for display in each session. The browsing display image must be erased after the session timeout of each session. However, to implement this processing, the browsing display image erase must be managed for each session.

Information processing apparatus for providing image to communication terminal and control method therefor


Provided is a communication unit that includes first and second power-amplification modules, which can be integrated. The first power-amplification module includes a first power-amplifier for a first frequency band in a first communication scheme, a second power-amplifier for a second frequency band in the first communication scheme, a third power-amplifier for a third frequency band in a second communication scheme, a fourth power-amplifier for a fourth frequency band in the second communication scheme, a first bias circuit that generates a first bias current to the first and second power-amplifiers, and a bias current circuit that converts the first bias current into a second bias current to the third and fourth power-amplifiers. The second power-amplification module includes a fifth power-amplifier for a fifth frequency band in the first communication scheme, and a second bias circuit that generates a third bias current to the fifth power-amplifier.

Field of the Disclosure
The present disclosure relates to a communication unit.
Description of the Related Art
A communication unit that includes a power amplification module for amplifying the power of a radio frequency (RF) signal that is to be transmitted to a base station is employed in a portable terminal that utilizes a cellular phone communication network. In recent years, the number of users of portable terminals has increased tremendously and the number of frequency bands utilized by cellular phones has increased in order to handle the communication traffic created by these users. Therefore, it is required that portable terminals support these frequency bands.
In addition, from the viewpoints of design restrictions, profile reduction and size reduction of portable terminals, it is required that such communication units be reduced in size. Accordingly, for example, a power amplification module is used in which a plurality of power amplifiers, which support a plurality of communication schemes (modes) and a plurality of frequency bands, are integrated into a single module, as described in "TQM7M9050 data sheet", TriQuint Corp., (online), web address: www.triquint.com/products/d/DOC-B-00000332.
The power amplification module disclosed in "TQM7M9050 data sheet", TriQuint Corp., (online), web address: www.triquint.com/products/d/DOC-B-00000332 supports the second generation mobile communication system (2G) and the third/fourth generation mobile communication system (3G/4G). This power amplification module includes a power amplifier for a low frequency band (LB) that is a 1 GHz band of the global system for mobile communications (GSM) (registered trademark), which is the 2G communication standard, a power amplifier for a high frequency band (HB) that is a 2 GHz band of GSM, a power amplifier for an LB that is a 1 GHz band of 3G/4G and a power amplifier for an HB that is a 2 GHz band of 3G/4G.
In this power amplification module, the 3G/4G LB power amplifier covers two frequency bands that are band 5 (B5: transmission frequency band of 824 MHz to 849 MHz) and band 8 (B8: transmission frequency band of 880 MHz to 915 MHz). In addition, the 3G/4G HB power amplifier covers four frequency bands that are band 1 (B1: transmission frequency band of 1920 MHz to 1980 MHz), band 2 (B2: transmission frequency band of 1850 MHz to 1910 MHz), band 3 (B3: transmission frequency band of 1710 MHz to 1785 MHz) and band 4 (B4: transmission frequency band of 1710 MHz to 1755 MHz).
In recent years, as a technique for improving the downlink communication speed from a base station to a portable terminal, downlink carrier aggregation (hereafter, "DLCA"), which is a technique in which a plurality of frequency bands are simultaneously used in the downlink has been focused upon in long term evolution (LTE) advanced, which is a 4G communication standard. Consequently, a communication unit that is suitable for downlink carrier aggregation has been demanded.

This patent is subject to a terminal disclaimer.

Power amplification module for multiple bands and multiple standards


In a magnetic recording medium, three sorts or more of magnetic patterns being different in the coercive force are combined corresponding to information, and the magnetic pattern with high coercive force is previously magnetized in required direction and the magnetization direction provides a part of the information. In this constitution, the codes for discriminating truth or falsehood of the card cannot be easily deciphered by a magnetic viewer on the market thereby the security can be improved.

1. Field of the Invention
The present invention relates to a magnetic recording medium, and more particularly to improvement of security.
The invention can be applied to a magnetic recording medium requiring illegal use preventing function and forgery and altering preventing function, for example, a magnetic card or the like.
2. Description of the Prior Art
In the prior art, such method is adopted that codes for discriminating truth or falsehood are formed on a part of a magnetic card, and read by a magnetic head so as to discriminate truth or falsehood thereby the security of the card is improved.
In the magnetic card of the prior art, such codes for discriminating truth or falsehood are formed by magnetic print patterns and non-magnetic dummy print patterns so that the codes cannot be easily deciphered. Material of high coercive force, such as magnetite (Fe.sub.3 O.sub.4) or maghemite (.gamma.-Fe.sub.2 O.sub.3), is used as material for the magnetic print pattern.
In the magnetic recording medium in the prior art, however, if external magnetic field is applied to read the codes for discriminating truth or falsehood, residual magnetization is produced in the magnetic print patterns thereby the codes for discriminating truth or falsehood can be visualized using a magnetic viewer or the like on the market.
In order to solve the problem, after the external magnetic field is applied for the reading or the like, it must be demagnetized every time resulting in complication of the system.


An apparatus is provided in one example embodiment and includes a light guide configured to couple to an electronic unit. The electronic unit is a replaceable unit of an electronic component, the light guide extending along a body structure of the electronic unit and signaling an operational state of the electronic unit. In more specific embodiments, the light guide communicates optical energy from a light source coupled to the electronic unit and configured to indicate the operational state of the electronic unit. In still other embodiments, the light source is a light emitting diode (LED) that indicates the operational state of the electronic unit. The light guide can include a light input that enhances an optical coupling between the light source the light guide. In still other embodiments, the light guide includes a curved portion that changes a direction of optical energy propagating within the light guide.

Computing devices typically incorporate field replaceable units such as cooling fans. These units may be quickly removed from the device hosting it and replaced if necessary. This procedure occurs, for example, if the unit fails. Electronic equipment can be sensitive to user mishandling when conducting such a procedure. In addition, miscalculations in identifying which components are faulty can waste time and result in damage to costly electronic equipment.

System and method for detecting a failure in a field replaceable unit


The disclosure relates to a scanning device for detecting the contour of an object. The scanning device has a light source for generating a light pattern on the surface area of the object, and a camera for detecting the light pattern on the surface area of the object. The disclosure describes that the one light source includes at least one incoherent spot light source, and that between the at least one spot light source and the object, a shadow caster defines the light pattern on the surface area of the object. The disclosure also relates to a method for detecting the contour of an object.

Such a scanning device and such a method relate to EP 1 178 878 B1 or from DE 196 04 254. In the grant procedure, the opposition procedure or the nullity procedure relating to these two protective rights, a great number of additional documents referring to similar scanning devices and methods have been cited, in particular JP 1132333 A or JP 7184534 A.
These conventional scanning devices serve to detect the outer contour of an object. Said object may be, in particular, a food product that is to be cut into constant-weight portions or slices. Distributed over the length of the object, a great number of contours is detected wherefrom a volume model of the object, i.e. a three-dimensional model of the object, can be subsequently calculated. If the weight force of the object is additionally measured, an average density of the product can be calculated from the weight and the overall volume, and on the basis thereof, taking into account the outer contour, cutting positions for constant-weight slices can be calculated.
In prior art, the peripheral contour of the object is often detected by means of the so-called light section technique. For this purpose, in the above-cited documents a line of laser light is projected onto the product by means of one or a plurality of overlapping line lasers. This linear projection of the laser light is imaged by means of a camera. From the course and the location of the light line on the object, the course of the respective surface contour can be derived.
Cutting machines for cutting up food products, so-called slicers, are for example known from the following documents: DE 3713536 A1, DE 3923337 A1, DE 4413568 C5, DE 10054514 A1, DE 10131701 A1, DE 19604254 B4, DE 10327249 A1, DE 19525741 A1, DE 19713163 A1, De 19839257 A1, DE 19844436 C2, and DE 102009023729 A1.
Some of these cutting machines already use scanning devices to detect the outer contour of the food products to be cut up. Frequently, the object of this contour detection is to cut up slices or portions of the product as constant as possible in weight.
Apart from the area of food processing, scanning devices for the detection of the contour or of the 3D coordinates of objects are also known. Thus, DE 10 2008 047 816 A1 describes a device for detecting the 3D coordinates of teeth or tooth models. This device, however, has among other problems the drawback that the scanner used therein must be guided around the whole object in order to obtain a sufficient number of data for the representation of the object. US 2007/0177160 A1 discloses a further device for obtaining 3D coordinates of an object, in particular a book. US 2010/0008588 A1 aims at the 3D localization of certain structures on objects, and not at the 3D detection of these objects themselves. Finally, US 2010/0007896 A1 discloses an apparatus for measuring, in particular, the height of electronic components.

Scanning device and method for detecting the contour of an object


Novel tools and techniques are described for protecting camera components on a surface and/or within an internal portion of a portable electronic device. In one aspect, an electronic device might comprise a camera mount, which might comprise a camera barrel assembly configured to have a camera affixed thereto, the camera barrel assembly being rotatably coupled with one of a front panel, a rear panel, or a chassis of the electronic device. The camera mount may further comprise a set of cantilever springs affixed to one of the front panel, the rear panel, or the chassis and biased against the camera barrel assembly to provide rotational friction on the camera barrel assembly. The set of cantilever springs might have sufficient compliance to allow the camera to retract into a body of the portable electronic device upon encountering an external force, which may include an impact force or a dropping force.

Traditionally, electronic devices, particularly portable electronic devices having a built-in camera (portions of which might extend beyond the housing of the devices), have been constructed to be as compact as the components within might allow. This approach saves costs, while allowing the electronic devices to be less bulky, and thus less cumbersome for a consumer to carry or otherwise transport. As a result, most portable electronic devices having such features lack mechanisms therein that protect internal and/or external camera components from impacts, e.g., due to daily handling, drops, collisions with other objects, etc. Such impacts may damage camera components on a surface of a portable electronic device, and/or may damage electronics components of the camera that are housed within the portable electronic device.
The embodiments disclosed herein are directed toward overcoming one or more of the problems discussed above.


Any of an improved conventional, a refillable, or a continuous ink supply system (CISS) ink delivery apparatus, including a housing comprising one or more walls defining a chamber therein, a structural feature configured during use to detachably engage with a reciprocal receiving portion of a printer device, a fluid dispensing port extending through a first wall of the housing, and a siphon structure comprising a curved fluid-conducting conduit originating at the chamber and extending to the fluid dispensing port. Additionally and/or alternatively with respect to the siphon structure, an improved ink delivery apparatus includes any one or more of an automatically resettable chipset, a detachable cover plate and/or a fluid (gaseous and/or liquid) input port.

Printing devices, referred to generally as printers herein for descriptive simplicity, are a nearly ubiquitous part of the modern world. Printers are used in every niche of society, from multi-national corporations and government entities, to elementary school students working on homework in the comfort of their homes. Among printer technologies, inkjet printers are one of the lower cost options, and therefore remain popular with consumers.
However, as users well know, replacement ink cartridges constitute a high, ongoing cost of ownership. Each cartridge has a limited usable life dictated primarily by its ink capacity. When no further ink can be usefully extracted, conventional ink cartridges must be disposed of and replaced. Periodically disposing of and replacing ink cartridges presents not only a substantial cost to the user, but also to the environment. Depleted ink cartridges are typically thrown away, after which their relatively non-degradable housings and chemical-containing inks end up in landfills. Further, producing replacement cartridges consumes a substantial amount of natural resources.
To reduce both the consumer cost and the environmental impact, numerous approaches have been developed to enable refilling of ink cartridges by the consumer or by a third-party. However, these efforts are both actively and passively discouraged by original equipment manufacturers (OEMs), who make a handsome income selling replacement ink cartridges for their printers.
Firstly, OEMs typically do not design ink cartridges to include provisions for relatively simple, clean, and reliable ink replenishment by the consumer. Rather, the consumer must use third-party tools and methods that typically breach the integrity of the ink cartridge, and are frequently difficult and messy to perform.
Secondly, OEMS typically do not provide a means for the consumer to reset the electronic chipset that counts ink dispense signals from the printer and indicates when ink in the cartridge may be low and/or empty. Therefore, although a consumer may successfully refill an ink cartridge, the chipset will continue to signal that the ink is low and/or empty.
Even when a consumer is able to successfully refill an ink cartridge, the internal design of conventional ink cartridges limits the amount of ink that can be provided therein. For example, conventional ink cartridges typically include an internal 'sponge' designed to distribute ink relatively evenly throughout the internal body of the cartridge. Thus, as ink is dispensed from one area within the cartridge, the dispensed ink is replaced by ink wicked through the sponge from another area of the cartridge body. However, this design has two cartridge-life-shortening deficiencies.
Firstly, the sponge itself consumes space within the cartridge body, thus reducing the amount of ink that can be contained therein. Secondly, when the amount of ink in the cartridge drops below the wicking capacity of the sponge, no further internal ink transfer occurs, despite the fact that ink remains in the cartridge. Thus, ink otherwise available for printing is wasted.
Further still, most ink cartridges provide for only a single mode of use. For example, conventional ink cartridges are designed to be used once and then discarded. Refillable ink cartridges produced by some third-party companies enable reuse, but still suffer from numerous problems, such as those inherent from inclusion of a sponge therein (as discussed above). Further still, neither conventional cartridges nor refillable cartridges are configured for use with a Continuous Ink Supply System (CISS).
Thus, existing ink cartridges, and indeed the structure of the OEM ink cartridge industry, entails elevated costs to consumers, and presents a tangible environmental burden. Thus far, incremental attempts fail to significantly alleviate either or both of these problems.


Various examples are provided related to hybrid multiple-input/multiple-output (MIMO) architectures. Beam steering can be provided using lens arrays. In one example, a hybrid antenna system includes a plurality of lens antenna subarrays (LAS), each of the LAS including a plurality of antenna elements configured to selectively receive a radio frequency (RF) transmission signal from RF processing circuitry, and a lens extending across the plurality of antenna elements. The RF transmission signal can be provided to a selected antenna of the plurality of antenna elements via a switching network and a common phase shifter for transmission. The lens can be configured to steer a RF transmission generated by the selected antenna in a defined direction. The selected antenna can be determined by the switching network configuration.

Wireless communications within mm-wave bands (28, 38, 60, 73 GHz, and beyond) attract growing interest due to the diminishing availability of open spectrum in lower frequency bands. One of the recognized benefits of mm-wave communications is the opportunity to employ electrically large antenna arrays to overcome the attenuation and blockage challenges in wide area operation. Unfortunately, the cost and power consumption of mm-wave mixed signal analog/digital components can make it prohibitively expensive to utilize an RF chain and analog-to-digital/digital-to-analog converter (ADC/DAC) for each of the antenna elements in a large array to enable multiple-input/multiple-output (MIMO) signal processing in the baseband. Novel architectures capable of simultaneously addressing the challenges of cost and power have the potential for broad impact in the next generation of wireless systems.

Hybrid MIMO architecture using lens arrays


A method is disclosed for braking electrically driven vehicles, in particular rail vehicles. In at least one embodiment, the behavior of the brake system is configured directly as a function of the system state, i.e. the operating conditions of the vehicle, such as for example the laden state of the vehicle, temperature of the engines and in particular of the magnets, as well as redundancy requirements, and therefore permit the fully functioning mechanical brake which is present in vehicles nowadays to be eliminated. The method of at least one embodiment for braking electrically driven vehicles which are equipped with spring-store-based friction brakes and whose motive drive is provided by way of permanently excited synchronous machines whose terminals are connected via switches to devices which generate a braking torque includes an open-loop or closed-loop controller being activated and the controller connecting the brake system of the engines which are present and the spring-store-based friction brakes into the circuit individually and successively as a function of the operating conditions of the vehicle and the required brake values.

According to the prior art, the braking of rail vehicles takes place by way of an electro-pneumatic braking arrangement. The design of such systems is based on the maximum vehicle loading under the assumption of adverse ambient conditions (for example friction value).
Unregulated braking would, for example under partial loading, result in the required deceleration values being exceeded. The adjustment/regulation of the mechanical brake usually takes place by way of a load-dependent variation of the brake pressure.
In the most recent stage of development, permanently excited synchronous machines with separate electric brake circuits are used for driving vehicles, in particular rail vehicles.
Document DE 10 2004 032 680 A1 discloses a motor brake for an electrically driven vehicle, in particular for a rail vehicle, having a permanently excited synchronous machine, with terminals of the synchronous machine being connected via switches to devices which generate a braking torque. Here, it is provided that a capacitor is connected in parallel at least to one of the devices which generate a braking torque, in order to ensure an increased braking power by varying the operating point of the synchronous machine.
The devices which generate a braking torque are for example brake resistances which can be variable.
By connecting a permanently excited synchronous machine in a circuit with ohmic resistances (R) or combinations of ohmic resistances and capacitors (RC), the action of the motor brake is optimized with respect to the rotational speed of the synchronous machine, and it is possible to realize a reliable electric brake, in particular for rail vehicles.
With the described circuit connection of the permanently excited synchronous machine, extremely different boundary conditions, such as for example load state of the vehicle, temperature of the motors and in particular of the magnets, and redundancy requirements, have the result that, for a fixed dimensioning of R or RC, the braking deceleration limit values prescribed by the operator or in standards are not always adhered to.
In the event of a simultaneous activation of all of the provided braking systems, that is to say without controlling intervention, the limit values for deceleration are exceeded in several system states.
Such behavior is not accepted by the operators and prevents the use of a reliable electric brake for rail vehicles.

Method for braking electrically driven vehicles


An electronic module has an electronic element 210; a connection body 250 provided on a front face of the electronic element 210; and a detection part 100 having a winding wire part 10 provided so as to surround the connection body 250, and a winding return wire part 50 connected to a terminal end part of the winding wire part 10 and returns from the terminal end part toward a starting end part.

Conventionally, using a Rogowski coil has been studied as a current detection sensor. The Rogowski coil is a coreless coil, and has a winding core, a winding wire wound around the winding core, and a return wire connected to the terminal end part of the winding wire and returning to a starting end part side (for example, see JP 2012-88224 A). In addition, the Rogowski coil is connected to an integrator, and a change in current in an object to be measured can be measured by integrating the output voltage with the integrator.
On the other hand, a sensor that detects a change in the current flowing through an electronic element (for example, a switching element) included in an electronic module has been proposed. In the related art, the electronic module uses a shunt resistor to detect the current, but a space for providing the shunt resistor is required. In particular, when the current is large, such as 200 A or more, the size of the shunt resistor has increased, so that there is a problem that it is difficult to mount the shunt resistor in the electronic module and the current accuracy is poor.

SHINDENGEN ELECTRIC MANUFACTURING CO., LTD.


An electrolytic capacitor having a low impedance characteristic, having a high withstand voltage characteristic of 100V class, wherein the electrolytic capacitor provides an excellent high temperature life characteristic.

An electrolytic capacitor typically has an anode electrode foil made of a band-shaped high purity aluminum foil where the effective aluminum foil surface has been enlarged through etching process chemically or electrochemically, and an oxide film is formed on the surface, through a chemical process of treating the aluminum foil with a chemical solution such as ammonium borate aqueous solution and the like. A cathode electrode foil is also made of an etched aluminum foil of high purity. Capacitor element is formed by the anode electrode foil and the cathode electrode foil, wound together with intervening separator made of manila paper and the like. Next, the capacitor element, after impregnating with an electrolyte solution for driving the electrolytic capacitors, is housed into a bottomed outer case made of aluminum and the like. The outer case is equipped at the opening with a sealing member made of an elastic rubber, and is sealed by drawing.
Herewith, as electrolyte solution for driving the electrolytic capacitor having high conductivity, and to be impregnated to the capacitor element, wherein γ-butyrolactone is employed as the main solvent composed of quaternized cyclic amidin compounds (imidazolinium cation and imidazolium cation) as the cationic component and acid conjugated bases as the anionic component are dissolved therein as the solute (refer to Unexamined Published Japanese Patent Application No. H08-321449 and No. H08-321441)
However, due to the remarkable development of digital information devices in recent years, the high-speed driving frequency of micro-processor which is a heart of these electronic information devices is in progress. Accompanied by the increase in the power consumption of electronic components in the peripheral circuits, the ripple current is increased abnormally, and there is a strong demand for the electrolytic capacitors used in these circuits to have a low impedance characteristic.
Moreover, in the field of vehicles, with the recent tendency toward improved automobile functions, a low impedance characteristic is in high demand. By the way, the driving voltage of the vehicle circuit of 14V has been progressed to 42V accompanied by the increase in the power consumption. To comply with such a driving voltage, the electrolytic capacitor requires the withstand voltage characteristic of 28V and 84V and more. Furthermore, the electrolytic capacitors must withstand high temperature in this field, and a high temperature life characteristic is in demand.
However, the electrolytic capacitor cannot cope with the low impedance characteristic as such. Moreover, although the withstand voltage of 28V is capable, the limit is 30V, and it cannot respond to the requirement of the high withstand voltage of 84V and more.

Electrolytic capacitor manufacturing method

Abstract: The electrolyte solution containing the aluminum tetrafluoride salt is used. The moisture content of the capacitor element is adjusted to 0.7% by weight or less, wit respect to the weight of the capacitor element, preferably 0.5% by weight or less, and most preferably 0.4% by weight or less. In this way, the electrolytic capacitor having the low impedance characteristic and the high resistance voltage characteristic, and the excellent high temperature life characteristic is provided.


System and method for calibrating a time constant R0Ci of an integrated electronic current-feedback continuous-time delta sigma analog/digital converter (modulator) having a variable-impedance filter coupled to input of the modulator, an analog input signal Vin of fixed frequency applied to the variable-impedance filter, wherein the analog input signal Vin attenuation engendered by the variable-impedance filter is measured, and the value of a time constant R0Ci in the modulator and value of the impedance of the variable-impedance filter are modified until an attenuation corresponding to the desired attenuation for the integrated electronic circuit modulator is obtained.

Certain signal processing functions used in analog integrated circuits are based on the value of a time constant RC. Typically, the coefficients of an analogue filter or else of an analog digital converter, such as a continuous-time delta-sigma analog digital converter, are achieved by means of resistance R and capacitances C.
The product RC of an analog filter corresponds to its cutoff frequency. For a continuous-time delta-sigma analog digital converter, this time constant RC is related to its sampling frequency. In both these cases, the precision of the time constant RC is important. For the cutoff frequency, if RC is estimated with too high a value, the filter cuts off a part of the signal, and if RC is too small, then the filter does not attenuate the signal sufficiently. In the case of the delta-sigma modulator, it is the performance and the stability of the modulator that depend directly on the precision of the value of RC. The RC coefficients achieve the transfer function of the current-feedback continuous-time delta-sigma analog digital converter.
Depending on the application, the precision with which the product RC must be known is higher or lower. A precision of the value of the time constant RC to +/−5% is generally sufficient.
However, an integrated resistance is accurate to +/−15% while the value of an integrated capacitance varies at least by +/−20% depending on the technology. In conclusion, the time constant RC has a precision of +/−35% which is not sufficient for the great majority of applications.
Various schemes for calibrating a time constant are already known in the prior art. Reference may be made in this regard to the documents U.S. Pat. Nos. 6,169,446, 6,262,603, 6,803,813 and 7,078,961.
The calibration described in these documents is based on a comparison of the value of the time constant defined by the product RC with a known and accurate time base formulated, for example, by a quartz-driven clock, or on a comparison of the voltage across the terminals of the resistance R with that present across the terminals of the capacitance C when they are traversed by the same current.
These schemes for calibrating the time constant RC merely deliver a digital word which directly controls a resistance or a variable capacitance.
Moreover, they are all sensitive to the analogue imperfections intrinsic to the hardware components used to make the converter, such as the offset voltage of an operational amplifier or of the comparators used.
Moreover it is known, in the prior art, to use a current-feedback continuous-time delta-sigma analog digital converter coupled to a filter at input receiving a sinusoidal input signal, so as to calibrate the time constant of another current-feedback continuous-time delta-sigma analog digital converter.
However, the use of a second current-feedback continuous-time delta-sigma analogue digital converter is expensive in terms of time and cost.
In view of the foregoing, it is proposed to circumvent most of these limitations related to the calibration of a time constant by carrying out a measurement of a time constant of an integrated circuit of increased precision.

System for calibrating a time constant of an integrated circuit, and integrated circuit provided with such a system