Compounds of the formula below are poly(ADP-ribosyl)transferase (PARP) inhibitors, and are useful as therapuetics in treatment of cancers and the amelioration of the effects of stroke, head trauma, and nuerodegenerative disease.

The invention pertains to compounds that inhibit poly(ADP-ribose) polymerases, thereby retarding the repair of damage to DNA strands, and to methods of preparing such compounds. The invention also relates the use of such compounds in pharmaceutical compositions and therapeutic treatments useful for potentiation of anti-cancer therapies and inhibition of neurotoxicity consequent to stroke, head trauma, and neurodegenerative diseases.
Poly(ADP-ribose) polymerases (PARPs), nuclear enzymes found in almost all eukaryotic cells, catalyze the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) to nuclear acceptor proteins, and are responsible for the formation of protein-bound linear and branched homo-ADP-ribose polymers. Activation of PARP and resultant formation of poly(ADP-ribose) can be induced by DNA strand breaks after exposure to chemotherapy, ionizing radiation, oxygen free radicals, or nitric oxide (NO).
Because this cellular ADP-ribose transfer process is associated with the repair of DNA strand breakage in response to DNA damage caused by radiotherapy or chemotherapy, it can contribute to the resistance that often develops to various types of cancer therapies. Consequently, inhibition of PARP may retard intracellular DNA repair and enhance the antitumor effects of cancer therapy. Indeed, in vitro and in vivo data show that many PARP inhibitors potentiate the effects of ionizing radiation or cytotoxic drugs such as DNA methylating agents. Therefore, inhibitors of the PARP enzyme are useful as cancer chemotherapeutics.
In addition, it has been shown that inhibition of PARP promotes resistance to brain injury after stroke (Endres et al., xe2x80x9cIschemic Brain Injury is Mediated by the Activation of Poly(ADP-Ribose)Polymerase,xe2x80x9d J. Cerebral Blood Flow Metab. 17:1143-1151 (1997); Zhang, xe2x80x9cPARP Inhibition Results in Substantial Neuroprotection in Cerebral Ischemia,xe2x80x9d Cambridge Healthtech Institute""s Conference on Acute Neuronal Injury: New Therapeutic Opportunities, Sep. 18-24, 1998, Las Vegas, Nev.). The activation of PARP by DNA damage is believed to play a role in the cell death consequent to stroke, head trauma, and neurodegenerative diseases. DNA is damaged by excessive amounts of NO produced when the NO synthase enzyme is activated as a result of a series of events initiated by the release of the neurotransmitter glutamate from depolarized nerve terminals (Cosi et al., xe2x80x9cPoly(ADP-Ribose) Polymerase Revisited: A New Role for an Old Enzyme: PARP Involvement in Neurodegeneration and PARP Inhibitors as Possible Neuroprotective Agents,xe2x80x9d Ann. N.Y. Acad. Sci., 366-379). Cell death is believed to occur as a result of energy depletion as NAD+ is consumed by the enzyme-catalyzed PARP reaction. Therefore, inhibitors of the PARP enzyme are useful inhibitors of neurotoxicity consequent to stroke, head trauma, and neurodegenerative diseases.
Further, inhibition of PARP should be a useful approach for treatment of conditions or diseases associated with cellular senescence, such as skin aging, through the role of PARP in the signaling of DNA damage. See, e.g., U.S. Pat. No. 5,589,483, which describes a method to extend the lifespan and proliferative capacity of cells comprising administering a therapeutically effective amount of a PARP inhibitor to the cells under conditions such that PARP activity is inhibited. Hence, inhibitors of the PARP enzyme are useful therapeutics for skin aging.
In yet a further application, PARP inhibition is being explored at the clinical level to prevent development of insulin-dependent diabetes mellitus in susceptible individuals (Saldeen et al., xe2x80x9cNicotinamide-induced apoptosis in insulin producing cells in associated with cleavage of poly(ADP-ribose) polymerase,xe2x80x9d Mol. Cellular Endocrinol. (1998), 139:99-107). PARP inhibitors should therefore be useful as diabetes-prevention therapeutics.
PARP inhibition is also an approach for treating inflammatory conditions such as arthritis (Szabo et al., xe2x80x9cProtective effect of an inhibitor of poly(ADP-ribose) synthetase in collagen-induced arthritis,xe2x80x9d Portland Press Proc. (1998), 15:280-281; Szabo, xe2x80x9cRole of Poly(ADP-ribose) Synthetase in Inflammation,xe2x80x9d Eur. J. Biochem. (1998), 350(1):1-19; Szabo et al., xe2x80x9cProtection Against Peroxynitrite-induced Fibroblast Injury and Arthritis Development by Inhibition of Poly(ADP-ribose) Synthetase,xe2x80x9d Proc. Natl. Acad. Sci. USA (1998), 95(7):3867-72). PARP inhibitors are therefore useful as therapeutics for inflammatory conditions.
Inhibition of PARP has usefulness for protection against myocardial ischemia and reperfusion injury (Zingarelli et al., xe2x80x9cProtection against myocardial ischemia and reperfusion injury by 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase,xe2x80x9d Cardiovascular Research (1997), 36:205-215). Therefore, PARP inhibitors are useful in therapy of cardiovascular diseases.
The PARP family of enzymes is extensive. It has recently been shown that tankrases, which bind to the telomeric protein TRF-1, a negative regulator of telomere length maintenance, have a catalytic domain that is strikingly homologous to PARP and have been shown to have PARP activity in vitro. It has been proposed that telomere function in human cells is regulated by poly(ADP-ribosyl)ation. PARP inhibitors have utility as tools to study this function. Further, as a consequence of regulation of telomerase activity by tankyrase, PARP inhibitors should have utility as agents for regulation of cell life-span, e.g., for use in cancer therapy to shorten the life-span of immortal tumor cells, or as anti-aging therapeutics, since telomere length is believed to be associated with cell senescence.
Competitive inhibitors of PARP are known. For example, Banasik et al. (xe2x80x9cSpecific Inhibitors of Poly(ADP-Ribose) Synthetase and Mono(ADP-Ribosyl)transferase,xe2x80x9d J. Biol. Chem. (1992) 267: 1569-1575) examined the PARP-inhibiting activity of 132 compounds, the most potent of which were 4-amino-1,8-naphthalimide, 6(5H)-phenanthridone, 2-nitro-6(5H)-phenanthridone, and 1,5-dihydroxyisoquinoline. Griffin et al. reported the PARP-inhibiting activity for a series of benzamide compounds (U.S. Pat. No. 5,756,510; see also xe2x80x9cNovel Potent Inhibitors of the DNA Repair Enzyme poly (ADP-ribose)polymerase (PARP),xe2x80x9d Anti-Cancer Drug Design (1995), 10:507-514) and quinalozinone compounds (International Publication No. WO 98/33802). Suto et al. reported PARP inhibition by a series of dihydroisoquinoline compounds (xe2x80x9cDihydroisoquinolines: The Design and Synthesis of a New Series of Potent Inhibitors of Poly(ADP-ribose) Polymerase,xe2x80x9d Anti-Cancer Drug Design (1991), 7:107-117). Griffin et al. have reported other PARP inhibitors of the quinazoline class (xe2x80x9cResistance-Modifying Agents. 5. Synthesis and Biological Properties of Quinazoline Inhibitors of the DNA Repair Enzyme Poly(ADP-ribose) Polymerase (PARP),xe2x80x9d J. Med. Chem., ASAP Article 10.1021/jm980273t S0022-2623(98)00273-8; Web Release Date: Dec. 1, 1998).
Nonetheless, there is still a need for small-molecule compounds that are potent PARP inhibitors, especially those that have physical and chemical properties desirable for pharmaceutical applications.
The present invention is directed to compounds that function as potent poly(ADP-ribosyl)transferase (PARP) inhibitors and are useful as therapeutics, especially in treatment of cancers and the amelioration of the effects of stroke, head trauma, and neurodegenerative disease. As cancer therapeutics, the compounds of the invention may be used in combination with DNA-damaging cytotoxic agents, for example, topotecan, irinotecan, or temozolomide, and/or radiation.
In particular, the present invention is directed to compounds of the general formula (I):
wherein:
R1 is:
H;
halogen;
cyano;
an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino, alkoxy, alkyl, and aryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, carboxy, and optionally substituted amino and ether groups (such as O-aryl)); or
xe2x80x94C(O)xe2x80x94R10, where R10 is: H; an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and alkyl and aryl groups unsubstituted or substituted with one or more substituents selected from halo, hydroxy, nitro, and amino); or OR100 or NR100R110, where R100 and R110 are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and alkyl and aryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and optionally substituted amino groups);
R2 is H or alkyl;
R3 is H or alkyl;
R4 is H, halogen or alkyl;
X is O or S;
Y is (CR5R6)(CR7R8)n or Nxe2x95x90C(R5), where:
n is 0 or 1;
R5 and R6 are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and lower alkyl, lower alkoxy, or aryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino); and
R7 and R8 are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and lower alkyl, lower alkoxy, and aryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino);
where when R1, R4, R5, R6, and R7 are each H, R8 is not unsubstituted phenyl.
The invention is also directed to pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates of such compounds. Preferred compounds of the formula (I) include those where R2 and R3 are each independently selected from H and methyl.
In a preferred embodiment, the inventive compounds include those of generic formula (II):
wherein:
p is 1 or 2;
R11 is H or alkyl;
R12 is halogen or an optionally substituted aryl, alkyl, alkenyl, alkynyl or acyl group xe2x80x94C(O)xe2x80x94R10 as defined above;
R13 is H or alkyl; and
R14 is H or halogen;
as well as pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates of such compounds.
In preferred compounds of the formula (II), R11 and R13 are each independently selected from H and methyl. More preferably, the invention is directed to compounds of formula (II) where R11 and R13 are each H, and R12 is optionally substituted aryl, and to pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates of such compounds. In another preferred embodiment of compounds of formula (II), R11 and R13 are each H, and R12 is halogen or optionally substituted aryl.
In another preferred embodiment, the inventive compounds include those of generic formula (III) below, as well as pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates thereof.
wherein:
R15 is H, halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and alkyl and aryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino;
R16 is H; halogen; cyano; or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and alkyl and aryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino;
R17 is H or alkyl; and
R18 is H, halogen, or alkyl;
where R15, R16, R17 and R18 are not all H.
In preferred compounds of the formula (III), R15 is substituted phenyl or (CH2)qaryl, where q is 1 or 2.
In other preferred compounds of the formula (III), R16 is substituted or unsubstituted aryl.
The present invention is also directed to a method of inhibiting PARP enzyme activity, comprising contacting the enzyme with an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof. The compounds of the invention are potent PARP inhibitors and preferably have a PARP-inhibiting activity corresponding to a Ki of 100 xcexcM or less in the PARP enzyme inhibition assay.
The present invention is further directed to a method of potentiating the cytotoxicity of a cytotoxic drug or ionizing radiation, comprising contacting cells with an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof, in combination with a cytotoxic drug or ionizing radiation. The compounds of the invention preferably have a cytotoxicity potentiation activity corresponding to a PF50 of at least 1 in the cytotoxicity potentiation assay.
The present invention is also directed to pharmaceutical compositions comprising an effective PARP-inhibiting amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof, together with a pharmaceutically acceptable carrier therefor.
The invention also provides therapeutic interventions appropriate in disease or injury states where PARP activity is deleterious to a patient, the therapeutic methods comprising inhibiting PARP enzyme activity in the relevant tissue of the patient by administering a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof. In one such therapeutic intervention method provided by the present invention, the effectiveness of a cytotoxic drug or radiotherapy administered to a mammal in the course of therapeutic treatment is improved by administering to the patient, e.g., a mammal in need of treatment, an effective PARP-inhibiting amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof, in conjunction with the administration of the cytotoxic drug or radiotherapy.
Another therapeutic intervention method provided by the present invention is for delaying the onset of cell senescence associated with skin aging in a human, comprising administering to fibroblast cells in the human an effective PARP-inhibiting amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof.
Yet another therapeutic intervention method provided by the present invention is a method for reducing the neurotoxicity consequent to stroke, head trauma, and neurodegenerative diseases in a mammal by administering an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof, to the mammal.
The compounds of the present invention provide a therapeutic approach to treatment of inflammatory conditions, comprising administering an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof, to a patient in need of treatment.
Yet a further therapeutic intervention method provided by the present invention is a cardiovascular therapeutic method for protecting against myocardial ischemia and reperfusion injury in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof.
The present invention is further directed to methods of synthesizing the tricyclic compounds of formula (I), wherein a 4-carboalkoxy indole (IV) is converted to an intermediate 3-substituted-4-carboalkoxy indole, thereby incorporating the intended ring carbon atoms, terminally substituted with one nitrogen atom, usually in the form of a nitro group. Additional functional groups, such as formyl or acyl, may be incorporated at the 3-position in this step. The nitro group is reduced to an amine and cyclized upon the 4-carboalkoxy group in an amide-forming reaction to yield the tricyclic heterocycle. The synthetic methods may further comprise derivatization at N-1 and C-2. The 3-formyl or 3-acyl intermediates can be converted to nitrogen-containing intermediates or to tricyclic indoles with Nxe2x80x94N bonds, such as the compounds of formula (III).
PARP-Inhibiting Agents
In accordance with a convention used in the art, the symbol
is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure. in accordance with another convention, in some structural formulae herein the carbon atoms and their bound hydrogen atoms are not explicitly depicted, e.g.,
represents a methyl group,
represents an ethyl group,
represents a cyclopentyl group, etc.
As used herein, the term xe2x80x9calkylxe2x80x9d means a branched- or straight-chained (linear) paraffinic hydrocarbon group (saturated aliphatic group) having from 1 to 10 carbon atoms in its chain, which may be generally represented by the formula CkH2k+1, where k is an integer of from 1 to 10. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, n-pentyl, isopentyl, neopentyl, and hexyl, and the simple aliphatic isomers thereof. A xe2x80x9clower alkylxe2x80x9d is intended to mean an alkyl group having from 1 to 4 carbon atoms in its chain.
The term xe2x80x9calkenylxe2x80x9d means a branched- or straight-chained olefinic hydrocarbon group (unsaturated aliphatic group having one or more double bonds) containing 2 to 10 carbons in its chain. Exemplary alkenyls include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, isobutenyl, and the various isomeric pentenyls and hexenyls (including both cis and trans isomers).
The term xe2x80x9calkynylxe2x80x9d means a branched or straight-chained hydrocarbon group having one or more carbon-carbon triple bonds, and having from 2 to 10 carbon atoms in its chain. Exemplary alkynyls include ethynyl, propynyl, 1-butynyl, 2-butynyl, and 1-methyl-2-butynyl.
The term xe2x80x9ccarbocyclexe2x80x9d refers to a saturated, partially saturated, unsaturated, or aromatic, monocyclic or fused or non-fused polycyclic, ring structure having only carbon ring atoms (no heteroatoms, i.e., non-carbon ring atoms). Exemplary carbocycles include cycloalkyl, aryl, and cycloalkyl-aryl groups.
The term xe2x80x9cheterocyclexe2x80x9d refers to a saturated, partially saturated, unsaturated, or aromatic, monocyclic or fused or non-fused polycyclic, ring structure having one or more heteroatoms selected from N, O, and S. Exemplary heterocycles include heterocycloalkyl, heteroaryl, and heterocycloalkyl-heteroaryl groups.
A xe2x80x9ccycloalkyl groupxe2x80x9d is intended to mean a non-aromatic monovalent, monocyclic or fused polycyclic, ring structure having a total of from 3 to 18 carbon ring atoms (but no heteroatoms). Exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, phenanthrenyl, and like groups.
A xe2x80x9cheterocycloalkyl groupxe2x80x9d is intended to mean a non-aromatic monovalent, monocyclic or fused polycyclic, ring structure having a total of from 3 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, and like groups.
The term xe2x80x9carylxe2x80x9d means an aromatic monocyclic or fused polycyclic ring structure having a total of from 4 to 18, preferably 6 to 18, ring carbon atoms (no heteroatoms). Exemplary aryl groups include phenyl, naphthyl, anthracenyl, and the like.
A xe2x80x9cheteroaryl groupxe2x80x9d is intended to mean an aromatic monovalent, monocyclic or fused polycyclic, ring structure having from 4 to 18, preferably 5 to 18, ring atoms, including from 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include pyrrolyl, thienyl, oxazolyl, pyrazolyl, thiazolyl, furyl, pyridinyl, pyrazinyl, triazolyl, tetrazolyl, indolyl, quinolinyl, quinoxalinyl, and the like.
The term xe2x80x9coptionally substitutedxe2x80x9d is intended to indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents. Unless indicated otherwise (e.g., by indicating that a specified group is unsubstituted), the various groups defined above may be generally unsubstituted or substituted (i.e., they are optionally substituted) with one or more suitable substituents.
The term xe2x80x9csubstituentxe2x80x9d or xe2x80x9csuitable substituentxe2x80x9d is intended to mean any substituent for a group that may be recognized or readily selected by the artisan, such as through routine testing, as being pharmaceutically suitable. Illustrative examples of suitable substituents include hydroxy, halogen (F, Cl, I, or Br), oxo, alkyl, acyl, sulfonyl, mercapto, nitro, alkylthio, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy, amino (primary, secondary, or tertiary), carbamoyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, and the like (e.g., as illustrated by the exemplary compounds described herein). Suitable substituents are seen from the exemplary compounds that follow.
Preferred optional substituents for alkyl and aryl groups in the compounds of the invention include halogens and aryl groups. Especially preferred for substituted alkyl groups are perfluoro-substituted alkyls. Especially preferred optional substituents for aryl moieties include halogen, lower alkyl, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, O-lower alkyl, aryl, xe2x80x94O-aryl, aryl-lower alkyl, xe2x80x94CO2CH3, xe2x80x94CONH2, xe2x80x94OCH2CONH2, xe2x80x94NH2, xe2x80x94SO2NH2, xe2x80x94OCHF2, xe2x80x94CF3, xe2x80x94OCF3, and the like. Aryl moieties may also be optionally substituted by two substituents forming a bridge, for example xe2x80x94Oxe2x80x94(CH2)zxe2x80x94Oxe2x80x94, where z is an integer of 1, 2, or 3.
A xe2x80x9cprodrugxe2x80x9d is intended to mean a compound that is converted under physiological conditions or by solvolysis, or metabolically, to a specified compound that is pharmaceutically active.
An xe2x80x9cactive metabolitexe2x80x9d is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound.
A xe2x80x9csolvatexe2x80x9d is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to mean a salt that retains the biological effectiveness of the free-acid or base form of the specified compound and that is pharmaceutically suitable. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, xcex3-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If an inventive compound is a base, a desired salt may be prepared by any suitable method known in the art, including treatment of the free base with: an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid such as glucuronic acid or galacturonic acid; alpha-hydroxy acid such as citric acid or tartaric acid; amino acid such as aspartic acid or glutamic acid; aromatic acid such as benzoic acid or cinnamic acid; sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid; or the like.
If an inventive compound is an acid, a desired salt may be prepared by any suitable method known in the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include: organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
In the case of compounds, salts, or solvates that are solids, it is understood by those skilled in the art that the inventive compounds, salts, and solvates may exist in different crystalline or polymorph forms, all of which are intended to be within the scope of the present invention and specified formulas.
In some cases, the inventive compounds will have chiral centers. When chiral centers are present, the inventive compounds may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the broad scope of the generic structural formulae (unless otherwise indicated). Preferably, however, the inventive compounds are used in essentially optically pure form (as generally understood by those skilled in the art, an optically pure compound is one that is enantiomerically pure). Preferably, the compounds of the invention are at least 90% of the desired single isomer (80% enantiomeric excess), more preferably at least 95% (90% e.e.), even more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.).
In some cases, compounds can occur in tautomeric forms. In such cases, it is intended that both tautomers are encompassed by the structural formulae.
The present invention is directed to the following PARP-inhibiting agents: compounds of the formula
wherein R1, R2, R3, R4, X, and Y are as defined above; and pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates thereof. In preferred embodiments, the PARP-inhibiting agents are compounds of the formula (I) where R2 and R3 are each independently H or methyl, and pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates thereof.
More preferably, the agents are compounds of formula (II) or (III):
wherein the variables are as defined above, or pharmaceutically acceptable salts, prodrugs, active metabolites, or solvates thereof. In preferred embodiments for formula (II) and (III), R11, R13, and R17 are each independently H or methyl.
In a preferred embodiment, the inventive agents are compounds of formula (II) and pharmaceutically acceptable salts, prodrugs, active metabolites and solvates, where R11 and R13 are each H, and R12 is an optionally substituted aryl group. In another preferred embodiment, the inventive agents are compounds of formula (III) and pharmaceutically acceptable salts, prodrugs, active metabolites and solvates, where R17 is H or methyl and R15 is optionally substituted aryl or alkyl.
In other preferred embodiments, R16 is substituted or unsubstituted aryl and R15 is hydrogen.
In other preferred embodiments, R16 is H, and R15 is substituted or unsubstituted aryl or alkyl.
Preferred compounds of the invention include:
Pharmaceutical Methods and Compositions
The invention is also directed to a method of inhibiting PARP enzyme activity, comprising contacting the enzyme with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof. For example, PARP activity may be inhibited in mammalian tissue by administering a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof. In addition to the compounds specified above, the following known compounds have been found to be useful for inhibiting PARP enzyme activity:
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d is intended to mean mitigating or alleviating an injury or a disease condition in a mammal, such as a human, that is mediated by the inhibition of PARP activity, such as by potentiation of anti-cancer therapies or inhibition of neurotoxicity consequent to stroke, head trauma, and neurodegenerative diseases. Types of treatment include: (a) as a prophylactic use in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but not yet diagnosed as having it; (b) inhibition of the disease condition; and/or (c) alleviation, in whole or in part, of the disease condition.
One treatment method involves improving the effectiveness of a cytotoxic drug or radiotherapy administered to a mammal in the course of therapeutic treatment, comprising administering to the mammal an effective amount of an agent (compound, pharmaceutically acceptable salt, prodrug, active metabolite, or solvate) in conjunction with administration of the cytotoxic drug (e.g., topotecan or irinotecan) or radiotherapy. The PARP-inhibiting agents may also be advantageously used in a method for reducing neurotoxicity consequent to stroke, head trauma, and neurodegenerative diseases in a mammal by administering a therapeutically effective amount of an inventive agent to the mammal. The PARP-inhibiting agents of the invention may also be used in a method for delaying the onset of cell senescence associated with skin aging in a human, comprising administering to fibroblast cells in the human an effective PARP-inhibiting amount of an agent. Further, the agents may also be used in a method for helping prevent the development of insulin-dependent diabetes mellitus in a susceptible individual, comprising administering a therapeutically effective amount of an agent. Additionally, the agents may also be employed in a method for treating an inflammatory condition in a mammal, comprising administering a therapeutically effective amount of an agent to the mammal. Moreover, the agents may also be used in a method for treating cardiovascular disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a PARP-inhibiting agent. As knowledge regarding the therapeutic roles of PARP inhibitors progresses in the art, other utilities of the PARP-inhibiting agents of the invention will become apparent.
The activity of the inventive compounds as inhibitors of PARP activity may be measured by any of the suitable methods known or available in the art, including by in vivo and in vitro assays. An example of a suitable assay for activity measurements is the PARP enzyme inhibition assay described herein.
Administration of the compounds of the formula (I) and their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates may be performed according to any of the accepted modes of administration available in the art. Illustrative examples of suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal delivery. Oral and intravenous delivery are preferred.
An inventive compound of formula (I) or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof may be administered as a pharmaceutical composition in any pharmaceutical form recognizable to the skilled artisan as being suitable. Suitable pharmaceutical forms include solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols. Pharmaceutical compositions of the invention may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents (including other PARP-inhibiting agents), depending upon the intended use.
Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions are known or may be routinely determined by those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and/or rectal administration.
Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers include syrup, peanut oil, olive oil, saline solution, and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., solution), or a nonaqueous or aqueous liquid suspension.
A dose of the pharmaceutical composition contains at least a therapeutically effective amount of a PARP-inhibiting agent (i.e., a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof), and preferably contains one or more pharmaceutical dosage units. The selected dose may be administered to a mammal, for example, a human patient, in need of treatment of a condition mediated by inhibition of PARP activity, by any known or suitable method of administering the dose, including: topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion. A xe2x80x9ctherapeutically effective amountxe2x80x9d is intended to mean the amount of an agent that, when administered to a mammal in need thereof, is sufficient to effect treatment for injury or disease condition mediated by inhibition of PARP activity, such as for potentiation of anti-cancer therapies and inhibition of neurotoxicity consequent to stroke, head trauma, and neurodegenerative diseases. The amount of a given compound of the invention that will be therapeutically effective will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, the identity of the mammal in need thereof, which amount may be routinely determined by artisans.
It will be appreciated that the actual dosages of the PARP-inhibiting agents used in the pharmaceutical compositions of this invention will be selected according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, and the host and condition being treated. Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage-determination tests. For oral administration, e.g., a dose that may be employed is from about 0.001 to about 1000 mg/kg body weight, with courses of treatment repeated at appropriate intervals.
Synthetic Processes
The present invention is further directed to methods of synthesizing the PARP-inhibiting agents by processes such as those set forth below for exemplary compounds of the invention. In the following examples, the structures of the compounds were confirmed by one or more of the following: proton magnetic resonance spectroscopy, infrared spectroscopy, elemental microanalysis, mass spectrometry, thin layer chromatography, high performance liquid chromatography, and melting point.
Proton magnetic resonance (1H NMR) spectra were determined using a 300 megahertz Tech-Mag, Bruker Avance 300DPX, or Bruker Avance 500 DRX spectrometer operating at a field strength of 300 or 500 megahertz (MHz). Chemical shifts are reported in parts per million (ppm, xcex4) downfield from an internal tetramethylsilane standard. Alternatively, 1 H NMR spectra were referenced to residual protic solvent signals as follows: CHCl3=7.26 ppm; DMSO=2.49 ppm; C6HD5=7.15 ppm. Peak multiplicities are designated as follows: s=singlet; d=doublet; dd=doublet of doublets; t=triplet; q=quartet; br=broad resonance; and m=multiplet. Coupling constants are given in Hertz (Hz). Infrared absorption (IR) spectra were obtained using a Perkin-Elmer 1600 series or a Midac Corporation FTIR spectrometer. Elemental microanalyses were performed by Atlantic Microlab Inc. (Norcross, Ga.) or Galbraith Laboratories (Nashville, Tenn.), and gave results for the elements stated within xc2x10.4% of the theoretical values. Flash column chromatography was performed using Silica gel 60 (Merck Art 9385). Analytical thin layer chromatography (TLC) was performed using precoated sheets of Silica 60 F254 (Merck Art 5719). Melting points (mp) were determined on a MelTemp apparatus and are uncorrected. All reactions were performed in septum-sealed flasks under a slight positive pressure of argon, unless otherwise noted. All commercial solvents were reagent-grade or better and used as supplied.
The following abbreviations may be used herein: Et2O (diethyl ether); DMF (N,N-dimethylformamide); DMSO (dimethylsulfoxide); MeOH (methanol); EtOH (ethanol); EtOAc (ethyl acetate); THF (tetrahydrofuran); Ac (acetyl); Me (methyl); Et (ethyl); and Ph (phenyl).
The general reaction protocols described below may be used to prepare the compounds of the invention.
In Scheme 1,4-carbomethoxyindole A is formylated or acylated under various vilsmeier or Friedel-Crafts conditions to yield B, where R23 is CHO or COR24. 4-Carbomethoxyindole A serves as substrate for a 1,4-addition reaction to yield the nitroethyl intermediate B, where R23 is CHR25CH2NO2. Intermediate B, where R23 is CHO, is transformed to the corresponding oxime (R27 is CHxe2x95x90NOH) or nitroalkene (R27 is CHxe2x95x90CHNO2) C, which is then catalytically reduced to the aminoalkyl derivative D. Nitroethyl intermediate B is transformed directly to D (when R23 is CHR25CH2NO2) by reduction in some cases. Compound D spontaneously cyclizes to tricyclic lactams E (n=2) and EE. Exposure of intermediate D to basic conditions also leads to tricyclic lactams E and EE. Compound E is optionally N-alkylated to form N-alkylated E or halogenated to yield F. Intermediate F can be transformed via a metal-catalyzed reaction (typically with palladium as catalyst) into a number of different substituted tricyclic lactams G, where R29 is aryl, alkyl, alkenyl or alkynyl. G is optionally further modified at R22, R29 and R30.
Acyl-substituted compounds of formula J (e.g., compound 42) can be made by reaction with CO and the corresponding alcohol with Pd/C catalyst. The esters J may be further converted to other acyl derivatives by hydrolysis to the free acid, followed by activation to xe2x80x94C(O)-Lv, where Lv is a leaving group, by standard methods (e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th edition, August 1992, John Wiley and Sons, New York, ISBN 0471601802), and, for example, conversion to amides or other acyl derivatives by reactions generally known in the art. Alternatively, the esters J can be directly converted to amides by standard aminolysis reactions, e.g., by reaction with primary or secondary amines such as dimethylamine or pyrrolidine.
R20=CO2CH3
R21, R22=H
R23=COR24, (R24=H, aryl, (CH)qaryl), q=1 or 2
R29=optionally substituted aryl, alkyl, alkenyl, alkynyl,
R32=H, aryl, (CH2)qaryl)
cycloalkyl, heterocycloalkyl, or heteroaryl, or H.
In Scheme 2, intermediate BB, where R23 is CHO, (CO)aryl, or CO(CH2)qaryl where q is 1 or 2, is transformed to tricyclic acyl hydrazone H by reaction with hydrazine.
In Scheme 3, the M, where Lv includes, for example, I, Br, or triflate, is coupled with a substituted alkyne T using palladium and copper catalysts (See e.g. Sonogashira, K., Tohda, Y., Ragihara, N. Tetrahedron Lett. 1975, 50, 4467-4470, incorporated herein by reference). The intermediate N can be cyclized with palladium catalyst (See e.g. Arcadi, A., Cacchu, S., Marinellito, F. Tetrahedron Lett. 1989, 30, 2581-2584, incorporated herein by reference) to give P which is further modified as described in Scheme 1 to the intermediate BB.

Tricyclic inhibitors of poly(ADP-ribose) polymerases

Abstract: As cancer therapuetics, the compounds of the invention may be used, e.g., in combination with cytotoxic agents and/or radiation.


An adjustable high pressure, low flow metering valve provides a sleeve extending about a restrictor shaft, the sleeve having a narrow helical groove formed in the inside diameter. A restrictor shaft within the sleeve encloses the groove and forms a sealed helical flow channel. The length of the flow channel is varied by withdrawing the restrictor shaft in the sleeve, whereby only a selected axial extent of the groove is enclosed by the sleeve to form a confined flow path. The shaft is provided with a threaded engagement in the body of the metering valve, so that rotation of an adjustment knob provides extremely fine control of the length of the flow path, and thus highly accurate selection of the flow resistance.

1. Field of the Invention
The present invention relates to fluid flow control, and, more particularly, to an improved method and apparatus to generate extremely low flow rates at high pressures that are accurately regulated for use in liquid chromatography and mass spectrometry.
2. Description of Related Art
In liquid chromatography, the liquid (solvent) flow rates generally used are between 100 μliters/min and 10 ml/min. However, more widespread use of capillary and micro-bore columns, as well as new applications such as combining liquid chromatography with mass spectrometry has created a requirement for flow rates that are as much as 100 times lower than the above mentioned flow rates. Very few HPLC pumps are capable of delivering accurate, stable flow rates in this range, and those that can do so are extremely expensive. As a result, most manufacturers have adopted a method known as flow splitting to achieve low flow rates with conventional high pressure liquid chromatography pumps. In the prior art, flow splitting is accomplished by using a tee to split the flow into two paths. Capillary tubes of different lengths and/or diameters are used on each path to create different fluid resistance in each path. Because these flow rates are all in the laminar flow regime, the resulting flow rates in each path can be found from the following relation:
      Δ                          P    =            μ                                      LQ              d      4      where P is pressure, μ is dynamic viscosity, L is capillary flow length, Q is flow rate, and d is effective capillary diameter.
The significant disadvantages of prior art include:                Capillary tube is easy to clog.        Split ratios may change during a chromatographic run because of changes in fluid viscosity that occur during the run. This may occur because the volume in the capillary tubing can be large enough that the composition of solvents can become different in the two legs when the pre-split composition is changing.        Difficult to adjust split flow ratio. It is necessary to cut the tubing to different lengths to adjust the split ratio. This is difficult to do because the capillary usually closes off due to crimping in the cutting process available to most chromatographers in the lab, and thus the fluid resistance changes unpredictably. Also, it is necessary to cut and join additional pieces of tubing to add resistance. This is a troublesome and time consuming process because of the small tube and fitting size.        Verifying the flow rate is extremely difficult. There are no commercially available flow meters that work at these low flow rates. Measuring flow rates as low as 100 nanoliters per minute must be done by weighing the effluent on the low path side over a known time interval. This is very time intensive. Using traditional methods, such as pressure drop through a known capillary, do not work because the viscosity of the fluids is often changing over time, and is unknown.When the capillary analytical column is added to the low flow path, the split ratio is changed. The resistance of analytical columns is usually unknown, and will change with a change in solvent viscosity. Thus, it is necessary for the user to measure flow rates after adding the column to the flow splitter.

High pressure, low flow rate fluid flow control


A radiation detector comprises a tool housing. The tool housing has a substantially cylindrical tubular shape. A radiation sensor generates a signal in response to detecting radiation. The radiation sensor is locatable within the tool housing. A signal processor is operably connectable with the radiation sensor. The signal processor receives the signal from the radiation sensor and generates an electrical signal as a function of the signal received. The signal processor is locatable within the tool housing. A flex-sleeve supports at least one of the radiation sensor and signal processor within the tool housing. The flex-sleeve comprises a substantially cylindrical portion and a coaxially extending polygonal portion for engagement and supportive interaction with the cylindrical portion.

The invention relates generally to radiation detectors. In particular, the invention relates to a flexible support mechanism for radiation detector components and a method of servicing the radiation detector.
Radiation detectors are known in the well drilling industry for logging and measure while drilling applications. When a radiation detector is incorporated into a logging tool of a tool string used for drilling of oil, gas and water wells, the logging tool identifies, locates and differentiates geologic formations along a well bore. Tool strings and logging tools for oil wells are often exposed to harsh operating environments including temperatures in the range of 175° C. to 200° C. and pressures in the range of 10,000 to 20,000 psi along with severe shock and vibration.
A known radiation detector includes a scintillator coupled to a photomultiplier tube. Radiation, such as gamma rays emitted by geologic formations adjacent to the well, is converted to light by the scintillator and conducted to the photomultiplier tube. The photomultiplier tube converts the light into an amplified electrical signal. The amplified electrical signal is then measured and used by monitoring electronics as a function of the radiation detected by the scintillator.
The components of the radiation detector are sensitive pieces of equipment. The components are typically mounted in a housing to withstand the harsh operating environment they are exposed to. The components of the radiation detector also require periodic individual inspection to assure that they are providing correct and repeatable information during their service lives. However, it has been found that the typical known mounting systems do not lend themselves to easy disassembly and separation of the components. It has also been found that disassembly can damage components of the radiation detector, the housing the radiation detector is supported in and the mounting system itself.
It is, therefore, advantageous to provide a radiation detector that is capable of withstanding the harsh operating environment it is exposed to while permitting ease of disassembly for inspection and repair with minimal or no damage to components of the radiation detector.


A verification method includes configuring a reference system, running on a computer, to have the same set of executables and customizations as an e-business system to be verified. The reference system is configured with one or more roles that have permissions to execute all transactions in a scope of a planned verification. One or more business processes that are implemented in the e-business system and are in the scope of the planned verification are mapped and are executed using the reference system. Reference data is created by merging records from logs of the permission checks with respect to at least one role in the scope of the verification. Permission settings for roles in the e-business system are compared with corresponding permission values in the reference data. Based on comparing the permission settings, an indication is displayed to a user of whether the permission settings match the corresponding permission values.

E-business involves business processes spanning the entire value chain: electronic purchasing and supply chain management, processing orders electronically, handling customer service, and cooperating with business partners. Special technical standards for e-business facilitate the exchange of data between companies. E-business software solutions allow the integration of intra and inter firm business processes. E-business can be conducted using the Web, the Internet, intranets, extranets, or some combination of these.
Enterprise Resource Planning (ERP) is one of the major areas of e-business applications. ERP is an enterprise-wide information system designed to coordinate all the resources, information, and activities needed to complete business processes such as order fulfillment or billing. A standard functionality of an ERP system is to implement the business processes of the organization. A business process is implemented as a sequence of transactions. The exact implementation depends on the specific ERP product and its architecture.
Standard business processes are usually defined within the relevant module of an e-business product. For example, these could be modules implementing financial operations, warehouse management, human resources, customer relations management and others.
A business process implemented within the e-business system may contain one or more sub-processes. For example, within the business process 'Purchase Order' the possible sub-processes may be 'Create Purchase Order', 'Change Purchase Order' and 'Display Order'. Execution of the sub-processes would mean a different sequence of transactions to be executed. Moreover, the same transaction might have different permission level when executed within the different sub-processes of the same business process. For example, a transaction handling documents would open a document for editing in 'Change Purchase Order' sub-process, but will only permit 'read' when reached through the 'Display order' sub-process.
Most e-business products provide a degree of flexibility in customizing the standard out-of-the-box business process to the specific needs of an organization. This is generally achieved by adding and removing transactions with their corresponding parameters to and from the originally defined sequence of processes and sub-processes.
There is a number of existing products assisting the user with configuring the permissions for the transactions in the system. These products either perform an audit of the already implemented permissions structure or alternatively suggest an optimal permissions structure in the context of business processes in the system. The core element of these products is a database containing restrictions on transactions that a certain user can access in accordance to Risk Management methodology, such as Sarbanes Oxley. Examples of these products are Virsa tools by SAP AG, Authorization Organizer and Authorization Auditor by CSI tools, Eurekify Enterprise Role & Compliance Management Suite by Eurekify Ltd. and others.
U.S. Pat. No. 6,005,571, 'Graphical user interface for managing security in a database system,' describes a method for management of security in an ERP system. The method includes producing a plurality of task groups, which include actions that may be performed by the users. The patent also covers a graphical user interface that can be used to perform these tasks.
U.S. Pat. No. 7,343,628, 'Authorization data model,' suggests a structure of security permissions and possible implementation of security authorization process in an enterprise system.


Ratcheting shape memory alloy actuators and systems and methods including the same are disclosed herein. The ratcheting shape memory alloy actuators include a ratcheting assembly that is operatively coupled to a first bracket and a shape memory alloy element that is operatively coupled to the ratcheting assembly and to a second bracket. The first bracket is configured to be operatively coupled to a first structure, while the second bracket is configured to be operatively coupled to a second structure. The shape memory alloy element is configured to apply a motive force to the ratcheting assembly upon deformation between a first conformation and a second conformation. The ratcheting assembly is configured to utilize the motive force to selectively adjust an orientation of the first structure relative to the second structure.

One or more actuators may be utilized to change, adjust, control, and/or regulate a relative orientation of two structures that are configured to translate and/or rotate relative to one another. As an illustrative, non-exclusive example, an aircraft may utilize an actuator to change an orientation of one or more actuatable components thereof. As a more specific but still illustrative, non-exclusive example, the actuator may be utilized to open and/or close a main landing gear door of the aircraft.
Traditionally, these actuators may be hydraulic actuators and/or motorized actuators. Hydraulic actuators may utilize a pressurized hydraulic fluid that provides a motive force to change the relative orientation of the two structures. Motorized actuators may utilize an electric motor to provide the motive force.
Hydraulic and/or motorized actuators are relatively complex systems that utilize a large number of moving parts, occupy a significant amount of space, and/or are heavy. In some applications, such as aircraft, simpler, smaller, and/or lighter actuators may be desirable, as these may decrease manufacturing costs, maintenance costs, and/or fuel consumption. Thus, there exists a need for improved actuators and/or for systems and methods that include improved actuators.


An improved viewing device which includes an adjustable support stand, a splash guard with an octagonally shaped open frame closing an open area to permit visual observation therethrough, with the frame having a surface thereon to receive and support a disposable transparent rectangular film positioned across the open area, and a releasable restraint in the form of a plurality of spaced posts or hooks which extend radially from the frame and which cooperate with the frame surface for releasable securement of the transparent film positioned somewhat under tension across the open viewing area. There are also adjusting components of the stand which permit the splash guard to be positioned in varying angular orientations and at varying heights relative to patient and medical attendant. A disposable transparent frontal drape adapted to be hung from one or more of the posts for enhanced body and clothes protection may also be provided. The device may be used with a variety of transparent films such as polyethylene, polypropylene, cellulose acetate, polyester, polyvinylidene chloride and polysulfone. The device is most valuable in medical emergency room use, but may also be used in a variety of other settings, including operating rooms, for out-patient examination, in individual physicians' offices, by veterinarians and for inspection and repair of small mechanical products where lubricants, cleaners or other liquids used with such products may be sprayed or splashed into the user's face or upper torso.

Scope of Invention
The invention herein relates to shield devices which permit a medical practitioner or similar viewer to perform surgery or other tasks while being protected from the spray of body fluids or other liquids.
When a doctor is performing surgery on or examining a patient, it is not uncommon for the patient's body fluids (such as blood, urine or pus) to be suddenly ejected from the patient's body or wound. Since the doctor's face is normally quite close to the surgical incision or wound for the surgery or examination, the doctor may get splattered with that body fluid. In addition to being unpleasant and impeding the doctor's work, such fluids can be dangerous to the doctor, since the body fluid frequently contains infectious organisms which can infect the doctor through contact with his or her eyes, mouth, nostrils or skin. For instance, when a doctor lances a wound, fistula, blister or other lesion, it is common for the liquid matter therewithin to be under pressure and to be ejected in a stream or spray which may carry for a distance of several inches or centimeters.
For protection of doctors against such liquid sprays or streams, there have been a number of prior art devices proposed in the form of air shields, vacuum cabinets, transparent tables and transparent enclosures such as boxes or tents. Such have had only limited success, since they are commonly bulky, often restrict the doctor's movements and commonly require auxiliary equipment to operate, such as vacuum pumps or extensive supporting frameworks.
Most importantly, however, all previous such devices have been useable only with a patient who is at rest and maintaining substantially the same position throughout the medical require auxiliary equipment to operate, such as vacuum pumps or extensive supporting frameworks.
Most importantly, however, all previous such devices have been useable only with a patient who is at rest and maintaining substantially the same position throughout the medical procedure. Thus such devices only have been useable with surgery patients who are comatose while under anesthesia on an operating table or with dental patients who are seated in a dentist's chair. None of the devices, however, are useable with a patient who is active.
In emergency room medical practice, physicians and other emergency room medical personnel must act very rapidly to treat a patient's injury or other acute medical condition. Patients are often in highly agitated states and are only restrained from movement with difficulty. Spurting of blood, pus, urine and similar body fluids is common. There is usually no time for the emergency room staff to assemble complicated equipment such as the prior art devices to provide shielding for the physician and other members of the staff from such fluids, and in any event the violent and frequent movements of many emergency room patients would render such complex and fixed devices unusable.
Further, since the prior art devices have normally been designed to be used in the controlled environment of an operating room, dentist office or the like, such devices have not provided for rapid changing or cleaning of any portion of the device which becomes soiled or contaminated by the patient's body fluids. Commonly the prior art devices have incorporated glass windows supported by complex metal frameworks, which must be carefully disassembled, then cleaned and reassembled for subsequent use. In an emergency room situation, however, it is not uncommon to have a number of patients present all with acute injuries or illnesses who must be attended to in rapid succession. There is no time for the prior art shielding devices to be disassembled, cleaned and reassembled between use for successive patients.
Consequently, it would be highly advantageous to have a viewing device which is readily portable, has a viewing shield which can be quickly and completely changed between patients or even during the course of examination of a single patient, requires little or no supporting structure or auxiliary equipment and which can accommodate reasonable movement by patients.
Applicant has invented one device disclosed in U.S. Pat. No. 5,360,018 which meets some, if not all of the above-described needs not found in prior art. This patent discloses a round splash guard as part of a viewing apparatus which includes a support stand, the splash guard supporting a replaceable transparent flexible film sheet which is held in position across the open central area of the frame of the splash guard by various modes all of which include additional components which interact with the disposable film and the outer periphery wall of the frame. However, the present invention discloses an extremely simplified and unobvious variation of applicant's prior invention which not only substantially reduces manufacturing costs, but is also considerably easier to use and to change under pressure conditions such as an emergency room setting.

Positionable viewing shield with disposable transparent medium


In a 3-D magnetic resonance flow imaging apparatus, the RF excitation field is applied so as to produce a spatial variation of the nuclear spin flip angle within the imaging volume. The spatial variation results in nuclear spins at the volume entrance plane experiencing a relatively small flip angle, and experiencing progressively larger flip angles as they progress into the volume.

1. Field of the Invention
The present invention relates to magnetic resonance (MR) imaging and, more particularly, to volumetric MR imaging of flow, i.e., 3-D MR angiography.
2. Description of the Prior Art
Any nucleus which possesses a magnetic moment will attempt to align itself with the direction of an applied magnetic field. In doing so, however, the nucleus processes around this direction at a characteristic angular frequency (the Larmor frequency) which is dependent on the strength of the magnetic field and on specific properties of the nuclear species (the magnetogyric constant of the nucleus).
When a substance such as human tissue is subjected to a static uniform magnetic field (polarizing field B.sub.o), the individual magnetic moments of paramagnetic nuclei in the tissue, in their attempt to align with this field, process about it in random order at their characteristic Larmor frequency. The net magnetic moment M.sub.O includes a component M.sub.L produced in the direction (z) of the polarizing field, however, the randomly oriented components M.sub.T in a plane which is transverse to the plane of the polarizing field (i.e., the x-y plane) cancel one another. If, however, the substance, or tissue, is irradiated with an additional magnetic field (RF excitation field B1), which is in the x-y plane and which is near the Larmor frequency, the longitudinal component of the magnetic moment M.sub.L can be rotated (flipped) into the x-y plane to produce a net transverse magnetic moment M.sub.T which is rotating in the x-y plane at the Larmor frequency. The degree to which the M.sub.L component is rotated into an component is referred to as the flip angle. The magnitude and the direction of the net magnetic moment (M=M.sub.L +M.sub.T) depends primarily on the amplitude and duration of the applied RF excitation field B1.
One practical value of this gyromagnetic phenomena resides in the radio frequency signal which is emitted as a result of the net transverse magnetic moment M.sub.T. A commonly used technique, referred to in the art as a "pulsed NMR measurement", applies the excitation field B1 for a short interval, and then receives the signal that is produced by the resulting transverse magnetic moment M.sub.T. Such pulsed NMR measurement cycles may be repeated many times to make the same measurement at different locations in the subject or to make different measurements using any of a number of preparative excitation techniques.
In MR imaging, magnetic field gradients are used in addition to the static magnetic field. Since the resonant frequency of the processing nuclei depends upon the precise magnetic field strength imposed upon it, the applied field gradients are used to provide a mechanism which encodes spatial information into the sensed frequency response signals. MR imaging devices correlate signal intensity at a given frequency with nucleus concentration and relaxation parameters at a given location. This provides spatial information which is used to make a map or image of the object, based upon signal intensity variations due to the concentration and/or relaxation time differences. Such techniques are now routinely used to form MR medical diagnostic devices which provide two-dimensional (2-D) images. Many pulse and gradient sequence variations are also known which can be used to enhance the diagnostic value of the images produced.
Until recently, the application of 3-D visualization methods in MR diagnostic imaging was rather tedious. Traditional 2-D acquisition techniques were not able to produce quality sufficient for 3-D display in a time frame which can be tolerated by a patient. Recent developments, such as described in my paper entitled "IMPROVEMENT OF 3-D ACQUISITION AND VISUALIZATION IN MRI" published in Magnetic Resonance Imaging, Vol. 9, No. 3, 1991, Pages 001-013 describes improvements in 3-D techniques which make 3-D MR imaging more attractive for medical diagnostic use.
One emerging MR imaging modality is flow or vascular imaging. One basic physical principle which is used to acquire flow images in the MR environment uses time-of-flight effects. Time-of-flight effects are based on the macroscopic motion of nuclear spins with longitudinal magnetization. Typically, the magnetization of a bolus of blood is labelled at one time (via a selective RF excitation) and detected at a later time (at readout). Because the bolus changes location between labelling and detection, the name time-of-flight is used. Inflow enhancement is a special case of time-of-flight, in which the bolus is excited and detected in the same slice. An example of inflow enhancement effects in MR imaging is shown in FIG. 1a, wherein the flow is perpendicular to the slice plane. During a single repetition time, some of the spins flow out of the slice and are replaced by others flowing into the slice. Repeated MR imaging sequences result in the stationary tissue becoming partially or fully saturated after a few repetition times, thereby diminishing any signal from the stationary tissue. The blood flowing into the selected slice provides unsaturated spins which produce high signal and high contrast relative to that of the adjacent stationary tissue. Thus, if the excitation pulse repetition time (TR) is short relative to the time required for the longitudinal magnetization to become substantially relaxed (T1), over the course of several TR intervals signal from stationary tissue will be attenuated as their spins become more and more saturated. Unfortunately, the flowing blood will also become partially saturated, which saturation manifests itself as a reduction in signal. However, some partially saturated spins in the blood will flow out of the slice and are replaced by unsaturated spins which have higher signal capability. As more unsaturated spins flow into the slice during each TR, more signal is available. The flow signal is maximized when all the partially saturated flowing spins in the slice are replaced each TR. Thus, signal enhancement is directly related to the flow velocity and slice thickness. Further information relating to time-of-flight effects can be found in the article "Time-of-Flight MR Flow Imaging: Selective Saturation Recovery with Gradient Refocusing", published in Radiology, 1986, No. 160, Pages 781-785.
Inflow enhancement also occurs in 3-D volume imaging. 3-D imaging sequences primarily differ from 2-D sequences in that a second spatial encoding gradient is used in combination with the RF excitation pulse to divide the imaging volume into N partitions. In 3-D imaging however, large volumes with many phase encoded partitions (N) results in saturation of flowing spins in the same manner as described above in 2-D imaging if velocities are low. As spins become progressively more saturated, they produce less transverse magnetization (M.sub.T), and consequently less signal, so enhancement will not be seen throughout the entire axial length of the volume, as shown in FIG. 1b. An illustration of the progressive saturation effects upon the net transverse magnetization is shown in FIG. 2 for flowing material at the flow entrance plane of the volume and again at the flow exit plane. The rate of signal attenuation depends primarily upon the repetition time TR, flip angle .alpha., and the longitudinal relaxation time T1.
Although various techniques such as Gradient Motion Rephasing (GMR), pulse sequences such as FISP (Fast Imaging with Steady Precession), FLASH (Fast Low Angle Shot), and MP RAGE (Magnetization Prepared Rapid Gradient Echo) and other techniques such as described in my above-mentioned paper, as well as my article entitled "INTRACRANIAL CIRCULATION: PULSE-SEQUENCE CONSIDERATIONS IN 3-DIMENSIONAL (VOLUME) MR ANGIOGRAPHY" published in Radiology 1989, Vol. 171, June 1989, Pages 785-791, are available, improvement is still desirable in order to overcome the problem illustrated in FIGS. 1b and 2. With existing MR angiographic techniques, a compromise between volume size, vessel contrast and scan time is made. As an example, the slab thickness must be relatively thin to avoid excessive spin saturation. In order to cover a sufficiently large area of the vasculature, the measurement has to be repeated at different positions, which undesirably increases the overall scan time.
The present invention is directed to reducing the effect of spin saturation which occurs when spins are repeatedly imaged while moving through a selected volume, without increasing the scan time and at the same time minimizing the requirement to modify existing hardware and software.

Inflow MR angiography with spatially variable flip angles


A media muxer node (10) of a local network (7) is configured to time-shift a live media stream, by storing the stream on a local network storage (3) during a pause, and providing the stored and time-shifted stream to a local network-UE (5) after the pause. The pausing and the resuming of the media stream can be initiated from an external network-connected UE (1) outside the local network, or directly from the local network UE (7). The system also comprises a media aggregating node (2) for authentication of the external network—connected UE (1), which are both connected to a virtual control node (4). If a pause in the replay is discovered, the media muxer node (10) sees to the storage of the media in a local network storage (3) until the discovery of a restart command.

A local network, e.g. a home network or an office network, may comprise several inter-connected consumer electronic devices, e.g. personal computers, mobile phones, set-top-boxes and gaming consoles. Electronic devices within a local network can be adapted to communicate with each other e.g. according to DLNA (Digital Living Network Alliance) standard, which allows electronic devices to communicate and share media content with each other, thereby enabling e.g. access of media files residing e.g. on a PC directly on a TV within the e.g. a DLNA home network, without a complicated configuration process.
A DLNA-compatible device is able to communicate with other DLNA-compatible devices within the DLNA network via the Universal Plug and Play (UPnP), which is a network protocol that is capable of establishing communication between DLNA-compatible devices within a DLNA network, without any configuration. By means of the UPnP, a DLNA device is able to e.g. discover and address other available DLNA devices within a DLNA network, and receive a description of their capabilities.
The DLNA-compatible devices within a DLNA network are typically of different types, based on their function in the media distribution and rendering, and the types involve a DMS (Digital Media Storage/Server), a DMP (Digital Media Player), a DMR (Digital Media Renderer), and a DMC (Digital Media Controller). A DMS may be e.g. a PC (Personal Computer) or a NAS (Network Attached Storage), and it is a device that stores media content and makes it available to a wired and/or wireless networked DMP or DMR. A DMP may be e.g. a TV, a stereo, a game console or a mobile phone, and it is a device that is able to find content on a DMS, and provide playback and rendering capabilities. Further, a DMC is a device that locates content on a DMS and plays it on a DMR, and a DMC may be e.g. a PDA (Personal Digital Assistant) or a mobile phone. Finally, a DMR is a device that plays content received from a DMC, and a DMR may be e.g. a TV, an audio/video receiver, a video display or remote speakers.
FIG. 1 illustrates a conventional DLNA network comprising four DLNA compatible devices, i.e. a DMP 5a, a DMR 5b, a DMS 5c and a DMC 5d. The DMC (Digital Media Controller) 5d is able to obtain a file structure from the DMS, and send a specific URL to the DMR, the URL received from the DMS file structure. The DMR 5b is able to connect to the specified URL, which in this case is the DMS 5c itself. Further, the DMP 5d is also able to obtain a file structure from the DMS, and play a link given in the DMS file structure.
An end-user may want to pause a live media session, e.g. for answering the phone, and then resume the watching of the media session after the phone call. Therefore, it would be advantageous to enable a time-shifting of live media content playing on a local network-device, e.g. in a DLNA network. However, a time-shifting of the live media stream is not possible on a local network-device that is not provided with a hard-drive, such as on a DMR (Digital Media Renderer), e.g. a TV. In order to pause the streaming of a live media session, and resume the streaming of the media session at the same position, a DLNA-device, e.g. a DMR, has to query the status from the media server before pausing the streaming, and perform a seek-command in order to resume the playing of the stream. However, even if a media server would support this functionality, a synchronization gap would exist between the instance when the seek-command was read by the media server, and when the streaming was really paused. Moreover, there is no way to stop an inline-frame in the media stream, so the media content will appear garbled for a while after resuming the play-out.
Thus, it still presents a problem to enable a time-shifting of a live media stream playing on a local network-device, e.g. on a DLNA-compatible device of a DLNA network.


The present invention relates to mutations in the SLC40A1 gene coding for the ferroportin 1, associated to impaired iron homeostasis or to non-HFE hereditary hemochromatosis and to methods for the diagnosis of these hereditary diseases based on the identification of said mutations.

Hemochromatosis is a genetic disorder characterized by an excess of iron accumulation in the body, causing in the course of the time injuries in different organs and tissues, particularly in liver, myocardium, pancreas, kidney, spleen, gonads and skin. Idiopatic Hemochromatosis is the most wide-spread hereditary disease in the Western population (incidence 1:300) and it is characterized by a recessive inheritance. This kind of Hemochromatosis was at first associated to HFE gene mutations (Hereditary Hemochromatosis described in Feder et al., Nat. Genet. 1996, 13:399-408). More recent studies have at first supposed and then proved that mainly in South-Western population, other genes in addition to HFE could have a role in Idiopatic Hemochromatosis (Piperno et al, Gastroenterology 1998, 114: 996-1002 and Borot et al, Immunogenetics 1997, 45: 320-324).
Some mutations in the ferroportin gene, recently named SLC40A1 and previously known as SLC11A3 or IREG-1 or MTP-1, have indeed already been identified both by the authors of the present invention and by others as described for instance in Montosi et al., J. Clin. Invest, 2001, 108:619 and In WO 02/033119; Devalia V. et al., Blood, 2002, 100:695; Cazzola et al., British Journal of Hematology 2002, 119:539; Wallace et al., Blood, 2002, 100:692; Njajou Nat. Genet. 2001, 28:213.
The identification of most of the genetic alterations responsible for Hereditary Hemochromatosis or diseases linked to impaired iron homeostasis is of great importance both in diagnostics and therapeutics. In fact, till today the diagnosis of Hemochromatosis is delayed and it is based on clinical symptomatology developed as a consequence of tissue injuries which are frequently irreversible. Moreover the diagnosis of such disease is made difficult by the fact that its symptoms are often similar to those of other diseases characterized by impaired iron homeostasis.
The development of methods of genetic screening for the early diagnosis in a presymptomatic stage, of the Hereditary Hemochromatosis would allow to operate in time by phlebotomy to prevent in this way damages to organs and tissues.
Moreover the identification of genetic alterations linked to Hereditary Hemochromatosis and the comprehension of their role in the development of the pathology, are most relevant for the optimization of new and improved therapeutic strategies.

Mutations in the SLC40A1 gene associated to impaired iron homeostasis


A method for planning trips to transport passengers on the basis of a preferably statistical predictive model, in particular to plan capacities, optimize the utilization of vehicle fleets, determine the routes to be taken, etc., preferably in short-distance passenger traffic, wherein the predictive model takes into account, using parameters, characteristic passenger patterns over the course of a day, week, and/or year, is characterized in that the predictive model additionally uses weather-specific parameters.

Technical Field
The invention relates to a method for the planning of trips in the transport of persons, based on a preferably statistical forecasting model, particularly for the purpose of capacity planning, for the purpose of optimizing the deployment of vehicle fleets, for the purpose of planning test runs, etc., preferably in the regional transit of persons, wherein the forecasting model takes into account the behavior of passengers over a profile of days, weeks, and/or years, via parameters.
This is basically a planning method for the purpose of controlling vehicle fleets in the regional transit of persons, wherein the method can also be used for planning test runs, by way of example. It does not matter whether the passenger transit takes places by road or by rail. In principle, the method can be used in the planning of any manner of passenger transit.
Description of Related Art
In practice, the classical approach is known wherein the number of passengers is detected, and the degree of usage—of what is most commonly public regional passenger transit—is determined in correlation with the line, the time, the day of the week, and the type of day—weekday, holiday, etc. The detection of entering and exiting passengers is carried out in automatic passenger counting via sensors in the vehicle doors, which continuously determine the degree of usage of each vehicle. For cost reasons, the amount of technology which must be deployed for this purpose is only used in a few vehicles of the vehicle fleet, by many transit operators, such that it is necessary to use the accordingly equipped counting vehicles specifically on the lines/circuits which are suitable to serve as the basis of calculations of required capacity using statistical models. The determination of routes which will be operated—also called test run planning—is very important for precisely specifying samples, particularly for the purpose of establishing a basis for a forecasting model for extrapolating a route network. The samples take into account the layering of process parameters, different types of times of day (holidays, weekdays, weekends), lines, and also sample sizes.
In current practice, a wide variety of forecasting models are known. The Association of German Transport Companies (VDV) presents, in the VDV Magazine No. 457, printed November 2006, under "Rahmenlastenheft [Framework Specifications Sheet]" automatic passenger counting systems, statistical foundations, notes, and recommendations. Information on passenger counting systems in rail transport is known from the Magazine No. 458, printed on November 2008. The recommendations of VDV are based on the considerations given above.
The forecasting models implemented to date approximate the actual conditions according to underlying basic parameters. Even though essential parameters are in fact taken into account, the quality of the forecasts is subject to enormous variations in the passenger occupancy, and particularly over the entire year. In particular, variability occurs when the weather affects the behavior of passengers. The statistical models are significantly skewed as a result. As a result, the number of planning parameters used to date is not adequate for representative samples. When the recommendations issued by the VDV are followed as closely as possible, the forecasts deviate from the real situation, at the latest, when unforeseeable weather changes have a drastic effect on the behavior of passengers.

Method for planning trips to transport passengers

INIT INNOVATIVE INFORMATIKANWENDUNGEN IN TRANSPORT-, VERKEHRS-UND LEITSYSTEMEN GMBH


An image forming apparatus which is capable of performing a failsafe image forming operation even when a memory device of a replaceable unit mounted thereon is faulty. A controller of the image forming apparatus determines whether or not a memory tag of a toner cartridge is faulty. If the memory tag is determined to be faulty, the controller causes image adjustment to be executed.

1. Field of the Invention
The present invention relates to an image forming apparatus, such as a color copying machine and a printer, which forms an image on a recording sheet by an electrophotographic printing method, and a control method therefor.
2. Description of the Related Art
Conventionally, in an image forming apparatus, such as a copying machine, a facsimile machine, and a printer, toners or developing materials are filled in respective cartridges (replaceable units) removable from the apparatus body, and these cartridges are mounted on the image forming apparatus, whereby the toners or developing materials are supplied to the image forming apparatus. Then, when any of the toners or developing materials in the cartridges runs out, the corresponding cartridge is replaced by a new one, whereby the tone or developing material is replenished.
Recently, as a means for detecting replacement of the existing cartridge by a new one or a depletion of a toner or developing material, there has been proposed a cartridge with a memory tag (memory device). By causing cartridge identification information, life information, image processing information, etc. to be stored on the memory tag, it is possible to grasp the latest state of the cartridge and perform the optimum image formation (see e.g. Japanese Laid-Open Patent Publications No. 2004-093693 and No. 2005-107113).
However, in the conventional technique, if a memory tag is faulty due to some cause, it is impossible to perform a failsafe image forming operation. Therefore, the user is required to procure a cartridge again, which can cause a marked degradation of working efficiency.

Image forming apparatus and control method therefor


A shielded electrical connector assembly includes a dielectric housing having at least one terminal-receiving passage. An opening is provided in an outside wall of the housing communicating with the passage. A terminal is inserted into the passage, with an engaging portion of the terminal aligned with the opening. A conductive shell is disposed about at least a portion of the housing. The shell includes a finger portion extending through the opening in the housing into engagement with the engaging portion of the terminal.

Generally, a typical electrical connector includes an insulating or dielectric housing having a plurality of terminal-receiving passages. A plurality of conductive terminals are inserted into the passages. The terminals may be terminated to discrete electrical wires, circuit traces on a printed circuit board or other appropriate terminal leads. A mating end of the housing is interengageable with the mating end of a complementary mating connector or other connecting device.
Some electrical connectors include a shield or shell about the connector housing to protect the terminal interface from ingress or egress of electromagnetic interference (EMI) and/or radio frequency interference (RFI). The shield often is a stamped and formed sheet metal shell, and it is desirable to connect the shell to ground. One method of grounding the shell is to attach a ground wire directly to the shell. This method has problems in requiring a separate connecting operation and also is relatively expensive. Another method of grounding the shell is to place a metal bracket around the connector housing, with the bracket being interengaged between the shell and a bare ground wire extending out of the rear of the connector housing. The bracket may include latches for engaging the mating connector. Such brackets also are relatively expensive and require separate connecting operations. In addition, the ground wire must be stripped to expose a bare portion thereof, and the ground wire is not supported to ensure good engagement between the bracket and the wire.
The present invention is directed to solving the grounding problems discussed above in a very simple and very efficient shielded electrical connector assembly wherein the connector shield or shell is grounded to a ground terminal in the connector housing automatically in response to assembling the shell to the housing.

Shielded electrical connector assembly with grounding system


A flow-through telescoping pole apparatus is provided for use in dispensing fluid from a suitable fluid source, such as a common garden hose. The apparatus includes an elongated hollow outer pole and an inner pole received in the outer pole for axial telescoping movement. A seal is provided in the space between the inner and outer poles to prevent leakage of fluids from between the poles. A locking assembly is also provided, and permits the inner pole to be locked against axial movement relative to the outer pole. The locking assembly includes a cam mounted on the inner pole and a friction member supported between the cam and the outer pole. The cam pinches the friction member against the outer pole when the inner pole is rotated relative to the outer pole to lock the axial position of the inner pole.

1. Field of the Invention
The present invention relates generally to fluid handling equipment and, more particularly, to a telescoping pole apparatus through which fluid can be delivered to any suitable fluid dispensing attachment.
2. Discussion of the Prior Art
It is known to provide a flow-through telescoping pole provided with an outer pole, an inner pole telescopically received within the outer pole, and a locking mechanism for fixing the relative axial position of the inner pole once it has been adjusted to a desired length.
According to this known construction, the locking mechanism includes a collet provided on the distal end of the outer pole which, when rotated, presses an intermediate member against the inner pole so as to pinch the inner pole to hold it in place axially against further telescoping movement. However, several drawbacks exist to the use of this construction.
For example, in using the known construction, the inner pole must first be positioned relative to the outer pole, and then retained in this position while the collet is rotated to lock the inner pole in place. This operation is cumbersome since the user must support both poles relative to one another while tightening the collet. Frequently, two hands are not quite enough to accomplish the task, especially when fluid is flowing through the pole.