text:
|Publication number
|Publication type
|Application number
|Publication date
|Dec 26, 2006
|Filing date
|Jul 18, 2003
|Priority date
|Jan 22, 2001
|Fee status
|Also published as
|Publication number
|Richard A. Schumacher, Allen T. Hopper, Ashok Tehim
|Original Assignee
|Memory Pharmaceuticals Corporation
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (69), Non-Patent Citations (33), Referenced by (9), Classifications (25), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
This application claims the benefit of U.S. Provisional Application No. 60/396,726, filed Jul. 19, 2002. This application is related to application Ser. No. 10/051,309 and its provisional applications, Ser. No. 60/262,651, filed Jan. 22, 2001, Ser. No. 60/267,196, filed Feb. 8, 2001, and Ser. No. 60/306,140, filed Jul. 14, 2001, their disclosures being hereby incorporated by reference in their entirety.
The present invention relates generally to the field of phosphodiesterase 4 (PDE4) enzyme inhibition. More specifically this invention relates to selective PDE4 inhibition by novel compounds, e.g., aminoindazole and aminobenzofuran analogs, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
The cyclic nucleotide specific phosphodiesterases (PDEs) represent a family of enzymes that catalyze the hydrolysis of various cyclic nucleoside monophosphates (including cAMP and cGMP). These cyclic nucleotides act as second messengers within cells, and as messengers, carry impulses from cell surface receptors having bound various hormones and neurotransmitters. PDEs act to regulate the level of cyclic nucleotides within cells and maintain cyclic nucleotide homeostasis by degrading such cyclic mononucleotides resulting in termination of their messenger role.
PDE enzymes can be grouped into eleven families according to their specificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds. For example, PDE 1 is stimulated by Ca2+/calmodulin. PDE 2 is cGMP-dependent, and is found in the heart and adrenals. PDE 3 is cGMP-dependent, and inhibition of this enzyme creates positive inotropic activity. PDE 4 is cAMP specific, and its inhibition causes airway relaxation, antiinflammatory and antidepressant activity. PDE 5 appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE 5 inhibitors may have cardiovascular activity. Since the PDEs possess distinct biochemical properties, it is likely that they are subject to a variety of different forms of regulation.
PDE4 is distinguished by various kinetic properties including low Michaelis constant for cAMP and sensitivity to certain drugs. The PDE4 enzyme family consists of four genes, which produce 4 isoforms of the PDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D [See: Wang et al., Expression, Purification, and Characterization of human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Res. Comm., 234, 320–324 (1997)] In addition, various splice variants of each PDE4 isoform have been identified.
PDE4 isoenzymes are localized in the cytosol of cells and are unassociated with any known membranous structures. PDE4 isoenzymes specifically inactivate cAMP by catalyzing its hydrolysis to adenosine 5′-monophosphate (AMP). Regulation of cAMP activity is important in many biological processes, including inflammation and memory. Inhibitors of PDE4 isoenzymes such as rolipram, piclamilast, CDP-840 and ariflo are powerful antiinflammatory agents and therefore may be useful in treating diseases where inflammation is problematic such as asthma or arthritis. Further, rolipram improves the cognitive performance of rats and mice in learning paradigms.
In addition to such compounds as rolipram, xanthine derivatives such as pentoxifylline, denbufylline, and theophylline inhibit PDE4 and have received considerable attention of late for their cognition enhancing effects. cAMP and cGMP are second messengers that mediate cellular responses to many different hormones and neurotransmitters. Thus, therapeutically significant effects may result from PDE inhibition and the resulting increase in intracellular cAMP or cGMP in key cells, such as those located in the nervous system and elsewhere in the body.
Rolipram, previously in development as an anti-depressant, selectively inhibits the PDE4 enzyme and has become a standard agent in the classification of PDE enzyme subtypes. Early work in the PDE4 field focused on depression and inflammation, and has subsequently been extended to include indications such as dementia. [see "The PDE IV Family Of Calcium-Phosphodiesterases Enzymes," John A. Lowe, III, et al., Drugs of the Future 1992, 17(9):799–807 for a general review). Further clinical developments of rolipram and other first-generation PDE4 inhibitors were terminated due to the side effect profile of these compounds. The primary side effect in primates is emesis, while the primary side effects in rodents are testicular degranulation, weakening of vascular smooth muscle, psychotrophic effects, increased gastric acid secretion and stomach erosion.
The present invention relates to novel compounds, e.g., aminoindazole and aminobenzofuran analogs, that inhibit PDE4 enzymes, and especially have improved side effect profiles, e.g., are relatively non-emetic, (e.g., as compared to the previously discussed prior art compounds). Preferably, the compounds selectively inhibit PDE4 enzymes. The compounds of this invention at the same time facilitate entry into cells, especially cells of the nervous system.
Still further, the present invention provides methods for synthesizing compounds with such activity and selectivity as well as methods of (and corresponding pharmaceutical compositions for) treating a patient, e.g., mammals, including humans, requiring PDE inhibition, especially PDE4 inhibition, for a disease state that involves elevated intracellular PDE 4 levels or decreased cAMP levels, e.g., involving neurological syndromes, especially those states associated with memory impairment, most especially long term memory impairment, as where such memory impairment is due in part to catabolism of intracellular cAMP levels by PDE 4 enzymes, or where such memory impairment may be improved by effectively inhibiting PDE4 enzyme activity.
In a preferred aspect, the compounds of the invention improve such diseases by inhibiting PDE4 enzymes at doses which do not induce emesis.
The present invention includes compounds of Formulas I and II:
wherein in Formula I both of R3 and R4 are other than H and in Formula II at least one of R3 and R4 is other than H; and
pharmaceutically acceptable salts thereof.
According to a further aspect of the invention there is provided a genus of novel compounds according to the formulas III and IV:
wherein R1, R2, R3, R4, R7 and R8 are as defined above. The compounds of this subgenus of Formulae I and II not only have PDE4 inhibitory activity, but also are useful as intermediates for preparing compounds of Formula II in which R3 and R4 are both other than H.
In addition, preferred compounds of Formulas I and II are those of subformulas V and VI
wherein R1, R2, R4, R7 and R8 are as defined in Formulas I and II and one of B, D and E is N and the others are C. Preferably, D is N. Also, R4 is preferably pyridyl or phenyl which in each case is substituted or unsubstituted.
In accordance with a further aspect of the invention the compounds of formulas I and II are selected from the following compounds:
wherein optically active compounds can be in the form of their separate enantiomers or mixtures thereof, including racemic mixtures.
The compounds of the present invention are effective in inhibiting, or modulating the activity of PDE4 in animals, e.g., mammals, especially humans. These compounds exhibit neurological activity, especially where such activity affects cognition, including long term memory. These compounds will also be effective in treating diseases where decreased cAMP levels are involved. This includes but is not limited to inflammatory diseases. These compounds may also function as antidepressants, or be useful in treating cognitive and negative symptoms of schizophrenia.
Assays for determining PDE inhibiting activity as well as selectivity of PDE 4 inhibiting activity and selectivity of inhibiting PDE 4 isoenzymes are known within the art. See, e.g., U.S. Pat. No. 6,136,821, the disclosure of which is incorporated herein by reference.
According to a further aspect of the invention there are provided compounds useful as intermediates for the production of the PDE4 inhibitors described herein (e.g., PDE4 inhibitors of Formulas I and II) and/or useful for the synthesis of radio-labeled analogs of the PDE4 inhibitors with in this application.
Thus, there are provided intermediate compounds which correspond to compounds of Formulas I and II, wherein R2, R3, R4 and R8 are as previously defined for Formulas I and II, but R1 or R7 is H, tert-butyldimethylsilyl-, or a suitable phenolic or indazolyl protecting group. Suitable protecting groups are described, for example, in Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, pp. 246–293. These intermediates are also useful for the synthesis of radio-labeled compounds, such as where R7 is 3H3CO—, 2H3CO—, 14CH3— or 11CH3—, for example by removing the protecting group and reacting the resultant compound in which R1 or R7 is H with suitable radio-labeled reagents. Such radio-labeled compounds are useful for determining compound tissue distribution in animals, in PET imaging studies, and for in vivo, ex vivo, and in vitro binding studies.
As previously described, compounds according to formula III, wherein R4, R7 and R8 are as previously described are useful intermediates for the production of compounds according to formula II where in R3 is other than H.
Also, as previously described, compounds according to formula IV, wherein R3, R7 and R8 are as previously described are useful intermediates for the production of compounds according to formula II where in R4 is other than H.
Halogen herein refers to F, Cl, Br, and I. Preferred halogens are F and Cl.
Alkyl, as a group or substituent per se or as part of a group or substituent (e.g., alkylamino, trialkylsilyloxy, aminoalkyl, hydroxyalkyl), means a straight-chain or branched-chain aliphatic hydrocarbon radical having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, especially 1 to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Other examples of suitable alkyl groups include 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl, and the like.
Substituted alkyl groups are alkyl groups as described above which are substituted in one or more positions by halogens, oxo, hydroxyl, C1-4-alkoxy and/or cyano. Halogens are preferred substituents, especially F and Cl.
Alkoxy means alkyl-O— groups and alkoxyalkoxy means alkyl-O-alkyl-O— groups in which the alkyl portions are in accordance with the previous discussion. Suitable alkoxy and alkoxyalkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy methoxymethoxy ethoxymethoxy, propoxymethoxy, and methoxyethoxy. Preferred alkoxy groups are methoxy and ethoxy. Similarly, alkoxycarbonyl means alkyl —O—CO— in which the alkyl portion is in accordance with the previous discussion. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and tert-butoxycarbonyl.
Cycloalkyl means a monocyclic, bicyclic or tricyclic nonaromatic saturated hydrocarbon radical having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, especially 3 to 6 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, 1-decalin, adamant-1-yl, and adamant-2-yl. Other suitable cycloalkyl groups include spiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl, spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, and spiro[3.5]nonyl. Preferred cycloalklyl groups are cyclopropyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be substituted, for example, substituted by halogens and/or alkyl groups.
Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which the cycloalkyl and alkyl portions are in accordance with previous discussions. Suitable examples include cyclopropylmethyl and cyclopentylmethyl.
Aryl, as a group or substituent per se or as part of a group or substituent, refers to an aromatic carbocyclic radical containing 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, especially 6 to 10 carbon atoms. Suitable aryl groups include phenyl, naphthyl and biphenyl. Substituted aryl groups include the above-described aryl groups which are substituted one or more times by, for example, halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, and phenoxy.
Arylalkyl refers to an aryl-alkyl-radical in which the aryl and alkyl portions are in accordance with the previous descriptions. Suitable examples include benzyl, 1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl, phenpentyl, and napthylmethyl.
Heteroaryl refers to an aromatic heterocyclic group having one or two rings and a total number of 5 to 10 ring atoms wherein at least one of the ring atoms is a heteroatom. Preferably, the heteroaryl group contains 1 to 3, especially 1 or 2, hetero-ring atoms which are selected from N, O and S. Suitable heteroaryl groups include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, dithialyl, oxathialyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl, indazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, purinyl, benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, and benzoxazinyl, e.g., 2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl.
Substituted heteroaryl refers to the heteroaryl groups described above which are substitued in one or more places by, for example, halogen, aryl, alkyl, alkoxy, carboxy, methylene, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino.
Heterocycles include heteroaryl groups as described above as well as non-aromatic cyclic groups containing at least one hetero-ring atom, preferably selected from N, S and O, for example, tetrahydrofuranyl, piperidinyl, and pyrrolidinyl.
Heterocycle-alkyl refers to a heterocycle-alkyl-group wherein the heterocyclic and alkyl portions are in accordance with the previous discussions. Suitable examples are pyridylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl, and isoquinolinylmethyl.
Partially unsaturated carbocyclic structures are non-aromatic monocyclic or bicyclic structures containing 5 to 14 carbon atoms, preferably 6 to 10 carbon atoms, wherein the ring structure(s) contains at least one C═C bond. Suitable examples are cyclopentenyl, cyclohexenyl, cyclohexadienyl, tetrahydronaphthenyl and indan-2-yl.
Alkenyl refers to straight-chain or branched-chain aliphatic radicals containing 2 to 12 carbon atoms in which one or more —CH2—CH2— structures are each replaced by —CH═CH—. Suitable alkenyl groups are ethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2-butene, 1-pentenyl, and 2-pentenyl.
Alkynyl refers to straight-chain or branched-chain aliphatic radicals containing 2 to 12 carbon atoms in which one or more —CH2—CH2— structures are each replaced by —C≡C—. Suitable alkynyl groups are ethynyl, propynyl, 1-butynyl, and 2-butynyl.
Acyl refers to alkanoyl radicals having 1 to 13 carbon atoms in which the alkyl portion can be substituted by halogen, alkyl, aryl and/or alkoxy, or aroyl radicals having 7 to 15 carbon atoms in which the aryl portion can be substituted by, for example, halogen, alkyl and/or alkoxy. Suitable acyl groups include formyl, acetyl, propionyl, butanoyl and benzoyl.
Substituted radicals preferably have 1 to 3 substituents, especially 1 to 2 substituents.
In the compounds of Formula I, R1 can be an alkyl group having preferably 2 to 4 carbon atoms which is optionally substituted by halogen, preferably fluorine or chlorine.
R1 can also preferably be cycloalkyl, particularly cyclopentyl or cyclohexyl.
R2 is preferably H or alkyl having 1 to 4 carbon atoms, especially C2H5.
R3 is preferably hydrogen, alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, or n-butyl), arylalkyl (e.g., substituted or unsubstitituted benzyl, phenethyl, and phenpropyl), or a heteroarylalkyl group (e.g., substituted or unsubstituted pyridylmethyl, furanylmethyl, thienylmethyl, pyrrolylmethyl, pyrimidinylmethyl, thiazolylmethyl, isoquinolinylmethyl and quinolinylmethyl). Preferred substituents for aryl and heteroaryl portions of R3 are F, Cl, CH3, C2H5, OCH3, and CN. In particular, R3 is preferably pyridylmethyl.
R4 is preferably aryl, or heteroaryl, especially phenyl, naphthyl, biphenyl, furanyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, and isoquinolinyl, which in each case is unsubstituted or is substituted one or more times. Preferred substituents are OH, F, Cl, CF3, alkyl (such as methyl or ethyl), alkoxy (such as methoxy and ethoxy), CN, vinyl, CH2OH, CONHOH, CONH2, methylenedioxy, COOH, and combinations thereof. For example, R4 can be phenyl substituted by halogen, COOH and/or CN.
In addition, when R4 is aryl, especially, phenyl, preferred substituents include R5-L-, e.g., R5—, R5—O—, R5—CO—, R5—NH—CO—, R5—SO2—NH—, R5—SO2—NH-alkylene-O—, NH2-alkyl-NH—CO—, R5-alkylene-NH—CO—, alkyl-CO—NH-alkyl- as well as methyl, ethyl, Cl, F, CN, OCH3, CF3, amino, nitro, HOCH2 and COOH.
When R4 is aryl substituted by R5—SO2—NH— it is preferably a substituted phenyl group and R5 is preferably methyl, ethyl, propyl or phenyl.
When R4 is aryl substituted by R5—SO2—NH-alkylene-O— it is preferably a substituted phenyl. In such cases, R5 is preferably methyl, ethyl, propyl or phenyl and alkylene is preferably —CH2—, —CH2CH2— or —CH2CH2CH2—.
When R4 is aryl substituted by R5-L- it is preferably substituted phenyl. In such cases, preferred R5 groups include phenyl, tetrazolyl, oxazinyl, piperazinyl, methylpiperazinyl, pyridyl, methylpyridyl, pyrrolinyl, methylpyrrolinyl, piperadinyl, or methylpiperadinyl, and L is preferably a single bond, —O—, —CO—, —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2—O—, —CH2CH2—O—, —CH2CH2CH2—O—, —CH2—NH—CH2CH2—O—, —CO—NH—, —NH—CO—, or —CONHSO2—.
R7 is preferably alkoxy having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, e.g., CH3 or C2H5.
R8 is preferably —CO—C1-4-alkyl, e.g., —COCH3.
R9 is preferably —CH3.
X and Y are preferably both O or S, especially O.
A is preferably —CH2CH2—.
In addition, preferred PDE4 inhibitors in accordance with the invention are compounds described by subformulas Ia to IIe which correspond to formulas I and II but exhibit the following preferred groups:
Preferred aspects include pharmaceutical compositions comprising a compound of this invention and a pharmaceutically acceptable carrier and, optionally, another active agent as discussed below; a method of inhibiting a PDE4 enzyme, especially an isoenzyme, e.g., as determined by a conventional assay or one described herein, either in vitro or in vivo (in an animal, e.g., in an animal model, or in a mammal or in a human); a method of treating neurological syndrome, e.g., loss of memory, especially long-term memory, cognitive impairment or decline, memory impairment, etc. a method of treating a disease state modulated by PDE4 activity, in a mammal, e.g., a human, e.g., those mentioned herein.
The compounds of the present invention may be prepared conventionally. All starting materials are known or can be conventionally prepared from known starting materials. Some of the processes which can be used are described below.
Starting material 6-amino-1-cyclopentyl-3-ethylindazole can be synthesized from the corresponding 6-carboxy-1-cyclopentyl-3-ethylindazole by a Curtius rearrangement. The starting 6-carboxy-1-cyclopentyl-3-ethylindazole can be prepared by methods common in the art (see, e.g., WO 098/09961). Alternatively, starting 6-amino-1-cyclopentyl-3-ethylindazoles can be synthesized by amination of 6-halo-1-cycloalkyl-3-ethylindazole or reduction of 6-nitro-1-cycloalkyl-3-etliylindazole. The indazole scaffold can be prepared by several methods common to the art, such as by reaction of cycloalkylhydrazine with 2,4-difluoropropiophenone.
Starting benzofurans are either commercially available or can be synthesized according literature methods by intramolecular aldol condensation of appropriately substituted beta-ketoethers of salicylaldehydes. (see Strategies for Organic Drug Synthesis and Design, Daniel Lednicer, Ed., 1998, John Wiley and Sons, Inc. Chapter 10 pp. 286–289). Nitration of 2-acetyl-7-methoxybenzofuran with nitric acid in acetic anhydride provides 2-acetyl-7-methoxy-4-nitrobenzofuran. (in the above scheme, DPA patent refers to U.S. patent application Ser. No. 10/051,309).
Protection of the carbonyl group with a suitable base stable protecting group such as a dioxane or dioxolane provides the desired starting 4-nitrobenzofurans. See also WO 99/40085 and WO 99/37640.
One of ordinary skill in the art will recognize that some of the compounds of Formulas I and II can exist in different geometrical isomeric forms. In addition, some of the compounds of the present invention possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers, as well as in the form of racemic or nonracemic mixtures thereof, and in the form of diastereomers and diastereomeric mixtures inter alia. All of these compounds, including cis isomers, trans isomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers, and substantially pure and pure enantiomers, are within the scope of the present invention. Substantially pure enantiomers contain no more than 5% w/w of the corresponding opposite enantiomer, preferably no more than 2%, most preferably no more than 1%.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, are also useful. The optically active compounds of Formulae I and II can likewise be obtained by chiral syntheses utilizing optically active starting materials.
In addition, one of ordinary skill in the art will recognize that the compounds can be used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C and/or 14C.
The present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts and prodrugs of all the compounds of the present invention. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, mangnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates.
Preferably, the salts formed are pharmaceutically acceptable for administration to mammals. However, pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, for isolating the compound as a salt and then converting the salt back to the free base compound by treatment with an alkaline reagent. The free base can then, if desired, be converted to a pharmaceutically acceptable acid addition salt.
The compounds of the invention can be administered alone or as an active ingredient of a formulation. Thus, the present invention also includes pharmaceutical compositions of compounds of Formulas I or II containing, for example, one or more pharmaceutically acceptable carriers.
Numerous standard references are available that describe procedures for preparing various formulations suitable for administering the compounds according to the invention. Examples of potential formulations and preparations are contained, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553–1593 (current edition).
In view of their high degree of PDE4 inhibition, the compounds of the present invention can be administered to anyone requiring or desiring PDE4 inhibition, and/or enhancement of cognition. Administration may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrastemally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration.
Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.
Various liquid oral dosage forms can also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms can also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.
Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art.
For topical administration the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches.
Aerosol formulations suitable for administering via inhalation also can be made. For example, for treatment of disorders of the respiratory tract, the compounds according to the invention can be administered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions. The aerosol formulation can be placed into a pressurized acceptable propellant.
The compounds can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and/or in the treatment of psychosis, e.g., other PDE4 inhibitors, calcium channel blockers, chloinergic drugs, adenosine receptor modulators, amphakines NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigimine, and glanthanamine). In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below its usual dosage range.
The present invention further includes methods of treatment that involve inhibition of PDE4 enzymes. Thus, the present invention includes methods of selective inhibition of PDE4 enzymes in animals, e.g., mammals, especially humans, wherein such inhibition has a therapeutic effect, such as where such inhibition may relieve conditions involving neurological syndromes, such as the loss of memory, especially long-term memory. Such methods comprise administering to an animal in need thereof, especially a mammal, most especially a human, an inhibitory amount of a compound, alone or as part of a formulation, as disclosed herein.
The condition of memory impairment is manifested by impairment of the ability to learn new information and/or the inability to recall previously learned information. Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline.
Dementias are diseases that include memory loss and additional intellectual impairment separate from memory. The present invention includes methods for treating patients suffering from memory impairment in all forms of dementia. Dementias are classified according to their cause and include: neurodegenerative dementias (e.g., Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease), vascular (e.g., infarcts, hemorrhage, cardiac disorders), mixed vascular and Alzheimer's, bacterial meningitis, Creutzfeld-Jacob Disease, multiple sclerosis, traumatic (e.g., subdural hematoma or traumatic brain injury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g., heavy metals, alcohol, some medications), metabolic (e.g., vitamin B12 or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g., depression and schizophrenia), and hydrocephalus.
The present invention includes methods for dealing with memory loss separate from dementia, including mild cognitive impairment (MCI) and age-related cognitive decline. The present invention includes methods of treatment for memory impairment as a result of disease. In another application, the invention includes methods for dealing with memory loss resulting from the use of general anesthetics, chemotherapy, radiation treatment, post-surgical trauma, and therapeutic intervention.
The compounds may be used to treat psychiatric conditions including schizophrenia, bipolar or manic depression, major depression, and drug addiction and morphine dependence. These compounds may enhance wakefulness. PDE4 inhibitors can be used to raise cAMP levels and prevent neurons from undergoing apoptosis. PDE4 inhibitors are also known to be anti-inflammatory. The combination of anti-apoptotic and anti-inflammatory properties make these compounds useful to treat neurodegeneration resulting from any disease or injury, including stroke, spinal cord injury, neurogenesis, Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), and multiple systems atrophy (MSA).
Thus, in accordance with a preferred embodiment, the present invention includes methods of treating patients suffering from memory impairment due to, for example, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia and other neurological conditions including acute neuronal diseases, as well as HIV and cardiovascular diseases, comprising administering an effective amount of a compound according to Formula I or II or pharmaceutically acceptable salts thereof.
The compounds of the present invention can also be used in a method of treating patients suffering from disease states characterized by decreased NMDA function, such as schizophrenia. The compounds can also be used to treat psychosis characterized by elevated levels of PDE 4, for example, various forms of depression, such as manic depression, major depression, and depression associated with psychiatric and neurological disorders.
As mentioned, the compounds of the invention also exhibit anti-inflammatory activity. As a result, the inventive compounds are useful in the treatment of a variety of allergic and inflammatory diseases, particularly disease states characterized by decreased cyclic AMP levels and/or elevated phosphodiesterase 4 levels. Thus, in accordance with a further embodiment of the invention, there is provided a method of treating allergic and inflammatory disease states, comprising administering an effective amount of a compound according to Formulas I or II or a pharmaceutically acceptable salt thereof. Such disease states include: asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, esoniophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, cystic fibrosis, arterial restenosis, artherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, chronic obstructive airways disease, chronic obstructive pulmonary disease, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritis in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, systemic lupus erythematosus, follicular and wide-area pyodermias, endogenous and exogenous acne, acne rosacea, Behcet's disease, anaphylactoid purpura nephritis, inflammatory bowel disease, leukemia, multiple sclerosis, gastrointestinal diseases, autoimmune diseases and the like.
PDE4 inhibitors for treating asthma, chronic bronchitis, psoriasis, allergic rhinitis, and other inflammatory diseases, and for inhibiting tumor necrosis factor are known within the art. See, e.g., WO 98/58901, JP-11-18957, JP 10-072415, WO 93/25517, WO 94/14742, U.S. Pat. No. 5,814,651, and U.S. Pat. No. 5,935,9778. These references also describe assays for determining PDE4 inhibition activity, and methods for synthesizing such compounds. The entire disclosures of these documents are hereby incorporated by reference.
PDE4 inhibitors may be used to prevent or ameliorate osteoporosis, as an antibiotic, for treatment of cardiovascular disease by mobilizing cholesterol from atherosclerotic lesions, to treat rheumatoid arthritis (RA), for long-term inhibition of mesenchymal-cell proliferation after transplantation, for treatment of urinary obstruction secondary to benign prostatic hyperplasia, for suppression of chemotaxis and reduction of invasion of colon cancer cells, for treatment of B cell chronic lymphocytic leukemia (B-CLL), for inhibition of uterine contractions, to attenuate pulmonary vascular ischemia-reperfusion injury (IRI), for corneal hydration, for inhibition of IL-2R expression and thereby abolishing HIV-1 DNA nuclear import into memory T cells, for augmentation of glucose-induced insulin secretion, in both the prevention and treatment of colitis, and to inhibit mast cell degranulation.
The compounds of the present invention can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and/or in the treatment of psychosis, e.g., other PDE4 inhibitors, calcium channel blockers, chloinergic drugs, adenosine receptor modulators, amphakines NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigimine, and glanthanamine). In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range.
The dosages of the compounds of the present invention depend upon a variety of factors including the particular syndrome to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, pharmacokinetic profile of the compound, and the presence of any deleterious side-effects, among other considerations.
The compounds of the invention are typically administered at dosage levels and in a mammal customary for PDE4 inhibitors such as those known compounds mentioned above. For example, the compounds can be administered, in single or multiple doses, by oral administration at a dosage level of, for example, 0.01–100 mg/kg/day, preferably 0.1–70 mg/kg/day, especially 0.5–10 mg/kg/day. Unit dosage forms can contain, for example, 0.1–50 mg of active compound. For intravenous administration, the compounds can be administered, in single or multiple dosages, at a dosage level of, for example, 0.001–50 mg/kg/day, preferably 0.001–10 mg/kg/day, especially 0.01–1 mg/kg/day. Unit dosage forms can contain, for example, 0.1–10 mg of active compound.
In carrying out the procedures of the present invention it is of course to be understood that reference to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein.
The entire disclosures of all applications, patents and publications, cited above and below, and of U.S. Provisional Application No. 60/396,726, filed Jul. 19, 2002, are hereby incorporated by reference.
The present invention will now be further described by way of the following non-limiting examples. In applying the disclosure of these examples, it should be kept clearly in mind that other and different embodiments of the methods disclosed according to the present invention will no doubt suggest themselves to those of skill in the relevant art.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.
To a mixture of 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (258 mg) and triethylamine (0.56 mL) in t-butanol (1 ml) was added diphenylphosphoryl azide (0.33 μL). The mixture was stirred at 100� C. for 4 h, then partitioned between water (25 mL) and ether (25 mL). The ether layer was collected, dried (MgSO4), and passed through a plug of silica. The silica was washed with an additional 25 mL of ether and the mixture was concentrated in vacuo. The residue was dissolved in THF (5 mL) and 6N aq. HCL (1 mL) was added and the mixture was stirred for 18 h. Ether (25 mL) and water (25 mL) were added and the ether layer was collected, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel to yield 0.14 g of 6-amino-1-cyclopentyl-3-ethyl-1H-indazole (59% yield). 1H NMR (300 MHz) δ 7.45 (d,J=8.4 Hz, 1H), 6.52 (m,2H), 4.74 (p,J=7.8 Hz, 1H), 3.86 (br,2H), 2.95 (q,J=7.7 Hz,2H), 2.3–1.8 (m,6H), 1.8–1.6 (m,2H), 1.37 (t,J=7.7 Hz,3H).
To a mixture of 3-pyridinecarboxaldehyde (106 mg, 1.0 mol) in methanol (5.0 mL) was added 6-amino-1-cyclopentyl-3-ethyl-1H-indazole (240 mg, 1.05 mmol) and p-toluenesulfonic acid monohydrate (2.0 mg). The reaction mixture was stirred for 4 h. The flask was then cooled to 0� C. and sodium borohydride (0.09 g, 2.3 mmol) was added portion-wise over 4 h. The reaction mixture was allowed to warm to room temperature over 16h with stirring. TLC indicated the reaction was complete (1:3 hex:EA). The solvent was evaporated and diluted with water (10 mL) and extracted with ethyl acetate (2�20 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, and concentrated to yield the desired product. 1H NMR (300 MHz) δ 8.64 (s,1H), 8.51 (m,1H), 7.70 (m, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.25 (m, 1H), 6.50 (m,1H), 6.33 (s,1H), 4.68 (p,J=7.8 Hz, 1H), 4.55 (br,1H), 4.40 (s,1H), 2.90 (q,J=7.7 Hz,2H), 2.1–1.8 (m,6H), 1.8–1.6 (m,2H), 1.34 (t,J=7.7 Hz,3H).
The following compounds were prepared in a similar manner as described above in Example 2.
To a 10 mL oven dried, argon flushed flask was added in the following order 0.06 g (0.61 mmol) of NaOtBu, 36 mg of Pd2 dba3, 2.0 mL of toluene, 0.014 mL of P(tBu)3, and a 2.0 mL solution of 140 mg (0.436 mmol) of 6-amino-1-cyclopentyl-3-ethyl-N-(3-pyridylmethyl)-1H-indazole in toluene. With stirring, 310 mg (1.5 mmol) of tert-butyl 3-iodobenzoate was added dropwise and the mixture was stirred for 18 hours. The reaction mixture was diluted with EtOAc and washed twice with H2O and extracted with 3�15 mL of 3N HCl. The combined acid extracts were washed with 15 mL of EtOAc and then carefully neutralized with 6N NaOH to pH greater than 12. The basic solution was extracted with 2�15 mL of EtOAc and the combined organic fractions were subsequently washed with 15 mL of H2O and brine, dried (MgSO4), and concentrated. The residue was purified by chromatography over silica gel (Biotage Flash 40M) eluting with 25% EtOAc in hexanes. 1H NMR (300 MHz) δ 8.65 (br, 1H), 8.51 (br,1H), 8.26 (d, J=8.4, 1H), 7.75 (m, 1H), 7.7–7.5 (m, 3H), 7.27 (m, 1H), 7.1–7.0 (m, 2H), 6.85 (d, J=8.4,1H), 5.22 (s,1H), 4.76 (p,J=7.8 Hz, 1H), 2.96 (q,J=7.7 Hz,2H), 2.1–1.8 (m,6H), 1.8–1.6 (m,2H), 1.54 (s,9H), 1.34 (t,J=7.7 Hz,3H).
The following compounds were prepared in a similar manner as described above in Example 3.
A solution consisting of 170 mg (0.344 mmol) of 6-amino-1-cyclopentyl-3-ethyl-N-[3-(1,1-dimethylethoxycarbonyl)phenyl]-N-(3-pyridylmethyl)-1H-indazole, 3.35 mL of dichloromethane and 0.84 mL of trifluoroacetic acid was stirred at room temperature for 5 hours. The solution was washed with 5.0 mL of H2O. Then 5.0 mL of H2O was added and the pH adjusted to 6 by the addition of 10% aqueous NaOH. The combined aqueous layers were extracted with 2�5 mL of dichloromethane. The combined dichloromethane extracts were evaporated and the remaining material was purified by flash chromatography over SiO2 using 10% MeOH in CH2Cl2 as eluant. 1H NMR (300 MHz) δ 8.90 (br, 1H), 8.70 (br,1H), 8.25 (d, J=8.4, 1H), 7.7–7.5 (m, 4H), 7.20 (m, 1H), 7.1–7.0 (m, 2H), 6.86 (d, J=8.4,1H), 5.20 (s,1H), 4.76 (p,J=7.8 Hz, 1H), 2.96 (q,J=7.7 Hz,2H), 2.05 (m,4H), 1.88 (m,2H), 1.65 (m,2H), 1.36 (t,J=7.7 Hz,3H).
The following compound was prepared in a similar manner as described above in Example 4.
To a solution of 2-acetyl-7-methoxybenzofuran (4.0 g) in acetic anhydride (50 mL) at 0� C. was added 70% nitric acid (1.5 mL) drop-wise. The mixture was warmed to room temperature and stirred for 3 h then poured into ice-cold saturated sodium carbonate (200 mL). Solid sodium carbonate was added carefully with stirring until basic (pH=8). The mixture was filtered and the solid collected by vacuum filtration. The solid was boiled in 100 mL (methanol) for 1 h, then cooled to 0� C. and filtered to give 2-acetyl-7-methoxy-4-nitrobenzpfuran (2.1 g). 1H NMR (300 MHz) δ 8.29 (d,J=8.9 Hz, 1H), 8.14 (s,1H), 7.00 (d,J=8.9 Hz, 1H), 4.14 (s,3H), 2.68 (s, 3H).
A mixture of 2-acetyl-7-methoxy-4-nitrobenzofuran (2.1 g), ethylene glycol (2 mL), and p-toluensulfonic acid (25 mg) in toluene (50 mL) was warmed to reflux with an attached Dean-Stark apparatus for 18 h. The mixture partitioned between sat. aq. NaHCO3 (50 mL) and ether (50 mL). The ether layer was collected, washed with water (25 mL) and brine (25 mL), dried (MgSO4) and concentrated to give pure 7-methozy-2-(2-methyl-(1,3-dioxolan-2-yl))-4-nitrobenzofuran (2.1 g). 1H NMR (300 MHz) δ 8.22 (d,J=9.0 Hz, 1H), 7.44 (s,1H), 6.84 (d,J=9.0 Hz, 1H), 4.11 (s,3H), 4.11 (m,4H), 1.86 (s,3H).
To a suspension of 10% Pd on activated carbon (200 mg) in ethanol (100 mL), under N2 protection, was added 7-methoxy-2-(2-methyl-(1,3-dioxolan-2-yl))-4-nitrobenzofuran (6.50 g, 23 mmol). The reaction mixture was degassed under vacuum three times. The reaction mixture was stirred vigorously while hydrogen gas was allowed to flow over the reaction mixture. After 4 h the reaction was complete by TLC (5:1 hex:EA). The reaction mixture was filtered through a pad of celite and the celite was rinsed with additional ethanol. The solvent was removed in-vacuo to obtain 5.1 g (88% yield) of the title compound as a yellow oil.
7-Methoxy-2-(2-methyl-1,3-dioxolan-2-yl)-4-(N-3-carboxyphenyl)-N-(3-pyridylmethyl)aminobenzofuran, t-butyl ester (120 mg) was taken up in CH2Cl2 (10 mL) and trifluoroacetic acid (2 mL) was added and the mixture was stirred for 4 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography eluting with a linear gradient from 0%–10% MeOH in EtOAc over 15 min to yield 65 mg of 2-acetyl-7-methoxy-4-(N-(3-carboxyphenyl)-N-)3 pyridylmethyl)aminobenzofuran. 1H NMR (300 MHz) □ 11.60 (br,1H,) 8.71 (br,1H), 8.56 (br,1H), 7.80 (d,J=7.5 Hz, 1H), 7.60–7>50 (m,2H), 7.35 (m,1H), 7.20 (t,J=7.9 Hz, 1H), 7.10–7.00 (m,2H), 6.95–6.80 (m,2H), 5.09 (s,2H), 4.01 (s,3H), 2.54 (s,3H).
The following compounds were prepared in a similar manner as described above in Example 8.
To a solution of 2-acetyl-7-methoxy-N-(4-carboxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzofuran (416 mg, 1.0 mmol), benzenesulfonamide (200 mg, 1.2 mmol), and DMAP (150 mg, 1.2 mmol) in dichloromethane (5 mL) at room temperature was added EDCI (230 mg, 1.2 mmol) in one portion and the mixture was stirred at room temperature for 16 h. The mixture was partitioned between water (25 mL) and EtOAc (25 mL) and the pH was adjusted to 5–6 with 1.0N HCl. The EtOAc was separated, washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography eluting with a linear gradient from 5% to 10% MeOH in EtOAc to give 2-Acetyl-7-methoxy-N-(4-phenylsulfonylaminocarbonylphenyl)-N-(3-pyridylmethyl)-4-aminobenzofuran (415 mg). 1H NMR (300 MHz) δ 8.53 (br,1H), 8.46 (br,1H), 8.06 (d,J=7.3 Hz,2H), 7.8–7.3 (m,6H), 7.21 (m,1H), 7.1–7.0 (m,2H), 6.91 (d,J=8.5 Hz,1H), 6.56 (d,J=7.3 Hz,2H), 4.99 (s,2H), 4.02 (s,3H), 2.54 (s,3H).
Human PDE4 was obtained from baculovirus-infected Sf9 cells that expressed the recombinant enzyme. The cDNA encoding hPDE-4D6 was subcloned into a baculovirus vector. Insect cells (Sf9) were infected with the baculovirus and cells were cultured until protein was expressed. The baculovirus-infected cells were lysed and the lysate was used as source of hPDE-4D6 enzyme. The enzyme was partially purified using a DEAE ion exchange chromatography. This procedure can be repeated using cDNA encoding other PDE-4 enzymes.
Type 4 phosphodiesterases convert cyclic adenosine monophosphate (cAMP) to 5′-adenosine monophosphate (5′-AMP). Nucleotidase converts 5′-AMP to adenosine. Therefore the combined activity of PDE4 and nucleotidase converts cAMP to adenosine. Adenosine is readily separated from cAMP by neutral alumina columns. Phosphodiesterase inhibitors block the conversion of cAMP to adenosine in this assay; consequently, PDE4 inhibitors cause a decrease in adenosine.
Cell lysates (40 ul) expressing hPDE-4D6 were combined with 50 ul of assay mix and 10 ul of inhibitors and incubated for 12 min at room temperature. Final concentrations of assay components were: 0.4 ug enzyme, 10 mM Tris-HCl (pH 7.5), 10 MM MgCl2, 3 uM cAMP, 0.002 U 5′-nucleotidase, and 3�104 cpm of [3H]cAMP. The reaction was stopped by adding 100 μl of boiling 5 mN HCl. An aliquot of 75 μl of reaction mixture was transferred from each well to alumina columns (Multiplate; Millipore). Labeled adenosine was eluted into an OptiPlate by spinning at 2000 rpm for 2 min; 150 μl per well of scintillation fluid was added to the OptiPlate. The plate was sealed, shaken for about 30 min, and cpm of [3H]adenosine was determined using a Wallac Triflux�.
All test compounds are dissolved in 100% DMSO and diluted into the assay such that the final concentration of DMSO is 0.1%. DMSO does not affect enzyme activity at this concentration.
A decrease in adenosine concentration is indicative of inhibition of PDE activity. pIC50 values were determined by screening 6 to 12 concentrations of compound ranging from 0.1 nM to 10,000 nM and then plotting drug concentration versus 3H-adenosine concentration. Nonlinear regression software (Assay Explorer�) was used to estimate pIC50 values.
The test was performed as previously described (Zhang, H.-T., Crissman, A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell, J. M., Neuropsychopharmacology, 2000, 23, 198–204.). The apparatus (Model E10-16SC, Coulboum Instruments, Allentown, Pa.) consisted of a two-compartment chamber with an illuminated compartment connected to a darkened compartment by a guillotine door. The floor of the darkened compartment consisted of stainless steel rods through which an electric foot-shock could be delivered from a constant current source. All experimental groups were first habituated to the apparatus the day before the start of the experiment. During the training, the rat (Male Spraque-Dawley (Harlan) weighing 250 to 350 g) was placed in the illuminated compartment facing away from the closed guillotine door for 1 minute before the door was raised. The latency for entering the darkened compartment was recorded. After the rat entered the darkened compartment, the door was closed and a 0.5 mA electric shock was administered for 3 seconds. Twenty-four hours later, the rat was administered 0.1 mg/kg MK-801 or saline, 30 minutes prior to the injection of saline or test compound (dosed from 0.1 to 2.5 mg/kg, i.p.), which was 30 minutes before the retention test started. The rat was again placed in the illuminated compartment with the guillotine door open. The latency for entering the darkened compartment was recorded for up to 180 seconds, at which time the trial was terminated.
All data were analyzed by analyses of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests. Na�ve rats required less than 30 seconds, on average, to cross from the illuminated compartment to the darkened compartment. However, 24 hours after the electric shock exposure, most rats pretreated with vehicle did not re-enter the darkened compartment; the average latency was increased up to 175 seconds (p<0.001). Pretreatment with MK-801 (0.1 mg/kg) markedly reduced this latency when compared to the vehicle (p<0.001). This amnesic effect of MK-801 is reversed in a statistically significant manner by actual test compounds in a dose-dependent fashion.
Radial Arm Maze Task in Rats, an in Vivo Test for Learning and Memory
The test was performed as previously described (Zhang, H.-T., Crissman, A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell, J. M., Neuropsychopharmacology, 2000, 23, 198–204.). Five days after initial housing, rats (male Spraque-Dawley (Harlan) weighing 250 to 350 g) were placed in the eight-arm radial maze (each arm was 60�10�12 cm high; the maze was elevated 70 cm above the floor) for acclimation for two days. Rats were then placed individually in the center of the maze for 5 minutes with food pellets placed close to the food wells, and then, the next day, in the wells at the end of the arms; 2 sessions a day were conducted. Next, four randomly selected arms were then baited with one pellet of food each. The rat was restricted to the center platform (26 cm in diameter) for 15 seconds and then allowed to move freely throughout the maze until it collected all pellets of food or 10 minutes passed, whichever came first. Four parameters were recorded: 1) working memory errors, i.e., entries into baited arms that had already been visited during the same trial; 2) reference memory errors, i.e., entries into unbaited arms; 3) total arm entries; and 4) the test duration (seconds), i.e., the time spent in the collection of all the pellets in the maze. If the working memory error was zero and the average reference memory error was less than one in five successive trials, the rats began the drug tests. MK-801 or saline was injected 15 minutes prior to vehicle or test agent, which was given 45 minutes before the test. Experiments were performed in a lighted room, which contained several extra-maze visual cues.
All data were analyzed by analyses of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests. Compared to control, MK-801 (0.1 mg/kg, i.p.) increased the frequencies of both working and reference memory errors (p<0.01). This amnesic effect of MK-801 on working memory is reversed in a statistically significant manner by the administration of actual test compounds in a dose-dependent fashion.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
While the invention has been illustrated with respect to the production and of particular compounds, it is apparent that variations and modifications of the invention can be made without departing from the spirit or scope of the invention.
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|Aventis Pharma Limited
|Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic-or heteroatom-containing linking group
|Aug 25, 1997
|Jul 17, 2001
|Pfizer Inc
|Indazole derivatives and their use as inhibitors of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF)
|Mar 26, 1998
|Oct 2, 2001
|Celltech Therapeutics Limited
|Trisubstituted phenyl derivatives and process for their preparation
|Jan 22, 2002
|Mar 2, 2004
|Memory Pharmaceuticals Corp.
|Phosphodiesterase 4 inhibitors
|Jan 22, 2002
|Oct 17, 2002
|Memory Pharmaceuticals Corp.
|Phosphodiesterase 4 inhibitors
|Nov 19, 2003
|Aug 5, 2004
|Schumacher Richard A.
|Phosphodiesterase 4 inhibitors
|Jul 21, 2003
|Jun 2, 2005
|Memory Pharmaceuticals Corp.
|Phosphodiesterase 4 inhibitors, including N-substituted aniline and diphenylamine analogs
|Dec 25, 1997
|Apr 19, 2000
|Nikken Chemicals Company, Limited
|3-anilino-2-cycloalkenone derivates
|Jul 27, 2000
|Jul 18, 2001
|Wella Aktiengesellschaft
|2-aminoalkyl-1,4-diaminobenzene derivatives and dye composition containing these compounds
|Title not available
|Title not available
|Title not available
|Jun 15, 1993
|Dec 23, 1993
|Celltech Limited
|Trisubstituted phenyl derivatives as selective phosphodiesterase iv inhibitors
|Jul 28, 1993
|Feb 3, 1994
|Rhone-Poulenc Rorer Limited
|INHIBITORS OF c-AMP PHOSPHODIESTERASE AND TNF
|Dec 22, 1993
|Jul 7, 1994
|Celltech Limited
|Tri-substituted phenyl derivatives as phosphodiesterase inhibitors
|May 24, 1994
|Dec 8, 1994
|Smithkline Beecham Laboratoires Pharmaceutiques
|Anti-arrhythmic n-substituted 3-benzazepines or isoquinolines
|Jul 2, 1994
|Jan 12, 1995
|Byk Gulden Lomberg Chemische Fabrik Gmbh
|Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors
|Jan 11, 1996
|Jul 18, 1996
|Euro-Celtique, S.A.
|Compounds for and method of inhibiting phosphodiesterase iv
|Jan 29, 1996
|Aug 8, 1996
|Smithkline Beecham Corporation
|Method for synthesis of aryl difluoromethyl ethers and the like
|May 20, 1996
|Nov 21, 1996
|Smithkline Beecham S.P.A.
|Diaryldiamine derivatives and their use as delta opioid (ant)-agonists
|Jun 18, 1996
|Jan 9, 1997
|4-phenylaminothiazole derivatives, method for preparing same, and pharmaceutical compositions containing said derivatives
|Jun 2, 1997
|Dec 31, 1997
|Pfizer Inc.
|Substituted indazole derivatives and their use as phosphodiesterase (pde) type iv and tumor necrosis factor (tnf) inhibitors
|Aug 25, 1997
|Mar 12, 1998
|Pfizer Inc.
|Indazole derivatives and their use as inhibitors of phosphodiesterase (pde) type iv and the production of tumor necrosis factor (tnf)
|Dec 25, 1997
|Dec 30, 1998
|Nikken Chemicals Co., Ltd.
|3-anilino-2-cycloalkenone derivates
|Dec 23, 1998
|Jul 8, 1999
|Ortho-Mcneil Pharmaceutical, Inc.
|4-[aryl(piperidin-4-yl)] aminobenzamides which bind to the delta-opioid receptor
|Apr 19, 2000
|Nov 2, 2000
|Merck Frosst Canada & Co.
|Heterosubstituted pyridine derivatives as pde 4 inhibitors
|May 4, 2000
|Nov 23, 2000
|Bayer Aktiengesellschaft
|May 16, 2000
|Nov 30, 2000
|Bristol-Myers Squibb Company
|Pyrrolotriazine inhibitors of kinases
|Mar 19, 2001
|Sep 27, 2001
|Merck Frosst Canada & Co.
|Tri-aryl-substituted-ethane pde4 inhibitors
|Dec 19, 2001
|Aug 1, 2002
|Glaxo Group Limited
|Pyrimidineamines as angiogenesis modulators
|Jan 22, 2002
|Sep 26, 2002
|Memory Pharmaceuticals Corporation
|Aniline derivatives useful as phosphodiesterase 4 inhibitors
|Anil S. Guram et al., "A Simple Catalytic Method for the conversion of Aryl Bromides to Arylamines," Angew. Chem. Int, Ed. Engl., 1995, vol. 34, No. 12, pp. 1348-1350.
|Barnes, Peter J., Am. J. Respir. Crit. Care Med., 160, S72-S79, 1999.
|Domine M. T. Chan et al., "New N- abd O-Arylations with Phenylboronic Acids and Cupric Acetate," Tetrahedron Letters, vol. 39, 2933-2936 (1998).
|Donald V. Daniels et al., "A Semiautomated Method for the Assay of Cyclic Adenosine 5'-Monophosphate Phosphodiesterase," Analytical Biochemistry, 1996, pp. 367-369, vol. 236.
|Elisabeth Boichot et al., "Anti-Inflammatory Activities of a New Series of Selective Phosphodiesterase 4 Inhibitors Derived from 9- Benzyladenine," The Journal Of Pharmacology And Experimental Therapeutics, 2000, pp. 647-653, vol. 292, No. 2.
|Giembycz, Mark A., Drugs, 59(2), 193-212, Feb. 2000.
|Golub et al., Science, 286, 531-537, Oct. 15, 1999.
|Han-Ting Zhang et al., "Effects of Rolipram on Scopolamine-induced Impairment of Working and Reference Memory in the Radial-arm Maze tests in Rats," Psychopharmacology (Berl) Jun. 2000;150(3):pp. 311-316.
|Han-Ting Zhang et al., "Inhibition of Cyclic AMP Phosphodiesterase (PDE4) Reverses Memory Deficits Associated with NDMA Receptor Antagonism," Neuropsychopharmacology, 2000, vol. 23, pp. 198-204.
|Heilman et al, "Synthesis and Antiinflammatory Evaluation of Substitued Isophthalonitriles, Trimesonitriles, Benzonitriles, and Terephthalonitriles", Journal of Medicinal Chemistry, 1978, vol. 21, No. 9, pp. 906-913, XP-002226236.
|Hiroyuki Sawanishi et al., "Selective Inhibitors of Cyclic AMP-Specific Phosphodiesterase: Heterocycle-Condensed Purines", J. Med. Chem., 1997, pp. 3248-3253, vol. 40.
|Inoue et al, "Steric Tuning in Chiral Ligand Mediated Enantioselective Alkylation of Imines", Tetrahedron: Asymmetry, 1993, vol. 4, No.7, pp. 1603-1606, XP002226237.
|J.E. Sounnes et al., "Proposal for Pharmacologically Distinct Conformers of PDE4 Cyclic AMP Phosphodiesterases", Cell Signal, 1997, pp. 227-236. vol. 9, No. 3-4.
|James E. Kelley et al., "Antirhinovirus structure-activity relationships of 6-substituted-9-(4-methylbenzyl)-2-trifluoromethyl-9H-purines," Eur. J. Med. Chem., 1990, pp. 131-135, vol. 25.
|James L. Kelley et al., "6-(Alkylamino)-9-alkylpurines. A New Class of Potential Antipsychotic Agents," J. Med. Chem., 1997, pp. 3207-3216, vol. 40.
|James L. Kelley et al., "Synthesis and Structure- Activity Relationships of 2-Substituted-6-(dimethylamino)-9-(4-methylbenzyl)-9H-purines with Antirhinovirus Activity," J. Med. Chem., 1989, pp. 218-224, vol. 32.
|Japanese Patent Abstract No. 7206789 dated Aug. 8, 1995.
|Jean-Jacques Bourguignon et al., "9-Benzyladenines: Potent and Selective cAMP Phosphodiesterase Inhibitors," J. Med. Chem, 1997, pp. 1768-1770, vol. 40.
|John Hartwig et al., "Room-Temperature Palladium-Catalyzed Amination of Aryl Bromides and Chlorides and Extended Scope of Aromatic C-N Bond Formation with a Commercial Ligand," J. Org. Chem., 1999, vol. 64, pp. 5575-5580.
|Mark Barad et al., "Rolipram, a Type IV-Specific Phosphodiesterase Inhibitor Facillitates the Establishment of Long-lasting Long-term Potentiation and Improves Memory," Proc. Natl. Acad. Sci., vol. 95, pp. 15020-15025 (Dec. 1998).
|Mary Elizabeth Bach et al., "Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway", Proc. Natl. Acad. Sci. USA, Apr. 1999, pp. 5280-5285, vol. 96.
|McGarry et al., Bioorganic and Medicinal Chemistry, 7, 1131-1139, 1999.
|Michael S. Driver et al., "A Second-Generation Catalyst for the Aryl Halide Amination: Mixed Secondary Amines from Aryl Halides and Primary Amines Catalyzed by (DPPF)PdC1<SUB>2</SUB>, " J. Am. Chem. Soc., 1996, vol. 118, pp. 7217-7218.
|Miles D. Houslay et al., "The Multienzyme PDE4 Cyclic Adenosine Monophosphate-Specific Phosphodiesterase Family: Intracelllular Targeting, Regulation, and Selective Inhibition by Compounds Exerting Anti-inflammatory and Antidepressant Actions," Advances in Pharmacology, vol. 44, pp. 225-342, 1998.
|Peng Wang et al., "Expression, Purification, and Characterization of Human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D,"Biochem. And Biophys. Research Comm., vol. 234, 320-324 (1997).
|Piaz et al., Eur. J. Med. Chem., 35, 463-480, 2000.
|Roger J. Schilling et al., "A High-Throughput Assay For Cyclic Nucleotide Phosphodiesterases," Analytical Biochemistry, 1994, pp. 154-158, vol. 215.
|T.W. Greene et al., Protective Groups in Organic Synthesis, 3<SUP>rd </SUP>Edition, Chapter 3, "Protection for Phenols and Catechols," pp. 246-292, John Wiley & Sons, 1999.
|Takashi Egawa et al., "Rolipram and its Optical Isomers, Phosphodiesterase 4 Inhibitors, Attenuated the Scopolamine-Induced Impairments of Learning and Memory in Rats," J. Pharmacol., vol. 75, 275-281(1997).
|Thomas C. McKenzie et al., "The Gomberg-Bachmann Reaction of Purines", J. Heterocyclic Chem., May-Jun. 1987, pp. 859-861, vol. 24.
|Vasu Nair et al., "Novel, Stable Congeners of Antiretroviral Compound 2', 3'-Dideoxyadenosine," J. Am. Chem. Soc., 1989, pp. 8502-8504, vol. 111.
|Vasu Nair et al., "Synthesis Of Congeners Of Adenosine Resistant To Deamination By Adenosine Deaminase," J. Chem. Soc Comm., 1989, pp. 878-879.
|Watanabe et al, "Structure-Activity Relationship and Rational Design of 3,4-Dephostatin Derivatives as Protein Tyrosine Phosphatase Inhibitors", Pergamon Tetrahedron, 2000, vol. 56, pp. 741-752.
|Citing Patent
|Filing date
|Publication date
|Dec 21, 2006
|Feb 2, 2010
|Memory Pharmaceuticals Corporation
|Phosphodiesterase 4 inhibitors, including aminoindazole and aminobenzofuran analogs
|Jun 27, 2006
|Jul 6, 2010
|Takeda Pharmaceutical Company Limited
|Jun 25, 2004
|Jun 29, 2006
|Fabien Schweighoffer
|Use of pyrazolopyridines for the treatment of cognitive deficits
|Jun 27, 2006
|Oct 26, 2006
|Shigenori Ohkawa
|Dec 21, 2006
|May 31, 2007
|Schumacher Richard A
|Phosphodiesterase 4 inhibitors, including aminoindazole and aminobenzofuran analogs
|Jul 2, 2009
|Feb 4, 2010
|Memory Pharmaceuticals Corporation
|Phosphodiesterase 4 inhibitors
|Dec 17, 2009
|Apr 15, 2010
|Schumacher Richard A
|Phosphodiesterase 4 inhibitors, including aminoindazole and aminobenzofuran analogs
|Dec 1, 2009
|Aug 12, 2010
|Exonhit Therapeutics Sa
|Molecular target of neurotoxicity
|Jan 10, 2013
|Jul 18, 2013
|President And Fellows Of Harvard College
|Beta-cell replication promoting compounds and methods of their use
|U.S. Classification
|514/337, 546/284.1, 546/268.4, 549/467, 514/470
|International Classification
|Cooperative Classification
|European Classification
|Aug 12, 2004
Owner name: MEMORY PHARMACEUTICALS CORPORATION, NEW JERSEY
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SCHUMACHER, RICHARD A.;HOPPER, ALLEN T.;TEHIM, ASHOK;REEL/FRAME:015674/0711;SIGNING DATES FROM 20040113 TO 20040119
|Nov 17, 2009
|Certificate of correction
|Aug 2, 2010
|Maintenance fee reminder mailed
|Dec 26, 2010
|Lapse for failure to pay maintenance fees


text:
June 29th, 2016
Toyota recalling Prius and Lexus models over faulty air bags
Car manufacturer Toyota is recalling more than a million cars, affecting Priuses and Lexus models from 2008-2012 models. Toyota says a small crack in the air bag may cause the bag to fail during an accident. (Run time: 0:23)

subset: commoncrawl


text:
About the Book
The Festival of Sail is a once every three years event featuring a parade of Tall Ships into San Francisco Bay. I took advantage of an opportunity to spend the day onboard the WWII-era Liberty Ship Jeremiah O'Brien while it cruised out the Golden Gate and brought up the rear of the Tall Ships parade.
The result was what photographers call a "target-rich environment".
Features & Details
- Category Travel
Large Square, 12×12 in, 30×30 cm
38 Pages
- Publish Date Jun 12, 2009
- Tags san francisco bay, uscgc eagle, tall ships, sailing
See More
About the Creator
Doc Michaels
San Francisco
Because, it is the older items that interest Doc the most. The cameras themselves are marvels of machined aluminum and sliding rails, with intricate shutter works and wonderful whrrrrllll-click-click noises...and that's part of the Artistic Experience, as well.
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text:
Two years ago Isaac Dunmall made the final of the Stawell Gift and his body let him down. His calves cramped up before the race and he ran a stinker. He thought you get one chance to win the Stawell Gift and his had come and gone in the tweak of a calf.
Last year he did nothing to disabuse himself of that notion when he ran poorly but on Easter Monday this year he came back and claimed the win he thought would always elude him.
"I have never known the meaning of speechless until now, this is unbelievable," Dunmall said. "I didn't know this day would ever come. I really didn't. This is just crazy. I thought I had blown my chance in that race [in 2014]. I thought 'I am gone, there is no way in the world I am going to win a Stawell Gift' but now I have come back and to actually do it, that's insane."
Dunmall won in 12.17 seconds running from 6.75 metres, ahead of Tjimarri Sanderson-Milera in 12.19s, with Tasmanian teenager Jack Hale, the backmarker in the final off 3.25m, third in 12.30s.
Dunmall didn't know if he had held on to win the race as he thew himself through the gates at the line, both he and Sanderson-Milera sprawling to the turf past the barriers.
"I got a good start and kicked on really well. I saw Tjimarri coming towards me in the last 20 and thought just hold on, hold on. But I wasn't sure if I got there because he was getting close. I didn't know what happened. I didn't know when I had it won, that's why I dipped on the line because I wanted it so bad," the 22-year-old said.
One of the first to embrace Dunmall after he crossed the line was Luke Versace, the man who won the Stawell Gift when Dunmall finished a disappointing seventh. On that day Dunmall was one of the first to congratulate him.
"That experience in the final two years ago was invaluable," said Dunmall, who works at a financial planning firm in Brisbane.
He hopes to be able to replicate the efforts of former Gift winners Aaron Stubbs and Mitchell Williams-Swain to translate the Gift win into performances at the national level.
"I have no idea how much more I can do in the sport, but would love to do that," he said, adding that he was now working out whether he could now get starts in Sydney next weekend at the national titles
"What Williams-Swain and Stubbs did it's very promising, I have won here. Maybe I can go on and do something and compete for the country but one step at a time. I will come back after this and see what I can do."


text:
Hey guys!
I got this huge problem and I wondered if anyone felt the same or if you could just help me somehow... I just can't look guys into the eyes. I don't have that problem with every person, just guys I don't know (my family, girl friends and even guys I know for a long time are fine). But as soon as a guy I don't know talks to me, I'm in trouble. I can talk to them just fine, but I can't keep eye contact or (even more difficult to me) touch him lightly on the arm to point something out etc.
Is that social anxiety? Can I do anything against it? I tried to just force me to keep eye contact or touch a guy... but I can't. It's like a primary instinct to look away :-/ I feel like Raj from the Big Bang Theory, HELP!
Most Helpful Guy
You don't have to stare. Eye contact 1/3 of the time when talking and 2/3 when listening is good.00|00|0
Well, maybe I didn't make the issue clear... I'm far from being able to stare at someone (not that I wanted to do that, anyway!). I don't think that I'll look s.o. into the eyes 1/3 of the time. Indeed, as I said above I have problems stretching the eye contact to a cpl. seconds at one time if I don't know the person =/


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Report summaryKarelsky Okatysh is an open pit mine located in the Republic of Karelia, Russia, 30 kilometres east of the border with Finland. It is 100% owned by Severstal who uses more than half of the mine's production in its own steel mills. The mine is Russia's fourth-largest iron ore producer and largest pellets producer with annual pellet production of more than 10 million tonnes. Karelsky Okatysh is a low grade magnetite ore deposit with a raw ore grade of 24.0% Fe. The mine has benefited greatly from the depreciation of the rouble, which has halved its cash costs.
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text:
Children spent the day in the life of a policeman as they flocked to a fun day.
Colindale Police Station held a community awareness day at Barnet Police Station, in High Street, on Saturday.
People took part in a game of giant chess, had their faces painted and took part in a treasure hunt.
The Bull Theatre also held a free music concert throughout the day.
Adults were also given tips on crime prevention and how to stay safe at home.


text:
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Unbelieveable! The only real Magic that is taking place here is just how great these guys are .... Many, many thanks for being there. Best supplier...
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Comes with TireGard, EtchGard, KeyGard, and DingGard with the purchase of any new vehicle at Don Davis Ford Lincoln. This is an $1195 value. A little more information about why to buy from Don Davis Ford Lincoln, Don Davis Ford Lincoln is part of Don Davis Auto Group which is family owned and we have been in business since 1979 proudly serving customer in the DFW Metroplex. We pride ourselves on being easy to do business with, which has resulted in not only Brand Loyal Customers but also Customers Loyal to Don Davis Auto Group. We know our repeat business is what has made us into what we are today. Everywhere you drive in Arlington and the surrounding areas you see the Don Davis Auto Group Badge on the back of vehicles we have sold and we are very proud of that. If you drive one of those vehicles with our Badge on the back we would like to thank you again and if you do not have a Don Davis Auto Group Badge being proudly displayed on the back of your current vehicle, stop by and see what we are all about. You will not be disappointed.
We proudly serve customers from the following cities - and many more:


text:
2017 Honda CR-V 4WD LX
Call For Price
Photo Gallery
Video Gallery
Call 902-453-1940
2657 Robie Street, Halifax, NS B3K 4N9,
Halifax, NS B3K 4N9
Halifax, NS B3K 4N9
Have a question or want more information about this vehicle? Call us now! 902-453-1940
Have a question or want more information about this vehicle? Call us now! 902-453-1940
Vehicle Summary
- Transmission w/Driver Selectable Mode
- Gas-Pressurized Shock Absorbers
- Front And Rear Anti-Roll Bars
- Electric Power-Assist Speed-Sensing Steering
- Quasi-Dual Stainless Steel Exhaust
- Strut Front Suspension w/Coil Springs
- Multi-Link Rear Suspension w/Coil Springs
- 4-Wheel Disc Brakes w/4-Wheel ABS, Front Vented Discs, Brake Assist, Hill Hold Control and Electric Parking Brake
- Automatic Full-Time All-Wheel Drive
- 36-Amp/Hr 410CCA Maintenance-Free Battery
- Permanent Locking Hubs
- 53 L Fuel Tank
- Steel Spare Wheel
- Compact Spare Tire Mounted Inside Under Cargo
- Clearcoat Paint
- Fully Galvanized Steel Panels
- Lip Spoiler
- Chrome Side Windows Trim and Black Front Windshield Trim
- Fixed Rear Window w/Fixed Interval Wiper, Heated Wiper Park and Defroster
- Deep Tinted Glass
- Liftgate Rear Cargo Access
- Tailgate/Rear Door Lock Included w/Power Door Locks
- Chrome Grille
- Front License Plate Bracket
- Body-Coloured Door Handles
- LED Brakelights
- Black Rear Bumper w/Metal-Look Rub Strip/Fascia Accent
- Splash Guards
- Chrome Bodyside Insert, Black Bodyside Cladding and Black Wheel Well Trim
- Body-Coloured Power Heated Side Mirrors w/Convex Spotter and Manual Folding
- Integrated Roof Antenna
- Audio Theft Deterrent
- 2 LCD Monitors In The Front
- Radio w/Seek-Scan, Clock, Steering Wheel Controls and Radio Data System
- Manual Tilt/Telescoping Steering Column
- Front Cupholder
- Rear Cupholder
- Valet Function
- Proximity Key For Doors And Push Button Start
- Remote Keyless Entry w/Integrated Key Transmitter, Illuminated Entry, Illuminated Ignition Switch and Panic Button
- Cruise Control w/Steering Wheel Controls
- Dual Zone Front Automatic Air Conditioning
- Driver Foot Rest
- Full Cloth Headliner
- Day-Night Rearview Mirror
- Front Map Lights
- Fade-To-Off Interior Lighting
- Full Carpet Floor Covering -inc: Carpet Front And Rear Floor Mats
- Cargo Space Lights
- Delayed Accessory Power
- Power Door Locks w/Autolock Feature
- Systems Monitor
- Outside Temp Gauge
- Trip Computer
- Seats w/Cloth Back Material
- Perimeter Alarm
- Engine Immobilizer
- Air Filtration
- Gauges -inc: Speedometer, Odometer, Engine Coolant Temp, Tachometer, Trip Odometer and Trip Computer
- Power Rear Windows and Fixed 3rd Row Windows
- Remote Releases -Inc: Mechanical Fuel
- HVAC -inc: Underseat Ducts and Console Ducts
- Locking Glove Box
- Cloth Door Trim Insert
- Urethane Gear Shift Knob
- Carpet Floor Trim
- Power 1st Row Windows w/Driver 1-Touch Up/Down
- Manual Adjustable Front Head Restraints and Manual Adjustable Rear Head Restraints
- 60-40 Folding Split-Bench Front Facing Fold Forward Seatback Rear Seat
- Driver And Passenger Visor Vanity Mirrors
- 3 12V DC Power Outlets
- Full Floor Console w/Covered Storage, Mini Overhead Console w/Storage, Conversation Mirror and 3 12V DC Power Outlets
- Driver / Passenger And Rear Door Bins
- FOB Controls -inc: Remote Engine Start
- Digital Display
- Distance Pacing w/Traffic Stop-Go
- Sliding Front Centre Armrest and Rear Centre Armrest
- Interior Trim -inc: Metal-Look/Piano Black Instrument Panel Insert, Metal-Look Door Panel Insert, Metal-Look Console Insert and Metal-Look Interior Accents
- Fabric Seating Surfaces
- ABS And Driveline Traction Control
- Side Impact Beams
- Dual Stage Driver And Passenger Seat-Mounted Side Airbags
- Low Tire Pressure Warning
- Dual Stage Driver And Passenger Front Airbags
- Curtain 1st And 2nd Row Airbags
- Airbag Occupancy Sensor
- Rear Child Safety Locks
- Back-Up Camera
- Electronic Stability Control (ESC)
- Outboard Front Lap And Shoulder Safety Belts -inc: Rear Centre 3 Point, Height Adjusters and Pretensioners
- Collision Mitigation Braking System Forward Collision
- HondaLink Emergency S.O.S
- Wheels: 17" Aluminum-Alloy
- Fixed Interval Wipers w/Heated Wiper Park
- Tires: P235/65R17 104H All-Season
- 5.64 Axle Ratio
- Road Departure Mitigation Lane Keeping Assist
- Road Departure Mitigation Lane Departure Warning
- Engine: 1.5L 16-Valve DOHC Turbocharged 4-Cylinder -inc: direct injection
- Transmission: Continuously Variable (CVT) -inc: grade logic control
- GVWR: 2,130 kgs (4,696 lbs)
- Body-Coloured Front Bumper w/Black Rub Strip/Fascia Accent and Metal-Look Bumper Insert
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text:
Study of Stereotactic Body Radiation Therapy Using Tomotherapy for Metastatic Tumors to the Liver
This study has been terminated.
(Low accrual rate)
New Mexico Cancer Care Alliance
Information provided by (Responsible Party):
New Mexico Cancer Care Alliance
ClinicalTrials.gov Identifier:
First received: December 9, 2009
Last updated: June 13, 2015
Last verified: June 2015
- Full Text View
- Tabular View
- Study Results
- Disclaimer
- How to Read a Study Record
Detailed Description:
The purpose of this study is to determine the response of liver tumors to radiation therapy using Tomotherapy.
|Liver Cancer
|Radiation: Tomotherapy treatment
|Phase 2
|Study Type:
|Study Design:
|Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:
|Phase II Study of Stereotactic Body Radiation Therapy Using Tomotherapy for Metastatic Tumors to the Liver
Resource links provided by NLM:
MedlinePlus related topics: Liver CancerU.S. FDA Resources
Further study details as provided by New Mexico Cancer Care Alliance:
Primary Outcome Measures:
- Tumor Response Rate (Complete Response + Partial Response). [ Time Frame: 1 year ]
Secondary Outcome Measures:
- Toxicity, Progression Free Survival, Clinical Benefit Rate (Complete Response + Partial Response + Stable Disease), Median Duration of Clinical Benefit, and Median Overall Survival of Subjects. [ Time Frame: 1 year ]
|Study Start Date:
|June 2009
|Study Completion Date:
|May 2013
|Primary Completion Date:
|May 2013 (Final data collection date for primary outcome measure)
|Assigned Interventions
Experimental: Tomotherapy
Intervention: Stereotactic Body Radiation Therapy using Tomotherapy. Tomotherapy treatment: A total of 60 Gy using 12 Gy per fraction over 5 fractions to be given within 10 calendar days. Each fraction of 12 Gy will be divided into 2 fractions of 6 Gy given in one day within 6 hours. Dose will be prescribed to the isodose line which covers at least 90% of the PTV.
Radiation: Tomotherapy treatment
Detailed Description:
The purpose of this study is to determine the response of liver tumors to radiation therapy. This study will be using a type of radiation therapy called tomotherapy. Tomotherapy is a relatively new kind of therapy which is able to focus a large amount of radiation to a small area with relatively less radiation to the surrounding non-cancerous part of the organ. This study is being done to find out if this technique is able to control the cancer better or not than the standard radiation and also to study its safety. The usual treatment for this type of disease for patients who are eligible is surgery to remove the tumors. For patients who aren't eligible for surgery or who chose not to have surgery, they are treated with low daily doses of radiation given over many weeks; however this type of treatment has not been very effective.
|Ages Eligible for Study:
|18 Years and older (Adult, Senior)
|Sexes Eligible for Study:
|Accepts Healthy Volunteers:
Inclusion Criteria:
- Histologic confirmation of solid primary tumor metastatic to liver
- Age greater than or equal to 18 years old
- Zubrod performance status less than or equal to 1
- Negative pregnancy test for women of child bearing potential
- Informed consent
- Less than or equal to 3 liver metastases
- Each lesion must be less than or equal to 6 cm in maximal diameter
- No prior radiation to lesions being treated
- Patient is not a surgical candidate or refuses surgery
- Absolute neutrophil count ≥ 1800
- Platelets ≥ 100000
- Hemoglobin ≥8.0
- Systemic therapy (chemotherapy) completed at least 2 weeks prior to SBRT
- At time of radiation treatment planning, at least 700 cc of normal liver must receive less than 15 Gy
Exclusion Criteria:
- Contraindications to radiation
- Pregnant or lactating females who chose to breast feed
- Patients must have recovered from toxicity of prior therapy
- Any co morbid condition that' in the view of the attending physician' renders the patient at high risk from treatment complications
- Patients currently receiving anticoagulation with coumadin or IV heparin
- Liver cirrhosis
- Clinical ascites
- Bilirubin > 3, Albumin < 2.5, liver enzymes 3 times above normal, Creatinine > 1.8
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01030757
Please refer to this study by its ClinicalTrials.gov identifier: NCT01030757
|United States, New Mexico
|University of New Mexico Cancer Center
|Albuquerque, New Mexico, United States, 87106
Sponsors and Collaborators
New Mexico Cancer Care Alliance
|Principal Investigator:
|Ben Liem, MD
|University of New Mexico Cancer Center
More Information
Additional Information:
Keywords provided by New Mexico Cancer Care Alliance:
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on August 21, 2017
Additional Information:
|Responsible Party:
|New Mexico Cancer Care Alliance
|ClinicalTrials.gov Identifier:
|NCT01030757 History of Changes
|Other Study ID Numbers:
NCI-2011-02945 ( Registry Identifier: NCI CTRP )
|Study First Received:
|December 9, 2009
|Results First Received:
|June 13, 2015
|Last Updated:
|June 13, 2015
Keywords provided by New Mexico Cancer Care Alliance:
Liver Cancer
Metastatic Liver Cancer
Stereotactic Body Radiation Therapy
Additional relevant MeSH terms:
Liver Neoplasms
Neoplasm Metastasis
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Neoplastic Processes
Pathologic Processes
ClinicalTrials.gov processed this record on August 21, 2017


text:
RALEIGH, N.C. — A significant percentage of people older than 50 are binge drinking, and experts fear the trend could cause severe health problems in the near future for baby boomers who continue their heavy drinking habits, according to a new study by Duke University Medical Center researchers.
5 drinks or more
Twenty-two percent of men and 9 percent of women 50 to 64 reported drinking five or more drinks at one time during the last month, according to the survey, which will be published in the online edition of the American Journal of Psychiatry this week. The study showed 19 percent of men and 13 percent of women in the same age group engaged in heavy or at-risk drinking -- two or more drinks per day.


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Service Related Conditions
The Veterans Health Administration offers a variety of web resources about service related conditions. The VHA Office of Public Health provides the most up-to-date information regarding Agent Orange, Military Exposures, Gulf War Veterans' Illnesses, HIV/AIDS and Tobacco Cessation, among many others.
Related Links
TriCare Online
Do you use TriCare Online? You can go directly to the TriCare Online site from My HealtheVet.


text:
I have a small network that has a domain controller (Active Directory) and clients inside the firewall and a couple web servers in the DMZ. We have static IP addresses pointed to the web servers in the DMZ. I can hit the web servers just fine from outside the network, but the PCs inside the network and inside the DMZ cannot bring up the web pages using the external IP address (or hostname).
I have no idea where to begin with this, so any direction would be greatly appreciated.
May 10, 2011 at 10:21 UTC
What do you have for DNS records for those DMZ hosts?
You need something like CNAME www --> x.x.x.x
5 Replies
May 10, 2011 at 10:21 UTC
What do you have for DNS records for those DMZ hosts?
You need something like CNAME www --> x.x.x.x
May 10, 2011 at 10:22 UTC
Firewalls? Got to start somewhere.
May 10, 2011 at 10:31 UTC
Looks like I need to set up split DNS on my DC.
I only have internal name resolution set up on my DC at the moment. If I understand correctly, I'll have to set up a new forward lookup zone to point those hostnames to their internal IP addresses.
Current lookup zone:
webserver.domain.local 192.168.1.xxx
New lookup zone:
www.whatever.com 170.xxx.xxx.xxx
Am I thinking that through correctly?
May 10, 2011 at 10:39 UTC
If you're using domain.local for internal and domain.com for external - then you're on the right path.
May 10, 2011 at 10:43 UTC
Thanks a bunch! It's working as intended now.
This discussion has been inactive for over a year.
You may get a better answer to your question by starting a new discussion.


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Watch "Why Our Work Matters"
Oregon ON members serve communities from Gold Beach to La Grande, Medford to St. Helens.
Learn more about us and our impact:
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Oregon ON 2013-14 Annual Report.pdf
It takes a Network.
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To be healthy and safe, you need a place to call home.


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Mental Health
Have Mental Health Questions? Ask a Psychiatrist Online
Hi, basically all you can do is what you are doing, listening and validating her concerns. You were smart to suggest she speak to a professional too. You are a good friend and that's what good friends do, listen. No apology necessary. Thanks for the information on programs, nice to know there will be more.