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|Publication number||US4863931 A|
|Application number||US 07/244,768|
|Publication date||Sep 5, 1989|
|Filing date||Sep 15, 1988|
|Priority date||Sep 15, 1988|
|Also published as||DE68927697D1, DE68927697T2, EP0359499A2, EP0359499A3, EP0359499B1, EP0434759A1, WO1990003375A2, WO1990003375A3|
|Publication number||07244768, 244768, US 4863931 A, US 4863931A, US-A-4863931, US4863931 A, US4863931A|
|Inventors||Doris P. Schumacher, Bruce L. Murphy, Jon E. Clark|
|Original Assignee||Schering Corporation|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (5), Non-Patent Citations (4), Referenced by (52), Classifications (10), Legal Events (4)|
|External Links: USPTO, USPTO Assignment, Espacenet|
The present invention relates to certain benzocycloheptapyridines having fluoro substitution across an exocyclic double bond.
Numerous benzocycloheptapyridine compounds having substitution on the tricyclic ring system and having hydrogenated exocyclic double bonds have been disclosed. See, for example, U.S. Pat. Nos. 3,326,924, 3,717,647 and 4,282,233, European published Application No. 0042544, Villani et al., Journal of Medicinal Chemistry, Vol. 15, No. 7, pp 750-754 (1972) and Arzneim. Forsch., 36, pp 1311-1314 (1986). However, fluoro-substitution across the exocyclic double bond has not previously been disclosed or suggested.
U.S. Pat. No. 4,731,447 in column 8, lines 31-35 discloses that in the preparation of certain benzocycloheptapyridine compounds using HF/BF3 the temperature may be controlled so as to minimize side reactions, such as HF addition to the double bond of the rings.
It has now surprisingly been found that antihistamine activity is possessed by compounds represented by structural formula I ##STR1## or a pharmacuetically acceptable salt thereof, wherein:
A, B, X and Y may be the same or different, and each independently represents H, halo, --CF3, --C(O)R10, --SR10, --N(R10)2, --NO2, --OC(O)R10, --CO2 R10, --OCO2 R11, alkyl, alkenyl or alkynyl, which alkyl or alkenyl groups may be substituted with halo, --OR10, or --CO2 R10 ;
each R10 independently represents H, alkyl or aryl;
R11 represents alkyl or aryl;
R1 and R2 represent H and F respectively or F and H respectively; and
R represents H, alkyl or --C2 R10 wherein R10 is as previously defined.
The invention also relates to a pharmaceutical composition comprising a compound of formula I in combination with a pharmaceutically acceptable carrier and to a method of treating allergic reactions by administering to a mammal in need of such treatment an antihistaminic effective amount of a compound of formula I.
In a preferred embodiment of the invention, one of A, B, X and Y is halo, e.g., chloro or fluoro, and the other groups are H.
In another preferred embodiment of the invention, R is --CO2 R10, where R10 is H or alkyl, and most preferably alkyl, e.g., ethyl. In yet another preferred embodiment of the invention, R1 is fluoro, and R2 is H.
Preferred species falling within the scope of formula I include: ethyl 4-[8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-4-fluoro-1-piperidinecarboxylate; and
Certain compounds of formula I may exist in different isomeric as well as conformational forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures.
The compounds of formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemihydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of the invention.
Certain compounds of formula I will be acidic in nature, e.g. those compounds which possess a carboxylic or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic compounds of formula II also form pharmaceutically acceptable salts, e.g., acid addition salts and quaternary ammonium salts. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to product a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate The quaternary ammonium salts are prepared by conventional methods, e.g., by reaction of a tertiary amino group in a compound of formula II with a quaternizing compound such as an alkyl iodide, etc. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid, base and quaternary salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
When utilized herein, the terms below, unless otherwise indicated, have the following scope:
halo--represents fluoro, chloro, bromo and iodo;
alkyl (including the alkyl portions of alkoxy, alkylamino and dialkylamino)--represents straight or branched carbon chains, which contain from 1 to 6 carbon atoms;
alkenyl--represents straight or branched carbon chains having at least one carbon to carbon double bond and preferably having from 2 to 6 carbon atoms;
alkynyl--represents straight or branched carbon chains having at least one carbon to carbon triple bond and preferably having from 2 to 6 carbon atoms;
aryl--represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., a phenyl or fused benzene ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted with 1 to 3 groups, each independently selected from halo, alkyl, hydroxy, alkoxy, phenoxy, amino, alkylamino, dialkylamino. Preferred aryl groups include phenyl and 4-chlorophenyl.
The lines drawn from the groups A, B, X and Y into the pyridine and benzene rings of formula I are intended to indicate that such groups may be substituted on any carbon of such rings.
Compounds A and B above were prepared as side-products of the reactions described in U.S. Pat. No. 4,731,447. The methods described in that patent may be employed to prepare the compounds of the invention as described further below.
Compounds of general formula I may be prepared as shown in Scheme 1 below wherein A, B, X, Y, R1, R2, R10 and R11 are as defined above and R6 and Ra are as defined below. The general method for producing compounds of general formula I from compounds of general formula 3 is outlined by reactions (a) through (g) in Scheme 1. Compounds of general formula 3 may be readily prepared as described in March, J. Advanced Organic Chemistry, 3rd Edition, John Wiley & Sons (1985), pp. 496-97; Villani et al, J. Heterocyclic Chem., 8, 73 (1971) or may be obtained from commercial sources, e.g. Reilly Tar and Chemical. ##STR2##
Reaction (a): A compound of formula 3, e.g., an unsubstituted or substituted 2-cyano-3-methyl-pyridine, can be converted into the corresponding carboxylic acid, e.g., an appropriate 3-methyl-2-pyridine carboxylic acid or activated ester thereof, e.g., a succinimide or hydroxysuccinimide ester, by reactions conventional in the art e.g., hydrolysis or esterification. The carboxylic acid or activated ester thereof can then be reacted with the appropriate amino compound of formula NH2 R6 to form a compound of formula 4 ##STR3## wherein R6 is a protecting group that will protect the N of the group CONHR6 in formula 4 from reaction with an alkylating agent. Preferably the protecting group is a tertiary butyl group.
A compound having such an R6 tertiary butyl group can also be obtained directly from a compound of formula 3, for example, by a Ritter reaction in which a tertiary butyl compound is reacted with a 2-cyano-3-methyl-pyridine compound to produce a compound of formula 4a. ##STR4## This reaction is generally performed in an acid such as concentrated sulfuric acid or concentrated sulfuric acid in glacial acetic acid. Suitable tertiary butyl compounds include, but are not limited to, t-butyl iodide, t-butyl chloride, t-butyl bromide, t-butyl iodide, isobutylene or any other compound which under hydrolytic conditions forms t-butyl carboxamides with cyano compounds. The temperature of the reaction will vary depending on the reactants, but generally is conducted in the range of from about 50° to about 100° C. with t-butyl alcohol. The reaction may be performed with inert solvents but is usually run neat.
Reaction (b): The compound of formula 4 may be reacted with an appropriate benzyl halide of the formula ##STR5## in the presence of a base to form the compound of formula 5 above. The halide is preferably Cl, Br or I, more preferably Cl. Examples of appropriate benzyl halides include, but are not limited to, benzyl chloride, 3-chlorobenzyl chloride, 3-fluorobenzyl chloride, 3,4-dichlorobenzylchloride, 4-fluorobenzyl chloride, 3-nitrobenzyl chloride, 3-methylbenzyl chloride, etc. Any suitable base can be employed, e.g., an alkyl lithium compound such as n-butyl lithium in tetrahydrofuran (THF). Preferably the base has a pKa of greater than 20 and more preferably greater than 30. This reaction can be conducted at any suitable temperature, e.g., temperatures of from about -78° C. to about 30° C., preferably from about -40° C. to about -30° C. The reaction can be performed in any suitable inert solvent such as THF, diethyl ether, etc.
Reaction (c): The amide of formula 5 may be converted to the cyano compound of formula 6 by the use of a suitable dehydrating agent such as POCl3, SOCl2, P2 O5, toluene sulfonyl chloride in pyridine, oxalyl chloride in pyridine, etc. This reaction can be performed in the absence of or with an inert co-solvent such as xylene. The dehydrating agent such as POCl3 is employed in equivalent amounts or greater and preferably in amounts of from about 2 to about 15 equivalents. Any suitable temperature and time can be employed for performing the reaction, but generally heat is added to speed up the reaction. Preferably, the reaction is performed at or near reflux.
Reaction (d): The cyano compound of formula 6 may be reacted with a Grignard reagent prepared from the appropriate 1-(N-protected)-4-halopiperidine. Any suitable N-protecting group known in the art to protect the piperidinyl nitrogen atom from reaction during formation of the Grignard reagent can be employed. Suitable N-protecting groups include alkyl (e.g. methyl), aryl (e.g. phenyl or substituted phenyl), alkyloxyalkyl (e.g. methoxymethyl), benzyloxyalkyl (e.g. benzyloxymethyl), substituted benzyloxyalkyl (e.g. (di-p-methoxyphenyl) methyl), triphenylmethyl, tetrahydropyranyl, diphenyl phosphinyl, benzene sulfenyl, etc. The N-protecting group can be later removed by conventional means once the Grignard reagent has been reacted with the compound of formula 6.
The reaction between compounds of formula 6 and the Grignard reagent are generally performed in an inert solvent such as an ether, toluene or tetrahydrofuran. This reaction is performed under the general conditions for a Grignard reactions, e.g., at temperatures of from about 0° C. to about 75° C.
Reaction (e): The resulting intermediate of formula 8, wherein Ra is an alkyl group, may be hydrolyzed, e.g., with aqueous acid such as aqueous HCl, to prepare the corresponding ketone of formula 9.
Reaction (f): The compound of formula 9 can be ring-closed to form the desired cycloheptene ring system (formula 10) by treating the compound 9 with a super acid having a Hammett acidity function of less than about minus 12, e.g., minus 13, minus 14, etc. This measure of acidity is defined in Hammett, Louis P., and Deyrup, Alden J., "Journal of the American Chemical Society", Vol. 54, 1932, p. 2721. Suitable super acids for this purpose include, for example, HF/BF3. The reaction can be performed in the absence of or with a suitable inert co-solvent such as CH2 Cl2. The temperature and time of the reaction vary with the acid employed.
The temperature may be controlled so as to maximize the side reaction of HF addition to the exocyclic double bond. Consequently, the temperature is generally in the range of from about +5° to -50° C., preferably from about 0° to +5° C.
Generally, the super acid is employed in excess, preferably in amount of from about 1.5 to about 30 equivalents. For example, with HF/BF3 as the super acid system the volume/weight ratio of HF to the compound of formula IX in the reaction mixture is preferably from about 30 to about 1.5, more preferably 2.5 to 1.5. In such system, the weight/weight ratio of BF3 to the compound of formula 9 in the reaction mixture is preferably from about 15 to about 0.75, more preferably from about 1 to about 0.75.
Reaction (g): The alkyl group (Ra) on the piperidyl ring (when it is methyl) may be converted to the alkyl esters of the formula Ia by reacting a compound of general formula 10 with an alkyl chloroformate, preferably ethyl chloroformate as described in Villani et al., Arzneim.--Forsch/Drug Research 1986, 36, 1311-1314 and in U.S. Pat. No. 4,731,447.
In the above processes a-g, it is sometimes desirable and/or necessary to protect certain A, B, X, Y, etc., groups during the reactions. Conventional protecting groups are operable. For example, the groups listed in column 1 of the following table may be protected as indicated in column 2 of the table:
______________________________________1. Group to be protected 2. Protected Group______________________________________COOH COOalkyl, COObenzyl, COOphenyl ##STR6## ##STR7## ##STR8## ##STR9## ##STR10##OH ##STR11##NH.sub.2 ##STR12##______________________________________
Of course, other protecting groups well known in the art may be used. After the reaction or reactions, the protecting groups may be removed by standard procedures.
Conversion of compounds of formula Ia to compounds of formula I wherein R is H can be accomplished by hydrolysis the --CO2 R10 group. Hydrolysis may occur in an organic or inorganic polar solvent by refluxing in the presence of a base or acid. A typical hydrolyzing reaction utilizes 30% HCl solution in ethanol.
The compounds of the present invention can be used as antihistamines. One method of measuring the antihistamine activity of the compounds of the present invention in vitro utilizes isolated preparation of guinea pig ileum as described below and in Tozzi et al., Agents and Actions, 4(4):264 (1974).
Antagonists were evaluated for their ability to inhibit the spasmogenic doses of histamine dihydrochloride (1.8×106 M) and acetylcholine chloride (1.3×10-7 M) on separate i1ea1 segments of guinea-pig intestine according to the classical isotonic technique described in Magnus, Pflugers Arch. Ges. Physiol., 102:123 (1904). Freshly cut 2 cm segments of ileum were removed from male albino guinea-pigs (300-500 g) and suspended in 10 ml perfusion baths containing Tyrode solution warmed to 32° C. and constantly aerated with 95% O2 and 5% CO2. Tissues were adjusted to 0.5-1 g tension and allowed to equilibrate for a period of 30 minutes. All responses were recorded by means of a Harvard smooth muscle transducer connected to a Harvard electronic recorder. Utilizing 3-4 logarithmically-spaced doses of the antagonist, a graded inhibition of the smooth muscle response to histamine or acetylcholine was obtained by alternating the dose of agonist with increasing doses of antagonist. The agonists, in volumes of 0.1 ml, were added to the bath and kept in contact with the tissues for 45 seconds before they were removed by washing. In general, 3 control contractions of approximately equal height were obtained prior to studying the antagonist. The antagonist, in volumes between 0.1 and 0.3 ml, was added to the bath and allowed to remain for 3 minutes before the agonist was added. Then both were removed by washing and the next log increment of the antagonist was used.
At least 5 separate dose-response patterns were attained in each drug assay utilizing 2-5 segments. The average percent inhibition of agonist in all trials was then calculated. The results for the compound 8-chloro-6,11-dihydro-11-fluoro-11-(1-methyl-4-piperidinyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine are shown in Table 1.
TABLE 1______________________________________ % of Maximum % of Maximum ResponseMolar Conc. of Response for Histamine in theHistamine for Histamine Presence of Test Compound______________________________________10.sup.-8 11 ± 3 2 ± 0.93 × 10.sup.-8 17 ± 4 5 ± 110.sup.-7 35 ± 7 8 ± 13 × 10.sup.-7 56 ± 4 18 ± 410.sup.-6 81 ± 7 32 ± 33 × 10.sup.-6 96 ± 3 42 ± 3______________________________________
The following test procedure may be used to demonstrate antihistaminic activity of compounds of formula I. Protection against histamine lethality in the following assay is indicative of strong antihistaminic properties.
Compounds may be evaluated for antihistamine activity by their ability to protect female albino guinea pigs (250-350 g) against death induced by the intravenous injection of histamine dihydrochloride at 1.1 mg/kg, which is approximately twice the LD99. Doses of the antagonists were administered orally to separate groups of fasted animals 1 hour prior to the challenge with histamine and protection from death recorded for 30 minutes after histamine.
At a dose of 1 mg/kg p.o. of ethyl 4-[8-chloro-11-fluoro-6,11-dihydro-5H-benzo[5,6]cyclohepta [1,2-b]pyridin-11-yl]-1-piperidinecarboxylate, 4 of 5 animals survived the dose of histamine dihydrochloride.
The compounds of formula I can be administered in any number of conventional dosage forms. Solid dosage forms include capsules, tablets, pills, powders, suspensions, solutions, cachets or suppositories. Parenteral preparations include sterile solutions or suspensions. Inhalation administration can be in the form of a nasal or oral spray, or by insufflation. Topical dosage forms can be creams, ointments, lotions, transdermal devices (e.g., of the conventional patch or matrix type) and the like.
The formulations and pharmaceutical compositions contemplated by the above dosage forms can be prepared with conventional pharmaceutically acceptable excipients and additives, using conventional techniques. Such pharmaceutically acceptable excipients and additives are intended to include carriers, binders, flavorings, buffers, thickeners, color agents, stabilizing agents, emulsifying agents, dispersing agents, suspending agents, perfumes, preservatives, lubricants, etc.
When used orally or parenterally as antihistamines, the compounds of the invention can be administered in an amount ranging from about 0.1 mg/kg to about 100 mg/kg, preferably from 0.01 mg/kg to about 25 mg/kg per day. Determination of the proper dosage of a compound of the invention for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The amount and frequency of administration of the compounds of formula I and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the disease being treated.
The following examples illustrate specific embodiments of the present invention including preparation of compounds, intermediates and starting materials.
A suspension of 2-cyano-3-methyl pyridine (400 g; 3.4 mol) in 800 mL of t-butanol was heated at 70° C. Concentrated sulfuric acid (400 mL) was added over 45 min. The reaction was complete after a further 30 min. at 75° C. The reaction mixture was diluted with water (400 mL) and toluene (600 mL) and brought to pH 10 with concentrated aqueous ammonia. The temperature was kept at 50°-55° C. during work-up. The toluene phase was separated, the aqueous layer extracted again with toluene and the combined toluene phases were washed with water. Removal of the toluene yielded 633 g (97%) of crystalline N-(1,1-dimethylethyl)-3-methyl-2-pyridinecarboxamide: m.p. 56°-58° C.; NMR 9200 MHz, CDCl3)δ1.52 (s,9H); 2.75 (s,3H); 7.25 (dd,1H, J=7.5, 5 Hz); 7.58 (dd,1H, J=7.5, 1.2 Hz); 8.08 (br s, 1H); 8.40 (dd,1H, J=5), 1.2 Hz); mass spectrum, m/e (rel intensity) 192M+ (12), 177 (49). Anal. Calcd for C11 H16 N2 O: C,68.68; H, 8.13; N,14.40. Found: C,68.71; H,8.39; N,14.57.
To a cold (-40° C.) solution of N-(1,1-dimethylethyl)-3-methyl-2-pyridinecarboxamide (31.5 g; 0.16 mol) in 600 mL of dry tetrahydrofuran was added n-butyllithium in hexanes (2.5 mol; 131 mL) while the temperature was maintained at -40° C. The solution turned deep red after one equivalent was added. Sodium bromide (1.6 g) was added and the mixture was stirred for 10 min. A solution of m-chlorobenzyl-chloride (26.5 g; 0.174 mol) in 125 mL of dry tetrahydrofuran (THF) was added while the temperature was again maintained at -40° C. The reaction mixture was stirred for a further 30 min. after which water was carefully added until the color dissipated. The product was isolated by extraction into ethyl acetate which was washed with water, dried (MgSO4) and concentrated to give 53.6 g (HPLC purity 89%; yield 92%) of 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide as an oil. This oil may be used directly in the next step or crystallized from hexanes to give 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide as a white solid: m.p. 45°-46° C.; NMR (200 MHz,CDCl3)δ1.50 (s,9H), 2.96 (t,2H,J=8 Hz); 3.40 (t,2H,J=8 Hz); 7.0-7.3 (m,5H); 7.39 (dd,1H,J=8, 2 Hz); 7.98 (br s, 1H); 8.30 (dd,1H, J=4, 1 Hz); mass spectrum, m/e (rel intensity) 316M+ (19). Anal. Calcd for C18 H21 N2 OCl: C,68.22; H,6.68; N,8.88; Cl,11.19. Found: C,68.25; H,6.59; N,8.78; Cl,11.10.
A solution of 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide (175 g; 0.55 mol) in 525 mL (5.6 mol) of phosphorous oxychloride was heated at reflux for 3 h. Excess phosphorus oxychloride (-300 mL) was removed by distillation and the remaining solution was carefully poured into ice-water. The pH of the solution was adjusted to 8 with 50% aqueous sodium hydroxide while the temperature was maintained at 25°-30° C. The mixture was stirred for 2h during which time the pH was maintained at 8. The product was collected by filtration, washed with water and dried in a vacuum oven at 50° C. to give 127 g (95%) of crystalline 3-[2-(3chlorophenyl)ethyl]-2-pyridinecarbonitrile: m.p. 72°-73° C.; NMR (200 MHz, CDCl3)δ2.9-3.1 (m,2H), 3.1-3.2 (m,2H), 7.0-7.1 (m,1H), 7.1- 7.3 (m,3H), 7.42 (dd,1H,J=7.3, 5 Hz); 7.56 (dd,1H,J=7.3, 1.2 Hz), 8.48 (dd,J=5, 1.2 Hz); mass spectrum, m/e (rel intensity) 242 M+ (18). Anal. Calcd for C14 H11 N2 Cl: C,69.28; H,4.59; N,11.54; Cl 14.61. Found: C,69.37; H,4.48; N,ll.39; Cl,14.48.
To a solution of compound 3-[2-(3-chlorophenyl) ethyl]-2-pyridinecarbonitrile (118 g; 0.49 mol) in 1.2 L of dry THF was added 395 mL (2.48 N; 0.59 mol) of N-methyl-piperidyl magnesium chloride over 0.5 h while the temperature was maintained at 40°-50° C. by cooling with water as necessary. The reaction mixture was maintained at 40°-50° C. for an additional 0.5 h. The reaction was quenched to below pH 2 by the addition of 2N hydrochloric acid and the resulting solution was stirred at 25°-30° C. for 1 h. The bulk of the THF was removed by distillation and the pH of the solution adjusted to 3.5 by the addition of aqueous sodium hydroxide. The mixture was cooled to 5° C. and the product was collected by filtration, washed with cold water and dried under vacuum at 60° C. to give 168 g (91%) of [3-[2-(3-chlorophenyl) ethyl]-2-pyridinyl]-1-methyl-4-piperidinyl methanone hydrochloride as a crystalline solid: mp 183°-185° C.; NMR (200 MHz, DMSO)δ2.72 (s,3H), 2.8-2.9 (m,2H) 3.0-3.2 (m,4H), 3.3-3.5 (m,3H), 3.9-4.1 (m, 1H), 7.2-7.3 (m,1H), 7.3-7.4 (m,3H), 7.57 (dd,1H,J=6, 4Hz), 7.84 (dd,1H, J=6, 1.2 Hz), 8.59 (dd,1H,J=4, 1.2 Hz), 10.95 (br s, 1H); mass spectrum m/e (rel intensity) 345M+2 (32), 343M+ (100). Anal. Calcd for C20 H24 N2 OCl2 : C,63.32; H,6.38; N,7.39; Cl,18.69. Found: C,63.45; H,6.47; N,7.40; Cl, 18.49.
To a solution of [3-[2-(3-chlorophenyl)ethyl]-2-pyridinyl]-1-methyl-4-piperidinyl methanone hydrochloride (59.0 g; 0.15 mol) in 120 mL (120 g; 6.0 mol) of hydrofluoric acid at -35° C. was added boron trifluoride (44.3 g; 0.66 mol) over 1 h. The reaction was quenched using ice water and potassium hydroxide to a final pH of 10. The product was extracted into toluene which was washed with water and brine. The toluene solution was concentrated to a residue which was triturated with hot hexanes. Insoluble salts were removed by filtration and the filtrate was concentrated to give as a main product 45.7 g (HPLC purity 96%, yield 91%) of 8-chloro-6,11-dihydro- 11-(1-methyl-4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine as an off-white solid: mp 116°-119° C.; NMR (200 MHz, CDCl3)δ2.0-2.2 (m,2H), 2.27 (s,3H), 2.3-2.6 (m,4H), 2.6-3.0 (m,4H), 3.3-3.6 (m,2H), 7.0-7.2 (m,4H), 7.44 (dd,1H,J=8, 2 Hz), 8.42 (dd,1H,J=3, 2 Hz); mass spectrum, m/e (rel intensity) 327M+3 (28), 325M+1 (100) Anal. Calcd. for C20 H21 N2 Cl: C,73.94; H,6.52; N,8.63; Cl,10.92. Found: C,73.88; H,6.48; N,8.69; Cl10.80. This material was found to include the two corresponding fluoro-substituted compound of the invention as discussed further below.
Ethyl chloroformate (40.4 mL; 45.9 g; 0.423 mol) was added slowly to a hot (-80° C) toluene solution (320 mL) of the 8-chloro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (45.7 g; 0.141 mol) from Example 1E containing the two corresponding fluoro-substituted compounds of the invention. Following complete addition, the temperature was maintained at 80° C. for 1 h. The reaction mixture was cooled to ambient temperature and the toluene solution washed with water which was adjusted to pH 10 with aqueous sodium hydroxide. The organic layer was concentrated to a residue which was dissolved in hot acetonitrile and decolorized with charcoal. The solution was concentrated to a crystalline slurry which was cooled (5° C). 8-chloro-6,11-dihydro-11-(1-ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta [1,2-b]pyridine containing the two corresponding fluoro-substituted compounds of the invention as discussed in Examples 1G below was isolated by filtration yielding 42.4 g: m.p. 134.5°-136° C.; NMR (400 MHz, CDCl3)δ1.25 (t,3H,J=8 Hz), 2.3-2.4 (m,3H), 2.4-2.5 (m,1H), 2.7-2.9 (m,2H), 3.1-3.2 (m,2H), 3.3-3.4 (m,2H), 3.81 (br s, 2H), 4.13 (q,2H,J=8 Hz), 7.1-7.3 (m,4H), 7.43 (dd,1H,J=9,2 Hz), 8.40 (d,1H,J=5 Hz); mass spectrum, m/e (relative intensity) 385M+3 (35), 383 M+1 (100). Anal. Calcd. for C22 H23 N2 ClO2 : C,69.00; H,6.05; N,7.32; Cl9.26. Found: C,69.37; H,6.09; N,7.35; Cl 9.37.
The mother liquor from Example 1F (9.8 g) was dissolved in methanol and chromatographed on 2 C-18 cartridges on a Waters Prep 500 eluted with 3:7 (pH 7.8 phosphate buffer:MeOH). Appropriate fractions were combined and concentrated to an aqueous solution. The products were extracted into methylene chloride which was dried (MgSO4) and concentrated to a residue. This resulted in 1.0 g of ethyl 4-[8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-4-fluoro-1-piperidenecarboxylate (Compound A) and 2.5 of ethyl 4-[8-chloro-11-fluoro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinecarboxylate (Compound B). These compounds had the characteristics as described in Example 2 and 3.
m.p. 149°-153° C.; NMR (200 MHz, CDCl3)δ1.24 (t,3H,J=6 Hz); 1.6-1.9 (m,4H); 2.7-3.2 (m,4H); 3.4-4.1 (m,4H); 4.14 (q,2H,J=6 Hz); 4.35 (d,1H,J=32 Hz); 7.0-7.2 (m,4H); 7.48 (dd,1H,J=8,1 Hz); 8.34 (dd,1H,J=4, 1Hz); mass spectrum, m/e (rel intensity) 403M+1 (34) Anal. Calcd. for C22 H24 N2 O2 ClF: C,65.91; H,5.90; N,6.70; Cl8.94. Found: C,66.00; H,5.91; N,6.78; Cl 8.94.
m.p. 62-73° C.; NMR (400 MHz, CDCl3)δ1.22 (t,3H,J=7 Hz); 1.2-1.3 (m,1H); 1.4-1.5 (m,1H); 1.5-1.7 (m,1H); 1.68 (s,2H); 2.5-2.7 (br s, 2H); 2.8-3.1 (m,2H); 3.3-3.5 (m,2H); 4.08 (q,3H,J=7 Hz); 4.1-4.2 (m,1H); 7.1-7.2 (m,2H); 7.25 (s,1H); 7.45 (d,1H,J=6 Hz); 7.63 (d,1H,J=6 Hz); 8.55 (s,1H). Mass spectrum, m/e (rel intensity) 403M+1 (72) Anal. Calcd for fC22 H24 N2 O2 ClF: C,65.91; H,5.90; N,6.70; Cl8.94. Found: C,65.58; H,6.00; N,6.95; Cl8.80.
The following examples illustrate the preparation of tablets and capsules using as the active compound any of the compounds of formula I, e.g., Compound A or B above.
______________________________________No. Ingredient mg/tablet mg/tablet______________________________________1. Active Compound 100 5002. Lactose USP 122 1333. Corn Starch, Food Grade, 30 40 as a 10% paste in Purified Water4. Corn Starch, Food Grade 45 405. Magnesium Stearate 3 7 Total 300 700______________________________________
Mix items nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with item no. 3. Mill the damp granules through a coarse screen (e.g., 1/4") if needed. Dry the damp granules. Screen the dried granules if needed and mix with item no. 4 and mix for 10-15 minutes. Add item no. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weight on a suitable tablet machine.
______________________________________CapsulesNo. Ingredient mg/capsule mg/capsule______________________________________1. Active Compound 100 5002. Lactose USP 106 1233. Corn Starch, Food Grade, 40 704. Magnesium Stearate NF 4 7Total 250 700______________________________________
While the present invention has been described in connection with certain specific embodiments thereof, it will evident to one of ordinary skill in the art that many alternatives, modifications and variations may be made. All such alternatives, modifications and variations are intended to be included within the spirit and scope of the invention.
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|US20040001885 *||Jun 27, 2002||Jan 1, 2004||Unchalee Kositprapa||Rapidly disintegrating antihistamine formulation|
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|EP0359499A2 *||Sep 11, 1989||Mar 21, 1990||Schering Corporation||Fluoro substituted benzocycloheptapyridine compounds, compositions and methods of use as antihistaminic compounds|
|EP0359499A3 *||Sep 11, 1989||Jun 20, 1990||Schering Corporation||Fluoro substituted benzocycloheptapyridine compounds, compositions and methods of use as antihistaminic compounds|
|WO1990003375A2 *||Sep 11, 1989||Apr 5, 1990||Schering Corporation||Fluoro substituted benzocycloheptapyridine compounds, compositions and methods of use|
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|U.S. Classification||514/290, 546/93|
|International Classification||A61P43/00, A61P37/08, C07D401/04, A61K31/55, A61K31/4427, A61K31/445|
|Oct 24, 1988||AS||Assignment|
Owner name: SCHERING CORPORATION, GALLOPING HILL ROAD, KENILWO
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:SCHUMACHER, DORIS P.;MURPHY, BRUCE L.;CLARK, JON E.;REEL/FRAME:004967/0742
Effective date: 19880915
Owner name: SCHERING CORPORATION, NEW JERSEY
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SCHUMACHER, DORIS P.;MURPHY, BRUCE L.;CLARK, JON E.;REEL/FRAME:004967/0742
Effective date: 19880915
|Feb 16, 1993||FPAY||Fee payment|
Year of fee payment: 4
|Feb 18, 1997||FPAY||Fee payment|
Year of fee payment: 8
|Feb 26, 2001||FPAY||Fee payment|
Year of fee payment: 12


text:
June 19th, 2021
Arundel Camera Club Field Trip
1001 Longwood Road, Kennett Square, PA 19348
10 am–10 pm, (610) 388-1000
Experience the world of Longwood Gardens…a place to see dazzling displays that elevate the art of horticulture …a place to enjoy performances that inspire… a place to watch majestic fountains spring to life…a place to relax and reconnect with nature.
Stroll through our gardens awash in brilliantly blooming annuals and perennials, or find a quiet, shaded spot among our towering trees and our serene woodland paths
You must purchase timed tickets before the event, please visit https://longwoodgardens.org/visit ASAP to purchase tickets
Timed tickets are for arrival time, one can stay till closing
Ticket Cost $25, $22 Senior, Veteran $22, Youth $13, Child $0
1 year membership costs: $90 one person, $135 to people, $200 five people
Events on Saturday, June 19
10:15 am 12:15 pm 2:15 pm 4:15 pm
Open Air Theatre Fountains
The Open Air Theatre comes alive with fountains set to music. Weather permitting.
11:15 am 1:15 pm 3:15 pm 5:15 pm 6:15 pm 7:15 pm 8:15 pm
Main Fountain Garden Performances
Enjoy the thrill of what 1,719 jets can do.
6:00 pm to 9:00 pm
Live Music in the Beer Garden
Live instrumental music sets the tone in our Beer Garden.
Main Fountain Garden Illuminated Fountain Performances
Enjoy a nighttime spectacle unlike any other.

domain: artistic


text:
Here you can read about my books, and find links to where you can buy them (this will right now be on Amazon.com, but in time you will be able to buy them more places, and in at least 3 different languages.
The first book I want to tell you about is a picture book for kids called
I finished all the drawings recently, and now you can find it as a Kindle on Amazon, in English.
MONS is a little kitten.
He is curious, cute, trusting and full of gumption.
He is convinced that life is good and that everything and everybody whishes him well.
Very much like must of the little kids I know :-)
I think, though, that these little kids will also recognize the kind of crazy situations MONS encounter because of his curiosity and his inexperience.
You can take a look at the first pages in the book here.
As you might notice, if you do take a look, there are several things that changes like mice running around and into their mouse holes, butterflies multiplying and changing color, and a picture of a fish that seems to keep an eye out for MONS and his activities.
All in all a lot of things to talk about with the kids when you read them the book.
MEET MONS is the first book in the MONS-series, and soon you will be able to follow this little ginger colored kitten in other books where we find him in the garden, at the beach, together with his friends and more.
Now you can also by this kindle picture book in Italian, if you follow the link here.
I am looking forward to make all the drawings for these next books, and I hope you will find them as funny and nice to read as the people who have helped me in the process of making this one.
This is really a wonderful book if you are going to have a puppy in the family!
I didn't write it, a friend of mine with a long, long story with dogs wrote it, and then it was illustrated by Clipartqueen.
"Puppy Training for Kids and Newbies" gives you week by week
advice on what to do with your new puppy.
If you have brought home a puppy, you might be feeling just a little nervous and overwhelmed – who would have thought a tiny, lovable creature like your new puppy could create so much confusion, right?
This ebook is here to help answer all your questions, clear up your confusion and let you become the best dog owner in town!
This is a no-nonsense guide, designed to lay out for you the exact practical steps you need to take at each stage of your puppy's development. You'll notice the guide is set
up according to time frames – the first four weeks of puppy care each get their own chapter, and then we'll cover the periods of 1-3 months, 3-6 months and beyond 6 months.
This is so you'll never be confused about what to do next at any time, or worry that you've missed out an important step – just work through each chapter and be confident you're doing everything necessary to ensure you raise a happy, healthy, well-trained puppy.
By the end of this ebook you'll know all the essentials of training and caring for a new puppy, from housetraining, to the basics of walking on a leash, through to more complicated tricks like the classic 'Roll Over.'
You can find this great ebook here.
If you want to stay in touch and hear about new pages, tips and ideas about arts & crafts, please sign up for my newsletter.
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Christmas Clip Art
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Christmas Coloring Pages
Free Christmas Clipart
Santa Claus Clipart
A charming picture book about the kitten MONS.
Everything You Need to Know About Your New Puppy!
I have made illustrations for this very, very good book where you get all the advice you need week by week.
Birthday clip art
Classic Car Pictures
Space clip art
Koi Fish Drawings
Penguin clip art
Wedding Cake Clipart
Dinosaur Clip Art
Animal clip art
Classic Car Pictures

domain: literature


Mississippi legislators have taken the first steps toward erasing the Confederate battle emblem from the state flag, a symbol that has come under intensifying criticism amid nationwide protests against racial injustice.
The second-ranking officer in the Mississippi house, Jason White, told his colleagues: “The eyes of the state, the nation and indeed the world, are on this house.”
The house voted by more than the required two-thirds majority to suspend legislative deadlines and file a bill to change the flag.
The senate is expected to vote on the suspension later, which will allow debate on a bill as soon as Sunday.
Republican governor Tate Reeves said for the first time that he would sign a bill to change the flag if the Republican-controlled legislature sends him one.
He had previously said that he would not veto one – a more passive stance.
Mr Reeves said on social media: “The legislature has been deadlocked for days as it considers a new state flag.
“The argument over the 1894 flag has become as divisive as the flag itself and it’s time to end it. If they send me a bill this weekend, I will sign it.”
A commission would design a new flag that cannot include the Confederate battle emblem but must include the phrase “In God We Trust”.
The new design would be put on the ballot for November 3. If a majority voting that day accepts the new design, it would become the state flag. If a majority rejects it, the commission would design a new flag using the same guidelines.
“I know there are many good people who … believe that this flag is a symbol of our Southern pride and heritage,” said Mr White, the Republican speaker pro tempore of the House.
“But for most people throughout our nation and the world, they see that flag and think that it stands for hatred and oppression.”
Republican representative Chris Brown of Nettleton appeared at a 2016 rally outside the state Capitol for people who want to keep the Confederate emblem on the flag.
“I don’t think we can move forward together if we say, ‘Ýou can have any flag you want except … this one,’” Mr Brown said.
“If we put the current flag on the ballot with another good design, the people of Mississippi will change it. I believe that. Let’s not steal their joy. They want to show the world that they’re moving on.”
Mississippi has the last state flag that includes the Confederate battle emblem – a red field topped by a blue X with 13 white stars.
The battle emblem has been in the upper-left corner of the Mississippi flag since 1894. White supremacists in the legislature put it there during backlash to the political power that African Americans gained after the Civil War.
The Mississippi supreme court ruled in 2000 that the flag lacked official status.
State laws were updated in 1906, and portions dealing with the flag were not carried forward. Legislators put forward a flag election in 2001, and voters kept the rebel-themed design.
The current flag has remained divisive in a state with a 38% black population. All of the state’s public universities and several cities and counties have stopped flying it because of the Confederate symbol.
Influential business, religious, education and sports groups are calling on Mississippi to drop the Confederate symbol. Flag supporters say the banner should be left alone, or put on the statewide ballot for voters to decide its fate.


text:
The dreaded “S” word.
It crops up from time to time and I just sigh.
In a recent conversation with (we’ll call this person Kate) Kate, I was asked if I was worried my kids weren’t getting enough socialization. I bit my tongue on what I wanted to say and instead gave her a more generic reply. There really is no reasoning with people who firmly believe children can only have socialization if enrolled in public or private school.
Kate has a little one who is soon ready to enter Pre-K. While Kate is wishy-washy on whether she wants to homeschool, her husband is adamantly against it because of socialization. The only thing that appears to matter is socialization and not education. Insert head scratch here.
I really do not like to argue with people who are incapable of doing some independent research on socialization in schools or elsewhere. So instead, I will tell you what it is I do to ensure my children are socialized.
First and foremost, I enroll my girls in activities that interest them. When my youngest was four, I found a place for her to do weekly gymnastics. We went to the playground a lot, went shopping together, interacted with family, friends and strangers.
She got older and we moved to a new city. It’s no easy task finding resources for your children when living in the middle of nowhere, so when we finally moved to a somewhat bigger city I was thrilled to find a great many activities for my children. There’s actually a lot available geared towards homeschoolers where we now live, so that is a great bonus!
The only downside was the lack of secular co-op and secular families with whom to connect with. Sooo after much persuasion from the dear hubby, I decided to start a Secular group! And boy am I glad that I did! We now have an active co-op with several secular families that are involved. We do field trips, activities, enroll the girls in interest-geared activities through the park district, and attempt to meet up at the park with other families and schedule playdates for the girls.
What I truly love about this is that my girls do not only interact with the same age kids. She is learning it’s OK to interact with those younger and older and that it can be a great deal of fun and an educational opportunity. With the younger children, my oldest has learned to be patient, to slow down a little. With the older ones, she has found camaraderie and does not feel intimidated by those older than her. With the co-op, my daughter has learned to respect other grown-ups since the moms are very much involved in our co-op and she is capable of holding a lovely conversation with those who are not only her peers.
My oldest has blossomed, has learned, and is in fact socializing with a great many people of all different ages and cultural backgrounds.
It does take some work and some effort on the parents part to make all this happen. But it is possible.
So I ask you, Kate, does your child socialize? Really and truly get an opportunity to socialize?

domain: sociology


text:
Walt Disney World is home to dark rides, family rides, thrill rides, and more at its four theme parks. While Disney does a great job of offering a diverse roster of attractions, a few rides may be a bit too intense for younger guests.
Only one ride goes upside down at Walt Disney World. Rock ‘n’ Roller Coaster at Disney’s Hollywood Studios takes guests upside down on a loop after a zero-to-57mph launch. That’s it! There’s other intense rides at Walt Disney World, but Rock ‘n’ Roller Coaster stands alone as the only ride with an inversion.
While there’s only one upside down ride, Walt Disney World has several rides that are pretty intense. There’s a few where you could lose your lunch. Be warned that Guardians of the Galaxy: Cosmic Rewind at EPCOT has controlled spins, and is known for being a potential recipe for motion sickness. Mission: SPACE (the orange side) is also a stomach-churning ride.
We also think Expedition Everest at Disney’s Animal Kingdom and TRON Lightcycle Run at Magic Kingdom are on the more intense side. Ultimately, your bar might be lower or higher in terms of intensity. You might disagree with us, but can we all agree that Living with the Land at EPCOT is the most relaxing ride at Walt Disney World?
Disappointed only one ride goes upside down? Don’t be! Disney excels by having well-themed attractions that just about anyone can enjoy. Each park even has great rides for adults. We outlined the best rides for adults at Magic Kingdom, EPCOT, and at Disney’s Hollywood Studios. There’s truly something for everyone!
Photo via Disney.

domain: entertainment


- Tommy Bahama Women's Swimwear Size Guide
- Swimwear that's flattering and sophisticated.
- LYCRA® XTRA LIFE™ fiber technology is designed to provide a long-lasting fit and resist degradation from chlorinated water, the heat, and sunscreen lotions up to 10 times longer than unprotected fabrics.
- UPF 50+ fabrication protects skin during outdoor activity by blocking harmful Ultraviolet A & B rays (UVA/UVB).
- Sweetheart neckline with chic crisscross bodice design.
- Foam cups provide support and shape.
- Shirred side seams and tummy-control panel create a slimming silhouette.
- Removable halter strap.
- Full rear coverage.
- 80% nylon, 20% LYCRA® XTRA LIFE™ spandex.
Foam: 100% polyurethane.
Lining: 100% nylon.
Powernet Lining: 85% nylon, 15% spandex.
- Hand wash, line dry.
- If you're not fully satisfied with your purchase, you are welcome to return any unworn and unwashed items with tags intact and original packaging included.
Tommy Bahama Pearl Shirred Front Bandeau One-Piece Royal Blue NQYFENA


text:
Premier was founded by pet-people, for pet-people. They believe in providing safe, innovative and effective tools that help improve relationships between people and their pets. It brings Premier great joy to manufacture and distribute amazing products for dogs, cats, birds, ferrets and even pot-bellied pigs. There's nothing more rewarding to Premier than to see happy people with happy pets.
When you buy a Premier Pet Magic Mushroom Dog Toy in Purple online from Wayfair, we make it as easy as possible for
you to find out when your product will be delivered.
You can check on a delivery estimate for the Premier Pet Part
#: BB MSH ML / BB MSH S
If you have any questions about your purchase or any
other Dog Toys product for sale our customer service representatives are
available to help. Whether you just want to buy a Premier Pet Magic Mushroom Dog Toy in Purple or shop for your entire home, Wayfair has a zillion things home.
Features: Lil Oscar large octopus. Color: Purple. Can
be used in the water. Entertain multiple dogs for hours. Made with 4 layers. Additional piece of black trim. Machine washable (air dry) and it floats!. For dogs over 20 lbs. With ...
Features: Dog toy. Available in Small, Medium and
Large sizes. Color: Purple. Bounces wildly when tossed and floats in water. Small and medium size have one slot for treats, large size has two. Durable.
Features: Dog toy. Color: Purple. Available in Small
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domain: pet


Throughout this summer, a look back 50 years at the Summer of Love in 1967.
It’s August 1967.
The many who’ve descended upon California are still there, but the ranks are beginning to thin.
As The Summer of Love winds down, an unlikely group has been moving up the charts.
Much of the popular music of the incredibly history-making period has been about love, love, and more love, and getting high, and the overwhelming law of order had actually been dictated a year earlier in 1966 by the Mamas and the Papas:
Do what you want to do
With whoever you want to do it with…
The Summer of Love. The Beatles and The Doors and Jefferson Airplane and Jimi Hendrix and Janis Joplin and…
Are you kidding me?
As Labor Day was approaching in 1967 The Monkees were making their first foray into psychedelia.
Their hit song at the time was widely considered to be about…
The composers were the immortals Gerry Goffin and Carole King who wrote it about Pleasant Valley Way in West Orange, New Jersey, where they lived at the time.
The Monkees (did they play their own instruments or didn’t they?) did play on this one – for the most part. Peter Tork played piano and Mike Nesmith played the famous opening guitar riff. Chip Douglas, a former member of The Turtles played bass and came up with the guitar part, which was based on The Beatles “I Want to Tell You.” He taught it to Nesmith, who overdubbed it twice.
Guitarist Mike Nesmith and drummer Micky Dolenz handled the vocals on this track.
Those who loved the recording saw it is a harmless commentary on the simple life in happy suburbia.
Others who were more critical saw it as a rip on the much too complacent suburbia.
Michael Nesmith told a reporter they were all wrong, that the song was about a mental institution. I’m not buying that.
The recording was big, big, big for the Monkees, landing at # 3 in late August 1967.
Here’s another “Sunday” song from the Summer of Love.
Spanky and Our Gang didn’t last too long in the music industry, about two years, but they had a few successful recordings.
The sunshine pop/folk rock band was led by vocalist Elaine “Spanky” McFarlane whose nickname came from her resemblance to “Spanky,” one of the members of the Our Gang comedies.
“Spanky” is on the left.
This 1967 hit was written by Terry Cashman and Gene Pistilli. Cashman recalls that the idea for the song came after Pistilli played a melody for him in their office.
“Most simple rock and roll chord progressions in the key of G would be G to E minor to A minor to D,” said Cashman. “And Gene came in with a change which was instead of going from G to E minor, he went to E major, and instead of going to an A minor – the typical rock and roll kind of thing – he went to an A major, so it made it sound different. And when he played it for me, I started singing this melody to it. And you know, it made me think of a girlfriend that I had a few years before. We used to walk in the park on Sundays, and that whole story became the idea for the song because she left him, and the love affair was over, that Sunday, that special day would never be the same.”
The Mamas and the Papas were originally asked to record the song, but turned it down. It went to #9 on the Billboard chart in the Summer of Love.
McFarlane is the only original member of the group left and still makes appearances.
Next week, our final installment in this series: The end of the Summer of Love.
OTHER SUMMER OF LOVE POSTS


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‘Give me 5-year deal’
Mario asks for more time to implement philosophy
Malawi National Football Team Coach Mario Marian Marinica has reiterated his appeal for more time to deliver positive results after disclosing that he needs five years to successfully implement his football “fast and very fast football philosophy”.
The Fifa-Pro Coaching Licence holder said his philosophy will become effective across the board (Under-17, 20 and 23) in five years.
“This is a philosophy which needs to be devised across the board from Under-17, 20 and 23 and all Super League teams and, then, at the national team.
“We are far away from countries like Morocco, Egypt, Senegal and Nigeria, just to mention a few. People need to be patient. We are not bad but what we need is time to be together and practice for a longer time,” he said.
Marinica’s charges are preparing for back-to-back 2023 Africa Cup of Nations Group D qualifiers against Egypt slated for later this month.
The coach feels that his side has chances to do well.
“We still have a chance to do better in this current campaign as all the teams in the group have five points. We are not an easy team to beat despite the fact that we do not score more goals,” he said.
Marinica singled out Flames forward Frank Gabadinho Mhango, who plays for Amazulu in South Africa, as one of the players who has mastered his philosophy.
However, former Flames forward Peterkins Kayira differed with Marinica’ on the five-year duration for his philosophy to work out.
“Firstly, I do not really understand him when he says ‘fast and very fast football’. This is what we have been doing as a country. Malawi’s football is about attacking. We have always played fast and attacking football spiced by passing.
“How different is this type of football pattern from that of Marinica, where, after only two or three touches, the ball finds itself at the feet of a striker. To me, a year is enough for a coach to start reaping fruits of his football style. I find five years too long,” he said.
Meanwhile, National Football Coaches Association Chairperson Aubrey Nankhuni, while agreeing with Kayira on the five-year duration, said the focus should be on the team’s preparations ahead of the Afcon qualifiers instead of debating on Marinica’s football style.
“One year to me is enough for a coach to set his philosophy and start getting results but I am much more concerned with how we can help the coach beat Egypt.
“Do we have a team? Do we need new players who were not at the Afcon finals in Cameroon? What training methods and partnerships are we trying with the boys?” Nankhuni asked.
Marinica is in his second year of the three-year contract as Flames head coach.
Peter Fote is a Sports Journalist with huge experience in radio and Television reporting, production and presentation. He once worked with Malawi Broadcasting Corporation (MBC) and is currently working for Times Media Group.

domain: news


Tapped In: Lenox Hill Recovers, Celebration Saved, Taxi Driver Rescued
LENOX HOSPITAL FUNDS EMPLOYEE HURRICANE RELIEF Lenox Hospital held its annual Autumn Ball on Monday evening, only this time the money raised did not benefit the hospital itself, but its employees. North Shore LIJ Health System announced last week that proceeds from the fundraising gala, which was held at the Waldorf Astoria Hotel in Midtown, would be donated to the health system's newly established Emergency Employee Resource Center, an initiative created to assist employees whose families and homes were harmed by Hurricane Sandy. "We as a health system can take great pride in how we responded during the storm," said North Shore-LIJ President and CEO Michael Dowling. "Our ability to meet the needs of communities we serve throughout New York City and Long Island and assist other New York area hospitals in distress was nothing short of remarkable. While Sandy has passed, much work remains. That includes taking care of our own employees, who continued to work even though many lost their homes, cars and personal possessions in the storm." North Shore-LIJ is a 16-hospital system that employs over 44,000 people in New York City and Long Island. The fundraiser honored Nobel Peace Prize recipient Elie Wiesel and included a performance by singer Cyndi Lauper. HALLOWEEN SURVIVES IN EVACUATION ZONE Flood damage was not the only scary thing last Wednesday at the Stanley M. Isaacs Houses, a public housing complex along the East River at East 93rd Street. A bunch of ghosts and goblins were out, too, with their parents and big bags of candy. Despite a mandatory evacuation notice from the New York City Housing Authority before Hurricane Sandy, many residents stayed in their homes after heat and elevators were shut down. Uprooted trees and debris-ridden streets made Halloween look unlikely, but parents in the buildings decided to let their children enjoy the holiday nonetheless. "It's good for the kids," resident Patrick Fraser told NY City Lens. "They don't need to worry about what's going on in the world right now." Parents walked door to door with kids whose costumes included witches, fairies, Batman, Spider-Man and a bumblebee. Elsewhere in the city, many Halloween happenings were canceled, including the Village's annual Halloween Parade, the largest public Halloween event in the country. LOCAL MAN SAVES TAXI DRIVER FROM DROWNING Jon Candelaria braved Hurricane Sandy last week to pull a taxi driver out of rushing floodwater. The 25-year-old was sipping coffee in his family's Upper East Side apartment on Monday during the storm when he saw an SUV taxi driving in water on a closed street. A sudden surge lifted the vehicle, then pulled it into deep water. "I acted on a reaction. I didn't think of my well-being," he told CNN of his heroic feat that followed. He rushed outside into waist-high water wearing basketball shorts and a jacket and waded to the vehicle. Wind, water and a rapid loss of strength prevented him from opening the SUV's door at first, but he told the driver that they were going to work together, and they managed to open the door on the count of three. "As soon as I got to three, the wind just stopped for that one second," Candelaria told CNN. "It was like something from a movie." The driver left the scene without identifying himself. The rescue was captured from above, though, on a nearby security camera. "At the end of the day, it wasn't about what I was getting in return," Candelaria said after joking with CNN that he should be granted unlimited cab rides in the city. "I couldn't just stand there and do nothing. If I knew that this was going on in front of me, I would have done it for anyone."
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A former high school coach will spend more than a decade in prison for having sex with a student.
A Denver jury on Friday found a former high school basketball coach guilty of having sex with his students.
Police arrested Wesley Specht last year after the alleged sexual relationships with three different girls. He’s now facing seven felony counts.
A former high school basketball coach accused of sexually assaulting two students appeared in court on Tuesday.


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domain: health


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Date: date unknown
Description: Oswald Neesvig, President of Madison (Wisconsin) Packing Company, draped in and standing among his quarry from a day of crow hunting.
Description: Group of men posed in front of small stone building with guns. Sign above doorway says "Waupun Hunters Club Home."
Date: 1840 ca.
Description: Photograph of a drawing of an Indian aiming his bow and arrow, with one foot standing on an earlier kill.
Date: 1908 ca.
Description: Flora Fels Weege seated on a white horse while wearing a men's suit, hat, and a belt containing ammunition. She has a rifle propped in her right arm.
Description: Indians on horseback hunting buffaloes (Plate 6).
"In this Plate, representing a numerous group in motion, and closely pursued by a party of Indians, wi...
Description: Indians on foot and horseback hunting buffaloes (Plate 7).
"The buffalo is a harmless and timid animal until severely wounded, or closely pursued, when it...
Description: Display of guns in the display window at Wisconsin-Felton Sporting Goods Company, 29 West Main Street.
Description: McCormick-Deering Farmall H tractor in a fall setting. A hunter, Mr. Vinson E. Gritten, holds up a dead rabbit for William Foreman and Junior Scott (boy in...
Description: This late 19th century map of northern Wisconsin and a portion of Michigan's Upper Peninsula shows the township and range grid, the (Lac du) Flambeau India...
Date: 1920 ca.
Description: A group of men stand with rifles at the Echo Lake Hunting Club Camp. Gutted deer hang to cure outside the cabin.
Description: Photographic mock-up for an Alfred Stanley Johnson photomontage postcard entitled "Kickers." A boy wearing waders and holding a rifle stands with his arms...
Description: A 14-point buck shot by Carl Laughnan 4138 Mandan Crescent, and a 10-point buck shot by Russell Hegg, 330 Dow Ct., are tied to the front fenders of the car...
Description: Albert Becker and Carl Van Skike, hunting partners for 32 years, pose in hunting clothes with shot guns while holding three geese they bagged while hunting...
Description: Two men standing holding guns, with birds draped around their necks from hunt. Line strung between trees shows additional kill from duck hunt. A dog sits i...
Description: Photographic postcard of a poster promoting Camp Milo on White Sand Lake. On it are photographs of the cabins, tents, lake, and boats on the shore.
Description: Four members of Ducks Unlimited inspect a gun at the annual banquet held at the Club Chanticleer. Left to right are Toby Sherry, banquet chairman; Fred Gag...
Date: 1914 ca.
Description: The Wolf River House. The advertisement reads: "The Wolf River House; Hunters' and Fishermen's Resort; Rates $1.50 per day - $9.00 per week; Special Rates...
Description: View of Sheep Hunters' Cache at the head of the Totlat River in Alaska featuring a hunter in a wooded campsite surrounded by trees and snow.
Description: Dr. James Jackson (left), and his brother Joseph W. Jackson (right), on a western hunting trip. The individual in the center is unidentified.
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domain: history


text:
Tennis Elbow Surgery in Bethesda, MD
Are you experiencing pain and swelling in your elbow? You may have developed a condition called tennis elbow. While you can get tennis elbow from playing racket sports, it derives from other repetitive motions as well, such as an action you perform daily at work. When you lift your arm repeatedly, especially when it bears weight, you’re at risk of developing tennis elbow.
Treatments for tennis elbow range from physical therapy to rest to anti-inflammatories. Sometimes the condition requires a more serious solution — surgery. We offer high-quality surgery for tennis elbow in Bethesda, MD. We thoroughly evaluate every patient and discuss their options to ensure they get the quality care they need for this condition, which is also referred to as lateral epicondylitis. We also welcome patient referrals from primary care doctors’ offices.
Tennis elbow is very treatable, and you don’t have to suffer — we can help you heal from this condition.
Symptoms of Tennis Elbow
Tennis elbow is a common ailment among individuals ages 30 to 50. You may feel mild pain to start, which develops into something sharper and more distracting. You may also notice that holding something makes the pain feel worse. Signs of tennis elbow include:
- Weakened grip strength
- A burning sensation on the edge of your elbow
- Difficulty shaking hands or working a wrench
Some people wear braces to lessen the pain of tennis elbow, but if your pain persists, you should see a doctor immediately.
Do I Need Lateral Epicondylitis Surgery?
When you come for treatment to our office in Bethesda, MD, we’ll begin with an initial evaluation, including X-rays. We encourage you to try physical therapy, and if the elbow does not feel better, we may try a cortisone steroid injection.
During your third visit, we’ll re-evaluate your case, and we may determine that surgery is necessary to remove the damaged tendon causing your pain. The surgery will be scheduled at the hospital or an outpatient facility, and afterward, we’ll follow up with another evaluation and X-ray. We perform regular post-op follow-ups as needed six months and a year after surgery as well.
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Vivekchand, S. R. C. and U, Ramamurty and Rao, C. N. R. (2006) Mechanical properties of inorganic nanowire reinforced polymer–matrix composites. NANOTECHNOLOGY, 17 . S344-S350.
Full text is not hosted in this archive but may be available via the Official URL, or by requesting a copy from the corresponding author.
The mechanical properties of poly(vinyl alcohol) matrix composites incorporating SiC and Al2O3 nanowires (NWs) have been investigated. A marked increase in the elastic modulus (up to 90%) has been observed even with the addition of a small quantity (0.8 vol%) of nanowires. This observation cannot be explained by iso-stress analysis, which is appropriate for describing the variation of properties with the reinforcement volume fraction in discontinuously reinforced composites. Crystallization of the polymer induced by the NWs, the high aspect ratio and the surface-to-volume ratio of the NWs as well as the possible in-plane alignment of the NWs during processing are considered to be responsible for the increase in the stiffness. A significant increase in the strength of the composite with the addition of NWs is also observed. This is due to the significant pull-out of the NWs and the corresponding stretching of the matrix due to the complete wetting of the NW surface by the polymer. The increase in tensile strength is found to saturate at higher vol% of NW addition due to the reduced propensity for shear-band induced plastic deformation.
|Subjects:||Physical Science > Nanophysics|
Material Science > Nanochemistry
|Divisions:||Faculty of Engineering, Science and Mathematics > School of Physics|
Faculty of Engineering, Science and Mathematics > School of Chemistry
|Deposited On:||20 Jan 2009 09:59|
|Last Modified:||20 Jan 2009 09:59|
Repository Staff Only: item control page

domain: chemistry


text:
Six-year-old accidentally shoots younger sisterJuly 1st, 2008 - 2:27 pm ICT by IANS
Raipur, July 1 (IANS) A six-year-old boy accidentally shot his three-year-old sister dead while they were playing with their father’s licensed gun at their home in Chhattisgarh’s Durg district, police said Tuesday. The tragic incident took place Monday evening in Borenda village in Durg, around 75 km from here.
“The boy Harsh pressed the trigger of a 12-bore loaded gun that he took out from a shelf while playing with his sister. He had no idea that the gun was real and loaded,” District Superintendent of Police Dipanshu Kabra told IANS.
The bullet hit his sister Khushi in the head and she died on the spot, he said.
Harsh and his sister were alone at home when the gun went off as their parents were away attending a religious function in the neighbourhood.
“We have registered a case under section 174 of the CrPC (criminal procedure code) and are investigating the matter. A post-mortem of the girl was carried out,” Kabra said.
“The gun was licensed and issued in the name of Harsh’s father, Jai Singh Thakur, a farmer. We think the unfortunate incident happened due to the parent’s negligence,” the officer said. “No arrest has been made so far,” he added.
- Omar speaks to Khurshid over custodial death - Oct 09, 2011
- Chhattisgarh cop suspended for custody death (Lead) - Feb 23, 2012
- Chhattisgarh cop suspended for youth's custodial death - Feb 22, 2012
- No police complaint filed after Gurgaon boy's death - Jul 06, 2012
- Man held for burying alive wife, three others - Jan 22, 2012
- Gas leak fire kills three of family - Oct 22, 2011
- Eight-year-old boy sells gun to classmate for $3.50 - Apr 30, 2011
- Two Delhi businessman found dead in car - Oct 10, 2011
- Two cases of suicide in Gurgaon - May 02, 2012
- Father throws newborn girl into river in Chhattisgarh - Sep 18, 2009
- Youth arrested for murdering four family members - Aug 13, 2010
- Three injured after 6-year-old US boy fires accidentally - Apr 20, 2011
- Kidnapped from Ludhiana, 6-year-old recovered in Ambala - Jul 09, 2012
- Delhi university student commits suicide - Apr 28, 2012
- Driver arrested for sexually assaulting minor - Sep 07, 2012


THORNWOOD, N.Y. For the first time, Westlake Middle School students will get on the bus every day with their high school counterparts as the Mount Pleasant Central School District combined the buses this year in a cost-saving move.
Its to consolidate the buses and bus stops, Schools Superintendent Susan Guiney said. We had a lot of buses last year that would loop around the same area when picking up middle school and high school students.
With the middle school and Westlake High School on the same campus and their start and dismissal times being in line together, the decision was an easy one for the district. Guiney said the district was able to eliminate one bus for the year by combining, which saves around $70,000. However, the topic was brought up at many Board of Education meetings and some parents had an issue putting their middle school child on the same bus with a potential upperclassman at the high school. Guiney said that those parents need not worry.
Many of our older students at the high school either drive themselves in or will get a ride from a friend, Guiney said. And the high school students that do ride the bus they already have their group of people who they socialize with and shouldnt be a bother to the other students.
With school starting Tuesday, the district will monitor behavior on the busses over the next few weeks and any issues that could arise when the two schools come together.
Any parent that has a concern with their child in regards to something that happens on the bus they should report it to us immediately, Guiney said.
Guiney said that the bus routes are very similar to last year and can be accessed by parents and students on the district website .
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Ryan Matheuszik joined Salter Vecchio as an articling student in 2018 and is interested in the fields of class action litigation, product liability, and personal injury. Ryan has a passion for litigation and enjoys helping clients navigate the litigation process.
Ryan has worked in such diverse fields as computer information technology, marketing and communications, advertising sales, and pharmacy before returning to school in 2008. Ryan attended the University of British Columbia where he obtained a Bachelor of Arts. He subsequently earned a Juris Doctor at the Peter A Allard School of Law at UBC. Before coming to Slater Vecchio, Ryan engaged in clerking duties for the Provincial Court of British Columbia as part of a judicial externship program. While in law school, Ryan was awarded the David Roberts Prize in Legal Writing.
Ryan is an avid backcountry hiker and has summited several peaks in British Columbia and Washington State. He currently resides in downtown Vancouver and is a pinball enthusiast.

domain: law


text:
One of the nation’s largest medical debt-collection companies has been charged by Minnesota's Attorney General with strong-arming people in emergency rooms and other hospital departments - including delivery rooms - for money before they can be treated. The Chicago-based Accretive Health Inc. train their “financial counselors” to track patients with outstanding balances on “stop lists” and hassle them when they turn up at the E.R. until they pay what they owe. Records show the company's income rose 130 percent last year; the level of care at those hospitals, as sick people declined to seek treatment, sank. Tell us again why we don't need universal health coverage.
"The Accretive culture has converted the hospital culture from that of a charitable organization to that of a collection agency. Perhaps the most damaging act by Accretive was to undermine the basic premise that a hospital is a sanctuary to treat the sick and infirm.''

domain: medical


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Matt Bilodeau Obituary – Death : Matt Bilodeau Cause Of Death: Funeral – We learnt on Wednesday, April, 7th, 2021, that Matt Bilodeau has died with loved ones left in total devastation.…
This is the full obituary where you can express condolences and share memories. Published in the Toronto Sun on 2012-11-16. Bilodeau – Barbara (Mullins), 68, of Jay, Maine died March 20, 2021 in Jay, Maine. Funeral services will be held at 2PM, on Saturday, March 27, 2021 at FINLEY FUNERAL HOME, 15 Church Street, Livermore Falls, Maine, livestreaming will be available on the Finley Funeral Home’s Facebook Page. Visiting hours will be held from 11AM – 2PM prior Jeanne BILODEAU passed away . This is the full obituary where you can express condolences and share memories.
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12, 1964, in Lewiston, to Normand Kenneth Joseph Bilodeau passed away 2020-03-13 in Merrimac, MA. This is the full obituary story where you can express condolences and share memories. The family of Joseph L Bilodeau sadly announces his sudden and unexpected passing on January 9,2021 at Baystate Medical in the comfort of their love. Born in Springfield on February 27,1961 to Ronald and Patricia (Davis) Bilodeau he was a lifelong Agawam resident. He was educated in Agawam graduating from Agawam high school class of 1979. 2020-10-15 · Obituary: Bryan Joseph Bilodeau. OCALA, Fla. - Bryan Joseph Bilodeau, 42, of Ocala, Fla. and Saco, passed away after a long illness on Oct. 7, Pauline (Hebert) Bilodeau, 94, of Fredericksburg, passed away on Saturday, August 1, 2020 at Bickford of Spotsylvania. She was born and raised in Fall River, MA. After graduation from Jesus Obituary.
Dorothy BILODEAU passed away . This is the full obituary where you can express condolences and share memories. Published in the Vancouver Sun and Province on 2020-11-22.
MANCINI, Matthew Mario “Matteo” ~ May 10, 2000 – May 8, 2013. Passed away peacefully in his Mommy and Daddy's arms at McMaster Children's Hospital af. Jul 16, 2010 Matt Bilodeau.
We are devastated to report the passing of Matt Bilodeau. Matt was a rising star and he was ready to run for Sportsman Rookie of the Year in 2021. Matt Bilodeau Obituary – Death : Matt Bilodeau Cause Of Death: Funeral – We learnt on Wednesday, April, 7th, 2021, that Matt Bilodeau has died with loved ones left in total devastation.… Matt Bilodeau Death - Obituary : Matt Bilodeau of vermont has Died.
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The family are yet to make public the obituary and funeral arrangements. Matt J. Bilodeau Utica Matt J. Bilodeau, 49, passed away unexpectedly at home on Saturday, November 10, 2012. Relatives and friends may call on Tuesday from 5-7 pm at The Matt Funeral Home, 700 Rutger View the profiles of people named Matt Bilodeau. Join Facebook to connect with Matt Bilodeau and others you may know. Facebook gives people the power to Donald P. Bilodeau April 26, 1952 - January 6, 2021 Obituary Matt Bilodeau is on Facebook.
Matt Bilodeau has died , according to the following statements posted on social media on April 7. 2021. Devil’s Bowl Speedway – West Haven, VT 1d · We are devastated to report the passing of Matt Bilodeau.
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Montano-Shea Funeral Home, Winsted, Connecticut. Sr. He was working at Bilodeau Construction in CT and FL where he felt like part of the family for many
2020-10-15 2019-09-03 2020-04-18 Bryan's Obituary. Bryan Joseph Bilodeau, 42, passed away after a long illness on October 7, 2020.


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The Undergraduate Journal of Service Learning and Community-Based Research is requesting submissions for a special issue of the journal entitled Social Justice in Service Learning and Community-Based Research.
This Special Issue of the Undergraduate Journal of Service Learning and Community-Based Research seeks to address students’ experiences with service learning and community-based research related to social justice. The objective is to provide a bigger-picture view of social justice and consider strategies for addressing multiple intersecting concerns that inevitably exist within the context of social justice and work in the community. This is an opportunity for students to discuss and reflect on the challenges they faced and the unique opportunities that may have presented themselves as issues related to social justice unfolded during a service learning or community-based research experience.
Potential areas to address may include (but are not limited to):
Critical service learning
Justice, Equity, Diversion, Inclusion
Cultural competencies that can be developed related to service learning and community-based research
How working with a community organization during a social justice/racial justice movement impacted the relationship you had with the community members, supervisors at the organization, and those impacted that you are/were working with?
How to effectively work within what community partners already doing and avoid doing harm with our good intentions.
What growth experiences did you encounter relating to research design, methods, and community partnerships? This can also include any reflective pieces regarding personal growth.
How did the challenges related to social justice impact the success/failure of the project?
What was the process you went through of reorganizing your research focus due to social justice/racial justice?
If your project didn’t succeed, what was learned?
Authors can reflect on how social justice/racial justice shifted their future approach to, mindset about, and understanding of, their project. For example, maybe you were surprised to see new needs arise that you never would have considered otherwise.
What advice can you give for future research projects (such as re-framing your research question) and student researchers related to social justice?
Social justice movements could include but are not limited to societal issues such as the Black Lives Matter Movement or the MeToo movements.
Submissions not related to social justice will still be accepted until January 31st and published in a different volume.
Submissions will be accepted through the journal website (ujslcbr.org) through January 31st. The special issue will be published in April or May 2022. If you have any questions, please contact the special issue guest editor Dr. Indranil Ghosh (email@example.com) or the general journal email address (firstname.lastname@example.org).


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Another edit. This was where I was when I wrote it. Looking at my money situation was challenging, and with the state of depression I was feeling, it felt hopeless. I’m doing a bit better now. I try to be pretty unfiltered here, mostly so that anyone starting where I am now, but in the future, can see the real struggles I’m going through. I hope that in the end, it’s a persistence pays off story, an exciting tale of making it despite adversity, but it’s way too early to tell yet.
Another side effect of this writing for a living thing is that I’m pretty broke. Like, extremely broke. I get a little bit of money coming in, and I have a larger chunk coming in soon. Thing is, it leaves me so short of money I’m having to make some compromises. I hope I can survive this period, at least until the larger money comes in.
It would help a great deal if I was selling books, or if I had subscribers to my Patreon (which I’ve decided is terrible and needs to be completely reworked – I have to figure out how to appeal to people).
So, for anyone who’s been following, I’m broke, severely depressed, and feeling pretty damned hopeless. Still, I keep writing. I think that in the end, that’s the only way through this… keep going no matter what happens, write as long as I can, try to market, try to get some sales, and hope that I can do enough in time. It’s going all in, trying everything to make this work. Sometimes you just need to take the leap.


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Pennsylvania State Police searched Wednesday for a Greencastle man who wandered off Tuesday morning.
According to police, Grant Allan Starkey, 77, arrived at Sheetz on Antrim Commons Drive in Antrim Township around 10:30 a.m. Tuesday. He parked his vehicle in the rear of the building in a non-parking stall and entered the convenience store, purchased miscellaneous items and left the store via the main front entrance.
Starkey then walked around the parking lot for several minutes and exited the side entrance walking towards Route 11.
After a search that included air units, Starkey was found Wednesday at 2:30 p.m.
Pennsylvania State Police provided no details on how or where he was located.


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text: It’s the ’90s Pacific Northwest refracted through a dark mirror, where meth and madness hash it out in the woods. . . . A band of hobo vampire junkies roam the blighted landscape—trashing supermarket breakrooms, praying to the altar of Poison Idea and GG Allin at basement rock shows, crashing senior center pancake breakfasts—locked in the thrall of Robitussin trips and their own wild dreams.A girl with drug-induced ESP and an eerie connection to Patty Reed (a young member of the Donner Party who credited her survival to her relationship with a hidden wooden doll), searches for her disappeared foster sister along “The Highway That Eats People,” stalked by a conflation of Twin Peaks’ “Bob” and the Green River Killer, known as Dactyl.With a scathing voice and penetrating delivery, Grace Krilanovich’s The Orange Eats Creeps is one of the most ferocious debut novels in memory.

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