text:
ANTI-MITOTIC ANTI-PROLIFERATIVE COMPOUNDS
Substituted triazole compounds and pharmaceutical compositions thereof are presented. Also presented are methods for treating a pathology linked to a hyperproliferative disorder by administering the substituted triazole compounds to a patient in need thereof.
Welsh, William J. (Princeton, NJ, US)
Peng, Youyi (Piscataway, NJ, US)
Wang, Xin (Piscataway, NJ, US)
Keenan, Susan M. (Franklin Park, NJ, US)
Zhang, Qiang (Piscataway, NJ, US)
Arora, Sonia (North Brunswick, NJ, US)
UNIVERSITY OF MEDICINE AND DENTISTRY OF NEW JERSEY (New Brunswick, NJ, US)
548/266.4, 548/269.4, 514/383
A61K9/00; A61K31/4196; A61P29/00; A61P35/00; C07D249/08
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SHAMEEM, GOLAM M
Fox Rothschild LLP (Lawrenceville, NJ, US)
1. A compound of Formula I: wherein Het is a substituted 1,2,4-triazole or 1,2,3-triazole; Z1, Z2, and Z3 are independently a bond or R1—X—R2, wherein X is NR3, O, S, SO, or SO2; R1 and R2 are independently a bond or substituted or unsubstituted, saturated or unsaturated, straight-chained or branched lower alkylene; and R3 is hydrogen, substituted or unsubstituted phenyl, or substituted or unsubstituted, saturated or unsaturated, straight-chained or branched lower alkyl; Ar1 and Ar2 are independently substituted or unsubstituted monocyclic aryl or heteroaryl ring systems of 5 or 6 ring atoms or bicyclic aryl or heteroaryl ring systems of 8 to 12 ring atoms, wherein each monocyclic ring may contain 0 to 3 heteroatoms, each bicyclic ring may contain 0 to 4 heteroatoms, and each heteroatom is independently selected from the group consisting of N, O, and S; Ra is hydrogen or a substituted or unsubstituted monocyclic, aryl, or heteroaryl ring system of 5 or 6 ring atoms or a bicyclic aryl or heteroaryl ring system of 8 to 12 ring atoms, wherein each monocyclic ring may contain 0 to 3 heteroatoms, each bicyclic ring may contain 0 to 4 heteroatoms, and each heteroatom is independently selected from the group consisting of N, O, and S; and the substituents of Ar1, Ar2, and Ra, when substituted, comprise one to three moieties independently selected from the group consisting of alkyl, alkenyl, alkynyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and dialkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono-alkylamido, di-alkylamido, N,N-cycloalkylamido, sulfonyl, mono-alkyl sulfonyl, di-alkyl sulfonyl, sulfamoyl, mono-alkyl sulfamoyl, di-alkyl sulfamoyl, halophenyl, benzoyl, alkylthio and alkylsulfinyl; or a hydrate thereof, solvate thereof, prodrug thereof or pharmaceutically acceptable salt thereof; provided that when Het is a 1,2,4-triazole; Z1, Z2, and Z3 are each a bond; Ra is a hydrogen at position 3 of the triazole; Ar1 is a 3,4,5-trimethoxyphenyl at position 4 of the triazole; and Ar2 is a substituted benzene at position 5 of the triazole, then Ar2 is substituted with other than the combination of a nitro and an amino group.
2. The compound of claim 1, wherein Ar1 and Ar2 are substituted or unsubstituted aromatic rings independently selected from the group consisting of benzene, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, 1,2,4-triazole, pyridine, 2(1H)-pyridone, 4(1H)-pyridone, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, tetrazole, naphthalene, tetralin, naphthyridine, benzofuran, benzothiophene, indole, 2,3-dihydroindole, 1H-indazole, indoline, benzopyrazole, 1,3-benzodioxole, benzoxazole, purine, coumarin, chromone, quinoline, tetrahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pyrido[3,2-c]pyridazine, pyrido[3,4-b]-pyridine, 1H-pyrazole[3,4-d]pyrimidine, pteridine, 2(1H)-quinolone, 1(2H)-isoquinolone, 1,4-benzisoxazine, benzothiazole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoxazine, phthalazine and cinnoline.
3. The compound of claim 1, wherein Ra is a substituted or unsubstituted aromatic ring selected from the group consisting of benzene, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, 1,2,4-triazole, pyridine, 2(1H)-pyridone, 4(1H)-pyridone, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, tetrazole, naphthalene, tetralin, naphthyridine, benzofuran, benzothiophene, indole, 2,3-dihydroindole, 1H-indazole, indoline, benzopyrazole, 1,3-benzodioxole, benzoxazole, purine, coumarin, chromone, quinoline, tetrahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pyrido[3,2-c]pyridazine, pyrido[3,4-b]-pyridine, 1H-pyrazole[3,4-d]pyrimidine, pteridine, 2(1H)-quinolone, 1(2H)-isoquinolone, 1,4-benzisoxazine, benzothiazole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoxazine, phthalazine and cinnoline.
4. The compound of claim 1, wherein each of Z1, Z2, and Z3 is a bond; Ar1 and Ar2 are each a substituted benzene; and Ra is hydrogen.
5. The compound of claim 4, wherein Ar1 and Ar2 are each substituted with 1 to 3 alkoxy groups.
6. The compound of claim 4, wherein Ar1 is substituted with 1 to 3 alkoxy groups and Ar2 is substituted with a dialkylamino group.
7. The compound of claim 4, wherein Ar1 is substituted with 1 to 3 alkoxy groups and Ar2 is substituted with a hydroxyl group and an alkoxy group.
8. The compound of claim 4, wherein Ar1 is substituted with 1 to 3 alkoxy groups and Ar2 is substituted with a halogen and an alkoxy group.
9. The compound of claim 2, wherein Ar1 is a benzene substituted with 1 to 3 alkoxy groups and Ar2 is a substituted indole.
10. The compound of claim 2, wherein Ar1 is a benzene substituted with 1 to 3 alkoxy groups and Ar2 is a substituted benzimidazole.
11. The compound of claim 1 having the formula:
14. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
15. A method for treating a pathology linked to a hyperproliferative disorder, said method comprising administering to a patient in need thereof an anti-mitotic effective amount of the compound of claim 1.
16. The method according to claim 15, wherein said pathology is restenosis.
17. A method of treating restenosis in a patient comprising administering to said patient in need of such treatment a pharmaceutically effective amount of the compound according to claim 1 at a predetermined site.
18. The method according to claim 15, wherein said hyperproliferative disorder is at a site of mechanical injury to an arterial wall produced by treatment of an atherosclerotic lesion by angioplasty.
19. The method according to claim 17, wherein the compound is administered by means of an angioplasty balloon coated with a hydrophilic film saturated therewith.
20. The method according to claim 17, wherein the compound is administered by means of a catheter comprising an infusion chamber containing a solution of the compound.
21. The method according to claim 17 wherein the compound is administered by means of a coating comprising said compound on a stent device.
22. The method according to claim 15 wherein the pathology linked to a hyperproliferative disorder is a cancer susceptible to treatment by inhibition of mitotic spindle formation.
23. The method according to claim 22 wherein the cancer is leukemia, lung cancer, colon cancer, central nervous system cancer, ovarian cancer, renal cancer, breast cancer, cervical cancer, prostate cancer, bladder cancer, liver cancer, lymphoma, pancreatic cancer, thyroid cancer, Kaposi's sarcoma, or malignant melanoma.
24. A method for treating inflammation in a patient suffering from such disorder comprising administering to said patient an effective amount of a compound according to claim 1.
25. A stent device coated with an anti-mitotic effective amount of the compound of claim 1.
This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Ser. No. 60/666,944, which was filed on Mar. 31, 2005 and U.S. Provisional Application Ser. No. 60/621,722, which was filed on Oct. 25, 2004. The disclosures of both of which are incorporated herein by reference.
Cancers are regarded as one of the most common human diseases in the world. According to the statistical data released by WHO (World Health Organization), more than 10 million people are diagnosed with cancer every year and 6 million people (representing 12% of deaths worldwide) die as a result of this deadly disease. Moreover, global cancer rates are projected to increase by 50% to 15 million by 2020. Although tremendous advances have been made in the understanding of the molecular pathology of malignant tumors, progress in the development of novel anti-cancer drugs has remained slow.
Cancer therapies attempt to exploit differences between malignant tumor cells and normal cells and often take advantage of major distinctions within cell-cycle control mechanisms. As compared to the majority of normal somatic cells that are in a quiescent phase of cell cycle, cancer cells undergo a much faster and more disorganized cell cycle. Mitosis is a stage of the cell cycle in which the microtubule system plays a crucial role. Disruption of the microtubule spindle formation either by inhibiting polymerization or preventing depolymerization of tubulin results in cell-cycle arrest and cell death. Therefore, the microtubule system of eukaryotic cells is widely regarded as a potent drug target for the development of anti-cancer therapeutic agents. The α- and β-tubulin heterodimer is the building block of microtubules and, as such, is the biochemical target for several clinically used chemotherapeutics. Tubulin binding compounds which interfere with the dynamic stability of microtubules and disrupt the formation of mitotic spindles are widely considered one of the most desirable classes of anti-cancer agents. Indeed, great commercial success has been achieved by paclitaxel, a small-molecule microtubule stabilizer.
Clinically used compounds which interfere with microtubule dynamics usually bind to one of three major binding sites named after representative inhibitory ligands: taxane, vinca alkaloid, and colchicines. However, these clinically used anti-tubulin drugs often face limitations such as neural and systemic toxicity, poor water solubility and bioavailability, and complex synthetic pathways and isolation procedures. Moreover, these clinically-used antimitotic drugs suffer from negative side effects such as the development of peripheral neurotoxicity and the induction of various drug resistance mechanisms. For example, P-gP (P-glucoprotein) and MRP (Multidrug Resistance Protein) are both efflux pumps that expel foreign toxicants from cells to reduce or even eliminate cytotoxicity as a result of decreased intracellular drug concentrations. Furthermore, existing chemotherapeutic agents have complex synthetic pathways and are often difficult to isolate.
Colchicine was one of the first natural anti-mitotic drugs to be investigated. It binds to a single site in β-tubulin and destroys mitotic spindle formation by inhibiting tubulin polymerization. However, colchicine treatment results in high cytotoxicity and multiple side effects.
Combretastatin A-4 (CA-4) is a potent tubulin polymerization inhibitor with one of the simplest chemical structures. It has a broad spectrum of activity. Moreover, it cannot be recognized by the multidrug resistance (MDR) pump. Association with the MDR results in drug resistance as drugs and other foreign molecules are rapidly ejected from the cytoplasm. CA-4 has also been reported to inhibit tumor growth by disrupting angiogenesis. Unfortunately, the structural instability of the cis-double bond of CA-4 has limited the compound's in vivo efficacy.
Therefore, a need exists for novel anti-mitotic compounds that exhibit fewer side effects, have higher anti-tubulin activity, and which arc easily synthesized and isolated.
This need is met by the present invention, which relates to a compound of Formula I:
Het is a substituted 1,2,4-triazole or 1,2,3-triazole;
Z1, Z2, and Z3 are independently a bond or R1—X—R2, wherein X is NR3, O, S, SO, or SO2; R1 and R2 are independently a bond or substituted or unsubstituted, saturated or unsaturated, straight-chained or branched lower alkylene; and R3 is hydrogen, substituted or unsubstituted phenyl, or substituted or unsubstituted, saturated or unsaturated, straight-chained or branched lower alkyl;
Ar1 and Ar2 are independently substituted or unsubstituted monocyclic aryl, or heteroaryl ring systems of 5 or 6 ring atoms or bicyclic aryl or heteroaryl ring systems of 8 to 12 ring atoms, wherein each monocyclic ring may contain 0 to 3 heteroatoms, each bicyclic ring may contain 0 to 4 heteroatoms, and each heteroatom is independently selected from the group consisting of N, O, and S;
Ra is hydrogen or substituted or unsubstituted monocyclic aryl, or heteroaryl ring systems of 5 or 6 ring atoms or bicyclic aryl or heteroaryl ring systems of 8 to 12 ring atoms, wherein each monocyclic ring may contain 0 to 3 heteroatoms, each bicyclic ring may contain 0 to 4 heteroatoms, and each heteroatom is independently selected from the group consisting of N, O, and S; and
the substituents of Ar1, Ar2, and Ra, when substituted, comprise one to three moieties independently selected from the group consisting of alkyl, alkenyl, alkynyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and dialkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono-alkylamido, di-alkylamido, N,N-cycloalkylamido, sulfonyl, mono-alkyl sulfonyl, di-alkyl sulfonyl, sulfamoyl, mono-alkyl sulfamoyl, di-alkyl sulfamoyl, halophenyl, benzoyl, alkylthio and alkylsulfinyl; or
a hydrate thereof, solvate thereof, prodrug thereof or pharmaceutically acceptable salt thereof;
provided that when Het is a 1,2,4-triazole Z1, Z2, and Z3 are each a bond; Ra is a hydrogen at position 3 of the triazole; Ar1 is a 3,4,5-trimethoxyphenyl at position 4 of the triazole; and Ar2 is a substituted benzene at position 5 of the triazole; then Ar2 is substituted with other than the combination of a nitro and an amino group.
Another aspect of the invention is a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of the present invention and a pharmaceutically acceptable carrier.
Another aspect of the present invention provides a method for treating a pathology linked to a hyperproliferative disorder by administering to a patient in need thereof an anti-mitotic effective amount of the compound of the present invention. One embodiment of this aspect of the present invention provides a method of treating or preventing restenosis in a patient by administering a pharmaceutically effective amount of the compound of the present invention at a predetermined site.
An additional aspect of the invention provides a method for treating inflammation in a patient by administering an effective amount of the compound of the present invention.
Another aspect of the present invention provides a stent device coated with an anti-mitotic effective amount of the compound of the present invention.
FIG. 1 is a table providing the anti-tubulin activity (μM) and cytotoxicity (nM) values for T111-T116;
FIG. 2 is a table illustrating the drug-like properties of triazole compounds;
FIG. 3 is a table providing the cytotoxicities of T115 in drug resistant cancer cell lines and cell line from normal tissue; and
FIG. 4 is a table demonstrating the growth inhibition (log10G150) of cancer cell lines by compounds T111-T115.
The present invention relates to substituted 1,2,4-triazole and 1,2,3-triazole compounds. Also disclosed are methods of treating a patient by administering the triazole compounds.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Patient" means a mammal including a human.
"Effective amount" means an amount of compound of the present invention effective in inhibiting cellular mitosis, and thus producing the desired therapeutic effect.
"Alkyl" means aliphatic hydrocarbon group which may be branched or straight-chained having about 1 to about 10 carbon atoms. Preferred alkyl is "lower alkyl" having about 1 to about 3 carbon atoms; more preferred is methyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. The alkyl group is also optionally substituted by alkoxy, halo, carboxy, hydroxy or R4R5N— (wherein R4 and R5 are independently hydrogen or alkyl, or R4 and R5 taken together with the nitrogen atom to which R4 and R5 are attached form azaheterocyclyl); and preferably optionally substituted by fluoro. Examples of alkyl include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl and hexyl.
"Cycloalkyl" means a non-aromatic monocyclic ring system of about 3 to about 7 carbon atoms. Preferred monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl; more preferred are cyclohexyl and cyclopentyl.
"Aryl" means aromatic carbocyclic radical containing about 6 to about 10 carbon atoms. Exemplary aryl include phenyl or naphthyl, or phenyl or naphthyl substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent" includes hydrogen, hydroxy, halo, alkyl, alkoxy, carboxy, alkoxycarbonyl or Y1Y2NCO—, wherein Y1 and Y2 are independently hydrogen or alkyl.
"Heteroaryl" means about a 5- to about a 10-membered aromatic monocyclic or bicyclic hydrocarbon ring system in which one to three of the atoms in a monocyclic ring system, and one to four of the atoms in a bicyclic ring system, is/are elements(s) other than carbon, for example nitrogen, oxygen or sulfur. The "heteroaryl" may also be substituted by one or more of the above-mentioned "aryl group substituents". Exemplary heteroaryl groups include substituted pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, imidazo[2,1-b]thiazolyl, benzofurzanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl and isoquinolinyl.
"Acyl" means an H—CO— or alkyl-CO— group in which the alkyl group is as previously described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and caproyl.
"Alkoxy" means an alkyl-O— group in which the alkyl group is as previously described. Preferred alkoxy is "lower alkoxy" having about 1 to about 3 carbon atoms; more preferred is methoxy. The alkoxy may be optionally substituted by one or more alkoxy, carboxy, alkoxycarbonyl, carboxylaryl or R4R5N— (wherein R4 and R5 are as defined above). Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, heptoxy, 2-(morpholin-4-yl)ethoxy and 2-(ethoxy)ethoxy.
"Aryloxy" means aryl-O— group in which the aryl group is as previously described.
"Acyloxy" means and acyl-O— group in which the acyl group is as previously described.
"Carboxy" means a HO(O)C— (carboxylic acid) group.
"R4R5N—" means a substituted or unsubstituted amino group, wherein R4 and R5 are as previously described. Exemplary groups include amino (H2N—), methylamino, ethylmethylamino, dimethylamino and diethylamino.
"R4R5NCO—" means a substituted or unsubstituted carbomoyl group, wherein R4 and R5 are as previously described. Exemplary groups are carbamoyl (H2NCO—) are dimethylaminocarbamoyl (Me2NCO—).
"AcylR4N —" means an acylamino group wherein R4 and acyl are as defined herein.
"Halo" means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro.
"Prodrug" means a form of the compound of formula I suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and effective for their intended use. A prodrug is transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, et., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
"Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule(s) is/are H2O.
"Substituted 1,2,4-triazole" means the formula:
wherein positions 3, 4, and 5 are independently substituted; or the formula:
wherein positions 1, 3, and 5 are independently substituted.
One embodiment of the present invention is a compound of formula I wherein Ar1 and Ar2 are independently substituted or unsubstituted benzene, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, 1,2,4-triazole, pyridine, 2(1H)-pyridone, 4(1H)-pyridone, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, tetrazole, naphthalene, tetralin, naphthyridine, benzofuran, benzothiophene, indole, 2,3-dihydroindole, 1H-indazole, indoline, benzopyrazole, 1,3-benzodioxole, benzoxazole, purine, coumarin, chromone, quinoline, tetrahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pyrido[3,2-c]pyridazine, pyrido[3,4-b]-pyridine, 1H-pyrazole[3,4-d]pyrimidine, pteridine, 2(1H)-quinolone, 1(2H)-isoquinolone, 1,4-benzisoxazine, benzothiazole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoxazine, phthalazine, or cinnoline.
Another embodiment of the present invention is a compound of formula I, wherein Ra is substituted or unsubstituted benzene, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, 1,2,4-triazole, pyridine, 2(1H)-pyridone, 4(1H)-pyridone, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, tetrazole, naphthalene, tetralin, naphthyridine, benzofuran, benzothiophene, indole, 2,3-dihydroindole, 1H-indazole, indoline, benzopyrazole, 1,3-benzodioxole, benzoxazole, purine, coumarin, chromone, quinoline, tetrahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pyrido[3,2-c]pyridazine, pyrido[3,4-b]-pyridine, 1H-pyrazole[3,4-d]pyrimidine, pteridine, 2(1H)-quinolone, 1(2H)-isoquinolone, 1,4-benzisoxazine, benzothiazole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoxazine, phthalazine, or cinnoline.
Another embodiment of the present invention is a compound of formula I, wherein Het is a substituted triazole; each of Z1, Z2, and Z3 is a bond; Ar1 and Ar2 are each a substituted benzene; and Ra is hydrogen.
Another embodiment of the present invention are compounds of formula I, wherein Ar1 and Ar2 are each substituted with 1 to 3 alkoxy groups. Species of this embodiment include compounds of formula I, wherein Ar1 and Ar2 are each benzene rings substituted with 1 to 3 alkoxy groups.
Another embodiment of the present invention are compounds of formula I, Ar1, and Ar2 are each substituted with 1 to 3 trifluoromethoxy groups. Species of this embodiment include compounds of formula I, wherein Ar1 and Ar2 are each benzene rings substituted with 1 to 3 trifluoromethoxy groups. Yet another embodiment of the present invention are compounds of formula I, wherein Ar1 is substituted with 1 to 3 alkoxy groups and Ar2 is substituted with a dialkylamino group. Species of this embodiment include compounds of formula I, wherein Ar1 is a benzene ring substituted with 1 to 3 alkoxy groups and Ar2 is a benzene ring substituted with a dialkylamino group.
Another embodiment of the present invention are compounds of formula I, wherein Ar1 is substituted with 1 to 3 alkoxy groups and Ar2 is substituted with a hydroxyl group and an alkoxy group. Species of this embodiment include compounds of formula I, wherein Ar1 is a benzene ring substituted with 1 to 3 alkoxy groups and Ar2 is a benzene ring substituted with a hydroxyl group and an alkoxy group.
Another embodiment of the present invention are compounds of formula I, wherein Ar1 is substituted with 1 to 3 alkoxy groups and Ar2 is substituted with a halogen and an alkoxy group. Species of this embodiment include compounds of formula I, wherein Ar1 is a benzene ring substituted with 1 to 3 alkoxy groups and Ar2 is a benzene ring substituted with a halogen and an alkoxy group.
Another embodiment of the present invention are compounds of formula I, wherein Ar1, is a benzene ring substituted with 1 to 3 alkoxy groups and Ar2 is a substituted indole ring.
Another embodiment of the present invention are compounds of formula I, wherein Ar1 is a benzene ring substituted with 1 to 3 alkoxy groups and Ar2 is a substituted benzimidazole ring.
Another embodiment of the present invention is a compound of Formula II:
wherein Ra, Ar1-3, and Z1-3 are the same as defined above for formula I.
Another embodiment of the present invention is a compound of Formula III:
Another embodiment of the present invention is a compound of Formula IV:
Another embodiment of the present invention are the compounds of Formula V:
wherein R′1, and R′2 are independently selected from:
OH, NH2, OCH3, N(CH3)2, CH2OH, CH2NH2, CH2OCH3, and CH2N(CH3)2.
Another embodiment of the present invention are the following compounds:
Substituents R′3, R′4, and R′5 in T117, T118, and T119 are independently selected from hydrogen and hydrogen bond donor groups containing oxygen and nitrogen, such as hydroxyl, unsubstituted amino, and monoalkylamino.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
The compounds of this invention may be prepared by employing procedures known in the literature starting from known compounds or readily prepared intermediates. Exemplary general procedures follow.
Compounds of formula I can be prepared according to the following scheme, wherein the variables are as described above, excepting those variables which one skilled in the art would appreciate would be incongruent with the method described.
As depicted above in Scheme I, 3,4,5-trimethoxyl benzoyl chloride is added slowly to 1.0 equivalent of amine solution, which is dissolved in chloroform, and mixed with 1.0 equivalent triethylamine at 0-5° C. After the reaction is complete, the chloroform solution is extracted three times by water and concentrated under vacuum. The amide precipitates immediately when the concentrated syrup is cooled to room temperature. The amide purity is sufficient to be used directly for the next step.
Amide is then dissolved in anhydrous chloroform, and 1.05 equivalent Lawesson's Reagent is added at room temperature. The solution is heated to 62° C. under inert gas. The color of the chloroform solution yellows slowly. After the reaction is complete, the product is purified by column chromatography using ethyl acetate and hexane as developing solvents.
The yellow thioamide is suspended in anhydrous alcohol under inert gas atmosphere. With vigorous stirring, the reactants are cooled to 0° C., and 5.0 equivalent of anhydrous hydrazine is slowly added, after which the thioamide is stirred at room temperature, preferably overnight. The alcohol and unreacted hydrazine are then evaporated under vacuum. The syrup is then dissolved in chloroform and extracted by water three times. The organic layer is dried and concentrated under vacuum. The resulting amidrozone is a white solid.
The amidrozone is dissolved in alcohol. 5.0 equivalent of trimethyl orthoformate is then added at room temperature. Several drops of sulfuric acid are added as a catalyst, and the solution is stirred vigorously for 2 hours. After neutralization, the alcohol is evaporated and a compound of formula I is purified by column chromatography using ethyl acetate and hexane as developing solvents.
The compounds of formula I can be included in pharmaceutical compositions to treat, for example, a pathology linked to a hyperproliferative disorder in a patient. Such pathologies include, but are not limited to, restenosis, inflammation, and cancers susceptible to treatment by inhibition of mitotic spindle formation, such as leukemia, lung cancer, colon cancer, central nervous system cancer, ovarian cancer, renal cancer, breast cancer, cervical cancer, prostate cancer, bladder cancer, liver cancer, lymphoma, pancreatic cancer, thyroid cancer, Kaposi's sarcoma, and malignant melanoma.
Therefore, also provided is a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula I and a pharmaceutically acceptable carrier.
In practice, a composition containing a compound of formula I may be administered in any variety of suitable forms, for example, by inhalation, topically, parenterally, rectally or orally. More specific routes of administration include intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, colonical, peritoneal, transepithelial including transdermal, ophthalmic, sublingual, buccal, dermal, ocular, nasal inhalation via insufflation, and aerosol.
A composition containing a compound of formula I may be presented in forms permitting administration by the most suitable route. The invention also relates to administering compositions containing a compound of formula I, which is suitable for use as a medicament in a patient. These compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of oral dosage forms, or injectable solutions, or suspensions.
The choice of vehicle and the compound of formula I in the vehicle are generally determined in accordance with the solubility and chemical properties of the product, the particular mode of administration and the provisions to be observed in pharmaceutical practice. When aqueous suspensions are used they may contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and chloroform or mixtures thereof may also be used. In addition, the compound of formula I may be incorporated into sustained-release preparations and formulations.
For parenteral administration, emulsions, suspensions or solutions of the compounds according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The injectable forms must be fluid to the extent that it can be easily syringed, and proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. Solutions of the compound of formula I as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, irradiation, microfiltration, and/or by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
Sterile injectable solutions are prepared by incorporating the compound of formula I in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
Topical administration, gels (water or alcohol based), creams or ointments containing the compound of formula I may be used. The compound of formula I may be also incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through transdermal barrier.
For administration by inhalation, the compound of formula I inhibitor may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
Compositions according to the invention may also be formulated in a manner which resists rapid clearance from the vascular (arterial or venous) wall by convection and/or diffusion, thereby increasing the residence time of the particles at the desired site of action. A periadventitial depot comprising a compound according to the invention may be used for sustained release. One such useful depot for administering a compound according to the invention may be a copolymer matrix, such as ethylene-vinyl acetate, or a polyvinyl alcohol gel surrounded by a Silastic shell. Alternatively, a compound according to the invention may be delivered locally from a silicone polymer implanted in the adventitia.
An alternative approach for minimizing washout of a compound according to the invention during percutaneous, transvascular delivery comprises the use of nondiffusible, drug-eluting microparticles. The microparticles may be comprised of a variety of synthetic polymers, such as polylactide for example, or natural substances, including proteins or polysaccharides. Such microparticles enable strategic manipulation of variables including total dose of drug and kinetics of its release. Microparticles can be injected efficiently into the arterial or venous wall through a porous balloon catheter or a balloon over stent, and are retained in the vascular wall and the periadventitial tissue for at least about two weeks. Formulations and methodologies for local, intravascular site-specific delivery of therapeutic agents are discussed in Reissen et al. (Am. C'oll. Cardial. 1994; 23: 1234-1244), the entire contents of which are hereby incorporated by reference.
A composition according to the invention may also comprise a hydrogel which is prepared from any biocompatible or non-cytotoxic (homo or hetero) polymer, such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge. Such polymers have been described, for example, in application WO93/08845, the entire contents of which are hereby incorporated by reference. Certain of them, such as, in particular, those obtained from ethylene and/or propylene oxide are commercially available.
In the use of compounds according to the invention for treating pathologies which are linked to hyperproliferative disorders, the compounds according to the invention can be administered in different ways. For the treatment of restenosis, the compounds of the invention are administered directly to the blood vessel wall by means of an angioplasty balloon, which is coated with a hydrophilic film (for example a hydrogel) which is saturated with the compound, or by means of any other catheter containing an infusion chamber for the compound, which can thus be applied in a precise manner to the site to be treated and allow-the compound to be liberated locally and efficiently at the location of the cells to be treated. This method of administration advantageously makes it possible for the compound to contact quickly the cells in need of treatment.
The treatment method of the invention preferably consists in introducing a compound according to the invention at the site to be treated. For example, a hydrogel containing composition can be deposited directly onto the surface of the tissue to be treated, for example during a surgical intervention.
Advantageously, the hydrogel is introduced at the desired intravascular site by coating a catheter, for example a balloon catheter, and delivery to the vascular wall, preferably at the time of angioplasty. In a particularly advantageous manner, the saturated hydrogel is introduced at the site to be treated by means of a balloon catheter. The balloon may be chaperoned by a protective sheath as the catheter is advanced toward the target vessel, in order to minimize drug washoff after the catheter is introduced into the bloodstream.
Another embodiment of the invention provides for a compound according to the invention to be administered by means of perfusion balloons. These perfusion balloons, which make it possible to maintain a blood flow and thus to decrease the risks of ischaemia of the myocardium, on inflation of the balloon, also enable the compound to be delivered locally at normal pressure for a relatively long time, more than twenty minutes, which may be necessary for its optimal action. Alternatively, a channeled balloon catheter ("channeled balloon angioplasty catheter", Mansfield Medical, Boston Scientific Corp., Watertown, Mass.) may be used. The latter consists of a conventional balloon covered with a layer of 24 perforated channels, which perfuse via an independent lumen through an additional infusion orifice.
Various types of balloon catheters, such as double balloon, porous balloon, microporous balloon, channel balloon, balloon over stent and hydrogel catheter, all of which may be used to practice the invention, are disclosed in Reissen et al. (1994), the entire contents of which are hereby incorporated by reference.
The use of a perfusion balloon catheter is especially advantageous, as it has the advantages of both keeping the balloon inflated for a longer period of time by retaining the properties of facilitated sliding and of site-specificity of the hydrogel are gained simultaneously.
Another aspect of the present invention relates to a pharmaceutical composition comprising a compound according to the invention and poloxamer, such as Poloxamer 407 is a non-toxic, biocompatible polyol, commercially available (BASF, Parsippany, N.J.).
A poloxamer impregnated with a compound according to the invention may be deposited directly on the surface of the tissue to be treated, for example during a surgical intervention. Poloxamer possesses essentially the same advantages as hydrogel while having a lower viscosity.
The use of a channel balloon catheter with a poloxamer impregnated with a compound according to the invention is especially advantageous. In this case, the advantages of both keeping the balloon inflated for a longer period of time while retaining the properties of facilitated sliding, and of site specificity of the poloxamer, are gained simultaneously.
The compounds of the present invention may also be formulated for use in conjunction with other therapeutic agents such as agents or in connection with the application of therapeutic techniques to address pharmacological conditions, which may be ameliorated through the application of a compound of formula I, such as in the following:
The compounds of the present invention may be used in the treatment of restenosis post angioplasty using any device such as balloon, ablation, or laser techniques.
The compounds of the present invention may be used in the treatment of restenosis following stent placement in the vasculature either as 1) primary treatment for vascular blockage, or 2) in the instance where angioplasty using any device fails to give a patent artery.
The compounds of the present invention may be used either orally, by parenteral administration or the compound could be applied topically through the intervention of a specific device or as a properly formulated coating on a stent device.
In one aspect, the coating on a stent device is formed by applying polymeric material in which the compound of the invention is incorporated to at least one surface of the stent device.
Polymeric materials suitable for incorporating the compound of the invention include polymers having relatively low processing temperatures such as polycaprolactone, poly (ethylene-co-vinyl acetate) or poly (vinyl acetate or silicone gum rubber and polymers having similar relatively low processing temperatures. Other suitable polymers include non-degradable polymers capable of carrying and delivering therapeutic drugs such as latexes, urethanes, polysiloxanes, styrene-ethylene/butylene-styrene block copolymers (SEBS) and biodegradable, bioabsorbable polymers capable of carrying and delivering therapeutic drugs, such as poly-DL-lactic acid (DL-PLA), and poly-L-lactic acid (L-PLA), polyorthoesters, polyiminocarbonates, aliphatic polycarbonates, and polyphosphazenes.
A porosigen may also be incorporated in the drug-loaded polymer by adding the porosigen to the polymer along with the therapeutic drug to form a porous drug-loaded polymeric membrane.
"Porosigen" means as any moiety, such as microgranules of sodium chloride, lactose, or sodium heparin, for example, which will dissolve or otherwise be degraded when immersed in body fluids to leave behind a porous network in the polymeric material. The pores left by such porosignes can typically be as large as 10 microns. The pores formed by porosignes such as polyethylene glycol (PEG), polyethylene oxide/polypropylene oxide (PEO/PPO) copolymers, for example, can also be smaller than one micron, although other similar materials which form phase separations from the continuous drug loaded polymeric matrix and can later be leached out by body fluids can also be suitable for forming pores smaller than one micron. The polymeric material can be applied to the stent while the therapeutic drug and porosigen material are contained within the polymeric material, to allow the porosigen to be dissolved or degraded by body fluids when the stent is placed in a blood vessel, or alternatively, the porosigen can be dissolved and removed from the polymeric material to form pores in the polymeric material prior to placement of the polymeric material combined with the stent within a blood vessel.
If desired, a rate-controlling membrane can also be applied over the drug loaded polymer, to limit the release rate of the compound of the invention. The rate-controlling membrane can be added by applying a coating form a solution, or a lamination. The rate-controlling membrane applied over the polymeric material can be formed to include a uniform dispersion of a porosigen in the rate-controlling membrane, and the porosigen in the rate-controlling membrane can be dissolved to leave pores in the rate-controlling membrane typically as large as 10 microns, or as small as 1 micron, for example, although the pores can also be smaller than 1 micron. The porosigen in the rate-controlling membrane can be, for example sodium chloride, lactose, sodium heparin, polyethylene glycol, polyethylene oxide/polypropylene oxide copolymers, or mixtures thereof.
In another aspect, the coating on the stent device can be formed by applying the compound of the invention to at least one surface of the stent device to form a bioactive layer and then applying one or more coats of porous polymeric material over the bioactive layer, such that the porous polymeric material has a thickness adequate to provide a controlled release of the compound.
In one aspect, the porous polymeric material is composed of a polyamide, parylene or a parylene derivative applied by catalyst-free vapor desposition. "Parylene" refers to a polymer based on p-xylylene and made by vapor phase polymerization as described in U.S. Pat. No. 5,824,049, incorporated herein by reference.
Alternatively, the porous polymeric material is applied by plasma deposition. Representative polymers suitable for plasma deposition include poly (ethylene oxide), poly (ethylene glycol), poly (propylene oxide), and polymers of methane, silicone, tetrafluoroethylene tetramethyldisiloxane, and the like.
Other suitable polymer systems include polymers derived from photopolymerizable monomers such as liquid monomers preferably having at least two cross linkable C—C (Carbon to Carbon) double bonds, and being a non-gaseous addition polymerizable ethylenically unsaturated compound, having a boiling point above 100° C., at atmospheric pressure, a molecular weight of about 100-1500 and being capable of forming high molecular weight addition polymers readily. More preferably, the monomer is preferably an addition photopolymerizable polyethylenically unsaturated acrylic or methacrylic acid ester containing two or more acrylate or methacrylate groups per molecule or mixtures thereof.
Representative examples of such multifunctional acrylates are ethylene glycol diacrylate, ethylene glycol dimethacrylate, trimethylopropane triacrylate, trimethylopropane trimethacrylate, pentaerythritol tetraacrylate, or pentaerythritol tetramethacrylate. 1 amides of (meth) acrylic acid, such as N-methylol methacrylamide butyl ether are also suitable, N-vinyl compounds such as N-vinyl pyrrolidone, vinyl esters of aliphatic monocarboxylic acids such as vinyl oleate, vinyl ethers of diols such as butanediol-1,4-divinyl ether and allyl ether and allyl ester are also suitable. Also included are other monomers such as the reaction products of di- or polyepoxides such as butanediol-1,4-diglycidyl ether or bisphenol A diglycidyl ether with (meth) acrylic acid. The characteristics of the photopolymerizable liquid dispersing medium can be modified for the specific purpose by a suitable selection of monomers or mixtures thereof.
Other useful polymer systems include a polymer that is biocompatible and minimizes irritation to the vessel wall when the stent is implanted. The polymer may be either a biostable or a bioabsorbable polymer depending on the desired rate of release or the desired degree of polymer stability. Bioabsorbable polymers that could be used include poly (L-lactic acid), polycaprolactone, poly (lactide-co-glycolide), poly (hydroxybutyrate), poly (hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly (glycolic acid), poly (D, L-lactic acid), poly (glycolic acidcotrimethylene carbonate), polyphosphoester, polyphosphoester urethane, poly (amino acids), cyanoacrylates, poly (trimethylene carbonate), poly (iminocarbonate), copoly (ether-esters) (e.g., PEO/PLA), polyalkylene oxlates, polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid. Also, biostable polymers with a relatively low chronic tissue response such as polyurethanes, silicones, and polyesters could be used and other polymers could also be used if they can be dissolved and cured or polymerized on the stent such as polyolefins, polyisobutylene and ethylene-alphaolefine copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitril-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; polyamides, such as Nylone 66 and polycaprolactam; alkyl reins, polycarbonates; polyoxymethylenes; polyimides, polyethers; epoxy reins, polyurethanes; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane, cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose.
In addition to plasma deposition and vapor phase deposition, other techniques for applying the various coatings on the stent surfaces may be employed. For example, a polymer solution may be applied to the stent and the solvent allowed to evaporate, thereby leaving on the stent surface a coating of the polymer and the therapeutic substance. Typically, the solution can be applied to the stent by either spraying the solution onto the stent or immersing the stent in the solution.
The compounds of the present invention may be used in the treatment of restenosis in combination with any anticoagulant, antiplatelet, antithrombotic or profibrinolytic agent. Often patients are concurrently treated prior, during and after interventional procedures with agents of these classes either in order to safely perform the interventional procedure or to prevent deleterious effects of thrombus formation. Some examples of classes of agents known to be anticoagulant, antiplatelet, antithrombotic or profibrinolytic agents include any formulation of heparin, low molecular weight heparins, pentasaccharides, fibrinogen receptor antagonists, thrombin inhibitors, Factor Xa inhibitors, or Factor VIIa inhibitors.
The compounds of the present invention may be used in combination with any antihypertensive agent or cholesterol or lipid-regulating agent in the treatment of restenosis or atherosclerosis concurrently with the treatment of high blood pressure or atherosclerosis. Some examples of agents that are useful in the treatment of high blood pressure include compounds of the following classes: beta-blockers, ACE inhibitors, calcium channel antagonists and alpha-receptor antagonists. Some examples of agents that are useful in the treatment of elevated cholesterol levels or disregulated lipid levels include compounds known to be HMGCoA reductase inhibitors and compounds of the fibrate class.
The compounds of the present invention may be used in the treatment of various forms of cancer either alone or in combination with compounds known to be useful in the treatment of cancer.
The percentage of compound of formula I in the compositions used in the present invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. A dose employed may be determined by a physician or qualified medical professional, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 10, mg/kg body weight per day by intravenous administration. In each particular case, the doses are determined in accordance with the factors distinctive to the patient to be treated, such as age, weight, general state of health and other characteristics, which can influence the efficacy of the compound according to the invention.
The compound of formula I used in the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the compound of formula I may be administered 1 to 4 times per day. Of course, for other patients, it will be necessary to prescribe not more than one or two doses per day.
The following non-limiting examples set forth hereinbelow illustrate certain aspects of the invention.
3-(3,4,5-trimethoxyl)phenyl-4-(4-methoxyl)phenyl-1,2,4(H) triazole (T111)
Compound T111 was prepared according to Scheme 1. The following physical data was obtained: 1H NMR (400 MHz, CDCl3), δ: 3.64 (s, 6H), 3.84 (d, 6H), 6.70 (s, 2H), 6.98 (d, 2H), 7.19 (d, 2H), 8.25 (s, 1H); MS (ESI): m/z=342 (M++1); Anal. (C18H19O4N3) C, H, O, N; mp: 163-165° C.
3-(3,4,5-trimethoxyl)phenyl-4-(N,N-dimethylamino)phenyl-1,2,4(H) triazole (T112)
Compound T112 was prepared according to Scheme 1. The following physical data was obtained: 1H NMR (400 MHz, CDCl3), δ: 2.99 (s, 6H), 3.65 (s, 6H), 3.83 (s, 3H), 6.71 (d, 2H), 6.76 (s, 2H), 7.09 (d, 2H), 8.22 (s, 1H); MS (ESI): m/z=355 (M++1); Anal. (C19H20O3N4) C, H, O, N; mp: 145-147° C.
3-(3,4,5-trimethoxyl)phenyl-4-(3-hydroxyl,4-methoxyl)phenyl-1,2,4(H) triazole (T113)
Compound T113 was prepared according to Scheme 1. The following physical data was obtained: 1H NMR (400 MHz, CDCl3), δ: 3.66 (s, 6H), 3.83 (s, 3H), 3.94 (s, 3H), 6.18 (s, 1H), 6.74 (m, 3H), 6.89 (m, 2H), 8.24 (s, 1H); MS (ESI): m/z=358 (M++1); Anal. (C18H19O5N3) C, H, O, N; mp: 197-198° C.
3-(3,4,5-trimethoxyl)phenyl-4-(3-fluoro,4-methoxyl)phenyl-1,2,4(H) triazole (T114)
Compound T114 was prepared according to Scheme 1. The following physical data was obtained: 1H NMR (400 MHz, CDCl3), δ: 3.67 (s, 6H), 3.89 (s, 3H), 3.93 (s, 3H), 3.69 (s, 2H), 7.05 (m, 3H), 8.25 (s, 1H); MS (ESI): m/z=360 (M++1); Anal. (C18H18O4N3F) C, H, O, N, F; mp: 151-152° C.
3-(3,4,5-trimethoxyl)phenyl-4-(N-methyl-6-(1H)indolyl)-1,2,4(H) triazole (T115)
Compound T115 was prepared according to Scheme 1. The following physical data was obtained: 1H NMR (400 MHz, CDCl3), δ: 3.52 (s, 6H), 3.80 (s, 3H), 3.84 (s, 3H), 6.51 (s, 1H), 6.73 (s, 2H), 7.04 (d, 1H), 7.17 (s, 1H), 7.37 (d, 1H), 7.559 (s, 1H), 8.30 (s, 1H); MS (ESI): m/z=365 (M++1); Anal. (C20H20O3N3) C, H, O, N; mp: 157-159° C.
Determination of Biological Activity
T112, T113, T115 and T116 demonstrate apparent inhibitory constants (IC50s) similar to those observed for known inhibitors (FIG. 1). Tubulin polymerization assays were conducted using the CytoDYNAMIX Screen™ 03 (Cytoskeleton Inc., CO.) assay system following the manufacturer's instructions. Tubulin (>99% pure, Cat# TL238) was reconstituted to 3 mg/ml using G-PEM buffer (80 mM PIPES pH6.8, 0.5 mM EGTA, 2.0 mM MgCl2, 1.0 mM GTP plus 5% glycerol). 100 μl of the reconstituted tubulin was added to each well of a pre-warmed 96-well plate. The tubulin polymerized efficiently at 37° C. reaching a maximum OD340nm of approximately 0.12 in 50 minutes (3000 seconds). Compounds were added at varying concentrations (ranging from 0.03-30 μM) and their effects on polymerization determined over a period of 60 minutes. The absorbance at OD340nm was recorded every 60 sec. using a TECAN GENios multifunction microplate reader (TECAN U.S. Inc., Research Triangle Park, N.C.) at 37° C. Apparent IC50 inhibitory values for the compounds were determined by a non-linear regression analysis with Prism 3.03 (Graphpad Software Inc., San Diego, Calif.) using area under curve (AUC) for the polymerization profiles.
In vivo drug effects require that a compound be readily absorbed into cells and maintained at therapeutic but not toxic doses. A measure of a compound's bioavailability can be estimated using values of the hydrophobic/hydrophilic balance, as measured by logP, and the compounds molecular weight. Calculated logP values were predicted using the ClogP program (Daylight Chemical Information Systems, Santa Fe, N. Mex.) and the molecular weight of a compound can be readily calculated as the sum of the weights of the individual atoms. A study by Lipinski et al. (Experimental and computational approaches to estimate solubility and permeability in drug discovery and developmental setting, Adv. Drug Del. Rev. 23, 3-25 (1997).) has shown that a value of ClogP≦5 and a molecular weight≦500 Daltons are exhibited by 'orally available druglike' compounds. Other "drug like" properties include: 0-5 hydrogen bond donor atoms; 5-10 hydrogen bond acceptor atoms; 1-4 rings; and 2-8 rotatable bonds. All compound tested adhere to these "rules of thumb" for drug-likeness (FIG. 2).
The cytotoxic effects of the compounds were examined using human cervix epithelial adenocarcinoma cell line (HeLa), human breast carcinoma cell line (ZR-75-1), human colon carcinoma cell line (HCT116), human cervix carcinoma cell line (KB-3-1) and its multiple drug resistance (MDR+) subclone (KB-V1) (FIG. 1). A further cytotoxic evaluation of T115 was also performed using major cancer cell lines and their drug resistant derivatives (FIG. 3). The cells were maintained at 37° C., 5% CO2 atmosphere in humidified incubator. Cells in logarithmic phase were diluted to a density of 20000-60000 cells/ml in culture media based on growth characteristics. For each well of a 96-well microplate, 100 μL cell dilution was seeded and allowed to attach overnight, then exposed to varying concentrations (10−5−10−12M) of compounds for 72-hours (37° C., 5% CO2 atmosphere). The cells were stained with 0.5 mg/ml MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliym bromide) and incubated at culture condition for 3 hours. After the media were removed, 150 μl DMSO was added into each well to dissolve the purple crystals and the absorbance of the solutions at OD595nm was recorded. Compounds were tested in triplicate in least three independent assays. The IC50 values were determined by a non-linear regression analysis using Prism 3.03 (Graphpad Software Inc., San Diego, Calif.). Average values are reported here (FIGS. 1 and 3).
A detailed evaluation of cancer cell growth inhibition effect for T111-T115 was conducted by the NIH-National Center Institute (NCI) Developmental Therapeutic Program (DTP) (FIG. 4). A large negative number denotes stronger activity. For example, compound T115 exhibits exceptionally strong activity against EKVX (<−8.00), NCI—H322M (<−8.00), NCI—H522 (<−8.00) cells associated with non-small cell lung cancer. Overall, T115 performed uniformly well across the 60-cell line panel.
The foregoing examples and description of the preferred embodiments should be taken as illustrating, rather than as limiting the present invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present invention as set forth in the claims. Such variations are not regarded as a departure from the spirit and script of the invention, and all such variations are intended to be included within the scope of the following claims.
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Every organization is guided by a particular set of values or principles, whether or not they are deliberately chosen and well-articulated. This course, designed for people who are new to SVP, uses storytelling and activities to illuminate SVP's shared principles, and invites participants to explore the intersection between their personal values and SVP's principles. The course is designs so that other organizations can easily swap in their values or principles and make it relevant for their new donors, volunteers or members.


text:
"Psycho Dandy" forced to police his moosetache
Author Topic: "Psycho Dandy" forced to police his moosetache (Read 3067 times)
via "The Chap."
A man has vowed to shave off his handlebar moustache after being convicted of assaulting some teenage boys who mocked his pride and joy.
The Chap, whose editorial staff are occasionally on the receiving end of casual insults and mockery on account of their eccentric appearance and striking facial furniture, at first sympathised with Mr. Law, even in the light of previous court appearances for affray and threatening behaviour. But when one discovers that Law also has a conviction for manslaughter - he was jailed in 2000 for four years after he stabbed his brother to death - one realises that this is no mere eccentric, but someone who has delved rather too deeply into the darker side of dandyism and moustache cultivation. Let us give thanks that for every crazed Charles Law, there are a dozen jovial Jimmy Edwards.
http://www.thechap.net/content/section_news/law.html
KickTheBobo
Re: "Psycho Dandy" forced to police his moosetache
geez. there are other ways of deflecting all that "What's up, Liam Neeson?" attention without growing that disease magnet. try a hat & shades next time, chap.
mike_b
This website is completely insane
Are these guys for real?
If so, they owe Billy Childish royalties.
Re: This website is completely insane
Quote from: mike_b on December 08, 2008, 11:02:07 PM
Billy Childish must owe Oliver Wendell Holmes, Jr. big time.
I really like that he has only vowed to shave off his handlebar moustache. If he was really going to do it, he would have shaved it right away. That moustache isn't going anywhere, because the moustache is running the show.
I bet that any time he gets in front of the bathroom mirror and the vaguest notion of shaving the moustache off creeps into his mind, his face muscles involuntarily twitch, making the ends of the moustache bob up and down, and he hears a voice in his head - most likely an old-timey boxer's voice - saying "You don't want to do this, Charles. What would you do without me, Charles? A day without a moustache? Why, Charles, that would be a day where they all have to die, wouldn't it? Let's just go buy some more moustache wax, old chum. That way, Charles, we won't have to hear the screaming again."
You know, this could have been Spoony, if he'd continued on in his role as a moustache enthusiast.
This may be the year I will disappear.
iAmBaronVonTito
i remain to this day a Spoony mustache enthusiast.

redpajama_set_name: RedPajamaCommonCrawl


text:
Councillor Sarah Kerr
Wokingham – Evendons Ward
Should Heathrow Grow?
It has been a little while since I last wrote a blog post. The summer holidays meant balancing my council duties with my two young boys, and of course the family holiday I desperately needed. Now school is back in action, I'm playing catch up.
There's a lot going on in local politics at the moment, and the big topic is the Heathrow expansion. I would like to give special thanks to my friend and colleague Paul Fishwick for all the research he has done regarding the proposed expansion of Heathrow Airport, which I am including in this article. Apologies for the length and detail of this article, but I hope it provides you with the facts that have helped determine my position on this.
Heathrow Airport is already the largest UK airport with a capped 480,000 annual flights. A third runway could mean 260,000 additional flights a year taking the total flight movements to 740,000[1], impacting on the surrounding area, including Wokingham Borough.
Why is a third runway required?
Apparently, there is an urgent need for new capacity for business travelers. However, according to the Civil Aviation Statistics report that looked at the UK's five largest airports (Heathrow, Gatwick, Luton, Stanstead and Manchester) between 2006 and 2016, the number of flights made for business at these airports has not increased.
Also, the Department for Transport (DfT) UK Aviation Forecasts (2017)[2] suggest that a new runway will make little difference to the number of flights taken for business across the UK in the future with the Transport Committee's report (page 17) stating that "the passenger growth facilitated by a North Western Runway scheme is accounted for almost entirely by leisure passengers and international transfer passengers".
Most flights are leisure flights, and most of these leisure flights are taken by a small number of wealthy fliers who take multiple flights each year. According to the Campaign for Better Transport, just 15% of the UK population take about 70% of all flights[3].
A bigger airport would only really serve the interests of frequent flyers, with the majority of the population paying for the consequences (of which I discuss below).
Impact on regional airports
The Department for Transport (2017)[4] indicates that the latest forecasts suggest that regional airports will lose out from a Heathrow Expansion since, with the third runway, they will have 17 million fewer passengers by 2050 than they would without it. This means people would be travelling further to get to larger airports like Heathrow, putting more traffic on the roads which is not only an inconvenience, but increases pollutants into the atmosphere.
The Effect on Climate Change
The Committee on Climate Change has stated that Heathrow is already the biggest single source of greenhouse gases in the UK[5].
According to the latest Department for Business, Energy & Industrial Strategy (DBEIS[6]), the 1990 to 2017 Greenhouse gas emissions for the UK Transport sector covers 27% which is now the largest of any sector. In addition, between 1990 and 2017 the percentage drop in greenhouse gas emissions has been a tiny 2%, and zero between the latest reporting years 2016-17. By contrast energy has reduced by 60% and waste management by 69%. The Aviation sector (Table 14) has not improved between 1990 and 2017. Adding another runway, with more flights will only make matters worse.
Heathrow's own figures[7] show a total of 173 MtCO2 MORE carbon emitted, over 2022-2050, with the 3rd runway than without building it. The emissions could reach 25MtCO2 per year from flights alone. The increased CO2 would be as much as 9MtCO2 per year more, in the peak year (2035) than with 2 runways. The total extra CO2 from more surface access transport would be 7MtCO2 over that time period. The extra CO2 from all the construction work would be 3.7MtCO2, to build it all. The total of all that would be 173MtCO2 MORE carbon produced in total (flights, surface access + construction) than if the runway was not built. The estimates may be on the low side, as Heathrow has factored in future carbon efficiencies. Heathrow has taken no account of the fact that we now have a net zero target for 2050.
Further Developments
Since the third runway was approved in June 2018, there have been several developments in climate science and policy that make an even stronger case for withdrawing and reviewing the decision to proceed.
In December 2015, the UK – along with almost every other country in the world – has agreed to a global deal to limit global warming to "well below" 2°C above pre-industrial levels, with an aspiration to limit rises to 1.5°C. However, emissions reduction commitments currently fall well short of what is needed to achieve this aim. Even if all existing commitments were met, the world would see warming of 3 to 4.5°C – which would be catastrophic for millions of people. In this context the UK must do far more to reduce emissions.
However, since Parliament approved the Airports National Policy Statement[8] (NPS) on 25 June 2018, several scientific and political developments have further demonstrated the incompatibility of the decision to expand Heathrow with meeting the UK's climate goals:
On 28 June 2018, the Committee on Climate Change's (CCC) annual progress report to Parliament[9] warned that "the UK is not on course to meet the legally binding fourth and fifth carbon budgets" as set out in the Climate Change Act, and that much greater action is required, particularly in the transport sector. The stalled progress of the last five years was described as "now an acute concern".
On 8 October, the IPCC's special report[10] laid out in sobering clarity the catastrophic impacts of 2 degrees' warming compared to 1.5 degrees. The report, coordinated between 2,000 climate scientists, reiterated the need for "rapid and far-reaching transitions in energy, land, urban and infrastructure (including transport and buildings), and industrial systems" and made clear the necessity of halving global emissions within just 12 years.
The following week, the UK, Welsh and Scottish governments formally requested updated advice from the CCC regarding tightening long-term emissions reduction targets and the transition to a net zero-carbon economy, in light of the Paris Agreement.
On 26 November the Met Office's UK Climate Prediction 2018[11] provided the clearest assessment yet of what the UK will experience from the changing climate: rising sea levels, increased temperatures, and changing patterns of rainfall[12].
On 27 November the UN's Emissions Gap Report 2018[13] set out the gulf between action required to meet Paris goals and that so far pledged by national governments. The report outlined humanity's current trajectory – more than 3 degrees of warming by 2100 – and the scale of action required to get back on track: a fivefold increase in ambition compared to current ambition.
Western Rail Link and Southern rail Access
As indicated in the DBEIS[14] all sectors of the economy, especially the transport sector must make deep cuts in emissions and that includes aviation. Expanding Heathrow Airport will only increase greenhouse gas emissions from more flights and road transport cars, vans, freight etc as there is no provision for expansion of the rail network to include the Western Rail Link from the Great Western railway and the Southern Access Link.
The Heathrow Airport Consultation document[15] page 4 table 2 only states "work with stakeholders to influence the delivery of the Western and Southern rail links". That statement provides little guarantee that either of the rail accesses will be provided at any time.
With no direct rail access to Heathrow Airport, residents living to the west and south west of the airport are more likely to drive or use a taxi, including those who live within Wokingham Borough area to get to the airport as the alternative modes are considerably lengthy and not cost effective for example via London Paddington.
Additional Housing
An expanded Heathrow Airport with an additional 123,000 jobs (currently 110,000) [16] will also put pressure on more housing development along the 'M4 commuter corridor' in areas such as Wokingham Borough where a recent Housing Consultation has given a 95% No to more housing[17]. Additional housing will also put pressure on the local and strategic highway network as there is no programme for the introduction of the two-rail links highlighted above.
More Air Pollution and noise
Air pollution locally is way above legal limits and gets worse towards Heathrow. Heathrow, and the surrounding area, already suffers from illegal levels of air pollution. Dirty air already causes over 9,000 early deaths in London each year[18]. Not only will expanding Heathrow mean more flights, but more traffic on the roads from people travelling to the airport. This is likely to cause even more air pollution, including additional traffic locally which will add to the poor air quality in many parts of the borough and make the goal of Wokingham Borough becoming carbon neutral by 2030 even more difficult.
The Heathrow Expansion summary document page 26[19] states; "When public transport improvements are in place, there could be a case for introducing a congestion charge." However, there is no time planned for the introduction of the Western and Southern Rail links and there are doubts now over the delivery of HS2.
Additional car parking
However, there are plans to construct a Southern and Northern Parkway car parks[20] within the phased development and this has been quoted as the "worlds largest car park for 50,000 vehicles".[21] The traffic for these car parks will use the existing highway network, where Heathrow Airport are planning on improvements to create more capacity at congested locations. More traffic getting to Heathrow Airport equates to more air pollution.
Flight Paths
Already local people must endure around 1,300 noisy planes landing and taking off at Heathrow every day, many flight paths are over Wokingham. It should be noted that this is with 2 runways with around 480,000 flights per annum. With a 3rd runway this could rise by 250,000 flights. There are significant differences in take-offs and landings when the wind is in the 'easterly' half as they fly low over this area including up to midnight and from 05:30am.
Wokingham Borough Council, along with many other local authorities and the UK Government, have agreed to a Climate Emergency[22]. The details of the Climate Emergency have yet to be developed and agreed, but there is only 10 years to take drastic action and if Wokingham Borough Council are serious about Climate Change they must object to the expansion of Heathrow as you can't be
Supporting the Climate Change Emergency and Heathrow Airport Expansion?
The two are incompatible and no amount of conditions being attached to the support of it will make a difference. Heathrow cannot as we've seen from the evidence comply with the emissions conditions that would need to be attached in order to make this compatible with our commitment to climate change. They claim they can and will proceed to build with conditional support, but it is only after it is built that we will see that they can't meet those conditions and then it's too late. The only way forward is for this council to firmly state that it does not support the expansion. Any conditions attached will just weaken that stance. My colleagues and I (the Wokingham Liberal Democrat Group) have submitted our own response to the Heathrow consultation giving a firm 'no.'
[1] https://www.heathrowexpansion.com/the-expansion-plan/facts-and-figures/
[2] https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/781281/uk-aviation-forecasts-2017.pdf?_ga=2.30499709.376903101.1566914938-1912789317.1546118658
[3] https://bettertransport.org.uk/sites/default/files/pdfs/Air%20Traffic%20Controls%20report.pdf
[4] https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/653879/updated-appraisal-report-airport-capacity-in-the-south-east.pdf
[5] Airportwatch
[6] https://www.gov.uk/government/statistics/final-uk-greenhouse-gas-emissions-national-statistics-1990-2017
[7] https://aec.heathrowconsultation.com/wp-content/uploads/sites/5/2019/06/11-Volume-1-PEIR-Chapter-9-Carbon-and-greenhouse-gases.pdf
[8] https://www.gov.uk/government/publications/airports-national-policy-statement
[9] https://www.theccc.org.uk/publication/reducing-uk-emissions-2018-progress-report-to-parliament/
[10] https://www.ipcc.ch/site/assets/uploads/2018/11/pr_181008_P48_spm_en.pdf
[11] https://www.metoffice.gov.uk/research/approach/collaboration/ukcp/index
[12] https://www.metoffice.gov.uk/research/collaboration/ukcp
[13] https://www.unenvironment.org/resources/emissions-gap-report-2018
[14] https://www.gov.uk/government/statistics/final-uk-greenhouse-gas-emissions-national-statistics-1990-2017
[15] https://aec.heathrowconsultation.com/
[16] https://b9kdp3cmc3m1gtje53fj9gdn-wpengine.netdna-ssl.com/wp-content/uploads/2017/08/Taking-Britain-Further-Summary-Pages-200dpi_easyread.pdf
[17] Wokingham Borough Council meeting of the Council 18th July 2019.
[18] https://www.london.gov.uk/what-we-do/environment/pollution-and-air-quality/health-and-exposure-pollution
[20] https://aec.heathrowconsultation.com/plans/phase-4/
[21] https://stopheathrowpollutingus.org/
[22] https://wokingham.moderngov.co.uk/ieListDocuments.aspx?CId=131&MId=3269
Author Sarah KerrPosted on 2019-09-19 Categories Uncategorized
2 thoughts on "Should Heathrow Grow?"
Mel Davies says:
Thanks for publishing this. Well done for researching this and writing a good precis. There's a heck of a lot of information here and it looks like Wokingham Borough Council have not thought too much about the consequences of the LHR expansion. This one thing will make the Climate Emergency Action Plan difficult to achieve.
Incidentally, as I skim through your attachments I noticed in Sect 9.2.5 of the Preliminary Environmental Report that Wokingham Borough are not among the councils that were considered!
What do the Lib Dems think should happen instead of a LHR expansion?
I must say, if it's all about the hub capacity thing, is it really such a terrible thing if some flights change in paris or amsterdam or gatwich instead of heathrow ? Obviously there are landing fees etc, but how much benefit is really derived from flights coming in and passengers transferring and going straight out on another flight ? and we should weigh that against environmental considerations. To be honest not so much for us, but for the poor sods that live closer to the airport. Pretty sure that there are plenty of people who live in our borough for whom, heathrow is a big boon to their businesses / jobs. Aren't we always being told the hub model is dying anyway ? and more point to point flights take place now, and that's why airbus can't sell the A380 ? Mind you on the other hand you could argue that the problem isn't runways, it's the number of flights. And that much less busy airports like say Madrid has 4 runways for a fraction of the traffic that heathrow handles with 2. That it's dangerous to have such little slack in the system and makes it a nightmare when there's any disruption to get back to normal. However, it would be niave in the extreeme to believe that they'll build another runway, especially at the cost that it would be at heathrow, and not be constantly pushing to increase the number of flights to fill the capacity. I can't help but wonder if an airport more central, Birmingham, swindon, etc, wouldn't better cater to the wider population rather than an ever increasing heathrow. Longer term, planes do get quieter and cleaner, at what point they'll be able to make "clean" passenger planes remains to be seen.
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Published and promoted by Sarah Kerr, 83 Evendons Lane, Wokingham, Berkshire, RG41 4AD.
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text:
Q: C++0x Initializer Lists and Direct3D 9 Vertex Declaration I am wanting to resolve the following warning when concatenating a vertex declaration for use in Direct3D 9.0
int elements = 1 + useNormals + useTextures + useColors + 1;
D3DVERTEXELEMENT9 customvertex[elements];
customvertex[0] = POSITIONELEMENT;
int i = 1;
if (useNormals) { customvertex[i] = NORMALELEMENT; i += 1; }
if (useTextures) { customvertex[i] = TEXTUREELEMENT; i += 1; }
if (useColors) { customvertex[i] = COLORELEMENT; i += 1; }
customvertex[i] = D3DDECL_END();

The very last line is the one that produces the following warning when compiled with MinGW.

Graphics_Systems/Direct3D9/DX9model.cpp:340:20: warning: extended initializer lists only available with -std=c++11 or -std=gnu++11 [enabled by default]

redpajama_set_name: RedPajamaStackExchange


text:
Helvetets portar () är en monumental skulpturgrupp av den franske konstnären Auguste Rodin med motiv från Inferno i Dante Alighieris Den gudomliga komedin. Hela monumentet är 635 centimeter högt, 400 centimeter brett och 85 centimeter djupt. Det innefattar 180 figurer med en höjd på mellan 15 centimeter och en meter. Verket beställdes 1879 av Edmond Turquet, fransk understatssekreterare för de sköna konsterna, som tilltänkt entréport för Musée des arts décoratifs i Paris. Rodin arbetade med verket från 1880 fram till sin död 1917.

Flera av figurerna har även gjutits som självständiga skulpturer och hör som sådana till Rodins mest välkända. Till dessa hör Tänkaren, placerad ovanför dörrpanelerna, och Kyssen, i monumentets övre högra hörn. Den ursprungliga gipsgjutningen av Helvetets portar finns utställd på Musée d'Orsay i Paris. Bronsavgjutningar finns utställda på Musée Rodin och ett antal andra museer.

Källor

Externa länkar

Dante-bearbetningar
Dörrar
Skulpturer med kristna motiv
Skulpturer av Auguste Rodin
Skulpturer i Paris
Konstverk 1917
Skulpturer 1917
Kulturella återgivningar av Adam och Eva

redpajama_set_name: RedPajamaWikipedia


FRECOGS has been in existence since the mid-1970s and incorporated as a non-profit Maryland corporation in December 1999.
Meetings are announced on the Frederick News Post Community News about 1 week before the meeting date.
To acquaint members with sources of genealogical and related historical materials in and for Frederick County and Maryland.
To educate members and the general public of the genealogical data and reserach techniques, with programs, classes, workshops, and publications.
To serve as a medium of exchang of genealogical onformation through its newsletters ans meetings.
To promote the collection, preservation, and utilization of manuscripts, documents and other material of genealogical and related historical value through reminders within the Society and promotional articles and speakers for the public.
To aid local libraries in their maintenace and acquisition of genealogical materials through member volunteerism and the encouragement of charitable cash and collection donations.


text:
/* eslint import/no-extraneous-dependencies: ["error", {"devDependencies": true}] */
import React from 'react';
import { storiesOf } from '@kadira/storybook';

import initialState from 'vclub/redux/initialClubState';
import ClubLayout from './ClubLayout';

const book = storiesOf('views.clubLayout.ClubLayout', module);

book.setInitialState(initialState);

book.addReduxStory('Default', dispatch => (
  <ClubLayout dispatch={dispatch} />
));

book.addReduxStory('Default2', dispatch => (
  <ClubLayout dispatch={dispatch} />
), {
  data: {
    authenticated: true,
  },
});

redpajama_set_name: RedPajamaGithub


They haven't slowed down their schedules either and both the Duke and Duchess of Sussex have been pictured at several royal engagements recently.
And Camilla, the Duchess of Cornwall, won't be far behind when it comes to bonding with the future Baby Sussex!
"Thomas has a record of this and this is exactly the man that she knows". "It's not nice to talk badly about someone else just because you can, as he or she takes advantage of the anonymity of the web".
Samantha yesterday also unleashed a string of cruel tweets, saying: "If I had 600 mill she would care".
"She loved Harry, but the fact that he was a prince was often more of a drawback for her than an advantage".
Meghan revealed in January that her baby is due around the end of April or beginning of May. But according to a source who spoke with Us Weekly, though Markle wasn't surprised at the leak, she was disappointed. "It's a very complex, very emotional situation, and let's not forget she is seven months pregnant".


text:
const assert = require("assert");
const should = require('should');

const settings = require("./../testsSettings");
// Chino library
const ChinoAPIBase = require("../../src/chinoBase");

const baseUrl     = settings.baseUrl;
const customerId  = settings.customerId;
const customerKey = settings.customerKey;

describe('Chino API Base class', function() {

  it("Test Chino API Base class: should return corresponding object",
      function (done) {
        const baseClass = new ChinoAPIBase(baseUrl, customerId, customerKey);

        baseClass.should.be.an.instanceOf(ChinoAPIBase);
        Object.keys(baseClass).length.should.be.above(0);
        should.equal(baseClass._customerKey, undefined);
        should.equal(baseClass.call.baseUrl, baseUrl);
        should.equal(baseClass.call.id, undefined);
        should.equal(baseClass.call.secret, undefined);

        done();
      }
  );
})


text:
Q: Assembly - cmp instruction always passes I am making A Tic-Tac-Toe game and when making the function to check if a player won.
For testing purposes, I made the program simply exit when A player won.
Just for starting I made the program check only the 1st row:

0, 0, 0  ==> this row
     0, 0, 0
     0, 0, 0

I ran into a problem that the program exists every time I change A position to either An X or O, except when I choose one of the positions that are checked by the program (so, if I choose any position in the 1st row).
The code of the function is at the end
I don't want to include the whole code because I'm not just printing it to the screen but drawing it in graphics mode (ah=13h int 10h)
I will just show you the main loop and checkIfWon function that I filtered for only important stuff.
This is the code:
the board definition:
.data
board   db 0,0,0
        db 0,0,0
        db 0,0,0

CheckIfWon function:
checkIfWon proc
    ; check rows
    ; Equal to: if (board[0] == board[1] && board[1] == board[2])
    movsx   eax, byte ptr [board]
    movsx   ecx, byte ptr [board+1]
    cmp     eax, ecx
    jne     cont

    movsx   eax, byte ptr [board]
    movsx   ecx, byte ptr [board+2]
    cmp     eax, ecx
    jne     cont

    mov ax, 4c00h
    int 21h

    cont:
    ret

ret
endp checkIfWon

.386
; mainloop
mainloop:
    ; check for exit button (ESC)...
    ; get mouse button and cursor position...
    ;;;;;;;;;;;;;;;;;;;;;;; Check if mouse is on one of the positions

        box0:
        ; check if it got clicked...
        drawXplayer0:
        ; draw X
        jmp boxHitten
        drawOplayer0:
        ; draw o

        jmp boxHitten

    box1:
        ; check if it got clicked...
        drawXplayer1:
            ; draw X
            jmp boxHitten
        drawOplayer1:
            ; draw o

        jmp boxHitten

    box2:
        ; check if it got clicked...
        drawXplayer2:
            ; draw X
            jmp boxHitten
        drawOplayer2:
            ; draw o

        jmp boxHitten

    box3:
        ; check if it got clicked...
        drawXplayer3:
            ; draw X
            jmp boxHitten
        drawOplayer3:
            ; draw o

        jmp boxHitten

    box4:
        ; check if it got clicked...
        drawXplayer4:
            ; draw X
            jmp boxHitten
        drawOplayer4:
            ; draw o

        jmp boxHitten

    box5:
        ; check if it got clicked...
        drawXplayer5:
            ; draw X
            jmp boxHitten
        drawOplayer5:
            ; draw o

        jmp boxHitten

    box6:
        ; check if it got clicked...
        drawXplayer6:
            ; draw X
            jmp boxHitten
        drawOplayer6:
            ; draw o

        jmp boxHitten

    box7:
        ; check if it got clicked...
        drawXplayer7:
            ; draw X
            jmp boxHitten
        drawOplayer7:
            ; draw o

        jmp boxHitten

    box8:
        ; check if it got clicked...
        drawXplayer8:
            ; draw X
            jmp boxHitten
        drawOplayer8:
            ; draw o

        jmp boxHitten

    boxHitten:
        ; Fix overdrawn borders
        call drawBoard

        ; set cursor position
        mov  dl, 1
        mov  dh, 1
        mov  bh, 0    ;Display page
        mov  ah, 02h  ;SetCursorPosition
        int  10h
        ;
        ; change player
        ; if player='x': player='O' else player=x'

        ; here im playing a sound that tells the user he clicked

        ; delay
        push 500 ; 0.5 secs
        call delay
        call checkIfWon
        jmp mainloop

    takenError:
        push 14000 ; frequency for bad answer
        push 200       ; duration milliseconds
        call play

        ; delay
        push 1000
        call delay
        jmp mainloop

The program doesn't exit (like I wanted):

Exists (not what I wanted):

What could be the reason that the program skips it?
EDIT:
I found the solution, see comment

A: I figured out the solution to my problem:
Thing is, since I defined board to be

board db 0,0,0
            db 0,0,0
            db 0,0,0

The check simply went trough every time, since they are both 0.
And when I click something in the position, the board changes to

board  X,0,0
             0,0,0
             0,0,0

Then it doesn't pass the check.
solution code:
checkIfWon proc
     ; check rows
     ; Equal to: if (board[0] != 0 && board[0] == board[1] && board[1] == board[2])
     movsx   eax, byte ptr [board]
     movsx   ecx, byte ptr [board+1]
     cmp     eax, 0
     je cont
     cmp     eax, ecx
     jne     cont

     movsx   eax, byte ptr [board]
     movsx   ecx, byte ptr [board+2]
     cmp     eax, ecx
     jne     cont

     mov ax, 4c00h
     int 21h

cont:
    ret

ret
endp checkIfWon


So far in my dating travels I have stumbled across some pretty cool eats. I am all about the casual dining experience. It is far less awkward, meals are always on the cheaper side and the food in these places is fantastic. The more steam, chattering and clanging about in the kitchen the better I think. So here are my current date night favourites.


text:
module.exports = function(config){
  config.set({
    basePath: '.',

    files : [
      'node_modules/document-register-element/build/document-register-element.js',
      'dist/brick-select.js',
      'test/browser.js',
      {pattern: 'dist/*', watched: true, included: false, served: true}
    ],

    autoWatch : true,

    autoWatchBatchDelay: 750, // Try not to race with gulp build

    frameworks: ['mocha', 'chai'],

    browsers : ['Firefox', 'Chrome'],

    reporters: ['spec'],

    plugins : [
      'karma-firefox-launcher',
      'karma-chrome-launcher',
      'karma-mocha',
      'karma-chai',
      'karma-spec-reporter'
    ],
  });
};


text:
Q: .NET Core msbuild ProjectReference I have a solution that contains a console application with a .csproj file like the this:
<Project Sdk="Microsoft.NET.Sdk">
  <PropertyGroup>
    <OutputType>Exe</OutputType>
    <TargetFramework>netcoreapp1.1</TargetFramework>
  </PropertyGroup>
</Project>

I also have a library project that uses the console application to generate a heap of C# code that get compiled into the library, the library .csproj file looks like this.
<Project Sdk="Microsoft.NET.Sdk" InitialTargets="RunGenerator">
  <PropertyGroup>
    <TargetFramework>netstandard1.4</TargetFramework>
  </PropertyGroup>
  <ItemGroup>
    <ProjectReference Include="../generator/generator.csproj">
      <ReferenceOutputAssembly>false</ReferenceOutputAssembly>
    </ProjectReference>
  </ItemGroup>
  <Target Name="RunGenerator">
    <Exec Command="dotnet run -p "../generator/generator.csproj" input output" />
  </Target>
</Project>

This fails because the dependency analysis says that a netstandard1.4 assembly cannot reference a netcoreapp1.1 assembly. That is correct except that I am not referencing the assembly.
I can work around that issue by building the generator project like this:
<Project Sdk="Microsoft.NET.Sdk" InitialTargets="RunGenerator">
  <PropertyGroup>
    <TargetFramework>netstandard1.4</TargetFramework>
  </PropertyGroup>
  <Target Name="RunGenerator">
    <Exec Command="dotnet build "../generator/generator.csproj"" />
    <Exec Command="dotnet run -p "../generator/generator.csproj" input output" />
  </Target>
</Project>

The problem is that the generator project no longer takes part in the dependency analysis when these projects are built using the containing solution file and the explicit build of the generator project sometimes runs concurrently with another build of the same project initiated by the solution build and this results in errors because files are locked etc.
Is it possible to have a project dependency without checking the target framework?
Can anyone suggest a workaround?
Thanks.

A: Here are some MSBuild tips. You might need to combine a few of these ideas.

*

*You can use your solution file to add an explicit project dependency. See https://learn.microsoft.com/en-us/visualstudio/ide/how-to-create-and-remove-project-dependencies (This question was originally asked here: Visual Studio 2010: How to enforce build order of projects in a solution?). Unfortunately, this is really hard to do if you don't have VS. The format is .sln files is kinda a nightmare.

*To avoid the concurrent build issue, use the MSBuild task instead of the Exec task. See https://learn.microsoft.com/en-us/visualstudio/msbuild/msbuild-task

    <Target Name="CompileAnotherProject">
       <MSBuild Projects="../generator/generator.csproj" Targets="Build" />
    </Target>

*dotnet-run invokes "dotnet build" automatically. This is actually problematic in concurrent builds. You can instead add a target to your generator.csproj that runs the app after it has been built. "dotnet filepath.dll" runs the compiled app without building it.

    <Target Name="RunCodeGen" AfterTargets="Build">
         <Exec Command="dotnet $(AssemblyName).dll input output"
           WorkingDirectory="$(OutDir)" />
    </Target>


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