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Year 7 Parents and Tutors "settling in" meetings|
On Wednesday 12th November, our Year 7 parents and tutors settling in evening took place here in school and we were delighted that 85% of parents attended with their children to discuss how the first few weeks of life at St Mary's was going and to learn about how we would be tracking their pupil's progress over the coming years.
As parents left we conducted an exit survey, the results of which are shown below. Your feedback is really important to us and where constructive criticisms have been made we are already looking at improvements we can make in response.
It was great to hear what a great year group we have in the Year 7s and to hear what a fabulous start they have made to high school life. Thanks are due to the Year 7 Pastoral Team, led by Mr Riley, and to all the staff who have helped to get the newest members of the family of Leyland St Mary's get off to such a great start. However, the greatest praise must go to the year 7s themselves who have adapted to high school life with great enthusiasm and determination.
Pupil of the Month|
Congratulations to the Year 7-11 pupils below, who have won the boy and girl 'PE Pupil of the Month for October'. All were presented with a certificate in assemblies and given a huge round of applause. 'November/December's Pupil of the Month' will be announced in the New Year
Year 9 Duke of Edinburgh's award Launch Evening Monday 10/11/2014|
Please click here to view a presentation from the Year 9 Duke of Edinburgh's award Launch Evening on Monday 10/11/2014
Running & Swimming Challenge|
Congratulations to Year 8's Dayna, who has completed two sport challenges. These consisted of a 5 mile run followed by a 50 length swim and then a 10 mile run finishing with a 100 length swim. This is an incredible achievement, especially as Dayna is not a member of a swimming club. Dayna has also won the Year 8 girl 'Performer of the Month' in PE, for her commitment to extra-curricular clubs and her outstanding effort in lessons. Well done Dayna.
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GCSE Exam Certificates 2014|
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All Certificates must be signed for and are kept at school for one year. After this you will need to contact examination boards for replacements.
Iceland Trip - Important Update|
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Andy Lopez
Protests Set As Sonoma Deputy Who Fatally Shot Teen Returns To Work
There will be an afternoon of protests Tuesday related to the fatal shooting of 13-year-old Andy Lopez by a Sonoma County sheriff's deputy in October.
Sonoma County Deputy Who Killed Boy Carrying Toy Gun Returns To Duty
The Sonoma County sheriff's deputy who shot and killed a 13-year-old boy after mistaking the airsoft pellet gun he was carrying for an assault rifle, is returning to duty on Monday.
Sonoma Co. Looks At Measures In Response To Lopez Shooting
On Tuesday, the Sonoma County Board of Supervisors discussed several measures in response to the fatal shooting of Andy Lopez. They include the creation of a Community and Law Enforcement Task Force, along with a park to honor the 13-year-old.
Effort Underway To Build Santa Rosa Park Honoring Andy Lopez
An effort is underway to convince the Sonoma County Board of Supervisors to build a park in honor of 13-year-old Andy Lopez, who was fatally shot by a sheriff's deputy in October.
New Rules For Toy Guns Sought After Santa Rosa Teen's Death
One month after a Santa Rosa teenager carrying a toy gun was fatally shot by a Sonoma County sheriff's deputy; state lawmakers are proposing new rules for imitation weapons.
Protesters In Bay Area, Across State Denounce Police Killing Of Andy Lopez
Protesters gathered in Santa Rosa and in cities throughout the Bay Area and the state to protest the police killing of 13-year-old Andy Lopez in Sonoma County last month.
Multiple Bay Area Protests Saturday Over Andy Lopez Shooting
Protests against the fatal shooting of a 13-year-old boy by a Sonoma County sheriff's deputy last month are planned Saturday afternoon in the Bay Area and elsewhere in California.
Community Sounds Off Over Shooting Of Teen At Sonoma Supervisors Meeting
Emotions ran high at Tuesday's Sonoma County Board of Supervisors meeting as leaders and community members discussed their feelings about the death of 13-year-old Andy Lopez.
13-Year-Old Shooting Victim's Family Files Federal Suit Against Sonoma Co., Deputy
The shooting of 13-year-old Andy Lopez in Santa Rosa two weeks ago has galvanized his family, friends, and the Latino community in Sonoma County. After nearly having seen daily demonstrations the family has now filed a federal lawsuit.
Family Of Sonoma Teen Killed By Deputy To File Civil Rights Suit
The attorney for the family of 13-year-old Andy Lopez Cruz will file a federal civil rights lawsuit in San Francisco Monday against Sonoma County and the sheriff's deputy who fatally shot the teen on Oct. 22.

subset: commoncrawl


text:
The invention relates to N-phenyl-2-pyrimidine-amine derivatives of formula (I)
1. A compound of formula I
R1 is pyridyl bonded at a ring carbon atom,
R2 and R3 are both hydrogen,
R4 is lower alkyl,
R5 and R6 are both hydrogen,
R7 is a radical of formula II
�N(R9)�C(═X)�(Y)n�R10 (II),
R9 is hydrogen,
X is oxo,
n is 0 and
R10 is phenyl which is substituted by piperazinyl-lower alkyl, and R8 is hydrogen, or a salt of such a compound having at least one salt-forming group.
2. A compound of formula I according to
The invention relates to N-phenyl-2-pyrimidine-amine derivatives, to processes for the preparation thereof, to medicaments comprising those compounds, and to the use thereof in the preparation of pharmaceutical compositions for the therapeutic treatment of warm-blooded animals, including humans.
The invention relates to N-phenyl-2-pyrimidine-amine derivatives of formula I
1-Methyl-1H-pyrrolyl R1 is preferably 1-methyl-1H-pyrrol-2-yl or 1-methyl-1H-pyrrol-3-yl.
Amino- or amino-lower alkyl-substituted phenyl R1 wherein the amino group in each case is free, alkylated or acylated is phenyl substituted in any desired position (ortho, meta or para) wherein an alkylated amino group is preferably mono- or di-lower alkylamino, for example dimethylamino, and the lower alkyl moiety of amino-lower alkyl is preferably linear C1-C3alkyl, such as especially methyl or ethyl.
1H-indolyl R1 bonded at a carbon atom of the five-membered ring is 1H-indol-2-yl or 1H-indol-3-yl.
Unsubstituted or lower alkyl-substituted pyridyl R1 bonded at a ring carbon atom is lower alkylsubstituted or preferably unsubstituted 2-, 4- or preferably 3-pyridyl, for example 3-pyridyl, 2-methyl-3-pyridyl or 4-methyl-3-pyridyl. Pyridyl substituted at the nitrogen atom by oxygen is a radical derived from pyridine N-oxide, i.e. N-oxido-pyridyl.
When X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino, the group C═X is, in the above order, a radical C═O, C═S, C═N�H, C═N-lower alkyl, C═N�OH or C═N�O-lower alkyl, respectively. X is preferably oxo.
n is preferably 0, i.e. the group Y is not present.
Y, if present, is preferably the group NH.
The term �lower� within the scope of this text denotes radicals having up to and including 7, preferably up to and including 4 carbon atoms.
Lower alkyl R2, R3 and R9 is preferably methyl or ethyl.
A radical selected from the above-mentioned list a) or b) is preferably bonded to phenyl R10 at postion 3 or 4 of the phenyl ring.
Phenyl R10 substituted by unsubstituted or substituted pyrrolidinyl-, piperidyl-, piperazinyl- or morpholinyl-lower alkyl is preferably phenyl R10 substituted by unsubstituted or substituted 1-pyrrolidinyl-, 1-piperidyl-, piperazin-1-yl- or morpholin-4-yl-lower alkyl, respectively.
Phenyl R10 substituted by unsubstituted or substituted pyrrolidinyl-, piperidyl-, piperazinyl- or morpholinyl-lower alkyl is preferably phenyl R10 substituted by unsubstituted or substituted pyrrolidinyl-, piperidyl-, piperazinyl- or morpholinyl-methyl, respectively.
Etherified hydroxy is preferably lower alkoxy. Esterified hydroxy is preferably hydroxy esterified by an organic carboxylic acid, such as a lower alkanoic acid, or a mineral acid, such as a hydrohalic acid, for example lower alkanoyloxy or especially halogen, such as iodine, bromine or especially fluorine or chlorine.
Alkylated amino is, for example, lower alkylamino, such as methylamino, or di-lower alkyl-amino, such as dimethylamino. Acylated amino is, for example, lower alkanoylamino or benzoylamino.
Esterified carboxy is, for example, lower alkoxycarbonyl, such as methoxycarbonyl.
Salt-forming groups in a compound of formula I are groups or radicals having basic or acidic properties. Compounds having at least one basic group or at least one basic radical, for example a free amino group, a pyrazinyl radical or a pyridyl radical, may form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-aminosalicylic acid, aromaticaliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane-, ethane- or 2-hydroxyethane-sulfonic acid, or aromatic sulfonic acids, for example benzene-, p-toluene- or naphthalene-2-sulfonic acid. When several basic groups are present mono- or poly-acid addition salts may be formed.
Compounds of formula I having acidic groups, for example a free carboxy group in the radical R10, may form metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethyl-amine or tri-(2-hydroxyethyl)-amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.
Compounds of formula I having both acidic and basic groups can form internal salts.
For the purposes of isolation or purification, as well as in the case of compounds that are used further as intermediates, it is also possible to use pharmaceutically unacceptable salts. Only pharmaceutically acceptable, non-toxic salts are used for therapeutic purposes, however, and those salts are therefore preferred.
Owing to the close relationship between the novel compounds in free form and in the form of their salts, including those salts that can be used as intermediates, for example in the purification of the novel compounds or for the identification thereof, hereinbefore and hereinafter any reference to the free compounds should be understood as including the corresponding salts, where appropriate and expedient.
A compound of formula I possesses valuable pharmacological properties and may, for example, be used as an anti-tumour agent, as an agent to treat atherosclerosis, as an agent to treat restenosis, for the prevention of transplantation-induced disorders, such as obliterative bronchiolitis, and/or for preventing the invasion of warm-blooded animal cells by certain bacteria, such as Porphyromonas gingivalis.
The phosphorylation of proteins has long been known as an essential step in the differentiation and division of cells. Phosphorylation is catalysed by protein kinases subdivided into serine/threonine and tyrosine kinases. The tyrosine kinases include PDGF (Platelet-derived Growth Factor) receptor tyrosine kinase.
PDGF is a very commonly occurring growth factor, which plays an important role both in normal growth and also in pathological cell proliferation, such as is seen in carcinogenesis and in diseases of the smooth-muscle cells of blood vessels, for example in atherosclerosis and thrombosis.
The inhibition of PDGF-stimulated receptor tyrosine kinase activity in vitro is measured in PDGF receptor immune complexes of A431 cells, as described by E. Andrejauskas-Buchdunger and U. Regenass in Cancer Research 52, 5353�5358 (1992). A compound of formula I inhibits PDGF-dependent acellular receptor phosphorylation. The inhibition of PDGF receptor tyrosine kinase is measured in a microtitre ELISA assay (cf Trinks et al., J. Med. Chem. 37, 1015�27 (1994). A compound of formula I inhibits the tyrosine kinase activity of the PDGF receptor at an IC50 (concentration at which activity is inhibited by 50% compared with the control) of between 1 nM and 1 μM, especially between 3 nM and 300 nM.
The inhibition of PDGF receptor tyrosine kinase makes a compound of formula I also suitable for the treatment of tumour diseases, such as gliomas, sarcomas, prostate tumours, and tumours of the colon, breast, and ovary.
A compound of formula I also inhibits cellular processes involving the so-called stem-cell factor (SCF, also known as the c-kit ligand or steel factor), such as SCF receptor (kit) autophosphorylation and the SCF-stimulated activation of MAPK kinase (mitogen-activated protein kinase).
A compound of formula I thus inhibits also the autophosphorylation of SCF receptor (and c-kit, a proto-oncogen). MO7e cells are a human promegakaryocylic leukaemia cell line which depends on SCF for proliferation. They are obtained from Grover Bagby, Oregon Health Sciences University, USA. The Cells are cultivated in RPMI 1649 medium supplemented with 10 FBS and 2.5 ng/ml GC-CMF. GM-SCF and SCF are commercially available. Serum-deprived MO7e cells are prepared and incubated for 90 min at 37� C. with the test substance before being stimulated with recombinant SCF for 10 min at 37� C. Identical quantities of cell lysates are analysed by Western blot using antiphosphotyrosine antibodies (Buchdunger et al., Proc. Natl. Acad. Sci (USA) 92, 2558�62 (1995)). The immunodecorated proteins are detected by means of the ECL Western blotting system from Amersham (Amersham, UK). A compound of formula I inhibits the autophosphorylation of the SCF receptor in the micromolar range.
On the basis of the described properties, a compound of formula I may be used not only as a tumour-inhibiting substance, for example in small cell lung cancer, but also as an agent to treat non-malignant proliferative disorders, such as atherosclerosis, thrombosis, psoriasis, scleroderma, and fibrosis, as well as for the protection of stem cells, for example to combat the haemotoxic effect of chemotherapeutic agents, such as 5-fluoruracil, and in asthma. It may especially be used for the treatment of diseases which respond to an inhibition of the PDGF receptor kinase.
In addition, a compound of formula I prevents the development of multidrug resistance in cancer therapy with other chemotherapeutic agents or abolishes a pre-existing resistance to other chemotherapeutic agents. Also regardless of the effect described hereinbefore, a compound of formula I may be used to advantage in combination with other antitumour agents.
Also abi kinase, especially v-abi kinase, is inhibited by a compound of formula I. The inhibition of v-abi tyrosine kinase is determined by the methods of N. Lydon et al., Oncogene Research 5, 161�173 (1990) and J. F. Gelssler et al., Cancer Research 52, 4492�8 (1992). In those methods [Val5]-angiotensin II and [γ-32P]-ATP are used as substrates.
By analogy, a compound of formula I also inhibits BCR-abi kinase (see Nature Medicine 2, 561�566 (1996)) and is thus suitable for the treatment of BCR-abi positive cancer and tumour diseases, such as leukaemias (especially chronic myeloid leukaemia and acute lymphoblastic leukaemia, where especially apoptotic mechanisms of action are found), and also shows effects on the subgroup of leukaemic stem cells as well as potential for the purification of these cells in vitro after removal of said cells (for example, bone marrow removal) and reimplantation of the cells once they have been cleared of cancer cells (for example, reimplantation of purified bone marrow cells).
In addition, a compound of formula I shows useful effects in the treatment of disorders arising as a result of transplantation, for example, allogenic transplantation, especially tissue rejection, such as especially obliterative bronchiolitis (OB), i.e. a chronic rejection of allogenic lung transplants. In contrast to patients without OB, those with OB often show an elevated PDGF concentration in bronchoalveolar lavage fluids. If a compound of formula I is administered to rats with tracheal allogenic transplants, for example in a dose of 50 mg/kg i.p., it can be shown after removal of 10 transplants per group after 10 and 30 days for morphometric analysis of possible epithelial lesions and occlusion of the airways, and investigation for immunohistochemical pathways of action that, although a compound of formula I has no significant effect on epithelial necrosis or infiltration by inflammatory cells, it does markedly reduce fibroproliferation and occlusion of the lumen compared with controls. Synergistic effects with other immunomodulatory or anti-inflammatory substances are possible, for example when used in combination with cyclosporin A (CsA), rapamycin, or ascomycin, or immunosuppressant analogues thereof, for example cyclosporin G, FK-506 or comparable compounds; corticosteroids; cyclophosphamide; azathioprine; methotrexate; brequinar; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualin; immunsuppressant antibodies, especially monoclonal antibodies for leucocyte receptors, for example MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands; or other immunomodulatory compounds, such as CTLA4lg. If CsA (1 mg/kg s.c.), for example, is combined with a compound of formula I (50 mg/kg), synergism may be observed.
A compound of formula I is also effective in diseases associated with vascular smooth-muscle cell migration and proliferation (where PDGF and PDGF receptor often also play a role), such as restenosis and atherosclerosis. These effects and the consequences thereof for the proliferation or migration of vascular smooth-muscle cells in vitro and in vivo can be demonstrated by administration of a compound of formula I and also by investigating its effect on the thickening of the vascular intima following mechanical injury in vivo.
A compound of formula I is used in 0.1N HCl or DMSO at a concentration of 10 mM for in vitro studies. The stock solution is further diluted with cell culture medium and used in concentrations of 10 to 0.1 μM for the experiments. For in vivo administration, a compound of formula I is dissolved for example in DMSO at a concentration of 200 mg/ml and then diluted 1:20 with 1% Tween in 0.9% saline solution. After sonication, a clear solution is obtained. The stock solutions are prepared fresh each day before administration. (The compound of formula I may also be dissolved simply in deionised water for oral administration or in 0.9% saline solution for parenteral administration). Administration is carried out 24 hours before the operation. A compound of formula I is administered to rats in one dose of 50 mg/kg i.p. per day for the entire observation period. Control rats are given the same formulation but without the presence of a compound of formula I. Oral administration is also possible.
Primary cultures of smooth-muscle aorta cells are isolated from 9 to 11-day-old DA (AG-B4, RT1a) rat aorta using a modification of the method described by Thyberg et al. (see Differentiation 25, 156�67 (1983)). The aorta is opened by means of a longitudinal incision and the endothelium carefully removed. The adventitia and the tunica media are separated, and the tunica media is digested with 0.1% collagenase and DNAse in phosphate-buffered physiological saline for 30 min at 37� C. The cells are centrifuged, suspended in culture medium, and then allowed to grow on plastic vials. The primary cells are used for the experiments after passages 2 to 6. Subcultures are kept in DMEM (Dulbecco's Modified Eagle's Medium), supplemented with 10% fetal calf serum, 2 mmol/ml glutamine, 100 mmol/ml streptomycin, and 100 IU/ml penicillin. For identification purposes, the cells are left to grow on glass slide covers and stained immunohistochemically using an anti-α-actin antibody obtained from smooth-muscle cells (see below).
The migration of smooth-muscle cells is quantified in vitro using a Transwell cell culture insert (Costar, Cambridge, Mass.) whose upper and lower compartments are separated by a polycarbonate membrane of 8 μm pore size. The cells (100 μl at a concentration of 1 million cells/ml) are exposed in the upper compartment. After 2 hours, 60 ng/ml PDGF-BB or PDGF-AA (Upstate Biotechnology Inc., Lake Placid, N.Y.) is added to the lower compartment, supplemented with 0.5% fetal calf serum and 0.1% bovine serum albumin, and the test compound of formula I is added in concentrations of 3, 1, 0.3, 0.1, 0.03, 0.01, and 0.003 μM. To measure fibronectin-dependent migration, the Transwell chambers are covered with fibronectin at a concentration of 10 μg/ml for 24 h at 4� C. (human cellular fibronectin, Upstate Biotechnology Inc.). After 24 hours' migration, the filters are removed, fixed in methanol, and stained with Mayer's haematoxylin and eosin. The migrated cells on the lower side of the filter membrane are determined by counting the specified sectional fields on the filters with the aid of a light microscope with a magnification of 400�. The inhibition of migration is quantified in terms of the percentage of cells versus with the control. To exclude the possibility of a toxic effect, the viability of the cells is tested by incorporation of 3H-thymidine in DMEM, supplemented with 10% fetal calf serum. An inhibition of migration induced by PDGF-AA and especially by PDGF-BB is observed with a compound of formula I.
Experimental animals: the aorta and carotid artery of male Wistar rats (purchased from the Laboratory Animal Center of the University of Helsinki, Finland) are denuded. The rats are anaesthetised with 240 mg/kg chloral hydrate i.p. and Buprenorphine (Temgesic, Reckitt & Coleman, Hull, UK) is administered for perioperative and postoperative alleviation of pain. All animals are given human care in keeping with the �Principles of Laboratory Animal Care� and the �Guide for the Care and Use of Laboratory Animals� of the NIH (NIH Publication 86-23, revised 1985). Rats weighing 200�300 g were used for the denudation procedure. The left common carotid artery is denuded of endothelium through the intraluminal passage of a 2F embolectomy catheter (Baxter Healthcare Corporation, Santa Ana, Calif., 27). To remove the endothelium, the catheter is passed through the lumen three times, inflated with 0.2 ml air. The external carotid is ligated after removal of the catheter and the wound closed. The histological changes are evaluated by reference to sections of mid-carotid 4 days after denudation. The thoracic aorta is denuded of endothelium using a 2F Fogarty arterial embolectomy catheter. The catheter is inserted into the thoracic aorta via the left iliac artery, inflated with 0.2 ml air, and passed through the lumen five times to remove the endothelium. The iliac artery is then ligated. Three times (3, 7 and 14 days) are selected for evaluation of the histological changes.
To quantify the proliferating cells, 3 different procedures are used for labelling the cells with bromodeoxyuridine (BrdU) after denudation of the rat carotid. In this model, the media cell proliferation begins 24 h after denudation; cells in the intima first appear after 72�96 hours. To quantify the proliferation of smooth-muscle cells before the appearance of cells in the intima, 0.1 ml BrdU-labelling reagent (ZYMED, San Francisco, Calif.) is administered i.v. during the postoperative period of 0 to 72 h post-denudation (in total 0.1 ml 6 times). To quantify the proliferation during the initial wave of migration, the rats were given 3�0.1 ml BrdU-labelling reagent at 8-hour intervals over a period of 72�96 hours after the operation. To quantify the proliferation at the end of the initial wave of migration, a third group of rats is given a pulsed dose of 0.3 ml BrdU three hours before sacrifice.
Histological samples are fixed in 3% paraformaldehyde solution for 4 h for embedding in paraffin. Morphological changes are evaluated from paraffin sections stained with Mayer's haematoxylin-eosin. The cell counts of different vessel sections are calculated at a magnification of 400�. To identify cells in culture and cells appearing in the neo-intima within four days of the denudation injury, immunohistochemical staining of acetone-fixed samples is carried out using an anti-α-actin antibody obtained from smooth-muscle cells (Bio-Makor, Rehovot, Israel). primary smooth-muscle cells are identified on acetone-fixed glass cover slides using the same staining method. The sections are incubated with the primary antibody (dilution 1:2000), washed, and incubated consecutively with peroxidase-conjugated rabbit-antimouse-lg and goat-antirabbit-lg, followed by treatment with substrate solution with the chromogen 3-amino-9-ethylcarbazol and hydrogen peroxide. BrdU stains are prepared from paraffin sections using a primary mouse antibody (Bu20a, Dako, A/S, Denmark) and the Vectastain Elite ABC-Kit (Vector Laboratories, Burliname, Calif.). The sections are deparaffinised and treated by microwave at 500 W (2�5 min in 0.1M citrate buffer, pH 6), followed by treatment with 95% formamide in 0.15 M trisodium citrate for 45 min at 70� C. Antibody dilutions are prepared according to the manufacturer's specifications. The sections are counterstained with Mayer's haematoxylin and eosin, and positive cells are counted separately for the initima, media, and adventitia.
In the carotid of treated animals, a significant decrease is found in the cell count for smooth-muscle cells. The adventitia and the media showed a significant reduction in the cell count. As a result of a compound of formula I, a slight decrease in the absolute number of BrdU-labelled cells is seen in the intima, media, and adventitia during the first two labelling periods (0�72 and 72�95 h), and after 93�96 h a decrease in the number of labelled cells is seen in all compartments. Decreases in the number of smooth-muscle cells are likewise found in the aorta-denuded animals.
According to these findings, a compound of formula I can thus inhibit the proliferation, and especially the migration, of vascular smooth-muscle cells.
A compound of formula I is also capable of inhibiting anglogenesis. This may be demonstrated as follows: a chamber containing agar (0.8%) and heparin (2 U/ml) with or without growth factor (VEGF 3 μg/ml, PDGF 1 μg/ml or bFGF 0.3 μg/ml) is implanted subcutaneously into normal mice (C57 BL/6). A compound of formula I is administered orally in a dose showing good anti-tumour activity in a nude mouse xenotransplant model. Dosing is started one day before implantation of the chambers. The chambers are removed after 5 days. The angiogenic efficacy is quantified by measuring both the vascularised tissue which has grown around the implant and the blood content of this tissue (external blood). The blood is determined by measuring the haemoglobin. Although the vessels do not grow into the agar, the agar becomes intensely red if an antiangiogenic effect is present. If a compound inhibits the increase in blood that is induced by the growth factor, this is seen as a indication that the compound in question is blocking the angiogenic effect of the growth factor concerned. Inhibition of the weight but not the volume of blood suggests an effect on the proliferation of fibroblasts. A suppression of the control response suggests an inhibition of wound healing. At an oral dose of 50 mg/kg once daily, a compound of formula I inhibits the angiogenic effect of all three growth factors (VEGF, PDFG, bFGF).
Interestingly, N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide represents the N-desmethyl metabolite of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-(4-methyl-piperazin-1-ylmethyl)-benzamide (STI571). STI571 is described in EP 0564 409 and, in the form of the methane sulfonate salt, in WO 99/03854. The N-desmethyl metabolite of STI571 is an active metabolite that is present in human plasma at concentrations from 30 to 50% of STI571 and the half-life is somewhat longer than that of STI571. Moreover, the N-desmethyl metabolite exhibits less inhibition of certain cytochrome P450 enzymes (see following paragraph), when compared with STI571. Cytochromes P450 are the principal, hepatic xenobiotic metabolizing enzymes and less inhibition of cytochromes P450 reduces the potential of a compound for clinical drug-drug interactions. Among the compounds of formula I, preference above all is therefore given for the N-desmethyl metabolite of STI571, namely N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide.
In order to evaluate the effect of the compounds of formula I on cytochromes P450 (CYPs), e.g. enzyme inhibition is routinely assessed by performing in vitro inhibition studies using cDNA-expressed enzymes or human liver microsomes (Parkinson, A., Toxicol. Pathol. 24, 45�57 [1996]). Specific drug marker substrate assays according to Tucker et al., Clin. Pharmacol. Ther. 70, 103�114 (2001) can be used to determine the 50% inhibition concentration (IC50) of a compound of formula I for the principal drug-metabolizing P450 enzymes such as e.g. CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 and CP4A9/11.
Inhibition constants Ki or IC50 values derived by these in vitro assays provide a measure for the inhibition capacity of the tested drug compound according to the ratio of drug concentration in plasma to the respective inhibition constant Ki, where a ratio of >1.0 results in a high risk, 1.0�0.1 in a medium risk, and <0.1 in a low risk of metabolic drug interaction. Based on this, N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide possesses a much lower risk of drug-drug interactions with the 2 most important P450 enzymes, CYP2D6 and CYP3A4/5, in human drug metabolism (see guidance document of the U.S. Food and Drug Administration) when compared with STI571.
Preference is given to compounds of formula I, wherein
Preference is also given to compounds of formula I, wherein
Special preference is given especially to compounds of formula I, wherein
Very special preference is given to compounds of formula I, wherein
Also very special preference is given to compounds of formula I, wherein
Most especially preferred are the compounds of formula I described in the Examples and pharmaceutically acceptable salts of such compounds having at least one salt-forming group.
The compounds of formula I and salts of such compounds having at least one salt-forming group are prepared in accordance with processes known per se. The process according to the invention is characterized in that:
The procedure for the above-mentioned process variants is explained in detail below:
General notes:
The end products of formula I may contain substituents that can also be used as protecting groups in starting materials for the preparation of other end products of formula I. Thus, within the scope of this text, only a readily removable group that is not a constituent of the particular desired end product of formula I is designated a �protecting group�, unless the context indicates otherwise.
Protecting groups, and the manner in which they are introduced and removed are described, for example, in �Protective Groups in Organic Chemistry�, Plenum Press, London, N.Y. 1973, and in �Methoden der organischem Chemie�, Houben-Weyl, 4th edition, Vol. 15/1, Georg-Thieme-Verlag, Stuttgart 1974 and in Theodora W. Greene, �Protective Groups in Organic Synthesis�, John Wiley & Sons, New York 1981. A characteristic of protecting groups is that they can be removed readily, i.e. without the occurrence of undesired secondary reactions, for example by solvolysis, reduction, photolysis or alternatively under physiological conditions.
Process i):
Preferably R11 and R12 are each methyl.
Free functional groups in a compound of formula III that are advantageously protected by readily removable protecting groups are especially amino groups in the radical R1 and the imino group of 1H-indolyl. The latter can be protected, for example, by benzyl.
Free functional groups in a compound of formula IV that are advantageously protected by readily removable protecting groups are especially amino groups, but also hydroxy and carboxy groups.
A salt of a compound of formula IV is preferably an acid addition salt, for example a nitrate or one of the acid addition salts mentioned for the end products of formula I.
The reaction is carried out in a suitable solvent or dispersing agent, for example a suitable alcohol, such as 2-methoxy-ethanol, or a suitable lower alkanol, for example isopropanol, at a temperature of from room temperature (approx. 20� C.) to 150� C., for example under reflux. Especially when the compound of formula IV is used in the form of a salt, that salt is converted into the free compound, preferably in situ, by the addition of a suitable base, such as an alkali metal hydroxide, for example sodium hydroxide.
The starting material of formula III is obtained by reacting a compound of formula IX
The starting material of formula III is alternatively obtained by reacting a compound of formula IX with an ester of the formula R3�C(═O)�O�CH2�CH3 wherein R3 is as defined above, and reacting the resulting product with an amine of the formula H�N(R11)�R12 wherein the substituents are as defined above.
The starting material of formula IV is obtained in the form of an acid addition salt by reacting a compound of formula XI
Free functional groups in a compound of formula V or VI that are advantageously protected by readily removable protecting groups are especially amino groups, but also hydroxy and carboxy groups, that are not intended to participate in the desired reaction, for example amino in the radical R1.
A reactive derivative of a compound of formula VI wherein X is oxo is especially a reactive (activated) ester, a reactive anhydride or a reactive cyclic amide. The same is true for the derivatives wherein X has one of the other definitions given above.
Reactive (activated) esters of an acid of formula VI are especially esters unsaturated at the linking carbon atom of the esterifying radical, for example esters of the vinyl ester type, such as actual vinyl esters (obtainable, for example, by transesterification of a corresponding ester with vinyl acetate; activated vinyl ester method), carbamoylvinyl esters (obtainable, for example, by treatment of the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method), or 1-lower alkoxyvinyl esters (obtainable, for example, by treatment of the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), or esters of the amidino type, such as N,N′-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with a suitable N,N′-disubstituted carbodiimide, for example N,N′-dicyclohexylcarbodiimide; carbodiimide method), or N,N-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with an N,N-disubstituted cyanamide; cyanamide method), suitable aryl esters, especially phenyl esters suitably substituted by electron-attracting substituents (obtainable, for example, by treatment of the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-methylsulfonyl-phenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachloro-phenol or 4-phenyldiazophenol, in the presence of a condensation agent, such as N,N′-dicyclohexylcarbodiimide; activated aryl esters method), cyanomethyl esters (obtainable, for example, by treatment of the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl esters method), thio esters, especially unsubstituted or substituted, for example nitro-substituted, phenylthio esters (obtainable, for example, by treatment of the corresponding acid with unsubstituted or substituted, for example nitro-substituted, thiophenols, inter alia by the anhydride or carbodiimide method; activated thiol esters method), amino or amido esters (obtainable, for example, by treatment of the corresponding acid with an N-hydroxy-amino or N-hydroxy-amido compound, for example N-hydroxy-succinimide, N-hydroxy-piperidine, N-hydroxy-phthalimide or 1-hydroxy-benzotriazole, for example by the anhydride or carbodiimide method; activated N-hydroxy esters method), or silyl esters (which are obtainable, for example, by treatment of the corresponding acid with a silylating agent, for example hexamethyl disilazane, and react readily with hydroxy groups but not with amino groups).
Anhydrides of an acid of formula VI may be symmetric or preferably mixed anhydrides of that acid, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtainable, for example, by treatment of the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides (obtainable, for example, from a corresponding acid ester via the corresponding hydrazide and treatment thereof with nitrous acid; azide method), anhydrides with carbonic acid semiderivatives, such as corresponding esters, for example carbonic acid lower alkyl semiesters (obtainable, for example, by treatment of the corresponding acid with haloformic, such as chloroformic, acid lower alkyl esters or with a 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example 1-lower alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; mixed O-alkylcarbonic acid anhydrides method), or anhydrides with dihalogenated, especially dichlorinated, phosphoric acid (obtainable, for example, by treatment of the corresponding acid with phosphorus oxychloride; phosphorus oxychloride method), or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtainable, for example, by treatment of the corresponding acid with an unsubstituted or substituted lower alkane- or phenylalkane-carboxylic acid halide, for example phenylacetic acid chloride, pivalic acid chloride or trifluoroacetic acid chloride; mixed carboxylic acid anhydrides method) or with organic sulfonic acids (obtainable, for example, by treatment of a salt, such as an alkali metal salt, of the corresponding acid, with a suitable organic sulfonic acid halide, such as lower alkane- or aryl-, for example methane- or p-toluene-sulfonic acid chloride; mixed sulfonic acid anhydrides method), and symmetric anhydrides (obtainable, for example, by condensation of the corresponding acid in the presence of a carbodiimide or of 1-diethylaminopropyne; symmetric anhydrides method).
Suitable cyclic amides are especially amides with five-membered diazacycles of aromatic character, such as amides with imidazoles, for example imidazole (obtainable, for example, by treatment of the corresponding acid with N,N′-carbonyldimidazole; imidazolide method), or pyrazoles, for example 3,5-dimethyl-pyrazole (obtainable, for example, by way of the acid hydrazide by treatment with acetylacetone; pyrazolide method).
Derivatives of acids of formula VI that can be used as acylating agents can also be formed in situ. For example, N,N′-disubstituted amidino esters can be formed in situ by reacting a mixture of the starting material of formula V and the acid used as acylating agent in the presence of a suitable N,N-disubstituted carbodiimide, for example N,N′-dicyclohexyl-carbodiimide. In addition, amino or amido esters of the acids used as acylating agents can be formed in the presence of the starting material of formula V to be acylated, by reacting a mixture of the corresponding acid and amino starting materials in the presence of an N,N′-disubstituted carbodiimide, for example N,N′-dicyclohexyl-carbodiimide, and an N-hydroxy-amine or N-hydroxy-amide, for example N-hydroxysuccinimide, where appropriate in the presence of a suitable base, for example 4-dimethylamino-pyridine.
The reaction is preferably carried out by reacting a reactive carboxylic acid derivative of a compound of formula VI with a compound of formula V wherein the amino group or hydroxy group participating in the reaction is in free form.
The reaction can be carried out in a manner known per se, the reaction conditions being dependent especially on whether, and if so how, the carboxy group of the acylating agent has been activated, usually in the presence of a suitable solvent or diluent or of a mixture thereof and, if necessary, in the presence of a condensation agent, which, for example when the carboxy group participating in the reaction is in the form of an anhydride, may also be an acid-binding agent, with cooling or heating, for example in a temperature range from approximately −30� C. to approximately +150� C., especially approximately from 0� C. to +100� C., preferably from room temperature (approx. +20� C.) to +70� C., in an open or closed reaction vessel and/or in the atmosphere of an inert gas, for example nitrogen. Customary condensation agents are, for example, carbodiimides, for example N,N′-diethyl-, N,N′-dipropyl-, N,N′-dichlorohexyl- or N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, for example 2-ethyl-5-phenyl-1,2-oxazolium 3′-sulfonate and 2-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. Customary acid-binding condensation agents are, for example, alkali metal carbonates or hydrogen carbonates, for example sodium or potassium carbonate or hydrogen carbonate (customarily together with a sulfate), or organic bases, such as, customarily, pyridine or sterically hindered tri-lower alkylamines, for example N,N-diisopropyl-N-ethyl-amine.
In a preferred variant of process ii) a compound of formula V is reacted with a compound of formula VI in a suitable solvent, such as e.g. N,N-dimethylformamide, in the presence of propylphosphonic anhydride (Fluka, Buchs, Switzerland) and triethylamine, preferably at room temperature.
Process iii):
A suitable oxidising agent for converting a compound of formula I wherein R1 is pyridyl into the N-oxido compound is preferably a suitable peracid, for example a suitable perbenzoic acid, such as especially m-chloro-perbenzoic acid. The reaction is carried out in an inert solvent, for example a halogenated hydrocarbon, such as preferably methylene chloride, at temperatures of approximately from −20� C. to +150� C., especially approximately from 0� C. to the boiling point of the solvent in question, in general below +100� C., and preferably at room temperature or at slightly elevated temperature (20� C.�70� C.).
Halogen in unsubstituted or optionally substituted halogen-lower alkyl-phenyl R23 is preferably chloro.
The reaction is carried out in a manner known per se, for example by dissolving the reactants in a suitable solvent, for example ethanol, and boiling under reflux for from 10 to 20 hours.
The starting material of formula VII is obtained by reacting a compound of formula XII
The synthesis of a compound of formula XII is described in EP 0 564 409.
Acid addition salts of compounds of formula I are obtained in customary manner, for example by treatment with an acid or a suitable anion exchange reagent.
Acid addition salts can be converted into the free compounds in customary manner, for example by treatment with a suitable basic agent.
Mixtures of isomers can be separated into the individual isomers in a manner known per se for example by fractional crystallization, chromatography, etc.
The processes described above, including the processes for removing protecting groups and the additional process steps, are, unless otherwise indicated, carried out in a manner known per se, for example in the presence or absence of preferably inert solvents and diluents, if necessary in the presence of condensation agents or catalysts, at reduced or elevated temperature, for example in a temperature range of from approximately −20� C. to approximately 150� C., especially from approximately 0� C. to approximately +70� C., preferably from approximately +10� C. to approximately +50� C., and more especially at room temperature, in a suitable vessel and if necessary in an inert gas atmosphere, for example a nitrogen atmosphere.
In those process steps, taking account of all the substituents in the molecule, if necessary, for example when readily hydrolysable radicals are present, especially mild reaction conditions should be used, such as short reaction times, the use of mild acidic or basic agents at low concentrations, stoichiometric quantity ratios, and the selection of suitable catalysts, solvents, temperature and/or pressure conditions.
The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out or the process is interrupted at any stage or a starting material is formed under the reaction conditions or is used in the form of a reactive derivative or salt. It is preferable to begin with those starting materials which in accordance with the process result in the compounds described above as being especially valuable.
Preferably the compounds of formula I are prepared according to the processes and process steps defined in the Examples.
The present invention relates also to novel starting materials and/or intermediates and to processes for the preparation thereof. The starting materials used and the reaction conditions chosen are preferably those which result in the compounds described in this Application as being especially preferred.
The invention relates also to a process for the treatment of warm-blooded animals, including humans, suffering from said diseases, especially a tumour disease, wherein a quantity of a compound of formula I which is effective against the disease concerned, especially a quantity with antiproliferative and especially tumour-inhibiting efficacy, is administered to warm-blooded animals, including humans, in need of such treatment. The invention relates moreover to the use of a compound of formula I for the inhibition of the above-mentioned tyrosine kinases, especially PDGF receptor kinase, v-abi kinase, and/or c-kit receptor kinase, or for the preparation of pharmaceutical compositions for use in treating the human or animal body, especially for the treatment of tumours, such as gliomas, ovarian tumours, prostate tumours, colon tumours, and tumours of the lung, such as especially small cell lung carcinoma, and tumours of the breast or other gynaecological tumours. Depending on species, age, individual condition, mode of administration, and the clinical picture in question, effective doses, for example daily doses of about 1�2500 mg, preferably 1�1000 mg, especially 5�500 mg, are administered to warm-blooded animals, including humans, of about 70 kg bodyweight.
The invention relates also to pharmaceutical preparations which contain an effective amount, especially an effective amount for prevention or treatment of one of the said diseases, of a compound of formula I together with pharmaceutically acceptable carriers which are suitable for topical, enteral, for example oral or rectal, or parenteral administration and may be inorganic or organic and solid or liquid. Especially tablets or gelatin capsules containing the active substance together with diluents, for example lactose, dextose, sucrose, mannitol, sorbital, cellulose, and/or glycerin, and/or lubricants, for example silica, talc, stearic acid, or salts thereof, typically magnesium or calcium stearate, and/or polyethylene glycol, are used for oral administration. Tablets may likewise contain binders, for example magnesium aluminium silicate, starches, typically corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if so desired, disintegrants, for example starches, agar, alginic acid, or a salt thereof, typically sodium alginate, and/or effervescent mixtures, or adsorbents, colouring agents, flavours, and sweetening agents. The pharmacologically active compounds of the present invention may further be used in the form of preparations for parenteral administration or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these possible being prepared before use, for example in the case of lyophilised preparations containing the active substance either alone or together with a carrier, for example mannitol. The pharmaceutical substances may be sterilised and/or may contain excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for the regulation of osmotic pressure, and/or buffers. The present pharmaceutical preparations which, if so desired, may contain further pharmacologically active substances, such as antibiotics, are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilising processes, and contain from about 1% to 100%, especially from about 1% to about 20%, of the active substance or substances.
The following Examples illustrate the invention but do not limit the invention in any way. The Rf values are determined on silica gel thin-layer plates (Merck, Darmstadt, Germany). The ratio to one another of the eluants in the eluant mixtures used is given in proportions by volume (v/v), and temperatures are given in degrees Celsius.
A suspension of 466 mg (1 mmol) of 4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide hydrochloride in 25 ml of dry ethanol is treated with 381 μl (3 mmol) N-ethylpiperazine and then heated under reflux for 16 hours. The yellow solution is cooled to room temperature and decanted from a small amount of a brown insoluble residue which forms on the wall of the flask. The solvent is evaporated and the residue taken up in citric acid solution (10% w/w) and washed with dichloromethane. The aqueous layer is made basic by addition of sodium bicarbonate and sodium carbonate solution and extracted three times with 150 ml of dichloromethane containing 2 ml of ethanol. The combined organic extracts are washed with conc. sodium chloride solution, dried over sodium sulfate, and evaporated. The residue was stirred with 3 ml of ethyl acetate and the crystalline product filtered and washed with a small amount of ethyl acetate to obtain 4-(4-ethyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; m.p. 209.5�210.5� C.; tR (HPLC) 1) 6.62 min.
Compounds are synthesized analogously to Example 1:
25.8 g (300 mmol) of piperazine are suspended in a mixture of 25 ml of ethanol and 25 ml of water. After almost a clear solution has formed, 12.9 g (30 mmol) of 4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide are added step by step. The yellow solution is boiled under reflux for 14 hours, cooled to room, temperature and filtered over Celite. 100 ml of water is added to the solution, the ethanol is evaporated under vacuum and 30 ml of 1N NaOH is added, leading to crystallization of the product. Drying at 50 mbar and 60� C. yields N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide; Rf=0.15 (methylene chloride:ethyl acetate:methanol:conc. aqueous ammonium hydroxide solution=60:10:30:2); tR (HPLC)2) 14.6 min.
4.8 g (10 mmol) of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide are dissolved in 20 ml of ethanol under heating and 0.99 g of methanesulfonic acid are added. After addition of ethyl acetate the product cristallizes. Drying at 50 mbar and 60� C. yields N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide methanesulfonate; Rf=0.17 (methylene chloride:ethyl acetate:methanol:conc. aqueous ammonium hydroxide solution=60:10:30:2); tR (HPLC)2) 14.6 min; m.p. 242�245� C.
A solution containing approximately 50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 700 μL, �1.2 mmol) is added in portions within 20 min to a stirred mixture of 4-methyl-N-3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine (221.9 mg, 0.8 mmol), 3-(dimethylamino)benzoic acid (Aldrich, Buchs, Switzerland; 132.2 mg, 0.8 mmol) and triethylamine (887 μL, 6.4 mmol) in 2 mL of dry N,N-dimethylformamide. After stirring for 48 hours at room temperature, the solvent is evaporated off under reduced pressure and the residue distributed between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The aqueous phase is extracted twice with ethyl acetate. The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure. The crude product is recrystallized from ethyl acetate/hexane to yield 3-dimethylamino-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide as a beige crystalline solid. 1H-NMR (300 MHz, DMSO-d6, δ): 2.18 (s, 3H); 2.92 (s, 6H); 6.87 (m, 1H); 7.12�7.51 (m, 7H); 8.03 (s, 1H); 8.39�8.50 (m, 2H); 8.64 (d, 1H); 8.95 (s, 1H); 9.24 (s, 1H); 10.05 (s, 1H).
A solution containing approximately 50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 700 μL, �1.2 mmol) is added in portions within 20 min to a stirred mixture of 4-methyl-N-3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine (221.9 mg, 0.8 mmol), 4-(dimethylamino)benzoic acid (Aldrich, Buchs, Switzerland; 132.2 mg, 0.8 mmol) and triethylamine (887 μL, 6.4 mmol) in 2 mL of dry N,N-dimethylformamide. After stirring for 48 h at room temperature, the solvent is evaporated off under reduced pressure and the residue distributed between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The aqueous phase is extracted twice with ethyl acetate. The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 1�4% methanol in dichloromethane. The fractions containing the pure product are combined and the solvent is evaporated off. Crystallization of the residue from acetone gives 4-dimethylamino-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide as a yellow crystalline solid. 1H-NMR (400 MHz, DMSO-d6, δ): 2.19 (s, 3H); 2.97 (s, 6H); 6.73 (m, 2H); 7.14 (d, 1H); 7.39 (d, 1H); 7.42�7.52 (m, 2H); 7.83 (m, 2H); 8.02 (d, 1H); 8.41�8.49 (m, 2H); 8.65 (dd, 1H); 8.93 (s, 1H); 9.24 (m, 1H); 9.79 (s, 1H).
The following compounds are prepared analogously by utilising the appropriate acids:
Utilising 4-acetamidobenzoic acid (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.06 (s, 3H); 2.20 (s, 3H); 7.18 (d, 1H); 7.41 (d, 1H); 7.45 (dd, 1H); 7.50 (ddd, 1H); 7.69 (m, 2H); 7.90 (m, 2H); 8.04 (d, 1H); 8.46 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H); 8.96 (s, 1H); 9.25 (dd, 1H); 10.05 (s, 1H); 10.20 (s, 1H).
Utilising 3-acetamidobenzoic acid (Fluks, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-D6, δ): 2.05 (s, 3H); 2.20 (s, 3H); 7.19 (d, 1H); 7.39�7.47 (m, 3H); 7.50 (ddd, 1H); 7.57�7.61 (m, 1H); 7.78�7.83 (m, 1H); 8.04�8.06 (m, 2H); 8.46 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H); 8.97 (s, 1H); 9.25 (dd, 1H); 10.15 (s, 1H); 10.21 (s, 1H).
Utilising 3-hydroxy-4-methylbenzoic acid (Fluka, Buchs, Switzerland). 1H-NMR (400 mhZ, DMSO-d6, δ): 2.16 (s, 3H); 2.20 (s, 3H); 7.17 (m, 2H); 7.30�7.34 (m, 2H); 7.41 (d, 1H); 7.45 (dd, 1H); 7.50 (m, 1H); 8.05 (m, 1H); 8.46 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H); 8.96 (s, 1H); 9.26 (m, 1H); 9.63 (s, 1H); 10.04 (s, 1H).
Utilising 4-tert-butylbenzoic acid (Fluks, Buchs, Switzerland). 1H-NMR (300 MHz, DMSO-d6, δ): 1.30 (s, 9H); 2.20 (s, 3H); 7.18 (d, 1H); 7.40 (d, 1H); 7.42�7.54 (m, 4H); 7.85 (m, 2H); 8.04 (d, 1H); 8.42�8.50 (m, 2H); 8.66 (dd, 1H); 8.95 (s, 1H); 9.24 (m, 1H); 10.10 (s, 1H).
Analytical HPLC Conditions:
1) HPLC-System: Kontron 420 System; column: CC 250/4,6 nucleosil 100-5 C18; flow rate: 1 ml/min. Eluents: A: water (+0.1% trifluoroacetic acid) B: acetonitrile (+0.1% trifluoroacetic acid) Gradient: 20%→0% A in B in 13 min and 100% B during 5 min.
2) HPLC-System: Column: 150�3.9 mm, packed with Symmetry C18 5μ (Waters), pre-equilibrated with eluent a); flow rate 1.2 ml/min, UV detection at 267 nm. Eluents: a): ion pair reagent and methanol (420 ml+580 ml)
b): ion pair reagent and methanol (40 ml+960 ml) ion pair reagent: 7.5 g of 1-octanesulfonic acid dissolved in about 800 ml H2O, pH value adjusted to 2.5 with phosphoric acid and diluted with water to 1000 ml Gradient: 0% b) in a) for 20 min, followed by 0%→30% b) in a) in 10 min and 30% b) in a) during 5 min.
Tablets containing 100 mg of a compound of formula I, for example one of the compounds of formula I described in the Examples 1�10, are usually prepared in the following composition:
Capsules containing 100 mg of a compound of formula I, for example one of the compounds of formula I described in the Examples 1�10, are usually prepared in the following composition:
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KETTERING -- A Kettering pharmacist lost his brother, an investigator, after he was exposed to the toxic air at ground zero in New York after the terror attacks of Sept. 11, 2001.
New York District Attorney Detective Fred Ghussin was one of the first investigators to enter the twin towers after the first fiery plane crash. He called his brother while inside.
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Sustainable Futures Collection
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Source: Museum Victoria
This collection encompasses a diverse range of material in the fields of animal husbandry, agriculture, economic botany, food technology and textile technology.
The most significant element of the collection relates to agricultural equipment manufacturer and innovator H.V. McKay. The history of this agricultural enterprise spans from its inception in the 1880s to the present day and forms one of the largest industrial collections in Australia. It provides a window on Australian innovation, agriculture, manufacture, working lives and community life.
The collections take on new meaning with passing time. The large collection of wax models of fruit and vegetables, originally developed for 19th century international exhibitions, now plays a vital role in contributing to our understanding of contemporary issues of biodiversity.
Significant items:
- Models of agricultural equipment commissioned by Museum's first director Frederick McCoy in the 1860s.
- Early stump jump plough and stump jump plough models.
- Early Victorian windmills made James Alston and John Abrahams.
- McCook Collection of models, photographs and trade literature relating to windmills.
- Dethridge irrigation meter.
- Humble & Nicholson portable steam engine.
- Cowley steam traction engine.
- Quinlivan 4-wheel-drive traction engine model.
- Ferguson TEA-20 tractor.
- H.V. McKay Collection: the original McKay farm smithy, 1906 stripper harvester, HST header harvester, Sunshine auto header, rare Sunshine tractor, equipment models, business archives, trade publications, films and photographs.
- International Harvester Collection: comprising images, trade literature, newspaper clippings and documents relating to the marketing and manufacture of agricultural equipment by the American based International Harvester Company.
- Daniel Harvey Collection of trade literture and photographs relating to a small specialist firm producing orcharding and fruit grading equipment at Box Hill.
- Women on Farms Gathering Collection.
- Trade literature of agricultural equipment manufacturers and distributors, including over 12,000 product catalogues and brochures and 3,500 advertisements.
- Extensive collection of economic botany samples, much of it originally displayed at 19th century exhibitions - including items prepared by government botanist Ferdinand von Mueller in the 1860s.
- More than 1,900 wax and vegetable fruit models with sketch books and moulds, many of which depict varieties no longer grown commercially.
- Jack Chisholm Fencing Collection - including 1,200 samples of barbed wire and fencing tools.
- May Vale painted timber samples - including many rare and endangered native Australian timbers.
- Pacific Hydro wind turbine.
Items per page: 10 50 (showing 21201 - 21210) 25526 items
Glass Negative - International Harvester, K Series Motor Trucks, Australian Military Force ...
Line up of military International K series trucks without bodies outside Harvester House, City Rd, South Melbourne.From: South Melbourne, Australia Images: 1
Glass Negative - by A.J. Campbell, Australia, circa 1900
3 tailed (freak) gecko.Images: 1
Photograph - H.V. McKay Massey Harris, Farm Equipment Manufacture & Field Trials, Moolap, ...
8ft Sunshine power-drive reaper & binder coupled to Sunshine Massey Harris tractor, cutting oats at Moolap, Victoria. Corio Bay and the You Yangs in background. Mr W.H. Williams, owner ...From: Moolap, Australia Images: 1
Photograph - H.V. McKay Massey Harris, Farm Equipment Manufacture & Field Trials, St Andre ...
'K' type auto header. A pneumatic tyre is visible on the offside wheel, while the main drive wheel is steel. Crop can be seen being taken over the finger guards on the pick up front.Images: 1
Photograph - H.V. McKay Massey Harris, Senior Engineering Staff Farewelling Mr George Bult ...
Photograph is located in an album: Volume No. 3: "Miscellaneous: H.V. McKay Ballarat, Sunshine Factories & Products; Maps, Plans & Charts; Passport Photographs; 1904-1945", page 128. T ...From: Sunshine, Australia Images: 1
Photograph - Massey Ferguson, Farm Equipment Manufacture & Field Trials, Murtoa, Victoria, ...
Unloading auger transferring grain into a portable field-bin for bagging-off.Images: 1
Photograph - H.V. McKay Massey Harris, Farm Equipment Manufacture & Field Trials, Sunshine ...
6 ft 6B ground drive binder on transport wheels fitted with an experimental flax spreader for retting (drying). Also fitted is an experimental P.T.O. To suit an international 'Farmall' ...From: Sunshine, Australia Images: 1


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The Holiday Season is a good time to start thinking about "Giving Back."
At this event on Dec. 1st, MWIB will be collecting donations to benefit Mrs. Wilson's Treatment Services for Women, an organization that supports women and empowers them with the skills they need to transform their lives.
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MWIB in the News…
5/19/14 - Morristown Green
A question of balance: Morristown businesswomen share tips for Success with Sanity
4/24/14 - Morristown Green
"Driven to distraction: Share these life-saving tips with friends…after they pull over"
3/31/14 - Morristown Green
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3/3/14 - Morristown Green
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1/10/14 - Morristown Green
"Maiden voyage: Women's biz group sets sail with full ship in Morristown"
Morristown Women in Business ~ Email: firstname.lastname@example.com


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Feedback & Suggestions
Have suggestions to make Kidzworld a better place? Got feedback? Let us know. Kidzworld loves to hear from you!
"brunostar" wrote:wat o.o
ah xD
"NachozRule" wrote:
"brunostar" wrote:
wat o.o
Definition of nostolgia - describes a sentimentality for the past, typically for a period or place with happy personal associations.
"hugebear" wrote:Old KW with the chips advert
"hugebear" wrote:hmm this one? and its the saint patricks day
"NachozRule" wrote:
"hugebear" wrote:
hmm this one? and its the saint patricks day
I remember that advertisement.
But nah, I meant the one blue one in 2009, when it was really clean and plain, remember that? =D
A great online version of the famous Candy Crush. This is the best game launched...
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Grilled Veggie Naan Pizzas with Goat Cheese
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MOLU comes to Metairie Academy
Mobile Oilfield Learning Unit comes to Metairie Academy The traveling Mobile Oilfield Learning Unit recently visited Metairie Academy. The unit is sponsored by the oilfield industry and has six, self-contained, kiosk-style learning stations. The stations feature curriculum-based, hands-on activities about energy, and the technologies and sciences involved with the oil and natural gas industry. "I […]
Family Potluck Dinner and Co-op Meeting 11/20/2014 @ 6pm
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Actors who make us laugh
Published: Mar 14 2013 10:30:22 AM EDT Updated On: Nov 12 2014 10:25:58 AM EST
This week funny actors Jim Carrey, Jeff Daniels and Steve Carell have movies coming out. Take a look at some of the best comedy actors and actresses of all time.
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Tech Helproom
It's free to register, to post a question or to start / join a discussion
Burning a 5+ hour long video onto DVD's
Likes # 0
Posted February 18, 2013 at 10:29PM
Have a video which runs for 5+ hours and would like to burn it onto some DVD's. Can I pause the video after 2 hours,replace with another DVD, and then continue doing this until I have the video in full ?
Type of File :Video Clip (.avi) Size 1.1 GB
Also do I need any particular software to do this ?
Thank You
Likes # 0
Posted February 20, 2013 at 11:00AM
You need something like this.
You can't do it by pausing in the way you suggest.
Likes # 0
Posted February 20, 2013 at 6:51PM
"Type of File :Video Clip (.avi) Size 1.1 GB"
A dvd-r holds 4.7 GB
Which program are you using to burn to dvd?
Likes # 0
Posted February 20, 2013 at 9:59PM
Forum Editor
Thanks for the info. Will look into that.
lotvic, haven't got one but will look into the one Forum Editor suggests. Clicking on 'properties' of the video I get the information that the size is 1.1GB, but when I play it the running time is 5+ hours ?
Thanks for your replies.
Likes # 0
Posted February 21, 2013 at 2:40AM
I use the free DVDFlick list of files supported (as with any free program during install don't forget to untick or tick so you don't get any extra progs installed with it - from memory I think you get offered 'Open Office' or something)
An .avi is just a container the actual files inside could be anything - see the list on my link. As regards the size, not sure about that it depends on the bit rate of the actual files inside the .avi container. Anyway DVDFlick would soon tell you if when it converted it, it was too big for a dvd. Suggest you download the guide .pdf and have a look at it before you decide anything.
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Lateral solid phase epitaxy (L‐SPE) of amorphous Si (a‐Si) films onto nonplanar SiO2 patterns on Si(100) substrates was investigated. The patterns were formed by local oxidation of silicon (LOCOS) and the thickness of the SiO2 films ranged from 60 to 470 nm. The L‐SPE characteristics similar to those for planar patterns were observed in dense a‐Si films prepared by high‐temperature vacuum deposition and subsequent ion implantation. The maximum L‐SPE lengths onto the LOCOS patterns were 4.5, 6.5, and 44 μm in undoped, B‐doped, and P‐doped samples, respectively.
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132-26 South Conduit Avenue • Jamaica, New York 11430 • United States • Map • Contact Us • Phone: (1)(718) 322-7190 • Fax: (1)(718) 322-7191 • Visit Our Site: sheratonjfk.com
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Sudarshan Sukhani, s2analytics.com advises to buy IDBI Bank at current levels.
Technical Analyst, s2analytics.com
Expertise : Equity - Technical
Sudarshan Sukhani, s2analytics.com advises to buy IDBI Bank at current levels.
Sukhani told CNBC-TV18, "IDBI Bank is one of the banking stocks that has been let aside. But now it seems that the first signs of bottoming out, reversal process is visible and because there is more scope for IDBI, stocks like IDBI to go up. The run up has not yet started, so buy IDBI Bank."
On April 18, IDBI Bank closed at Rs 86.25, up Rs 1.80, or 2.13 percent. It has touched an intraday high of Rs 86.80 and an intraday low of Rs 84.25.
READ MORE ON IDBI Bank, Sudarshan Sukhani, s2analytics.com
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Samsung Galaxy S III 3 - Hard Reset Factory Reset
What do you think about this video?
Josue Sanchez: It keeps getting stuck on the samsung logo, what do i do?
Anoop m.r: hi jef...my s3 is dead while i was using it.i just used the factory reset on the settings,after that i installed some applications like facebook,whats app.now its dead condition i tried this video option but...didnt worked...can u help me ..???
bryan brierley: it is stuck on SAMSUNG LOGO , what do i do ?
Gautam Kumar: Hello Jef My S3 is heating up intermittently in idle condition and battery is draining out far quickly. What should i do?
Ивайло Иванов: I have some problem with my phone after rebooting it... My phone started to charge soooo slowly... If I charge the battery for an hour, it reaches only 15% ... How can I fix this problem? :(
Claro Manulat: Jef how to back my galaxy s3 to original version from slimkat?
Ando Pot: Hi Jef)) In Your video within 0.37-0.41 seconds your wi-fi was available)))I have a problem with it... I cannot coonect to wi-fi when it is not protected__could you give me some advice?
Diego Paucar: I chose the fist option and it froze in tmobile screen thing... what should I do?
cj0e: We enjoyed the hand modeling
Hanad Abdullah: thanks alot
Luis Iglesias: hi jeff i got the same problem.phone turn on and stuff and even comunicate with my pc but it has a BLACK SCREEN SO I CANT DO ANYTHING.
bob dylan: does this unlock your phone? as in network unlock?
Caine Paulina: Hi Jef my S has the problem when i want to start up he keeps showing SAMSUNG while flashing blue slowly and he keeps repeating that for like all the time how do i fix that ? i already tryed to Reset it to factory multiple times and i dont have any exess to my phone at all now :(
christvbible: Backup and reset does not appear in the list. Neither does the magic number work. Samsung on my hit list for a terrorist attack!!
LittleMiss Dangerous: I know how to save photos & videos.. But can you tell me how to save (to my pc) my desktop shortcut links & bookmarks as well?
Naylise Sifonte: Thanks for the video man!!
Stacy Ortega: mines just say its wiping factory but takes me back to the retting menu does not erase ???
Ervin Flores: ey Jef, I want to reset my galaxy s iii but I dont see it any option reset factory, Can you help me please.
Anyop Makol: 👏👏👏👏👏 thank u soo much 😘😘😘
Giovanni Kearney: What does a hard reset do vs. regular reset?
Sujan Pak: I tried the first option and it made my phone freeze when restarting. Therefore, I tried the second method but for some reason it takes me to a page where it asks about downloading a custom OS. What is going on here?
nataly cando: how long did it take for ur fone to turn back on cus mine is stuck w a white screen and sas tmobbile 4g lte its been like that more the 10 mins
Kostas Harvatis: My Siii (GT-I9300) won't enter boot mode with this key combo :(
Kassy Sanchez: I did the combination keys and it worked. i selected wipe data/factory set. and it started to work but its still stuck on the android system recovery page. do i turn ut off and back on now or what do i do next?pls help
Crystal Ray: all of them were wrong
Crystal Ray: dude you are the greatest I've been 15 other sites and all off them we're all you are the only one that was able to show me how to unlock my phone thanks again you are a lifesaver #Jef rocks
Linda Cina: will this allow me to change carriers? From AT&T to prepaid. I am running 4.3 android version
Patrick Oostrom: Thank you man, my phone works :D
Matty Banks: Say you got a virus on your phone ? Would this clear it ? Please help
Carlos Valdez: help.. can this remove/unroot my phone?
Merle Bowers: My keyboard would not come up to send a text or email. Your solution was the only thing that worked. Thank you.
mnhm gadka: thanks
John Allen: Jef, worked great! Thanks!
Jackson Hei: thanks a lot! my phone is fine now!
Deshawn Watkins: thank you so much i love you
kirk park: at&t did update to 4.3 now foxfi don't work. how can i fix
سيف الاسود: Thank u man
sujinthan srikantha: reset language is chines my phone
Vivek Jain: thanks
harish hirani: Top man all working phone Thanks
Soccercrazyigboman: Will this affect the Unlocked status of my phone?
Theresa B: BTW, Why is your site ALL about Body beast!!!
anthonyxfss: Why it stuck on the samsung logo there? i choose factory reset and reboot..and it stuck at the logo there like forever..Help! =)
xXYoguiPRXx: My s3 wont boot so I tried the second method and it restart right before it goes to the wipe cache settings. In fact it restart when the android robot shows
Pashen Thompson: What if your phone still be stuck wit the attached logo on it
Adam Novicki: You should run for President of the USA.
swa43615: Worked well thanks
warlyn bacalso: WHAT IF YOU HARDLY RESET YOUR SAMSUNG S3??
Cornelius Fillmore: my s3 is on android 4.3, will it reset back to 4.1 or something because thats my goal
Theresa B: Will This change it from 4.3 to 4.1.2???
Samsung Galaxy S III 3 - Hard Reset Factory Reset 4.5 out of 5


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- NPR Morning Edition Features Doug Seegers
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- "15 Songs That Changed Country Music" to Air Before CMA's
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- Interview with New Studio 'A' Owner Aubrey Preston
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Thank God For Marty Stuart (Nashville Vol. 1 Review)
Whatever your country music question is, Marty Stuart is the answer.
Are you looking for more twang? Look to Marty Stuart. Do you want music that respects the roots? You want Marty Stuart. Are you searching for that one artist that can appeal to the young, to the old, to the hardcore country fans, to fans of country from the outside looking in, and whose appeal spans from gospel fans to punk kids? Then Marty Stuart is your man.
Marty Stuart is on an amazing roll ladies and gentlemen. What he's doing right now with lead guitar player "Cousin" Kenny Vaughan and The Fabulous Superlatives is stuff that legends are made of. You know those periods in an artists' career that you look back on like they can't do wrong, churning out amazing songs and albums one after another? Hank Jr. from Whiskey Bent & Hell Bound to The Pressure Is On, Willie & Waylon after they'd shaken loose from the grips of RCA in the mid 70′s. That's the kind of epic and influential period were in the midst of right now with Marty Stuart, and what a blessing it is to realize this and to be able to experience it all in the present instead of trying to relive it through the past.
Everything is firing on all cylinders, from Marty's live show, to The Marty Stuart Show on RFD-TV, to his last album The Ghost Train, to now Nashville Vol. 1 – Tear The Woodpile Down. Say what you want about the Marty Stuart of the past, and who knows what the future will hold, but right now, as simply as it can be said, Marty Stuart is single handedly saving country music.
And this is no accident. Oh no. Marty knows exactly what he's doing, and he knows exactly why it needs to be done. At some point he identified the need and then decided to roll up his sleeves, reach down deep into the roots of the music, and resurrect them with such fervor that nobody could ever accuse the music of being boring or outmoded or in need of progress.
First and foremost this is guitar music. Over-twangy, too-loud, sexy, dirty, evil, beautiful, in-your-face, unapologetic guitar music punching and kicking its way into you by-God American country soul until sitting down or standing still is no option. The dueling Telecaster work between Marty and Kenny Vaughan is something so tasteful and technically superior, it transcends the entire country genre to elevate these two men and the groove they evoke into the guitar god stratus.
Songs like "Tear The Woodpile Down", the instrumental "Hollywood Boogie", and the mandolin-driven "Truck Drivers' Blues" (which you have to listen closely for the Mick Jagger-like "Uh!" in the intro) have the stones enough to make country converts out of rock fans. Marty's gospel fan club may not want to hear it characterized like this, but there's sex embedded in this music from its swagger. Its got balls, and don't be thrown off by the silver hair, Marty brings a young, enthusiastic approach, winding you up in the intros, and then letting you go like a spinning top in a swirl of dizzying, Jerry Reed-style close guitar harmonies and hot lick tradeoffs.
But all this is just noise without the gift of good songwriting. Even the slow songs bring such passion, conveyed in the studio in no less measure than they would be live. That is what you get in songs like the subtle, but stabbing indictment of Music City "Sundown in Nashville" written by Dwayne Warwick, and sad songs like the Stuart-penned run that takes you toward the end of the album from "Going, Going, Gone" to "A Song of Sadness". I can't help but hear a little of the Dwight Yoakam, West Coast approach in these songs, and in the tear-jerking, swinging waltz "A Matter of Time", the usually-composed and perfect Marty Stuart let's his voice crack with emotion in one of the most stirring vocal performances I've heard from the man. With every one of The Fabulous Superlatives boasting superlative abilities at composing and performing harmonies, the only way to characterize the caliber of vocal performances on this album is "unfair."
Something else remarkable about Nashville Vol. 1 is how similar it is to his previous The Ghost Train. Traditionally this is an unwise decision, but when you're in such a groove and hitting on all cylinders, why shake it up? At some point the need for change will present itself, but for right now ride that groove until it's worn out. What Marty has found with The Fabulous Superlatives is too good not to.
One of the great things about Marty Stuart is that he can be all things to all people. The gospel crowd can't help but love him. Mainstream and young fans can't help but pick up on the guitar work if they're exposed to it. And even the punk and heavy metal country converts can find what they're looking for here. Marty helps point them the way by including Hank Williams III on the final track, "Pictures From Life's Other Side" written by Hank Sr. A perfect gospel tune sung with such heart and grace by both men, it chills your bones with the stark, ancient country language portraying a haunting, unveiled moral. Even without the loud Tele or the original songwriting that defines most of this album, this might be one of the album's best tracks.
But let me waste no more time slaving away with mortal words trying to describe this music, just go listen. Get this album, listen to it loud and frequently, and save your country soul.
Thank God for Marty Stuart! (Please, somebody put that on a T-shirt. I'd buy two.)
Two guns way up!
- – - – - – - – - – - – - – - – - – - – - – - – -
Preview & Purchase Tracks of Nashville, Vol. 1 – Tear The Woodpile Down
You can also listen to four complete songs, including the duet with Hank3 on Soundcloud.
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Town Square
Shirley Temple Black dies at her home in Woodside
Original post made on Feb 11, 2014
Read the full story here Web Link posted Tuesday, February 11, 2014, 8:47 AM
Comments (6)
a resident of another community
on Feb 11, 2014 at 12:57 pm
Shirley Temple -- America's Sweetheart -- woke me up in bed one morning!
It was about 7 a,m, on a Saturday, and the Redwood City Tribune had gone to press about five hours earlier. I was city editor.
Mrs. Black telephoned me to complain that we had associated her with the wrong charity in a story in that morning's newspaper.
I have forgotten the details, but who forgets being awakened in bed at home by the once most popular movie star in America!
a resident of Menlo Park: Central Menlo Park
on Feb 11, 2014 at 1:05 pm
Thank you, Shirley Temple, for the countless hours of joy you created and leave behind. More than that, thank you for the example of a life well lived.
a resident of another community
on Feb 11, 2014 at 1:15 pm
Dennis Anderson, is that you (former sports writer for the Redwood City Tribune)?. Hope you remember me as an old M-A jock.
I saw Mrs. Black at my home on Eleanor Drive often. She was my mother's bridge partner. This was in the late 50's.
a resident of another community
on Feb 11, 2014 at 2:34 pm
I remember seeing Shirley Temple Black dining at the O'Mei restaurant and in line at Draeger's.
a resident of Menlo Park: Park Forest
on Feb 11, 2014 at 4:53 pm
A year younger than Ms. Black, I remember my father taking me to my first movie, in Ludwigshafen, Germany. I must have been four or five. It was "The Little Colonel" and probably had been dubbed into German although I can't recall that. I do remember that I was dazzled by the entire experience. Shirley Temple was my wonderful introduction to cinema, which I have loved all my life. Those too young to have seen early Shirley Temple films of the '30s would be amazed to see the enormous talent and charisma displayed by this precocious prodigal performer.
Thank you, Shirley Temple Black.
a resident of another community
on Feb 12, 2014 at 8:54 am
A beautiful person. A life well lived. Thank you for the inspiration you had provided to millions around the world.
From Roc, in Malaysia.
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