text:
A compound of the formula: ##STR1## where in x-y is --CO--CH2 --, --COCR10-, --CHOHCHR8-, --CH═CR8 -- or ##STR2## and R9 is various, R1 and R8 are alkyl, R2 is H or alkyl and R1 and R2 are alkylene, are disclosed as useful as intermediates for cardiovascular agents.
1. A compound of the formula ##STR8## wherein --X--Y-- is (a) --CO--CR10 --, or (b) --CH═CR8 --
R9 is CHO, ACO, AOOC, NO2, CN, Br, H2 NCO or H2 NCS,
A is alkyl having 1-6 carbon atoms,
R10 is alkylidene having 1-6 C atoms,
R1 and R8 are in each case independently A,
R2 is H or A, or
R1 and R2 together are alkylene having 3-6 C atoms.
2. 2,2-dimethyl-3-methylene-6-cyano-4-chromanone, a compound of claim 1.
3. A compound of claim 1, wherein --X--Y-- is --CO--CR10 --.
4. A compound of claim 1, wherein R8 is C1-3 -alkyl.
The present invention relates to novel chroman derivatives of the formula I ##STR3## in which R1 and R8 are in each case A,
R2 is H or A,
R1 and R2 together are also alkylene having 3-6 C atoms,
R3 is OH or OAc,
R4 is H,
R3 and R4 together are also a bond,
R5 is a pyridyl-oxy, pyridazinyl-oxy, pyrimidinyl-oxy, pyrazinyl-oxy, oxo-dihydro-pyridyl-oxy, oxo-dihydropyridazinyl-oxy, oxo-dihydro-pyrimidinyl-oxy, oxo-dihydropyrazinyl-oxy, 1H-2-pyridon-1-yl, 1H-6-pyridazinon-1-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl, 1H-2-pyrazinon-1-yl, 3H- or 5H-2-pyrrolinon-1-yl or 1H-2-thiopyridon-1-yl radical which is unsubstituted or monosubstituted or disubstituted by A, F, Cl, Br, I, OH, OA, OAc, NO2, NH2, AcNH, HOOC and/or AOOC, where these radicals may also be completely or partially hydrogenated,
R6 and R7 are in each case H, A, HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO--CS, ACOO, A--CS--O, hydroxyalkyl having 1-6 C atoms, mercaptoalkyl having 1-6 C atoms, NO2, NH2, NHA, NA2, CN, F, Cl, Br, I, CF3, ASO, ASO2, AO--SO, AO--SO2, AcNH, AO--CO--NH, H2 NSO, HANSO, A2 NSO, H2 NSO2, HANSO2, A2 NSO2, H2 NCO, HANCO, A2 NCO, H2 NCS, HANCS, A2 NCS, ASONH, ASO2 NH, AOSONH, AOSO2 NH, ACO-alkyl, nitroalkyl, cyanoalkyl, A--C(═NOH) or A--C(═NNH2),
A is alkyl having 1-6 C atoms,
alkyl is alkylene having 1-6 C atoms and
Ac is alkanoyl having 1-8 C atoms or aroyl having 7-11 C atoms,
and their salts.
Similar compounds are known from EP-A1-76,075 and EP-A1-173,848.
The invention was based on the object of finding novel compounds having useful properties, in particular those which can be used for the preparation of pharmaceuticals.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
It has been found that the compounds of the formula I and their physiologically acceptable salts possess, combined with good tolerability, useful pharmacological properties. Thus, they show effects on the cardiovascular system, it being possible to observe a selective effect on the cardiovascular system at lower doses and a hypotensive effect at higher doses. In the coronary system, for example, decreases in resistance and increases in flow occur, with the influence on the heart rate remaining low. Furthermore, the compounds show a relaxant effect on various smooth muscle organs (e.g., gastrointestinal tract, respiratory system, and uterus). The effects of the compounds can be determined with the aid of methods which are known per se, as are given, for example in EP-A1-173,848 or AU-A-45,547/85 (Derwent Farmdoc No. 86081769) and by K. S. Meesmann et al., Arzneimittelforschung 25 (11), 1975, 1770-1776. Suitable experimental animals are, for example, mice, rats, guinea pigs, dogs, cats, apes, or pigs.
The compounds can, therefore, be used as active medicament compounds in human and veterinary medicine. In addition, they can be used as intermediates for the preparation of further active medicament compounds.
In the formulae given, A is a preferably unbranched alkyl group having 1-6, preferably 1-4, in particular 1, 2 or 3 C atoms, in detail preferably methyl, in addition preferably ethyl, propyl, isopropyl, butyl, isobutyl, and furthermore preferably sec.-butyl, tert.-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methylpentyl).
If R1 and R2 together are alkylene, the alkylene group is preferably unbranched, in detail preferably --(CH2)n--, where n is 3, 4, 5 or 6.
The group "alkyl" preferably stands for --CH2 -- or --CH2 CH2 --.
Ac is preferably alkanoyl having 1-6, in particular 1, 2, 3 or 4 C atoms, in detail preferably formyl or acetyl, furthermore preferably propionyl, butyryl, isobutyryl, pentanoyl or hexanoyl, and in addition preferably benzoyl, o-, m- or p-toluyl, 1- or 2-naphthoyl.
R1 and R2 are preferably each alkyl, in particular each methyl or ethyl, preferably each methyl.
R3 and R4 are preferably together a bond. If R4 is H, R3 is preferably OH, O--CHO or O--COCH3.
R5 is preferably unsubstituted 1H-2-pyridon-1-yl, 2-hydroxy-4-pyridyl-oxy, 6-hydroxy-3-pyridazinyl-oxy, 1,6-dihydro-1-methyl- or 1,6-dihydro-1-ethyl-6-oxo-3-pyridazinyl-oxy, furthermore 2-, 3- or 4-pyridyl-oxy, 3-hydroxy-1H-6-pyridazinon-1-yl or 1H-4-hydroxy-2-pyridon-1-yl, in addition preferably unsubstituted 1H-2-pyrazinon-1-yl, 1H-6-pyridazinon-1-yl, 4,5-dihydro-1H-6-pyridazinon-1-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl, 3H- or 5H-pyrrolinon-1-yl or 1H-2-thiopyridon-1-yl. If R5 is an unsubstituted pyridone or thiopyridone ring, this ring is preferably monosubstituted in the 3-, 4- or 5-position or disubstituted in the 3-and 5-position. Particularly preferred substituents are OH, NO2 and NH2, in addition AOOC, OA, Cl, Br and NHCOCH3, particularly preferred substituted radicals R5 in detail being 4-, hydroxy; in addition 3-, 5- and 6-hydroxy-, 3-, 4-, 5- or 6-methoxy-, 3-, 4-, 5- or 6-acetoxy-, 3-, 5-or 6-chloro-, 3-or 5-nitro-, 3- or 5-amino-, 3- or 5-methoxycarbonyl-, 3- or 5-ethoxycarbonyl-, 3- or 5-acetamido-, 3,5-dichloro-, 3,5-dibromo-, 3-chloro-5-nitro-, 3-nitro-5-chloro-, 3-bromo-5-nitro-, 3-nitro-5-bromo-, 3,5-dinitro-, 3-chloro-5-amino-, 3-amino-5-chloro-, 3-bromo-5-amino-, 3-amino-5-bromo-, 3-chloro-5-acetamido-, 3-acetamido-5-chloro-, 3-bromo-5-acetamido-and 3-acetamido-5-bromo-1H-2-pyridon-1-yl or -1H-2-thiopyridon-1-yl, 1H-4- or 1H-5-hydroxy-6-pyridazinon-1-yl, 1H-3-, 1H-4-or 1H-5-methoxy-6-pyridazinon-1-yl, 1H-3-, 1H-4- or 1H-5-ethoxycarbonyl-6-pyridazinon-1-yl, 1H-4-, 1H-5- or 1H-6-hydroxy-2-pyrimidinon-1-yl, 1H-2- or 1H-4-hydroxy-6-pyrimidinon-1-yl.
R5 can in addition preferably be: 3,4-dihydro-1H-2-pyridon-1-yl, 2,3-dihydro-6H-2-pyridon-1-yl, 5,6-dihydro-1H-2-pyridon-1-yl, 2-piperidinon-1-yl, 2,3-dihydro-1H-6-pyridazinon-1-yl, 1,2-dihydro-5H-6-pyridazinon-1-yl, 4,5-dihydro-1H-6-pyridazinon-1-yl, 2,3,4,5-tetrahydro-1H-6-pyridazinon-1-yl, 3,4-dihydro-1H-2-pyrimidinon-1-yl, 1,6-dihydro-3H-2-pyrimidinon-1-yl, 5,6-dihydro-1H-2-pyrimidinon-1-yl, 3,4,5,6-tetrahydro-1H-2-pyrimidinon-1-yl, 2,3-dihydro-1H-6-pyrimidinon-1-yl, 1,2-dihydro-5H-6-pyrimidinon-1-yl, 4,5-dihydro-1H-6-pyrimidinon-1-yl, 2,3,4,5-tetrahydro-1H-6-pyrimidinon-1-yl, 3,4-dihydro-1H-2-pyrazinon-1-yl, 1,6-dihydro-3H-2-pyrazinon-1-yl, 5,6-pyrazinon-1-yl, 1,6-dihydro-3H-2-pyrazinon-1-yl, 5,6-dihydro-1H-2-pyrazinon-1-yl, 3,4,5,6-tetrahydro-1H-2-pyrazinon-1-yl, 2-pyrrolidinon-1-yl, 3,4-dihydro-1H-2-thiopyridon-1-yl, 2,3-dihydro-6H-2-thiopyridon-1-yl, 5,6-dihydro-1H-2-thiopyridon-1-yl.
In R6 and R7, the following are preferably:
A: methyl, and in addition ethyl;
AO: methoxy, and in addition ethoxy;
ACO: acetyl, and in addition propionyl;
ACS: thioacetyl, and in addition thiopropionyl;
AOOC: methoxycarbonyl, and in addition ethoxycarbonyl;
AO-CS: methoxy-thiocarbonyl, and in addition ethoxy-thiocarbonyl;
ACOO: acetoxy, and in addition propionoxy;
ACSO: thio(no)acetoxy, and in addition thio(no)propionoxy;
hydroxyalkyl: hydroxymethyl or 1- or 2-hydroxyethyl;
mercaptoalkyl: mercaptomethyl or 1- or 2-mercaptoethyl;
NHA: methylamino, and in addition ethylamino;
NA2 : dimethylamino, and in addition diethylamino;
ASO: methylsulfinyl, and in addition ethylsulfinyl;
ASO2 : methylsulfonyl, and in addition ethylsulfonyl;
AO-SO: methoxy-sulfinyl, and in addition ethoxysulfinyl;
AO-SO2 : methoxy-sulfonyl, and in addition ethoxysulfonyl;
Ac-NH: acetamido, and in addition formamido, propionamido or benzamido;
AO-CO-NH: methoxycarbonylamino, and in addition ethoxycarbonylamino;
HANSO: methylaminosulfinyl, and in addition ethylaminosulfinyl
A2 NSO: dimethylaminosulfinyl, and in addition diethylaminosulfinyl;
HANSO2 : methylaminosulfonyl, and in addition ethylaminosulfonyl;
A2 NSO2 : dimethylaminosulfonyl, and in addition diethylaminosulfonyl;
HANCO: N-methylcarbamoyl, and in addition N-ethylcarbamoyl;
A2 NOC: N,N-dimethylcarbamoyl, and in addition N,N-diethylcarbamoyl;
HANCS: N-methyl-thiocarbamoyl, and in addition N-ethyl-thiocarbamoyl;
A2 NCS: N,N-dimethyl-thiocarbamoyl, and in addition N,N-diethyl-thiocarbamoyl;
ASONH: methylsulfinylamino, and in addition ethylsulfinylamino;
ASO2 NH: methylsulfonylamino, and in addition ethylsulfonylamino;
AOSONH: methoxysulfinylamino, and in addition ethoxysulfinylamino;
AOSO2 NH: methoxysulfonylamino, and in addition ethoxysulfonylamino;
ACO-alkyl: 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl;
Nitroalkyl: nitromethyl, 1- or 2-nitroethyl;
Cyanoalkyl: cyanomethyl, 1- or 2-cyanoethyl;
A--C(═NOH): 1-oximinoethyl, and in addition 1-oximinopropyl;
A--C(═NNH2): 1-hydrazinoethyl, and in addition 1-hydrazinopropyl.
The radicals R6 and R7 are preferably in the 6-and 7-position of the chroman system. However, they may also be in the 5- and 6-, 5- and 7-, 5- and 8-, 6- and 8-and 7- and 8-position.
One of the radicals R6 and R7 is preferably H, whereas the other is different from H. This other radical is preferably in the 6-position, but also in the 5-, 7-or 8-position, and is preferably CN or NO2, in addition preferably CHO, ACO (in particular acetyl), AOOC (in particular methoxycarbonyl or ethoxycarbonyl), ACOO (in particular acetoxy), and furthermore preferably F, Cl, Br, I, CF3, H2 NCO, H2 NCS or NH2.
Accordingly, the invention in particular relates to those compounds of the formula I in which at least one of the radicals mentioned has one of the previously mentioned preferred meanings. Some preferred groups of compounds can be expressed by the formulae Ia to Ii below, which correspond to the formula I and in which the radicals not designated in more detail have the meaning indicated in the formula I, in which however
in Ia R1 and R2 are each A;
in Ib R1 and R2 are each CH3 ;
in Ic R1 and R2 together are alkylene having 3-6 atoms;
in Id R5 is 1H-2-pyridon-1-yl, 2-pyrrolidinon-1-yl, 2-hydroxy-4-pyridyl-oxy-, 6-hydroxy-3-pyridazinyl-oxy, 1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy or 1,6-dihydro-1-ethyl-6-oxo-3-pyridazinyl-oxy;
in Ie R5 is 2-hydroxy-4-pyridyl-oxy, 6-hydroxy-3-pyridazinyl-oxy, 1,6-dihydro-1-met hyl-6-oxo-3-pyridazinyl-oxy or 1,6-dihydro-1-ethyl-6-oxo-3-pyridazinyl-oxy;
in If R5 is 6-hydroxy-3-pyridazinyl-oxy;
in Ig
R1 and R2 are each CH3 and
R5 is 1H-2-pyridon-1-yl, 2-pyrrolidinon-1-yl, 2-hydroxy-4-pyridyl-oxy, 6-hydroxy-3-pyridazinyl-oxy, 1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy or 1,6-dihydro-1-ethyl-6-oxo-3-pyridazinyl-oxy;
in Ih
R1 and R2 are each CH3 and
R5 is 2-hydroxy-4-pyridyl-oxy, 6-hydroxy-3-pyridazinyl-oxy, 1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy or 1,6-dihydro-1-ethyl-6-oxo-3-pyridazinyl-oxy;
in Ii
R1 and R2 are each CH3 and
R5 is 6-hydroxy-3-pyridazinyl-oxy.
Compounds of the formulae I' and Ia' to Ii' are furthermore preferred which correspond to the formulae I and Ia to Ii, but in which in each case R3 is additionally OH, OCHO or OCOCH3 and R4 is H.
Compounds of the formulae I" and Ia" to Ii" are furthermore preferred which correspond to the formulae I and Ia to Ii, but in which in each case R3 and R4 together are additionally a bond.
Compounds of the formulae I, I', I", Ia to Ii, Ia' to Ii', and Ia" to Ii" are in addition preferred, in which in each case additionally
R6 is different from H and
R7 is H;
R6 is different from H and is in the 6-position and
R7 is H;
R6 is NO2, CN, CHO, ACO, HOOC, AOOC, ACOO, F, Cl, Br, I, CF3, H2 NCO, H2 NCS or NH2 and
R7 is H;
R6 is NO2, CN, CHO, ACO, HOOC, AOOC, ACOO, F, Cl, Br, I, CF3, H2 NCO, H2 NCS or NH2 and is in the 6-position and
R7 is H;
R6 is NO2, CN, CHO, CH3 CO, CH3 OOC, C2 H5 OOC or CH3 COO and
R7 is H;
R6 is NO2, CN, CHO, CH3 CO, CH3 OOC, C2 H5 OOC or CH3 COO and is in the 6-position and
R7 is H;
R6 is NO2 or CN and
R7 is H;
R6 is NO2 or CN and is in the 6-position and
R7 is H;
R6 is CN and
R7 is H;
R6 is CN and is in the 6-position and
R7 is H.
Compounds of the formulae I, I', I", Ia to Ii, Ia' to Ii', Ia" to Ii" and the remaining groups of compounds previously indicated as preferred are particularly preferred, in which R8 is additionally CH3.
Otherwise, the radicals R1 to R8, A, "alkyl" and Ac above and below have the meanings given in formula I, if not expressly stated otherwise.
The invention in addition relates to a process for the preparation of chroman derivatives of the formula I, characterized in that a 3,4-epoxychroman of the formula II ##STR4## in which R1, R2, R6, R7 and R8 have the meanings given in formula I, is reacted with a compound of the formula III
in which R5 has the meaning given in formula I or with one of its reactive derivatives
and/or in that a compound of the formula I, in which R3 is OH and R4 is H, is dehydrated and/or in that one or more of the radicals R3, R5, R6 and/or R7 are converted into other radicals R3, R5, R6 and/or R7 in a compound of the formula I and/or in that a basic compound of the formula I is converted into one of its acid addition salts by treating with an acid.
The compounds of the formula I are otherwise prepared by methods which are known per se, as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; and in the abovementioned patent applications), in particular under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se but which are not mentioned in more detail here.
The starting materials may also be formed, if desired, in situ in such a way that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
Preferably, the compounds of the formula I are prepared by reacting compounds of the formula II with compounds of the formula III, preferably in the presence of an inert solvent at temperatures between about 0� and 150�.
The starting materials of the formula III are usually known. If they are not known, they can be prepared by methods which are known per se. The starting materials of the formula II are obtainable by reacting 2-hydroxyacetophenones of the formula 2--HO--R6 R7 C5 H2 --COCH3 with ketones of the formula Va, ##STR5## condensing with aldehydes of the formula R9 --CHO (R9 =alkyl having 1-5 C atoms) to give 3-alkylidene-4-chromanones of the formula Vb, reducing, for example with NaBH4, to give 3-alkyl-4-chromanols of the formula Vc, dehydrating, for example with p-toluenesulfonic acid, to give chromenes of the formula Vd and oxidizing, for example with 3-chloroperbenzoic acid. The last-mentioned oxidation can also be carried out in a number of steps. Thus, for example, the bromohydrins of the formula Ve can initially be prepared using N-bromosuccinimide in aqueous solution and these can subsequently be treated with a base, for example sodium hydroxide solution.
The chromenes of the formula Vd can also be obtained by condensation of salicylaldehydes of the formulation of 2--HO--R6 R7 C6 H2 --CHO with ketones of the formula R1 --CO--CH2 --R8 to give hydroxyketones of the formula 2--HO--R6 R7 C6 H2 --CH═CR8 --CO--R1, reaction with organolithium compounds of the formula R2 --Li and subsequent hydrolysis to give diols of the formula 2--HO--R6 R7 C6 H2 --CH═CR8 --CR1 R2 --OH, and cyclization with elimination of water.
Reactive derivatives of III which are suitable are the corresponding salts, for example the Na or K salts, which can also be formed in situ. Different products of formula I can be formed by the reaction of II with III, dependent in particular from the structure of the starting materials and from the reaction conditions.
For instance, the formation of compounds of formula I containing an oxygen bridge (R5 =unsubstituted or substituted pyridyl-oxy, pyridazinyl-oxy, pyrimidinyl-oxy, pyrazinyl-oxy, oxo-dihydro-pyridyl-oxy, oxo-dihydropyridazinyl-oxy, oxo-dihydro-pyrimidinyl-oxy or oxo-dihydro-pyrazinyl-oxy) is favored if the compound III contains at least one OH group as a substituent in addition to the lactame or lactime group and/or if the reaction is carried out under relatively mild conditions, e.g., in the presence of a weak base such as pyridine in an alcohol. For instance, from 2,2,3-trimethyl-3,4-epoxy-6-cyano-chromane ("IIa") and 1H-2-pyridone with NaH in DMSO there are formed predominantly 2,2,3-trimethyl-4-(1H-2-pyridon-1-yl)-6-cyano-2H-chromene ("A") and 2,2,3-trimethyl-4-(1H-2-pyridon-1-yl)-6-cyano-chroman-3-ol ("B"), whereas with pyridine in ethanol there are formed about equal parts of "B" and 2,2,3-trimethyl-4-(2-pyridyl-oxy)-6-cyano-chroman-3-ol. From 2,4-dihydroxypyridine (=4-Hydroxy-1H-2-pyridone) and IIa in pyridine/ethanol there are formed 2,2,3-trimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-cyano-chroman-3-ol and 2,2,3-trimethyl-4-(4-hydroxy-1H-2-pyridon-1-yl)-6-cyano-chroman-3-ol in a weight ratio of about 9:1. In each single case optimal reaction conditions can be worked out easily. The reaction products can be separated and isolated without difficulties, e.g., by crystallization and/or chromatography.
It is preferable to work in the presence of a base. Suitable bases are, for example, hydroxides, hydrides and also amides of alkali metals or alkaline earth metals, such as NaOH, KOH, Ca(OH)2, NaH, KH, CaH2, NaNH2, KNH2, and in addition organic bases such as triethylamine or pyridine which can also be used in excess and then simultaneously serve as the solvent.
Suitable inert solvents are, in particular, alcohols such as methanol, ethanol, isopropanol, n-butanol or tert.-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; nitriles such as acetonitrile; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; amides such as dimethylformamide (DMF), dimethylacetamide or hexamethylphosphoramide; sulfoxides such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons such as dichloromethane, chloroform, trichloroethylene, 1,2-dichloroethane or carbon tetrachloride; hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another are furthermore suitable.
The epoxide II can also be prepared in situ, for example by the action of a base on the corresponding bromohydrin Ve.
A compound of the formula I, in which R3 =OH and R4 =H can be converted into a compound of the formula I, in which R3 and R4 are together a bond, by treating with a dehydrating agent. This is carried out, for example, by the action of one of the bases mentioned, for example NaOH, KOH or NaH, in one of the solvents mentioned, for example tetrahydrofuran, dioxane or DMSO, at temperatures between 0� and 150�.
Furthermore, one or more of the radicals R3, R5, R6 and/or R7 can be converted into other radicals R3, R5, R6 and/or R7 in a compound of the formula I.
For example, it is possible to replace an H atom by a halogen atom by means of a halogenation or by a nitro group by means of a nitration and/or to reduce a nitro group to an amino group and/or to alkylate or acylate an amino or hydroxyl group and/or to convert a cyano group (for example with HCl in water/methanol at 20�-100�) into a carboxyl group or (for example with Raney nickel in water/acetic acid/pyridine in the presence of sodium phosphate) into a formyl group or (for example with KOH in tert.-butanol) into a carbamoyl group or (for example with H2 S in pyridine/triethylamine) into a thiocarbamoyl group and/or to convert a substituted or unsubstituted 1H-2-pyridon-1-yl radical (for example with P2 S5 or with Lawesson reagent in toluene) into the corresponding 1H-2-thiopyridon-1-yl radical.
Nitration is carried out under customary conditions, for example using a mixture of concentrated HNO3 and concentrated H2 SO4 at temperatures between 0� and 30�. If at least one of the substituents R6 and R7 is an electronegative group such as CN or NO2, the nitration predominantly takes place at the radical R5 ; otherwise mixtures are usually obtained in which the nitro groups are on the radical R5 or on the chroman ring.
This applies analogously to the halogenation which can be carried out, for example, using elemental chlorine or bromine in one of the customary inert solvents at temperatures between about 0� and 30�.
A primary or secondary amino group and/or an OH group can be converted into the corresponding secondary or tertiary amino group and/or alkoxy group by treating with alkylating agents. Suitable alkylating agents are, for example, compounds of the formulae A--Cl, A--Br or A--I or corresponding sulfuric acid or sulfonic acid esters, such as methyl chloride, bromide or iodide, dimethyl sulfate or methyl p-toluenesulfonate. In addition, for example, one or two methyl groups can be introduced with formaldehyde in the presence of formic acid. The alkylation is preferably carried out in the presence or absence of one of the inert solvents mentioned, for example DMF, at temperatures between about 0� and about 120�, in which case a catalyst can also be present, preferably a base such as potassium tert.-butoxide or NaH.
Suitable acylating agents for the acylation of amino or hydroxyl groups are preferably the halides (for example chlorides or bromides) or anhydrides of carboxylic acids of the formula Ac--OH, for example acetic anhydride, propionyl chloride, isobutyryl bromide, formic acid/acetic anhydride and benzoyl chloride. The addition of a base such as pyridine or triethylamine during the acylation is possible. The acylation is preferably carried out in the presence or absence of an inert solvent, for example a hydrocarbon such as toluene, a nitrile such as acetonitrile, an amide such as DMF or an excess of a tertiary base such as pyridine or triethylamine, at temperatures between about 0� and about 160�, preferably between 20� and 120�. Formylation is also carried out using formic acid in the presence of pyridine.
A base of the formula I can be converted into the respective acid addition salt using an acid. Acids which give physiologically acceptable salts are particularly suitable for this reaction. Thus, inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene monosulfonic and disulfonic acids, and laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for purifying the compounds of the formula I.
The compounds of the formula I may possess one or more chiral centres. They can therefore be obtained during their preparation as racemates or also, if optically active starting materials are used, in optically active form. If the compounds have two or more chiral centres, they may be obtained during synthesis as mixtures of racemates from which the individual racemates can be isolated in pure form, for example by recrystallizing from inert solvents. Thus, for example, compounds of the formula I in which R1 =R2, R3 =OH and R4 =H have two chiral centres; during preparation by reaction of II with III, however, very predominantly only one racemate having the trans-position of the substituents R3 =OH and R5 is formed. Racemates obtained can, if desired, be separated mechanically or chemically into their enantiomers by methods known per se. Thus, diastereomers can be formed from the racemate by reaction with an optically active resolving agent. Suitable resolving agents for basic compounds of the formula I are, for example, optically active acids, such as the D- and L-forms of tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, camphorsulfonic acids, mandelic acid, malic acid or lactic acid. Carbinols (I, R3 =OH) can in addition be esterified and then resolved with the aid of chiral acylating reagents, for example D- or L-α-methylbenzyl isocyanate (cf. EP-A1-120,428). The different forms of the diastereomers can be separated in a manner known per se, for example by fractional crystallization, and the enantiomers of the formula I can be liberated in a manner known per se from the diastereomers. Resolution of enantiomers is in addition carried out by chromatography on optically active support materials.
The compounds of the formula I and their physiologically acceptable salts can be used for the production of pharmaceutical preparations, in particular in nonchemical ways. In this connection, they can be brought into a suitable form for administration together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and, if desired, in combination with one or more further active compound(s).
The invention in addition relates to agents, in particular pharmaceutical preparations, containing at least one compound of the formula I and/or one of its physiologically acceptable salts.
These preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc or petroleum jelly. Tablets, coated tablets, capsules, syrups, elixirs or drops are used in particular for oral administration, suppositories are used in particular for rectal administration, solutions, preferably oily or aqueous solutions, and in addition suspensions, emulsions or implants are used in particular for parenteral administration, and ointments, creams or powders are used in particular for topical application. The new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations mentioned can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and flavourings and/or aromatizers. They can, if desired, also contain one or more further active compounds, for example one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts can be administered to humans or animals, in particular mammals such as apes, dogs, cats, rats or mice and can be used in the therapeutic treatment of the human or animal body and also in the control of diseases, in particular in the therapy and/or prophylaxis of disturbances of the cardiovascular system, in particular decompensated cardiac insufficiency, angina pectoris, peripheral or cerebral vessel disorders, and disease conditions which are connected with high blood pressure, and in addition disorders which are connected with changes in the non-vascular musculature, for example asthma or urinary incontinence.
In this connection, the substances according to the invention are usually administered analogously to known antianginals or hypotensives, for example nicorandil or cromakalim, preferably in doses between about 0.01 and 5 mg, in particular between 0.02 and 0.5 mg per dose unit. The daily dose is preferably between about 0.0001 and 0.1, in particular between 0.0003 and 0.01 mg/kg of body weight. The specific dose for each particular patient depends, however, on a variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, the general state of health, sex, on the food, on the time and route of administration, on the excretion rate, medicament combination and severity of the particular disease to which the therapy applies. Oral administration is preferred.
The invention also relates to the novel intermediates of the formula IV ##STR6## in which --X--Y-- denotes (a) --CO--CH2 --, (b) --CO--CR10 -- (c) --CHOH--CHR6, (d) --CH═CR6 --, or ##STR7## R9 denotes CHO, ACO, AOOC, NO2, CN, Br, H2 NCO, or H2 NCCS, wherein A is as defined above, and
R10 denotes alkylidene having 1-6 C atoms, and
R1, R2, and R8 have the meaning given in Formula I.
These intermediates can be used to form compounds of Formula I.
These novel intermediates can be prepared according to the instructions in Example 1 or analogously thereto.
In the following examples, "customary working up" means: water is added, if necessary, and the mixture is extracted using an organic solvent such as ethyl acetate; the organic phase is separated off, dried over sodium sulfate, filtered, and evaporated; and the residue is purified by chromatography and/or crystallization.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.
The entire texts of all applications, patents and publications, if any, cited above and below, and of corresponding applications P Nos. 38 15 504.4 and P 38 35 011.4, filed in West Germany on May 6, 1988, and Oct. 14, 1988, respectively, are hereby incorporated by reference.
A mixture of 21.5 g of 2,2,3-trimethyl-3,4-epoxy-6-cyanochroman ("IIa"), 9.5 g of 1H-2-pyridone ("pyridone"), 3 g of an 80% dispersion of NaH in paraffin oil and 600 ml of DMSO is stirred at 20� for 16 hours and poured into water, and the mixture is extracted using ethyl acetate. The extract is evaporated and the residue is chromatographed on silica gel. 2,2,3-Trimethyl-4-(1H-2-pyridon-1-yl)-6-cyano-2H-chromene ("A"; m.p. 212�) is eluted using dichloromethane, then 2,2,3-trimethyl-4-(1H-2-pyridon-1-yl)-6-cyano-chroman-3-ol ("B"; m.p. 185�-186�) using ethyl acetate.
Preparation of the starting material:
(a) A mixture of 81 g of 3-acetyl-4-hydroxybenzonitrile, 48 ml of acetone, 11.8 ml of pyrrolidine and 300 ml of toluene is allowed to stand at 20� for 1 hour, then boiled for 2 hours in a water separator and cooled. After customary working up, 2,2-dimethyl-6-cyano-4-chromanone is obtained, m.p. 119�-120�.
(b) A solution of 24 g of the chromanone, 12 g of paraformaldehyde and 24 ml of piperidine in 300 ml of ethanol is heated at 70� for 3 hours and evaporated. The residue is taken up in dichloromethane/petroleum ether 1:1, the mixture is filtered through silica gel and evaporated, and 2,2-dimethyl-3-methylene-6-cyano-4-chromanone is obtained as an unstable oil.
(c) 6 g of NaBH4 are added to a solution of 25 g of the above chromanone in 500 ml of methanol, and the mixture is stirred at 20� for 1 hour and evaporated. After customary working up, 2,2,3-trimethyl-6-cyano-4-chromanol is obtained as an oily isomer mixture.
(d) A solution of 27 g of the above mixture and 1.2 g of p-toluenesulfonic acid in 400 ml of toluene is boiled in a water separator for 3 hours. The mixture is evaporated, the residue is dissolved in dichloromethane/petroleum ether 1:1, the solution is filtered through silica gel and evaporated again, and 2,2,3-trimethyl-6-cyano-2H-chromene is obtained, m.p. 55�.
(e) A solution of 6.4 g of m-chloroperbenzoic acid in 40 ml of dichloromethane is added dropwise with stirring to a solution of 6.8 g of the above chromene in 100 ml of dichloromethane. The mixture is stirred for 16 hours, filtered, dilute sodium hydroxide solution is added, and the mixture is worked up as usual and 2,2,3-trimethyl-3,4-epoxy-6-cyanochroman (IIa) is obtained, m.p. 118�.
The enantiomers of IIa are obtainable by reaction of 2,2,3-trimethyl-6-cyano-2H-chromene with N-bromosuccinimide to yield 2,2,3-trimethyl-3-bromo-6-cyano-chroman-4-ol, esterification with (+)- or (-)-camphanic acid chloride to give the diastereomeric camphanic acid esters, separation of the enantiomers by crystallization or chromatography and treatment with base, thereby effecting saponification and cyclization to the enantiomeric epoxide IIa.
The following are obtained analogously:
2,2,3-trimethyl-4-(1H-2-pyridon-1-yl)-6-nitro-chroman-3-ol, m.p. 220�-222�
2,2-pentamethylene-3-methyl-4-(1H-2-pyridon-1-yl)-6-cyano-chroman-3-ol, m.p. 204�-206�
2,2,3-trimethyl-4-(1H-3-amino-6-pyridazinon-1-yl)-6-cyano-chroman-3-ol, m.p. 239�-242�
2,2,3-trimethyl-4-(2-pyrrolidon-1-yl)-6-cyano-2H-chromene, m.p. 186�
2,2,3-trimethyl-4-(2-pyrrolidon-1-yl)-6-cyano-chroman-3-ol, m.p. 195�-197�
A mixture of 21.5 g of IIa, 11.2 g of 3,6-pyridazinediol, 12 ml of pyridine and 600 ml of ethanol is boiled for 72 hours. About 300 ml of solvent is distilled off, the mixture is cooled, unreacted 3,6-pyridazinediol is filtered off and the filtrate is evaporated. The 2,2,3-trimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol [=2,2,3-Trimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol] obtained is recrystallized from isopropanol. m.p. 240�.
The following are obtained analogously from the corresponding 3,4-epoxychromans:
A mixture of 10 g of "B", 3 g of sodium hydroxide and 350 ml of dioxane is boiled for 20 min. The mixture is cooled, filtered, and the filtrate is evaporated and "A" is obtained, m.p. 212�.
A mixture of 2 g of "B", 11.7 ml of formic acid and 3.3 ml of acetic anhydride is allowed to stand at 20� for 16 hours and subsequently heated at 40�-42� for 2 hours. After evaporating and customary working up, 2,2,3-trimethyl-3-formyloxy-4-(1H-2-pyridon-1-yl)-6-cyano-chroman is obtained.
The following are obtained analogously from the corresponding 3-hydroxy-chromans:
A mixture of 1 g of "B" and 5 ml of acetic anhydride is boiled for 1 hour. The mixture is cooled, worked up as usual and 2,2,3-trimethyl-3-acetoxy-4-(1H-2-pyridon-1-yl)-6-cyano-chroman is obtained.
2.96 g of "B" are suspended in 100 ml of water and 3.2 g of bromine are added dropwise with stirring at 10�-20�. The substance dissolves and 2,2,3-trimethyl-4-(1H-3,5-dibromo-2-pyridon-1-yl)-6-cyano-chroman-3-ol precipitates and is filtered off.
2.78 g of "A" are dissolved in a mixture of 10 ml of concentrated nitric acid (68%; density 1.41) and 12 ml of concentrated sulfuric acid, stirred at 20� for 3 hours and poured onto ice, the precipitate is filtered and washed with water, and a mixture of 2,2,3-trimethyl-4-(1H-3-and -5-nitro-pyridon-1-yl)-6-cyano-2H-chromene is obtained, which can be separated chromatographically.
A solution of 1 g of 2,2,3-trimethyl-4-(1H-3-nitro-2-pyridon-1-yl)-6-methoxycarbonyl-chroman-3-ol in 25 ml of methanol is hydrogenated to completion at 20� and 1 bar on 0.5 g of 5% Pd-C. The mixture is filtered, the filtrate is evaporated and 2,2,3-trimethyl-4-(1H-3-amino-2-pyridon-1-yl)-6-methoxycarbonyl-chroman-3-ol is obtained.
A solution of 1 g of 2,2,3-trimethyl-4-(1H-3-amino-2-pyridon-1-yl)-6-cyano-2H-chromene in 15 ml of HCOOH and 1 ml of pyridine is boiled for 19 hours and evaporated. After customary working up, 2,2,3-trimethyl-4-(1H-3-formamido-2-pyridon-1-yl)-6-cyano-2H-chromene is obtained.
A mixture of 1 g of 2,2,3-trimethyl-4-(1H-5-amino-2-pyridon-1-yl)-6-cyano-2H-chromene, 10 ml of acetic anhydride and 10 ml of pyridine is allowed to stand at 20� for 16 hours. The mixture is evaporated, the residue is purified chromatographically and 2,2,3-trimethyl-4-(1H-5-acetamido-2-pyridon-1-yl)-6-cyano-2H-chromene is obtained.
HCl is passed into a boiling solution of 1 g of "A" in 50 ml of methanol and 2 ml of water with stirring for 14 hours. The mixture is allowed to cool and to stand overnight. The precipitated 2,2,3-trimethyl-4-(1H-2-pyridon-1-yl)-2H-chromene-6-carboxylic acid is filtered off.
A mixture of 2.78 g of "A", 31 g of Na3 PO4.12H2 O, 28 ml of pyridine, 28 ml of water, 67 ml of acetic acid and 25 g of Raney Ni (moistened with water) is stirred at 20� for 3 hours. After filtering, customary working up gives 2,2,3-trimethyl-4-(1H-2-pyridon-1-yl)-6-formyl-2H-chromene.
The following are obtained analogously
2.78 g of "A" are dissolved in 40 ml of tert.-butanol and 5.6 g of powdered KOH are added with stirring. After boiling for 1 hour and customary working up, 2,2,3-trimethyl-4-(1H-2-pyridon-1-yl)-6-carbamoyl-2H-chromene is obtained.
The following are obtained analogously
H2 S is passed into a solution of 2.78 g of "A" in a mixture of 20 ml of pyridine and 10 ml of triethylamine at 20� for 5 hours, the mixture is evaporated and worked up as usual, and 2,2,3-trimethyl-4-(1H-2-pyridon-1-yl)-6-thiocarbamoyl-2H-chromene is obtained.
The following are obtained analogously
A mixture of 310 mg of "B", 808 mg of Lawesson reagent and 50 ml of toluene is boiled under N2 for 1 hour. Customary working up gives 2,2,3-trimethyl-4-(1H-2-thiopyridon-1-yl)-6-cyano-chroman-3-ol.
2,2,3-Trimethyl-4-(1H-2-thiopyridon-1-yl)-6-cyano-2H-chromene is obtained analogously from "A".
The following are obtained analogously to Example 1:
A mixture of 6.5 g of IIa, 3.1 g of pyridone, 3 ml of pyridine and 100 ml of ethanol is refluxed for 72 hours. After cooling and working up as usual, the mixture is chromatographed over silica gel. There is eluted with dichloromethane/petroleum ether (85:15) 2,2,3-trimethyl-4-(2-pyridyl-oxy)-6-cyano-chroman-3-ol (m.p. 105�-107�) subsequently with dichloromethane/ethyl acetate (85:15) "B", m.p. 185�-186�; weight ration about 1:1.
A mixture of 21.5 g of IIa, 11.1 g of 2,4-dihydroxypyridine (=4-hydroxy-1H-2-pyridinone), 12 ml of pyridine and 360 ml of ethanol is refluxed for 48 hours. After cooling and working up as usual, the mixture is chromatographed over silica gel. 2,2,3-Trimethyl-4-(4-hydroxy-1H-2-pyridon-1-yl)-6-cyano-chroman-3-ol (m.p. 225�-227�) is eluted with dichloromethane/ethyl acetate (85:15), followed by 2,2,3-trimethyl-4-(1,2-dihydro-2-oxo-4-pyridyl-oxy)-6-cyano-chroman-3-ol [2,2,3-trimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-cyano-chroman-3-ol, F. 198�-200�, m.p. 198�-200�], with ethyl acetate/methanol (90:10); weight ratio about 1:9.
Analogously to Example 2, there are obtained from IIa or from the corresponding 2,2,3-trimethyl-3,4-epoxy-chromanes
with 3-hydroxypyridine:
with 4-hydroxypyridine:
with 3-hydroxypyridazine:
with 4-hydroxypyrimidine:
with 2-hydroxypyrazine:
with 2,4-dihydroxypyridine:
with 2,3-dihydroxypyridine:
with 2,5-dihydroxypyridine:
with 4,6-dihydroxypyrimidine:
with 3,6-dihydroxypyridazine:
2,2,3-trimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-nitro-chroman-3-ol, m.p. 223�-225�
2,2-pentamethylen-3-methyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol, no m.p. until 275�
Analogously to Example 4, there are obtained by formylation of the corresponding chroman-3-ols:
Analogously to Example 5, these are obtained by acetylation of the corresponding chroman-3-ols;
A mixture of 327 mg of 2,2,3-trimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol, 20 ml of acetone, 400 mg of K2 CO3 and 0.2 ml of dimethyl sulfate is refluxed for 2 hours. The mixture is filtered, concentrated and chromatographed on silica gel. There is obtained with ethyl acetate/methanol (9:1) 2,2,3-trimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol, m.p. 197�-199�.
Analogously, there are obtained by alkylation:
2,2,3-trimethyl-4-(1,6-dihydro-1-ethyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol, m.p. 166�-168�.
The examples below relate to pharmaceutical preparations which contain the compounds of the formula I or their physiologically acceptable salts:
A mixture of 1 kg of 2,2,3-trimethyl-4-(1H-2-pyridon-1-yl)-6-cyano-2H-chromene, 4 kg of lactose, 1.2 kg of potato starch, 0.2 g of talc and 0.1 kg of magnesium stearate is pressed to give tablets in a customary manner, in such a way that each tablet contains 0.1 mg of active compound.
Tablets are pressed analogously to Example A, and are subsequently coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Hard gelatin capsules are filled in a customary manner with 1 kg of 2,2,3-trimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol so that each capsule contains 0.5 mg of active compound.
A solution of 1 kg of 2,2,3-trimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-cyano-chroman-3-ol in a mixture of 20 l of 1,2-propanediol and 10 l of double-distilled water is sterile filtered, the solution is filled into ampoules and the ampoules are sealed in a sterile manner. Each ampoule contains 0.1 mg of active compound.
Analogously, tablets, dragees, capsules or ampoules are obtainable which contain one or more of the other active compounds of the formula I and/or their physiologically acceptable salts.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make varoius changes and modifications of the invention and adapt it to various usagess and conditions.
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VIEWS: 24 PAGES: 2 CATEGORY: Software POSTED ON: 10/26/2013
Hypertext Preprocessor well known as PHP is an emerging web programming language due to its incredible benefits that includes but not limited to – flexible data handling, user-friendly and most importantly PHP is free of cost.
10 Essential Pre-requisites to look for before you Hire PHP Developers The success of any Web development project greatly depends on the developer's expertise in the meadow. Thus, to enjoy the benefits of PHP to the fullest you need a highly skilled PHP developer. Here are few points that you need to bear in mind before you hire PHP developers. 1. Check how well experienced the PHP developer is The PHP developer should have sound knowledge and experience in various web applications; after all it is professionalism that counts. Only an experienced PHP developer can make your website look professional, thus enhancing your users experience. 2. Evaluate the past work done It's never a bad idea to evaluate some of the past projects done by the PHP developer you look to hire. You need to evaluate not based on the design features but based on the success of the website in business. 3. Authenticate the PHP developer's coding skills You can verify this by contacting the website owner for whom the PHP developer has worked for. Another best way is to ask the developer for a demonstration which will help you judge his coding abilities precisely. 4. Does the PHP developer own Project Management Tools? Ensure that the developer owns a staging server. This will help you to track the progress of the project time and again. 5. Don't miss NDA Even before you kick off the project, get a NDA [Non-disclosure agreement] to ensure privacy and confidential upkeep of source code. 6. CMS and Integration A well experienced PHP programmer should have extensive knowledge about Content Management System Development and Integration 7. Ensure About the Knowledge in Data Management System Make sure that the PHP developers you hire have sufficient knowledge about HTML, XHTML, AJAX, MySQL, Zend, CakePHP, etc. It's always safe to hire PHP developers from experienced / professional companies. This helps you ensure that you receive quality services. 8. Does the developer develop SEO friendly website? Confirm whether the PHP developer designs and develops websites that is search engine friendly and visually pleasing which helps in driving huge traffic to your website and boost up sales. 9. Browser Compatibility This is a major aspect. The developer you hire should be well versed in developing websites that is compatible in multiple browsers regardless of version. 10. Dedicated Customer Service Last but not the least; hire PHP programmers who are always available to answer your queries pooled with outstanding co-ordination. This helps in completing the project successfully on time.
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Please help to identifying this mint plant
my neighbor throw it away, I save it by putting in my pot. Does anyone know what mint plant is this?
I think it is cuban oregano, Plectranthus amboinicus.
Check out google images for cuban oregano. Seems to vary some in habit and appearance - probably different varieties but I still say Plectranthus amboinicus. You can ask on "Name that Plant" for many other opinions, if you wish.
Here is a link that might be useful: Google Images - Plectranthus amboinicus
I am pretty sure that the original photo is more closely related to the mints in the lamiacea family than it is to Plectranthus amboinicus. Here is an article I wrote a couple years ago about Cuban Oregano. http://dtlherbsltd.blogspot.com/2011/02/herb-of-week-cuban-oregano.html?m=1
We have grown it for several years now and have really enjoyed it.
Is it fruity sage- salvia dorisiana, with a fruit scented peach smell, soft bendable leaves?
Compare to the picture here: http://www.colonialcreekfarm.com/search.asp?keyword=salvia+dorisiana&search.x=0amp;search.y=0amp;search=GO
or the broadleaf thyme cuban oregano, with a strong lemon thyme scent, with thick leaves?
I hope this helps
that looks a lot like Indian oregano, called karpooravalli. I remember munching on it when i was a kid. very strong flavor. It was never used in cooking though. More like a medicinal herb.
This post was edited by archoo16 on Sat, Apr 6, 13 at 11:37


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Army Game Proves U.S. Can't Lose 636
from the propaganda-machine dept.
We've improved Slashdot's video section; now you can view our video interviews, product close-ups and site visits with all the usual Slashdot options to comment, share, etc. No more walled garden! It's a work in progress -- we hope you'll check it out (Learn more about the recent updates).
It stands to reason that you can't lose if you can type iddqd whenever you get into trouble.
That'd actually be pretty cool. Crash your car and have to call the police, then phone up your Geiko representative to come down and check your car out to see if he'll total it. Then when the ambulance shows up they cart you off to the hospital where the car simulation turns into a medical simulation for 3 *real* weeks. When they discharge you it then turns into an insurance simulation where you have to fight with your insurance company to get your car fixed or written off. Then car buying simulation kicks into effect!I mean how fun it will be drving a car simulator and if you crash you will need to repair the car yourself after staying 3 weeks in hospital.
Don't underestimate the fighting ability of an angry, drunken Scotsman wielding a farm tool.However, don't count on an Iraq-style insurgency, as Westerners aren't as prepared to sacrifice their lives for their faith/nation.
If nuclear war ever looks eminent I'll probably be taking a trip to the Greenbrier to "play golf" and "take in the sights."
Forget that. If I find out the nukes are in the air, I'm going after that hot business analyst a couple cubes over. "Hey, baby, it's our last few minutes on earth
American army technical superiority is great when they need to go somewhere, do the job and get away quickly or simply sterilize an area from the stratosphere, but when they have to stay somewhere, they suffer from their low headcount.
[Crash programs] fail because they are based on the theory that, with nine women pregnant, you can get a baby a month. -- Wernher von Braun


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Karl Burkart
After receiving a masters in architecture, Karl earned a LEED certification and created one of the green building industry's first web-based design tools, the GreenMatrix, later adopted in California by the county of Alameda. Realizing the power of the web to illuminate the complex world of "green" he helped launch several websites including EVO.com, developed a variety of social network widgets, and lectured internationally on the subject of digital media, technology and the environment. Karl has his own blog called Greendig: real dirt on the environment, and he consults with both nonprofits and corporations. His goal -- to leverage the power of the internet to bring about a new age of solar-powered enlightenment, one in which people and nature happily coexist.
Read Karl's MNN Technology blog.
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- How to make overnight oats
- 7 cultural concepts we don't have in the U.S.
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- Parallel worlds exist and interact with our world, say physicists
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2015 Event Planning
We have some exciting events in store for you in 2015. Details will be announced soon.
3/22/2015 - The NCBA IP Section's annual one-day CLE conference is scheduled for Friday, March 20, 2015 in Cary, NC. The inimitable Tom Irving will be speaking again, as well as many others to be announced soon.
When: March 20, 2015
Where: North Carolina Bar Center, 8000 Weston Parkway, Cary, NC 27513


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Rome Lunch Bag
The latest lunchtime accessories, no-one would ever guess that inside these glossy bags are snacks and sandwiches rather than make-up and mobiles! Roomy enough to cater for the heartiest appetites, their insulated linings and zip closures ensure lunches stay cool and fresh.
Cat Ref: SKU 44076
25 x 9 x 35cm H. (10" x 3½" x 13¾"). (ht. includes handles)
The Rome Lunch Bag product has been discontinued.
Customer Reviews - Rome Lunch Bag
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I've created a frenzy!" by Alison
I've wanted this for a while and thought it a bit pricey to be fair. Now it's in the sale at £9.99 I snapped one up and used it straight away. The girls at work went into a "well jel" rage and have now all gone out and bought the Paris and London ones! Excellent product and really keeps your lunch cool until you want to ear. Great idea Lakeland!
Writing reviews for this product has been disabled
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Arizona Cardinals
Updated Aug 6, 2013 - 9:08 am
Arizona Cardinals working out center Kyle Quinn
According to a report from Baltimore Ravens reporter Aaron Wilson, the Arizona Cardinals are giving a workout to free agent center Kyle Quinn at their training camp in Glendale Tuesday morning.
Quinn, a former University of Arizona standout, went unpicked in the 2013 NFL Draft and signed as a free agent with the Philadelphia Eagles in April. The Eagles released Quinn last month before the start of training camp.
The 6-foot-3, 300-pound Quinn earned honorable mention All-Pac-12 accolades as a junior in 2011 and as a senior in 2012. He started 22 games over the last two seasons for the Wildcats.
Most Popular
Cardinals Audio
- Kurt Warner- NFL Network analyst - Tuesday March 31Kurt Warner describes what he saw at Jameis Winston's pro day.
- Daniel Jeremiah- NFL Network analyst - Friday March 27Daniel Jeremiah could see the Cardinals drafting a running back in a round after the first round.
- Kevin Guy, AZ Rattlers head coach - Friday March 27Coach Guy talks about losing players to the NFL and the challenges the Rattlers face this season.
- Charles Robinson, Yahoo! Sports NFL reporter - Tuesday March 24Charles Robinson believes that Adrian Peterson's relationship with the Vikings will only get worse.
- Sal Paolantonio- ESPN NFL analyst - Tuesday March 24Bruce Arians told Sal Paolantonio that there are "no serious discussions" about trading for Adrian


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The ENIGMA Network brings together researchers in imaging genomics, to understand brain structure, function, and disease, based on brain imaging and genetic data.
Not signed up? Join ENIGMA at any time!
We welcome brain researchers, imagers, geneticists, methods developers, and others interested in cracking the neuro-genetic code!
The ENIGMA Network and active Working Groups:
The ENIGMA Network with other Consortia
Exciting news- ENIGMA is performing Genome-Wide Complex Trait Analysis (GCTA). The effort is lead by Roberto Toro and JB Poline with methodological support from Tom Nichols, with many ENIGMA working groups already involved. Click the GCTA link for more information!
**NEW for 2015** Latest GWAS is out in Nature
30,000 individual MRIs and genomes from 33 countries — a collaborative effort from 190 institutions
Hibar, DP and 300+ co-authors. Common genetic variants influence human subcortical brain structures. Nature, 2015
2014: The ENIGMA Consortium in Review
Thompson, PM and 300+ co-authors. The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data. Brain Imaging and Behavior. SI: Genetic neuroimaging in aging and age-related diseases. DOI 10.1007/s11682-013-9269-5
The ENIGMA Network has several goals:
- To create a network of like-minded individuals, interested in pushing forward the field of imaging genetics.
- To ensure promising findings are replicated via member collaborations, in order to satisfy the mandates of most journals.
- To share ideas, algorithms, data, and information on research studies and methods.
- To facilitate training, including workshops and conferences on key methods and emerging directions in imaging genetics.
Data sharing with other members of the ENIGMA Network is optional and by no means a requirement of joining the network.
The support group for the ENIGMA project: Jason Stein (IGC), Sarah Medland (QIMR Berghofer), Alejandro Arias Vasquez (UMC Radboud), Derrek Hibar (IGC), Neda Jahanshad (IGC),Barbara Franke (UMC Radboud), Nick Martin (QIMR Berghofer), Margie Wright (QIMR Berghofer), Paul Thompson (IGC)


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'And the Burned Moths Remain' on Tor.com. Long ago Jingfei sold the world of her birth, Tiansong, to the Hegemony. Kept as a political prisoner, she bides her eternal sentence in the company of her countless bodies. An envoy arrives with an offer: a bargain to undo history and redeem Jingfei's name. 6,100 words.
Scale-Bright, a novella from Immersion Press. Shortlisted for the British SF Association Award.
'Chrysalises' in Dangerous Games, edited by Jonathan Oliver (Solaris Books).
'The Governess and We' in Steampunk World, edited by Sarah Hans (Alliteration Ink).


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These Are Funny Stories About Candy That Children Wrote.
All work and no play is no fun. So why not have some fun with candy. We are compiling a great log of funny candy stories by kids. I hope you enjoy reading these stories about candy.
CXP A Teenagers View, How and why to buy candy and some fun candy history
Candy Nightmare Story
Skittles Musical Candy & Theater Story


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Today on Vetstreet
Bald Eaglets Arrive in Pennsylvania
A pair of eagles, who made headlines for protecting their snow-covered eggs, welcomed two eaglets.
Cat Taken Into Custody by NYPD
A 10-month-old cat turned himself in at the New York Police Department's 34th precinct in the Bronx this week.
Expert Tips for Traveling With Pets
Going out of town with your cat or dog? Here's our checklist for accommodations, ID, carriers, medications and much…
Not a Cat Person? You're Missing Out
For those of you who aren't feline fans, we bet we can convince you that they are fantastic pets who deserve your…
Should Your Pets Sleep on Your Bed?
Sharing your bed with your cat or dog is a nice way to bond, but is it a good idea? Our expert has the answer.
Decoding Your Pet's Food Label
How can you tell which pet food is best for your cat or dog? Learning how to decipher the label is a great place to…
This Cat Will Bring You Good Fortune
In his home country of Thailand, the intelligent and attention-loving Korat is a living symbol of luck and prosperity.
Thank you for subscribing to Petwire. Look for the latest newsletter each Wednesday.
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Antonio y Cleopatra
Grenadiers · 6.25 × 33 ACG
Homogenized Tobacco Leaf
Caribbean Basin Cuban Seed
Puerto Rico
Medium Brown / EMS
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1 out of 1 found this review helpful.
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Timofmaine on 02/22/15
I've been buying these cigars for well over 10 years, and have to say that the consistency of the product has decreased within the last year or so. Freshness is the major problem, as some orders are very fresh, some are somewhat stale and hard, and some are mixed (one box good, one box stale)..
1 out of 1 found this review helpful.
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Still Great after all these years
EduranManilla on 02/25/15
I've been smoking these babies for many years. I've tried other domestic cigars but I keep coming back. The natural wrapper on these offer up a taste that is close to the premium brands.


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not a poem or a song. a thingy i write and dedicated to baal and for3ve3er lost and whoever i cant remeber but they love my work so here it is.
not a song or poem!!!
this is the 5th time ive done this in a week, and im starting to worry my self. ive cheated on my husband so many times only because he cant fulfill my sexual needs when he is with me. it's a shame i have to go out and fine a perfect staranger to make love to just to get my 5 minutes of pleasure. it's been going on for months now and he has no idea how deceitful i am being. i feel so bad and like a tatal tramp just thinking of how my loving husband would react. we been together since grade school and our friendship escaleted to love. he is so fine and i couldnt wait till he took my virginity but it was a huge dissappoitment. ever since then ive been getting my pleasure by myself or with one of my many lovers. i am a deceitful wife and to think i gave birth to his children. my kids dont know and if they did i still dont think i would stop. for some reason the slightest sex related thing gets me aroused. i tried to stop cheating but it's not working. so 5 out of the 7 days of the week, i go and see, kel, daniel, mark, and tyler. i even had an orgy or 2 if i was that turned on.
cantwrite anymore. for baal and forever lost. my fans on this site.


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- Musician's Friend Best Selection, Price & Service. Guaranteed.
Call our Gear Heads
at: 800-449-9128
Call our Gear Heads
at: 800-449-9128
Find a similar product below or contact our experts for a recommendation of great alternatives. Call us at 800-449-9128.Similar Items:
Find a similar product below or contact our experts for a recommendation of great alternatives. Call us at 800-449-9128.Similar Items:
An envelope pedal that recreates the classic effect perfected for flexibility, tone, and user-friendly operation.
Inspired by one of the great envelope filter pedals of the 1970's and developed with guitarist Mark Karan (The Other Ones, Bob Weir & Ratdog), the Hartman Envelope Filter is a recreation of a classic effect optimized for tone, flexibility, and ease-of-use. "Mark wanted a pedal with a certain tone, range, and feel that could be adjusted fluidly via a simple user interface and of course analog," says Hartman. "I was intrigued by the idea of tailoring the Mutron circuit to his requirements, so we set to work. The result is a pedal that is well-voiced, versatile, and that has the raw immediacy of first-generation analog."
In addition to authentic timbre and response, the Envelope Filter's second foot switch permits changing the filter sweep direction for on-the-fly access to a broad palette of classic filter sounds from funky chirps and saturated quacks to subtler flute-like attacks and horn-tones. Active Mix control blends the effect output signal with dry for subtler applications.
Expand your tonal repertoire with Hartman Electronics today. Order now!
Envelope Filter Guitar Effects Pedal
Our product catalog varies by country due to manufacturer restrictions. If you change the Ship-To country, some or all of the items in your cart may not ship to the new destination.


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Empire State Building Tickets - Observatory and Optional Skip the Line Tickets
Read what other Viator.com travelers think about the Empire State Building Tickets - Observatory and Optional Skip the Line Tickets. What they loved, what they liked and what they think could be improved, it's all here to help you make the most of your next trip.
Click here for tour details, schedule and pricing
Upgrade and go to the 102nd floor, completely worth it!!
Amazing! Definately recommend doing this on an evening!
We were fast tracked past the queues.
The experience of being up the Empire State Building doth spectacular views was amazing. So glad we pre booked with viator. We had a fantastic time.
Michele R
The skip the line ticket was good to have and the staff was very kind in guiding us to where we were going
Not much of a queue which was good, really glad we did it
The skip the line option is totally worth every penny. At no less than 5 points there were long lines, and when we identified ourselves to the staff at each point we bypassed the line completely, and continued on our way.
It may have been cold the day we went, but it was awesome. The skip the line option was worth it. Make sure you go!
United States of America
Great views and nice to skip some of the lines. Went at night and the lights were spectacular!
This tour was amazing!
Victor made it so easy. Walked in with ticket and exchanged for tickets to the top. We added the extra bit on and went right to the top!!!.......we decided to do this at night and it was a fabulous view. It happened to be Halloween so there was a light show on when we were at the top. Recommend!
Fantastic views that really show New York off. Bitterly cold but well worth it! Would certainly visit again.
well worth the extra money booking skip the line tickets - we were whisked up to the observation deck in minutes. Really impressed with the service, and such a fantastic occasion.
We really enjoyed this tour. It gave us a brilliant start to our time in NYC and our super guide, Justina, pointed out and explained buildings and points of interest I know we would have passed by without knowing their significance. I would recommend this tour. It lasted just about the right time and we had opportunity to explore and then meet up again.
This tour was amazing!
Amazing!! The skip the line tickets were an absolute must! We collected them on the day they were booked for, but were advised to return another day as visibility that day was poor. We returned a couple of days later to see the sunset. Fantastic to watch the city views change and a quick trip back to the ground floor with our speedy tickets!! The highlight of our trip!


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April Fools' Day 2015: The best stories from around the web4 hours ago
Check the calendar before you read any overly exciting news stories today, it's April Fools' Day and as such everyone pushing pranks - especially on the internet. In the past we've been treated to some real corkers, such as the Playmobil Apple Store,... >>
These robo butterflies could be the future of flying drone factory workers30 March 2015
It's no secret that technology, such as 3D printing and drones, can revolutionise manufacturing and other industries. German-based Festo, for instance, has just invented something which proves just that. It used 3D printers to manufacturer flying drones... >>
Best 3D prints: The crazy and coolest things people have printed30 March 2015
The world of 3D printing is well and truly here with printers in homes, online stores and even supermarkets offering 3D printing services. The result is all manner of weird and wonderful 3D printed objects. In the home people can download or design files... >>
Amazon Prime Air drones tested in Canada: Deliveries within 30-minutes of orders30 March 2015
Amazon is testing its drone delivery service, Prime Air, in Canada. This brings it closer to real world use in the US and Europe. Amazon Prime Air wants to have packages dropped at people's door steps within 30-minutes of ordering. According to The Guardian,... >>
Why is the Olio Model One smartwatch such a threat to Pebble, Android Wear and Apple Watch?30 March 2015
What happens when a former Apple and HP product designer creates a smartwatch from scratch? Olio. Smartwatches are now coming thick and fast with Android Wear in many forms and the Apple Watch ready to hit wrists the world over. But the Olio is different,... >>
MotionX technology explained: What is it, and why are Swiss smartwatches using it?27 March 2015
Swiss watch makers are finally stepping into the 21st century by announcing smartwatches. Within the last few weeks, notable Swiss watch makers like Frederique Constant, Alpina, and Mondain have unveiled new timepieces. Although they're luxury watches... >>
Google is making surgical robots with Johnson & Johnson27 March 2015
It looks like your medical surgeon might one day be, or at least be assisted by, a Google robot. Google has partnered with a lot of companies in recent years on various different projects, but it's latest partnership is a bit of surprise. Medical and... >>
Valve hopes to let devs sign up for a free HTC Vive VR headset by next week27 March 2015
The recently-announced HTC Vive virtual-reality headset from HTC and Valve will launch this spring, but in order to get one of the earliest versions, you'll have to first apply. Unfortunately, only developers will be able to get their hands on the headset.... >>
Where can you try on the Apple Watch? Selfridges, Isetan, Galleries Lafayette, and more27 March 2015
Previous Apple products may not have needed a real world hands-on experience before buying, but the Apple Watch changes that. To make sure everyone can try before they buy, Apple is extending their retail reach and opening shops-in-shops worldwide. The... >>
Blurred lines: Up close with the Frédérique Constant and Alpina smartwatches at Baselworld27 March 2015
First came the Withings Activité with its analogue approach and intelligent invisible smart capabilities. Now more Swiss companies are offering smartwatches with similar technologies, but are they as good? We caught up with watch makers Frédérique... >>


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The Alvanley Arms - Inn, Cheshire (county)
The Alvanley Arms - Inn is situated in Tarporley and area attractions include Delamere Forest. Additional regional attractions include Chester Zoo and Chester Cathedral.
Property Features.
Dining options at this Tarporley bed & breakfast include a restaurant and a bar/lounge. This is a smoke-free property.
The 7 guestrooms at The Alvanley Arms - Inn include coffee/tea makers and hair dryers. Guests can use the in-room complimentary wireless high-speed Internet access. Rooms are equipped with LCD TVs. Bathrooms offer separate bathtubs and showers and designer toiletries.
Lovely Pub and food
Most enjoyable, well looked after, beautiful food, nice warm atmosphere, would strongly…
Enter dates to check prices
Hotel Info: 866-539-8117from $77
- Double Room, 1 Double Bed, Ensuite (The Cob)
- Standard Double Room Single Use, 2 Single Beds (The Suffolk Punch)
- Standard Double Room Single Use, 2 Single Beds (The Pecheron)
- Standard Double Room Single Use, 1 Double Bed (The Clydesdale)
- Deluxe Double Room, 1 King Bed, Ensuite (The Shire)
- Deluxe Double Room, 1 Double Bed, Ensuite (The Clysdale)
- Standard Double Room Single Use, 1 Double Bed (The Ardenne)
- Twin Room, 2 Single Beds (The Suffolk Punch)
- Double Room, 1 Double Bed, Ensuite (The Ardenne)
- Standard Double Room Single Use, 1 King Bed (The Shire)
- Single Room, 1 Single Bed (The Shetland)
- Twin Room, 2 Single Beds (The Pecheron)
- Standard Double Room Single Use, 1 Double Bed (The Cob)
Recommended hotels
At a glance
Key facts
Hotel size
- This hotel has 7 rooms
- This hotel is arranged over 2 floors
- Check-in time 5:30 PM-10:30 PM
- Check-out time is 10 AM
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
Travelling with others
- Pets not allowed
- Free WiFi in rooms
Other information
- Smoke-free property
Nearby Four Star Cheshire (county) hotels
In the hotel
- Restaurant
- Bar/lounge
- Barbeque grills
- Bicycle rentals nearby
- Golfing nearby
- Mountain biking nearby
In the room
- Coffee/tea maker
- Iron/ironing board
- Sofa bed
- Sofa bed size double
- Private bathroom
- Separate bathtub and shower
- Designer toiletries
- Hair dryer
- Free WiFi
Top Cheshire (county) hotels
Recently reviewed hotels in Cheshire (county)
- Roscoe House by The Roscoe CollectionFrom
"Loved staying here. Big room, comfortable bed, garden view, big bathtub, friendly & helpful staff, great neighborhood. I shall stay there again!"Mar 7, 2015
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- Malmaison LiverpoolFrom
"Hotel was lovely, great facilities. Bed was quite hard so woke up with back pain. Shower was great with loads of pressure. We ate in the restaurant and Natalia was amazing, very…"Mar 4, 2015


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Hotel Relax
No availability found through our partners. Please contact the business directly or check some of our recommended alternatives.
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TripAdvisor Reviews Hotel Relax Syracuse
Travel Blogs from Syracuse
Duomo di Siracusa
This cathedral is truly a rarity. One can see the transformation this sacred place has gone through from an ancient Greek temple to a cathedral with Medieval and Baroque architecture. Its metamorphosis throughout history is evident just by looking at the architecture of this church.
This sacred place has over 2,400 years of history. The cathedral was founded on the ruins of the Temple of Athena, built by the tyrant Gelon. The Doric ...
Temple of Athena
... preserved in a glass case below a large portrait of them. It was the only building I saw in Sicily that was in any way comparable to the vast beauty of the basilica's we visited in Rome. The architectural design of the building was nearly identical to the churches erected in Rome during the Christian era, and the columns of the once Temple of Athena reflected the same design of the temples created in Ancient ...
St. Mary's at Siracusa
... occurred. Christians took this central and important location, filled in the columns, filled the space with their art, and used it as a church. A place of worship for the virgin Artemis became a place of worship for the Virgin Mary. This building is a testament to the importance, and maybe even dependence, of religion in Roman culture, no matter the ...
From Naples to Sigonella, Sicily
I was trying to catch a flight to Shannon from Sigonella NAS, so I fight an overnight ferry from the port of Naples, to the port of Catania. From there I took a cab to the NAS. The flight to Shannon was canceled, so I am doing the waiting game thing again. I need some rest, so I am staying in an actual hotel room for the night. Hopefully there is a flight tomorrow to get ...
Rome- Catania
... and few people. Buildings were all designed by one architect after town destroyed by Etna in 1660- lots black stone used which gives city a dirty look. Stopped in trendy little wine bar in a small square and had a couple of wines and plate of olives, bread, cheese etc for dinner- only cost 20€ for 4 drinks and food. Amazing crowds in pedestrianised main street on Sunday evening- lots of families out for a stroll and a shopping expedition. Big crowds in ...


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The only thing more satisfying than drinking wine...
is discovering it
An experienced wine educator and presenter, Jerry offers educational,
entertaining wine seminars, trains restaurant wait staffs, blogs and writes
regular columns for several magazines and newspapers, consults with
restaurants on their wine selections, and has published several books.
He also hosts wine tastings for parties in private homes, and at
many charity events. His audio-visual presentations on wine
appreciation are widely viewed.
Jerry "de-mystifies" the subject of wine and his writings and
live presentations offer useful hints, tips, and information
that add elegance and fun to every lifestyle.
Or, How I Learned to Drink Wine and Found Ecstasy, Joy, Peace, Happiness, Life and Salvation
Cover Price $17.95
Plus FREE SHIPPING!
I've mentioned before that Southwest Florida is home to two of the top ten charity wine events in the country. Well, the folks in Palm Beach were kind enough to invite wife Debi and me to the Palm Beach Wine Auction in late January, and it turns out they have their charity chops over there, just like we do.
Unlike the Naples and Fort Myers approach, which involves an afternoon outdoor event with grand tastings (lots of tasting), mingling, and somewhat frenetic auction activity, the Palm Beach event, spearheaded by a very civic-minded Ted Mandes, is a bit more sedate, but no less lively. For one thing, it's held in the evening, starting off with a Cham...
Click to Read More
When the impulse hits, and you run off to Napa to make wine, just hope you do it as well as Tor KenwardClick to Read More
We know all about Australia, but what about the great wines from Austria? Find out here!Click to Read More
Nemorino is a blend of three reds that adds up to more than the sum of its parts. Sensational.Click to Read More
Zinfandel is "America's Grape." Here's why!Click to Read More


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Iggy Azalea Talks Britney Spears Duet 'Pretty Girls' [VIDEO]
We can't wait for Iggy Azalea and Britney Spears' duet "Pretty Girls," so of course we were psyched when the "Fancy" rapper opened up about the collab to Access Hollywood.
Britney Spears has been a provocative dance-pop phenomenon and tabloid-headline mainstay since she burst onto the scene in the late '90s. Born in Mississippi in 1981, Britney first tasted fame as a member of the Mickey Mouse Club, featuring fellow superstars-in-training Justin Timberlake and Christina Aguilera. The iconic music video for her supremely catchy debut single, '…Baby One More Time,' features the teen singer dressed as a Catholic schoolgirl as she performs in a school's halls. Her sophomore release, 'Oops! …I Did It Again,' continued her chart supremacy and cemented her place as pop's reigning princess. Plagued by emotional upheaval in her personal life, including public breakdowns and custody battles over her children (as well as conservatorship of the singer herself), the ever-resilient Britney continued her career resurgence in 2013 with a best-selling Las Vegas residency.
We can't wait for Iggy Azalea and Britney Spears' duet "Pretty Girls," so of course we were psyched when the "Fancy" rapper opened up about the collab to Access Hollywood.
Momney! Britney Spears opened up about life with her sons Sean Preston and Jayden James in this week's issue of People magazine.
In an interview from 2000 that many fans probably haven't seen before, Britney Spears talks about how she and Justin Timberlake first started dating.
Called "Pretty Girls," the collaboration between Iggy Azalea and Britney Spears will be the first single off the Australian rapper's next album, due in 2015.
Lady Gaga's Little Monsters and Britney Spears' Britney Army are going head-to-head in the semi-finals of March Madness! Who should win the title of Best Fanbase?
It's hard to top Katy Perry's shark-tastic Super Bowl performance, but if anyone can, it's Britney Spears! The "Perfume" singer is rumored to be playing the 2016 Half Time show!
Britney Spears won't be putting out a new album any time soon.
Who has the better fanbase: Britney Spears' Britney Army or Adam Lambert's Glamberts?
In a new interview, Britney Spears' ex-husband Kevin Federline remembers the brief marriage as a "good time" and gives advice on making co-parenting work.
From her red latex bodysuit to the all-too-relevant Titanic reference, Britney Spears' "Oops! I Did It Again" music video was instantly iconic. Even with that status, we saw the video in an entirely new light after watching it without music.


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Hot answers tagged replication
You are correct that showing the self-financing condition for the BS-portfolio is not as straightforward as one may think: A portfolio $V_t(\alpha_t,\beta_t)$ (for stock $S_t$ and zerobond $B_t$) is self-financing iff: $$V_t=\alpha_tS_t+\beta_t B_t$$ It further implies $$dV_t=\alpha_tdS_t+\beta_tdB_t$$ To replicate a derivative $C(S_t,t)$ by a ...
I think the title here is misleading. Let's go back to the BS world with $r=0$ to $a(S_t)=S_t \sigma.$ In that case, all you are saying is that you can replicate a call option by holding $N(d_1)$ units of stock at time $t.$ What does this have to do with the second equation? I am guessing that this is the price process of an asset of nothing option with ...
if you let the implied vol depend on K you get two terms the first is $N(d_2) $ but you get a correction term which is the slope times the vega $$ \frac{\partial C}{\partial \sigma} \frac{\partial \sigma}{\partial K}.$$ (see eg my book)
Only top voted, non community-wiki answers of a minimum length are eligible


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New Release: Pillars of Eternity, a new RPG perfect for fans of Baldur's Gate and Icewind Dale!
Title screen (EGA/Tandy/MCGA)
Selecting a character (EGA/Tandy/MCGA)
Part of the introduction sequence (EGA/Tandy/MCGA)
The rhymes are all mixed up! (EGA/Tandy/MCGA)
Here's a character who lost an item (EGA/Tandy/MCGA)
Ah, the old woman who lived in a shoe! (EGA/Tandy/MCGA)
The nursery rhyme plays when you return an item (EGA/Tandy/MCGA)
Wow, a giant pumpkin! (EGA/Tandy/MCGA)
Exploring the lands (EGA/Tandy/MCGA)
Hmm, who lives in this house? (EGA/Tandy/MCGA)
A picture of the item you need to find (EGA/Tandy/MCGA)
Hmm, now where can a pail be found? (EGA/Tandy/MCGA)
Talk to characters to find out what they need (EGA/Tandy/MCGA)
Humpty Dumpty needs a ladder (EGA/Tandy/MCGA)
Visit the castle (EGA/Tandy/MCGA)
Uh oh, a spider frightens Miss Muffet! (EGA/Tandy/MCGA)
Even the king is missing something (EGA/Tandy/MCGA)
I found a quaint little house (EGA/Tandy/MCGA)
I located a mouse (EGA/Tandy/MCGA)
This sure is a crooked old house (EGA/Tandy/MCGA)
Hmm, the path splits off into two directions here (EGA/Tandy/MCGA)
Title screen (CGA)
The old woman who lived in a shoe (CGA)
You need to find a little dog somewhere (CGA)
The game begins at Mother Gooses house (CGA)
Hmm, a giant pumpkin! (CGA)
Where would a breadknife go? (CGA)
The mouse runs up the clock... (CGA)
Title screen (Hercules Monochrome)
It's a giant pumpkin! (Hercules Monochrome)
A picture of the item you need to find (Hercules Monochrome)
Humpty Dumpty needs a ladder (Hercules Monochrome)
Inside Mother Goose's home.
The giant pumpkin is the only "house" where no item is ever placed - otherwise you could get stuck because you can't reenter it after the wife returns.
Inside the crooked house - quite a cosy place anyway
The castle from a distance
I like this house most - it's a pity you can't go there, it's "just for decoration".
The cat and the fiddle - well, tigers are orange and not yellow, but due to his size I always considered him quite tiger-like (and "normal" cats just don't compare to tigers ;)).
"I" have the medal from Mother Goose, but "my mum" will surely tell me it was all a dream...
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Thank You For Supporting Us in 2014
Because of you, we saw over 1.5 million children in poverty go from weak to strong, from hungry to fed, and from lost to found. Thank you for a year full of lives changed in the name of Jesus!
One Word To Lead 2015
Time used to dance slowly for me. I remember my creeping countdown to Christmas break. Spring break. Summer…The beginning of our lives was marked with seasons broken up for us, with rest. Then there was college and marriage and all the responsibility that piles itself high. It feels like a new kind of time that…
A Christmas Miracle
A woman came running to our business and amid uncontrollable emotions and said, "I have seen some abandoned bags at a bush near our house and I think it may be the things stolen from you."
Valerie's First Christmas
I was about 3 years old in my earliest Christmas memory. I had chickenpox, and because I was quarantined, my stepfather dressed as Santa to cheer me up. I don't remember the gifts I got that year, but I remember feeling so special that Santa had made a house call to visit me. That memory…
Does My Sponsored Child Know My Name?
Do the children we sponsor know how much they mean to us? Do they know our name?
World Cup Fever
The 2014 World Cup. Thirty-two teams. Twelve stadiums. Sixty-four soccer matches. Thirty-one days. More than 715 million people around the world tune in! But what does World Cup Fever have to do with you?
Experience Compassion Conference: June 27-28, 2014 in beautiful Colorado Springs. We'd love to celebrate with you and give you the opportunity to learn more about what we do. Learn more and Register today!
Become a Missionary Without Leaving Home
We as sponsors have the ability to make a difference in the life of a child living in poverty and fulfill our individual calling here at home.
What's the Language of Love?
What is the language of love? Is it French (ooo la la!)? Spanish? And, how do we express love to our sponsored child when there is a language barrier?
Once a child is fully enrolled in our sponsorship program, each of our partner countries begin working to link the child with a sponsor. While this occurs, the staff in our Ghana country office and at our church partners begin praying for kind hearted individuals to see the pictures of the children and pick…
Our tendency, when we get a little more money, is to live up to our means. A slightly larger house or a slightly larger car, and we have the same stress each month when our bills arrive and the same feeling that we're poor compared to so and so up the road.
God Prepares Our Hearts to Answer His Call
Although I would struggle with letting go of control, God showed me from the start that this was His work to do and I was able to go back to that truth every time things got really hard.
You have a few different options for sending a monetary gift. Each year, you can send $10 to $50 as a birthday gift, $10 to $50 as a general gift, and $25 to $1,000 as a family gift. You also have the option of donating any amount, we typically suggest $20, to the Christmas Gift…
What Do You See in This Picture?
There are many things to notice in this picture, but perhaps what stands out are the things you wouldn't normally notice.
Who is Your Hero?
You, the sponsor of a child living in poverty, are a hero. And you may not feel like a hero, but you are one.
I've taken many calls from sponsors about their children's pictures. "Why is my child wearing such nice clothing?" "Why is my child not smiling?" "My child's newest picture doesn't look like my child. Why?"
Five Ways to Take Great Photographs of Kids
How can we take photographs of people that treat them with dignity? Here are five ways in which our photographers strive to take great photos of kids.
Feeling low on creativity about what larger mail pieces to send? Here are some really cute ideas for things you can send your sponsored child.
Questions about letter writing are the most common ones I hear in the contact center. Many sponsors call or write us because they are frustrated with the quality of the letters they receive from their sponsored children.
A few days ago, I spoke with Judy because she was upset that her sponsored child, Carlos, doesn't…
Happy New Year!
As you reflect back upon the blessings and trials of the past year and pray about what the Lord has in store for you in 2014, we want to thank you so much for your commitment to children in poverty.
Merry Christmas!
On this day we hope you feel the presence of our Savior as we celebrate His grand love and His perfect will to move us closer to Himself.
"Behold, the virgin shall be with child and shall bear a Son, and they shall call His name Immanuel," which translated means, "God with us."
– Matthew…
Only God Could Bring These Results
Dawn Williams, Compassion's Vice President of Finance, talks about the stability and growth God has blessed us with this past year.
Choose One Word to Embody 2014
Prayerfully choosing one word that embodies the promise of the upcoming year is a discipline we've shared with you for many years. This practice of asking God for His yearly theme in our lives endows us with strength in the tough times. It renews the spirit and imbues us with purpose.


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LAS VEGAS, Nev. - A husband and wife who went on a deadly shooting rampage in Las Vegas harboured anti-government beliefs and left a swastika and a "Don't tread on me" flag on the body of one of the two police officers they killed, authorities said Monday.
Jerad and Amanda Miller had been kicked off a Nevada ranch where anti-government protesters faced down federal agents earlier this year because they were "very radical," according to the son of rancher Cliven Bundy.
Assistant Sheriff Kevin McMahill said the Millers had ideology shared by "militia and white supremacists," including the belief that law enforcement was the "oppressor."
Police believe the shootings were an isolated act, not part of a broader conspiracy to target law enforcement, McMahill said.
Ammon Bundy, one of Cliven Bundy's sons, said by telephone that the Millers were at his father's ranch for a few days this spring before they were asked to leave by militia members for unspecified "conduct" problems. He called the couple "very radical" and said they "did not align themselves" with the beliefs of other protesters, who thwarted a roundup of Cliven Bundy's cattle by the U.S. Bureau of Land Management, which wants to collect more than $1 million in grazing fees and penalties.
While thousands of people have been to the site over the last couple of months, "Not very many people were asked to leave. I think they may have been the only ones," Ammon Bundy said.
On Sunday, the two Las Vegas police officers were having lunch at a pizza buffet in an aging strip mall about 5 miles northeast of the Las Vegas Strip when the Millers fatally shot them. The attack at a CiCi's Pizza killed officers Alyn Beck, 41, and Igor Soldo, 31, both of whom were husbands and fathers.
About 100 people attended a candlelight vigil for the slain officers at CiCi's Pizza on Monday night, the Las Vegas Review-Journal reported (http://bit.ly/1uOYPSo).
According to McMahill, this is how Sunday's events unfolded:
The Millers left a neighbour's apartment where they had been staying around 4:30 a.m. and walked for hours, eventually reaching the strip mall, about 5 miles away.
Around 11:20 a.m., Jerad Miller went briefly into the restaurant, then left and got his wife, leaving their backpacks outside.
The two officers were sitting in a booth. Jerad Miller fatally shot Soldo in the back of his head. As his partner tried to react, Miller shot him once in the throat. Amanda Miller then pulled her own gun and both shot Beck several times.
Police believe that while the Millers wanted to target police, the choice of Soldo and Beck was random.
Pulling the mortally wounded officers from the booth, they took their guns and ammunition and put a yellow Gadsden flag featuring the phrase "Don't tread on me" and a swastika on Beck's body. The flag, with its roots in the American Revolution, is a symbol for anti-government groups. Police said they believe the swastika was intended to paint police as Nazis, not necessarily as an expression of the Millers' own white-supremacist views.
The couple also told restaurant patrons that their act was "the beginning of the revolution," the same message as a note they left at the restaurant. That was what the Millers told customers at a Wal-Mart about a block away, where the couple fled. Jerad Miller entered, fired one round and "told the people to get out and this was a revolution and that the police were on the way."
In the frenzy, shopper Joseph Wilcox decided to confront Jerad Miller — not realizing that Amanda Miller was his accomplice. Wilcox went from the checkout area to Miller and pulled his concealed firearm. But before he could fire, Amanda Miller shot him in the ribs and Wilcox collapsed.
"Joseph died trying to protect others," Sheriff Doug Gillespie said.
By now, police had arrived, and two five-officer teams entered the massive store. Near the back, one team confronted the Millers, and exchanged fire. At one point, Jerad Miller tried to blast a rear emergency exit door open with a shotgun, but police had blocked it with a car and he could not escape.
One officer went with store security to screens showing feeds from surveillance cameras and saw that Jerad Miller had built a makeshift barricade around his wife.
As police closed in, Amanda Miller shot her husband several times with a handgun, killing him. She then shot herself in the head. When officers arrived, she was still breathing, and was taken to the hospital. She later died.
Police found hundreds more rounds of unspent ammunition in the Millers' bags.
The couple moved to the Las Vegas area in January, police said. Amanda Miller had worked at a Hobby Lobby craft store there until she was fired in April, the chain store said in a written statement.
Jerad Miller, 31, was convicted of felony vehicle theft in Washington state, and several other offences, including phone harassment, driving under the influence, theft and malicious mischief, between 2001 and 2003, according to a Washington State Patrol database.
He also had a criminal record in Indiana.
Miller attended Kennewick High School in Washington state for one semester in 1999, his freshman year, district spokeswoman Robyn Chastain said. The district had no other record of him attending schools in the district, or of what he did when he left the school.
He and his 22-year-old wife were married in August 2012, according to a marriage license on file in Indiana.
When police descended on their apartment complex Sunday night in a rundown neighbourhood, officers evacuated other residents.
On Monday, Sheriff Gillespie said he was pairing officers together for safety and that, for now, 300 will be on patrol — twice what is normal.
Asked about worries that more officers may be targeted, he responded: "Is that weighing? Sure, there's no doubt about it."
Ammon Bundy said supporters of his father are saddened by the killings and "have had no quarrel" with Las Vegas police.
"The only thing worse than (government) tyranny is anarchy," he said. "And we certainly recognize that."
Pritchard reported from Los Angeles. Associated Press writer Eugene Johnson in Seattle and researcher Judith Ausuebel in New York contributed to this report.
By Michelle Rindels And Justin Pritchard, The Associated Press
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