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Justia Patents Plural Ring Hetero Atoms In The Additional Hetero RingUS Patent for Phenyl-piperazine derivatives as serotonin reuptake inhibitors Patent (Patent # 10,844,029)
Phenyl-piperazine derivatives as serotonin reuptake inhibitors
Jun 15, 2017 - H. Lundbeck A/S
The invention provides compounds represented by the general formula I wherein the substituents are defined in the application. The compounds are useful in the treatment of an affective disorder, including depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder.
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This application is a continuation of U.S. application Ser. No. 14/744,197, filed Jun. 19, 2015, now U.S. Pat. No. 9,708,280, which is a continuation of U.S. application Ser. No. 13/927,678, filed Jun. 26, 2013, now U.S. Pat. No. 9,090,575, which is a continuation of U.S. application Ser. No. 13/367,065, filed Feb. 6, 2012, now U.S. Pat. No. 8,476,279, which is a divisional of U.S. application Ser. No. 12/700,521, filed Feb. 4, 2010, now U.S. Pat. No. 8,110,567, which is a divisional of U.S. application Ser. No. 11/551,188, filed Oct. 19, 2006, now U.S. Pat. No. 7,683,053, which is a continuation of U.S. application Ser. No. 10/488,280, filed Jun. 15, 2004, now U.S. Pat. No. 7,144,884, which is a 35 U.S.C. § 371 National Stage of International Application No. PCT/DK2002/00659, filed Oct. 2, 2002, which claims priority of Danish Application No. PA 2001 01466, filed Oct. 4, 2001. The contents of all of the prior applications are herein incorporated by reference.
The present invention relates to novel compounds which are serotonin reuptake inhibitors and as such effective in the treatment of for example depression and anxiety.
Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) have become first choice therapeutics in the treatment of depression, certain forms of anxiety and social phobias, because they are effective, well tolerated and have a favourable safety profile compared to the classic tricyclic antidepressants.
However, clinical studies on depression indicate that non-response to SSRIs is substantial, up to 30%. Another, often neglected, factor in antidepressant treatment is compliance, which has a rather profound effect on the patient's motivation to continue pharmacotherapy.
First of all, there is the delay in therapeutic effect of SSRIs. Sometimes symptoms even worsen during the first weeks of treatment. Secondly, sexual dysfunction is a side effect common to all SSRIs. Without addressing these problems, real progress in the pharmacotherapy of depression and anxiety disorders is not likely to happen.
In order to cope with non-response, psychiatrists sometimes make use of augmentation strategies. Augmentation of antidepressant therapy may be accomplished through the co-administration of mood stabilizers such as lithium carbonate or triiodothyronin or by the use of electroshock.
The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HT1A receptor antagonist has been evaluated in several studies (Innis et al. Eur. J. Pharmacol. 1987, 143, 1095-204 and Gartside Br. J. Pharmacol. 1995, 115, 1064-1070, Blier et al. Trends in Pharmacol. Science 1994, 15, 220). In these studies, it was found that 5-HT1A receptor antagonists would abolish the initial brake on 5-HT neurotransmission induced by the serotonin reuptake inhibitors and thus produce an immediate boost of 5-HT transmission and a rapid onset of therapeutic action.
Several patent applications have been filed, which cover the use of a combination of a 5-HT1A antagonist and a serotonin reuptake inhibitor for the treatment of depression (see e.g. EP-A2-687472 and EP-A2-714663).
Another approach to increase terminal 5-HT would be through blockade of the 5-HT1B autoreceptor. Microdialysis experiments in rats have indeed shown that increase of hippocampal 5-HT by citalopram is potentiated by GMC 2-29, an experimental 5-HT1B receptor antagonist.
Several patent applications covering the combination of an SSRI and a 5-HT1B antagonist or partial agonist have also been filed (WO 97/28141, WO 96/03400, EP-A-701819 and WO 99/13877).
It has previously been found that the combination of a serotonin reuptake inhibitor with a compound having 5-HT2C antagonistic or inverse agonistic effect (compounds having a negative efficacy at the 5-HT2C receptor) provides a considerable increase in the level of 5-HT in terminal areas, as measured in microdialysis experiments (WO 01/41701). This would imply a shorter onset of antidepressant effect in the clinic and an augmentation or potentiation of the therapeutic effect of the serotonin reuptake inhibitor (SRI).
The present invention provides compounds which are serotonin reuptake inhibitors for the treatment of affective disorders such as depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder. Some of the compounds also have a combined effect of serotonin reuptake inhibition and 5-HT2C receptor modulation, which according to WO01/41701 would imply a faster onset of anti-depressant activity.
A few of the compounds embraced by the present invention have previously been described in WO 01/49681 and in WO02/59108 However, the compounds of WO01/49681 are not disclosed as having any therapeutic or biological activity. The compounds of WO02/59108 are disclosed as intermediates in the synthesis of compounds different from the compounds of the present invention with a therapeutic activity as melanocortin receptor agonists. One compound, 1-(2-phenoxyphenyl)-piperazine, embraced by the present invention, is disclosed in U.S. Pat. No. 4,064,245 as being useful in the treatment of metabolic disorders.
The present invention provides compounds of the general formula I
Y is N, C or CH;
X represent O or S;
m is 1 or 2;
p is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
q is 0, 1, 2, 3 or 4;
s is 0, 1, 2, 3, 4 or 5;
The dotted line represents an optional bond;
Each R1 is independently selected from the group represented by C1-6-alkyl, or two R1 attached to the same carbon atom may form a 3-6-membered spiro-attached cycloalkyl;
Each R2 is independently selected from the groups represented by halogen, cyano, nitro, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, C1-6-alk(en/yn)yloxycarbonyl, C1-6-alk(en/yn)ylsulfonyl, or —NRxRy;
Each R3 is independently selected from a group represented by halogen, cyano, nitro, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)ylsulfonyl, aryl, C1-6-alk(en/yn)yloxycarbonyl, acyl, —NRxCO—C1-6-alk(en/yn)yl, CONRxRy or NRxRy;
or two adjacent R3 substituents together form a heterocycle fused to the phenyl ring selected from the group consisting of
wherein W is O or S, and R′ and R″ are hydrogen or C1-6-alkyl:
or two adjacent R3 substituents together form a fused heteroaromatic system containing one, two or three heteroatoms,
wherein each Rx and Ry is independently selected from the group represented by hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or aryl; or Rx and Ry together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one further heteroatom;
or an acid addition salt thereof.
The invention also provides compounds as above provided that the compound is not 1-(2-phenoxyphenyl)-piperazine;
The invention also provides compounds as above provided that the compound is not 1-[2-(2-Methoxyphenoxy)phenyl]piperazine, 1-[2-(2,6-dimethoxyphenoxy)phenyl]-[1,4]-diazepane, 1-{2-[3-(dimethylamino)phenoxy]phenyl}piperazine, 1-[2-(4-methylphenoxy)phenyl]piperazine, 1-[2-(3-methylphenoxy)phenyl]piperazine, 1-[2-(3-chlorophenoxy)phenyl]piperazine, 1-[2-(3-methoxyphenoxy)phenyl]piperazine and 1-(2-phenoxyphenyl)-piperazine;
The invention provides a compound according to the above for use as a medicament.
The invention provides a pharmaceutical composition comprising a compound according to the above or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.
The invention provides the use of a compound according to the above or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders, such as depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder.
The invention provides a method for the treatment of an affective disorder, including depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder in a living animal body, including a human, comprising administering a therapeutically effective amount of a compound according to the above or a pharmaceutically acceptable acid addition salt thereof.
Preferred embodiments of the invention are wherein p is 0;
Preferred embodiments of the invention are wherein m is 1 or 2;
Preferred embodiments of the invention are R2 is trifluoromethyl, or C1-6-alkyl;
Preferred embodiments of the invention are wherein R3 is selected from the group consisting of halogen, C1-6-alkoxy, C1-6-sulfanyl, C1-6-alkyl, hydroxy or trifluoromethyl;
Particularly preferred embodiments of the invention are wherein the compound of the invention is any of the following:
1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl]piperazine,
1-[2-(4-Bromophenylsulfanyl)phenyl]piperazine,
1-{2-[4-(Methylsulfanyl)phenylsulfanyl]phenyl}piperazine,
1-{2-[4-Hydroxyphenylsulfanyl]phenyl}piperazine,
1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine,
1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl][1,4]diazepane,
1-[2-(3-Methylphenylsulfanyl)phenyl]-[1,4]-diazepane,
1-[2-(4-Butylphenoxy)phenyl]piperazine,
1-[2-(4-Methoxyphenoxy)phenyl]piperazine,
2-(4-Methylphenylsulfanyl)phenyl-1-piperazine,
1-[2-(4-Chlorophenylsulfanyl)phenyl]-piperazine,
1-[2-(4-Methoxyphenylsulfanyl)-4-chlorophenyl]piperazine,
1-[2-(4-Methoxyphenylsulfanyl)-4-methylphenyl]piperazine,
1-[2-(4-Fluorophenylsulfanyl)-5-methylphenyl]piperazine,
1-[2-(4-Methoxyphenylsulfanyl)-5-trifluoromethylphenyl]piperazine,
1-[2-(4-Chlorophenylsulfanyl)phenyl]-3-methylpiperazine,
1-[2-(4-Chlorophenylsulfanyl)phenyl]-3,5-dimethylpiperazine,
4-[2-(4-Methylphenylsulfanyl)phenyl]-3,6-dihydro-2H-pyridine,
4-[2-(4-Methoxyphenylsulfanyl)phenyl]-3,6-dihydro-2H-pyridine or
4-[2-(4-Methylphenylsulfanyl)phenyl]piperidine
or a pharmaceutically acceptable acid addition salt thereof.
Definition of Substituents
Halogen means fluoro, chloro, bromo or iodo.
The expression C1-6-alk(en/yn)yl means a C1-6-alkyl, C2-6-alkenyl or a C2-6-alkynyl group. The expression C3-8-cycloalk(en)yl means a C3-8-cycloalkyl- or cycloalkenyl group.
The term C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
Similarly, C2-6 alkenyl and C2-6 alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond respectively, including but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
The term C3-8 cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc.
The term C3-8 cycloalkenyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms and including one double bond.
In the term C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C1-6-alk(en/yn)yl are as defined above.
The terms C1-6-alk(en/yn)yloxy, C1-6 alk(en/yn)ylsulfanyl, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfonyl etc. designate such groups in which the C1-6-alk(en/yn)yl are as defined above.
As used herein, the term C1-6-alk(en/yn)yloxycarbonyl refers to groups of the formula C1-6-alk(en/yn)yl-O—CO—, wherein C1-6-alk(en/yn)yl are as defined above.
As used herein, the term acyl refers to formyl, C1-6-alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C1-6-alk(en/yn)ylcarbonyl, C3-8-cycloalk(en)ylcarbonyl or a C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl-carbonyl group.
The term 3-7-membered ring optionally containing one further heteroatom as used herein refers to ring systems such as 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolyl or pyrazolyl, all of which may be further substituted with C1-6-alkyl.
The heterocycles formed by two adjacent R3 substituents and fused to the parent ring may together form rings such as 5-membered monocyclic rings such as 3H-1,2,3-oxathiazole, 1,3,2-oxathiazole, 1,3,2-dioxazole, 3H-1,2,3-dithiazole, 1,3,2-dithiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isoxazole, oxazole, isothiazole, thiazole, 1H-imidazole, 1H-pyrazole, 1H-pyrrole, furan or thiophene and 6-membered monocyclic rings such as 1,2,3-oxathiazine, 1,2,4-oxathiazine, 1,2,5-oxathiazine, 1,4,2-oxathiazine, 1,4,3-oxathiazine, 1,2,3-dioxazine, 1,2,4-dioxazine, 4H-1,3,2-dioxazine, 1,4,2-dioxazine, 2H-1,5,2-dioxazine, 1,2,3-dithiazine, 1,2,4-dithiazine, 4H-1,3,2-dithiazine, 1,4,2-dithiazine, 2H-1,5,2-dithiazine, 2H-1,2,3-oxadiazine, 2H-1,2,4-oxadiazine, 2H-1,2,5-oxadiazine, 2H-1,2,6-oxadiazine, 2H-1,3,4-oxadiazine, 2H-1,2,3-thiadiazine, 2H-1,2,4-thiadiazine, 2H-1,2,5-thiadiazine, 2H-1,2,6-thiadiazine, 2H-1,3,4-thiadiazine, 1,2,3-triazine, 1,2,4-triazine, 2H-1,2-oxazine, 2H-1,3-oxazine, 2H-1,4-oxazine, 2H-1,2-thiazine, 2H-1,3-thiazine, 2H-1,4-thiazine, pyrazine, pyridazine, pyrimidine, 4H-1,3-oxathiin, 1,4-oxathiin, 4H-1,3-dioxin, 1,4-dioxin, 4H-1,3-dithiin, 1,4-dithiin, pyridine, 2H-pyran or 2H-thiin.
The term aryl refers to carbocyclic, aromatic systems such as phenyl and naphthyl.
The acid addition salts of the invention are preferably pharmaceutically acceptable salts of the compounds of the invention formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
Further, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
Some of the compounds of the present invention contain chiral centres and such compounds exist in the form of isomers (i.e. enantiomers). The invention includes all such isomers and any mixtures thereof including racemic mixtures.
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can also be resolved into their optical antipodes, e.g. by fractional crystallization of d- or l-(tartrates, mandelates or camphorsulfonate) salts. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981).
Optically active compounds can also be prepared from optically active starting materials.
Pharmaceutical Compositions
The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example: Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.
Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilising the solution and filling it in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
The pharmaceutical compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.
Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg. The total daily dose is usually in the range of about 0.05-500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.
The compounds of the invention are prepared by the following general methods:
a) Deprotection or cleavage from a polymer support of a compound with formula II
wherein Z represents
and R1, R2, R3, m, p, q, s, X, Y and the dotted line are described above, and R′″ is a tert-butyl, methyl, ethyl, allyl or benzyl group or
is a solid supported carbamate group, such as the Wang resin-based carbamate linker.
b) Chemical Transformation of a Compound with Formula III
wherein R1, R2, m, p, q, Y and the dotted line are as described above, to the corresponding diazonium compound, and subsequently reacting with a compound HXZ, wherein X and Z are as defined above.
c) Reacting a Compound with Formula IV
wherein R2, R3, X, s and q are as described above with an alkylating agent of formula (Cl—(CH2)m+1)NH(CH2)2Cl or (Br—(CH2)m+1)NH(CH2)2Br wherein m are as defined above.
d) Reacting a Compound with Formula V
wherein R2, R3, X, s and q are as described above and G is a bromine or iodine atom with a compound of formula VI
wherein R1, m and p are as defined above.
e) Dehydrating and Optionally Simultaneously Deprotecting a Compound of Formula VII
wherein R1, R2, R3, X, m, p, q and s are as described above and R is either a hydrogen atom or a BOC group.
f) Hydrogenate the Double Bond in a Compound of Formula VIII
wherein R1, R2, R3, X, m, p, q and s are as described above.
The deprotection according to method a) was performed by standard techniques, known to the persons skilled in the art and detailed in the textbook Protective Groups in Organic Synthesis T. W. Greene and P. G. M. Wuts, Wiley Interscience, (1991) ISBN 0471623016.
Starting materials of formula II wherein R′″=tert-Bu were prepared according to the procedure as outlined below. Fluoronitrobenzene derivatives were reacted with phenols or thiophenols according to the procedure of Sawyer et al. J. Org. Chem. 1998, 63, 6338 followed by reduction using standard procedures known to the persons skilled in the art. This includes reduction to the corresponding aniline using a metal hydride salt such as sodium borohydride in conjunction with palladium on carbon catalyst in an alcoholic solvent or reduction using a metal chloride salt such as zinc chloride or tin chloride. The resulting aniline was then converted to a properly substituted 3,5-diketopiperazine in a modification of the procedure of Kruse et al. Recl. Trav. Chim. Pays-Bas 1998, 107, 303 using N-butyloxycarbonyliminodiacetic acid. The 3,5-diketopiperazine derivative was then reduced with for example borane to the corresponding BOC protected piperazine, which was then deprotected to the piperazine in situ.
The compounds shown in formula II, wherein Y═CH and the optional double bond is reduced, were prepared from their tertiary alcohol precursors VII wherein R is a BOC group, by a modified Barton reduction in a similar manner as described in Hansen et al. Synthesis 1999, 1925-1930. The intermediate tertiary alcohols were prepared from the corresponding properly substituted 1-bromo-phenylsulfanylbenzenes or their corresponding ethers by metal-halogen exchange followed by addition of an appropriate electrophile of the formula IX in a similar manner as described in Palmer et al. J. Med. Chem. 1997, 40, 1982-1989. The properly substituted 1-bromo-phenylsulfanylbenzenes were prepared in a similar manner as described in the literature by reaction of properly substituted thiophenols with properly substituted aryliodides according to Schopfer and Schlapbach Tetrahedron 2001, 57, 3069-3073 Bates et al., Org. Lett. 2002, 4, 2803-2806 and Kwong et al. Org. Lett. 2002, 4, (in press). The corresponding substituted 1-bromo-phenoxybenzenes may be prepared as described by Buck et al. Org. Lett. 2002, 4, 1623-1626.
The cleavage from a polymer support, such as from the Wang resin based carbamate linker, according to method a) was performed according to literature known procedures (Zaragoza Tetrahedron Lett. 1995, 36, 8677-8678 and Conti et al. Tetrahedron Lett. 1997, 38, 2915-2918).
The starting material of formula II may also be prepared according to the methods described in patent application WO 01/49681. The diamines were either commercially available or synthesised by methods known to chemists skilled in the art. Iron-complexes, like η6-1,2-dichlorobenzene-η5-cyclopentadienyliron(II) hexafluorophosphate and substituted analogues were synthesised according to literature known procedures (Pearson et al. J. Org. Chem. 1996, 61, 1297-1305) or synthesised by methods known to chemists skilled in the art.
The diazotation followed by reaction with a compound HXZ according to the method b) was performed by addition of the diazonium salt of the corresponding aniline to a solution of sodium salt of a thiophenol or a phenol in an aqueous suspension of copper. The starting material of formula III was prepared as outlined in the following. A fluoronitrobenzene derivative was reacted with a piperazine derivative in a solvent such as DMF, NMP or other dipolar aprotic solvent containing an organic base such as triethylamine to afford the orthonitophenylpiperazine derivative. The intermediate orthonitrophenylpiperazine was subsequently reduced using standard procedures as stated above to give the starting material of formula III.
The reaction of a compound of formula IV with an alkylating agent of formula (Cl—(CH2)m+1)NH(CH2)2Cl or (Br—(CH2)m+1)NH(CH2)2Br as its hydrobromide or hydrochloride salt, wherein m is as defined above was performed in a similar manner as described in Sircar et al. J. Med. Chem. 1992, 35, 4442-4449. Starting materials of formula IV were prepared as described above for starting materials of formula II.
The reaction of a compound of formula V with a diamine of formula VI in method d) was performed in a similar manner as described in Nishiyama et al. Tetrahedron Lett. 1998, 39, 617-620. The starting material of formula V was prepared in a similar manner as described in Schopfer et al. Tetrahedron 2001, 57, 3069-3073.
The dehydration reaction and optional simultaneous deprotection of a compound of formula VII in method e) was performed in a similar manner as described in Palmer et al J. Med. Chem. 1997, 40, 1982-1989. The starting material of formula VII wherein R═H was prepared from a compound of formula VII wherein R is a BOC group (see above) by deprotection with hydrochloric acid in methanol. Compounds of formula VII wherein R=BOC, may be prepared as described in Palmer et al. J. Med. Chem. 1997, 40, 1982-1989.
The reduction of the double bond according to method f) was generally performed by catalytic hydrogenation at low pressure (<3 atm.) in a Parr apparatus, or by using reducing agents such as diborane or hydroboric derivatives as produced in situ from NaBH4 in trifluoroacetic acid in inert solvents such as tetrahydrofuran (THF), dioxane, or diethyl ether. The starting material of formula VIII was prepared from II as described in method a).
Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with Ion Spray source and Shimadzu LC-8A/SLC-10A LC system. Column: 30×4.6 mm Waters Symmetry C18 column with 3.5 μm particle size; Solvent system: A=water/trifluoroacetic acid (100:0.05) and B=water/acetonitrile/trifluoroacetic acid (5:95:0.03); Method: Linear gradient elution with 90% A to 100% B in 4 min and with a flow rate of 2 mL/min. Purity was determined by integration of the UV (254 nm) and ELSD trace. The retention times (RT) are expressed in minutes.
1H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250 instrument. Deuterated methylene chloride (99.8% D), chloroform (99.8% D) or dimethyl sulfoxide (99.8% D) were used as solvents. TMS was used as internal reference standard. Chemical shift values are expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: s=singlet, d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet, dq=double quartet, tt=triplet of triplets, m=multiplet and b=broad singlet.
For ion-exchange chromatography, the following material was used: SCX-columns (1 g) from Varian Mega Bond Elut®, Chrompack cat. No. 220776. Prior to use, the SCX-columns were pre-conditioned with 10% solution of acetic acid in methanol (3 mL). For de-complexation by irradiation, a ultraviolet light source (300 W) from Philipps was used. As starting polymer supports for solid phase synthesis, Wang-resin (1.03 mmol/g, Rapp-Polymere, Tuebingen, Germany) was used.
Preparation of Intermediates
η6-1,2-Dichlorobenzene-η5-cyclopentadienyliron(II) hexafluorophosphate
Ferrocene (167 g), anhydrous aluminium trichloride (238 g) and powdered aluminium (24 g) were suspended in 1,2-dichlorobenzene (500 mL) and heated to 90° C. in a nitrogen atmosphere for 5 h with intensive stirring. The mixture was cooled to room temperature and water (1000 mL) was added carefully in small portions while cooling on an ice bath. Heptane (500 mL) and diethylether (500 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with diethylether (3×300 mL). The aqueous phase was filtered, and aqueous ammonium hexafluorophosphate (60 g in 50 mL water) was added in small portions under stirring. The product was allowed to precipitate at room temperature. After 3 hours the precipitate was filtered off, washed intensively with water and dried in vacuo (50° C.) to give 81 g (21%) of the title compound as a light yellow powder. 1H NMR (D6-DMSO): 5.29 (s, 5H); 6.48 (m, 2H); 7.07 (m, 2H).
Preparation of Polystyrene-Bound Amines
4-[(Piperazin-1-yl)carbonyloxymethyl]phenoxymethyl polystyrene
4-[(4-Nitrophenoxy)carbonyloxymethyl]phenoxymethyl polystyrene (267 g, 235 mmol) was suspended in dry N,N-dimethylformamide (2 L). N-Methylmorpholine (238.0 g, 2.35 mol) and piperazine (102.0 g, 1.17 mol) were added and the mixture was stirred at room temperature for 16 h. The resin was filtered off and washed with N,N-dimethylformamide (2×1 L), tetrahydrofuran (2×1 L), water (1×500 mL), methanol (2×1 L), tetrahydrofuran (2×1 L) and methanol (1×1 L). Finally, the resin was washed with dichloromethane (3×500 mL) and dried in vacuo (25° C., 36 h) to yield an almost colourless resin (240.0 g).
The following polystyrene bound diamines were prepared analogously: 4-[(1,4-Diazepan-1-yl) carbonyloxymethyl]phenoxymethyl polystyrene
Preparation of resin-bound η6-aryl-η5-cyclopentadienyliron(II) hexafluorophosphates 4-({4-[η6-(2-Chlorophenyl)-η5-cyclopentadienyliron(II)]piperazin-1-yl}carbonyloxymethyl)phenoxymethyl Polystyrene Hexafluorophosphate (Intermediate for 1a-1h and 1k-1l)
4-[(Piperazin-1-yl)carbonyloxymethyl]phenoxymethyl polystyrene (115.1 g, 92 mmol) was suspended in dry tetrahydrofuran (1.6 L), and η6-1,2-dichlorobenzene-η5-cyclopentadienyliron(II) hexafluorophosphate (76.0 g, 184 mmol) was added followed by potassium carbonate (50.9 g, 368 mmol). The reaction mixture was stirred at 60° C. for 16 h. After cooling to room temperature, the resin was filtered off and washed with tetrahydrofuran (2×500 mL), water (2×250 mL), tetrahydrofuran (2×500 mL), water (2×250 mL), methanol (2×250 mL), dichloromethane (2×250 mL) and methanol (2×250 mL). Finally, the resin was washed with dichloromethane (3×500 mL) and dried in vacuo (25° C., 36 h) to yield a dark orange resin (142 g).
The following polystyrene bound iron-complex was prepared analogously: 4-({4-[η6-(2-Chloro-phenyl)-η5-cyclopentadienyliron(II)]-[1,4]-diazepan-1-yl}carbonyloxymethyl)phenoxymethyl Polystyrene Hexafluorophosphate (Intermediate for 1i and 1j)
Preparation of Further Intermediates 1-tert-Butoxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]piperidin-4-ol
A solution of BuLi (2.5 M in hexane, 12.0 ml, 30 mmol) was slowly added to a stirred solution of 1-bromo-2-(4-methylphenylsulfanyl)benzene (30 mmol) in dry THF (75 ml) under Argon at −78° C. The solution was stirred for 10 min before 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.98 g, 30 mmol) was added in one portion. The solution was allowed to warm up to room temperature and then stirred for 3 h. Saturated aqueous NH4Cl (150 ml) was added and the solution was extracted with ethylacetate (150 ml). The organic phase was washed with brine, dried (MgSO4) and the solvent was evaporated in vacuo. Crude 1 was purified by flash chromatography on silica gel (eluent: Ethylacetate/heptane 20:80) to produce the target compound as a white foam. LC/MS (m/z) 399.3 (MH+); RT=3.82; purity (UV, ELSD): 98%, 100%; yield: 5.02 g (42%).
1-tert-Butyloxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]-3,5-dioxopiperazine (Intermediate for 2a)
2-(4-Methylphenylsulfanyl)aniline (2.9 g, 13.5 mmol) was dissolved in dry THF (200 mL) and placed under a nitrogen atmosphere. N-(tert-butyloxycarbonyl)iminodiacetic acid (4.7 g, 20.2 mmol) and carbonyl diimidazole (4.2 g, 40.4 mmol) were added to the solution and the reaction was refluxed for 60 hours. The reaction mixture was cooled to room temperature and ethyl acetate (500 mL) was added. The resulting solution was then washed with 2 N NaHCO3 (2×200 mL), 2 N HCl (2×200 mL) and saturated sodium chloride solution (100 mL) and the solvents evaporated in vacuo. Yield 6.0 g, 107%, 1H NMR (CDCl3) 1.5 (s, 9H); 2.32 (s, 3H); 4.4-4.6 (m, 4H); 7.02-7.18 (m, 3H); 7.2-7.45 (m, 5H).
The following 3.5 diketopiperazine derivatives were prepared in an analogous fashion:
1-tert-Butyloxycarbonyl-4-[2-(4-chlorophenylsulfanyl)phenyl]-3,5-dioxopiperazine (Intermediate for 2b)
1-tert-Butyloxycarbonyl-4-[2-(4-methoxyphenylsulfanyl)-4-chlorophenyl]-3,5-dioxopiperazine (Intermediate for 2c)
1-tert-Butyloxycarbonyl-4-[2-(4-methoxyphenylsulfanyl)-4-methylphenyl]-3,5-dioxopiperazine (Intermediate for 2d)
1-tert-Butyloxycarbonyl-4-[2-(4-methoxyphenylsulfanyl)-5-methylphenyl]-3,5-dioxopiperazine (Intermediate for 2e)
1-tert-Butyloxycarbonyl-4-[2-(4-fluorophenylsulfanyl)-5-methylphenyl]-3,5-dioxopiperazine (Intermediate for 2f)
1-tert-Butyloxycarbonyl-4-[2-(4-methoxyphenylsulfanyl)-5-trifluoromethylphenyl]-3,5-dioxopiperazine (Intermediate for 2g)
2-(3-Methylpiperazin-1-yl)phenylamine (Intermediate for 3a)
Fluoronitrobenzene (7.1 g, 50 mmol) was dissolved in DMF (100 mL) containing triethylamine (10 g, 100 mmol) and placed under a nitrogen atmosphere. To the solution was added 2-methyl-piperazine (5.5 g, 55 mmol). The reaction was heated to 80° C. for 16 hours. The reaction was allowed to cool to room temperature before the solvent was reduced to half volume in vacuo. Ethyl acetate (200 mL) and ice-water (250 mL) were added to the solution and the product was extracted with diethylether (2×200 mL). The aqueous phase was saturated with sodium chloride and extracted with ethyl acetate (2×200 mL). The organic phases were combined, washed with saturated brine, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The product (10.5 g) was dissolved in ethanol (250 mL). Palladium on charcoal catalyst (10% w/w, 2.2 g) was added to the solution and the solution was hydrogenated in a Parr apparatus at 3 bar for 3 hours. The solution was filtered and the solvents evaporated in vacuo to give the aniline product. Yield (8.0 g, 83%).
The following intermediates were prepared in an analogous fashion: 2-(3,5-Dimethylpiperazin-1-yl)phenylamine (intermediate for 3b)
Compounds of the Invention Example 1 1a, 1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl]piperazine
To a solution of 2-trifluoromethylthiophenol (1.75 g, 9.8 mmol) in a 1:1 mixture of tetrahydrofuran/dimethylformamide (30 mL), sodium hydride (7.4 mmol, 60% in mineral oil) was carefully added at room temperature (Caution: Generation of hydrogen). The mixture was stirred for an additional 30 min after the generation of hydrogen had ceased. Subsequently, 4-({4-[η6-(2-chloro-phenyl)-η5-cyclopentadienyliron(II)]piperazin-1-yl}carbonyloxymethyl)phenoxymethyl polystyrene hexafluorophosphate (3.5 g, 2.45 mmol) was added and the mixture was stirred at 55° C. for 12 h. After cooling to room temperature, the resin was filtered off and washed with tetrahydrofuran (2×50 mL), tetrahydrofuran/water (1:1) (2×50 mL), N,N-dimethylformamide (2×50 mL), water (2×50 mL), methanol (3×50 mL), tetrahydrofuran (3×50 mL), and subsequently with methanol and tetrahydrofuran (each 50 mL, 5 cycles). Finally, the resin was washed with dichloromethane (3×50 mL) and dried in vacuo (25° C., 12 h) to yield a dark orange resin. The thus obtained resin and a 0.5 M solution of 1,10-phenanthroline in 3:1 mixture of pyridine/water (20 mL) was placed in light-transparent reactor tube. The suspension was agitated by rotation under irradiation with visible light for 12 h. The resin was filtered and washed with methanol (2×25 mL), water (2×25 mL) and tetrahydrofuran (3×25 mL) until the washing solutions were colourless (approx. 5 cycles) and the irradiation procedure was repeated until decomplexation was complete (approx. 5 cycles). After the decomplexation was completed, the resin was washed with dichloromethane (3×25 mL) and dried in vacuo (25° C., 12 h) to obtain a light brown resin. 100 mg (77 μmol) of the thus obtained resin were suspended in a 1:1 mixture of trifluoroacetic acid and dichloromethane (2 mL) and stirred at room temperature for 2 h. The resin was filtered off and washed with methanol (1×0.5 mL) and dichloromethane (1×0.5 mL). The filtrates were collected and the volatile solvents evaporated in vacuo. The crude product was purified by preparative LC-MS and subsequently by ion-exchange chromatography. LC/MS (m/z) 339 (MW); RT=2.39; purity (UV, ELSD): 92%, 100%; overall yield: 1 mg (4%).
The following arylpiperazines and aryl[1,4]diazepanes were prepared analogously:
1b, 1-[2-(4-Bromophenylsulfanyl)phenyl]piperazine: LC/MS (m/z) 350 (MH+); RT=2.46; purity (UV, ELSD): 75%, 92%; yield: 2 mg (7%).
1c, 1-{2-[4-(Methylsulfanyl)phenylsulfanyl]phenyl}piperazine: LC/MS (m/z) 317 (MH+); RT=2.39; purity (UV, ELSD): 91%, 100%; yield: 2 mg (8%).
1d, 1-[2-(4-Hydroxyphenylsulfanyl]phenyl}piperazine: LC/MS (m/z) 287 (MH+); RT=1.83; purity (UV, ELSD): 84%, 100%; yield: 3 mg (13%).
1e, 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine: LC/MS (m/z) 299 (MH+); RT=2.48; purity (UV, ELSD): 95%, 100%; yield: 4 mg (17%).
1f, 1-[2-(3,5-Dimethylphenylsulfanyl)phenyl]piperazine: LC/MS (m/z) 299 (MH+); RT=2.51; purity (UV, ELSD): 96%, 100%; yield: 5 mg (21%).
1g, 1-[2-(2,6-Dimethylphenylsulfanyl)phenyl]piperazine: LC/MS (m/z) 299 (MH+); RT=2.42; purity (UV, ELSD): 97%, 100%; yield: 4 mg (17%).
1h, 1-[2-(2,5-Dimethylphenylsulfanyl)phenyl]piperazine: LC/MS (m/z) 299 (MH+); RT=2.46; purity (UV, ELSD): 97%, 100%; yield: 1 mg (4%).
1i, 1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl]-[1,4]-diazepane: LC/MS (m/z) 353 (MH+); RT=2.46; purity (UV, ELSD): 70%, 96%; yield: 1 mg (4%).
1j, 1-[2-(3-Methylphenylsulfanyl)phenyl]-[1,4]-diazepane: LC/MS (m/z) 299 (MH+); RT=2.44; purity (UV, ELSD): 76%, 93%; yield: 1 mg (4%).
1k, 1-[2-(4-Butylphenoxy)phenyl]piperazine: LC/MS (m/z) 311 (MH+); RT=2.77; purity (UV, ELSD): 91%, 100%; yield: 4 mg (17%).
1l, 1-[2-(4-Methoxyphenoxy)phenyl]piperazine: LC/MS (m/z) 285 (MH+); RT=2.08; purity (UV, ELSD): 93%, 100%; yield: 4 mg (18%).
Example 2 2a, 2-(4-Methylphenylsulfanyl)phenyl-1-piperazine hydrochloride
1-tert-Butyloxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]-3,5-dioxo-piperazine (5.5 g, 13 mmol) was dissolved in dry THF (50 mL) and placed under a nitrogen atmosphere. Borane tetrahydrofuran complex (50 mmol, 1.0 M) in tetrahydrofuran was added and the reaction was refluxed for ten minutes. Excess borane was quenched by the addition of an excess of ethyl acetate and the reaction was refluxed for a further 20 minutes. The reaction was allowed to cool to room temperature before hydrogen chloride dissolved in methanol (50 mL, 4 M) was added and the reaction was refluxed for 4.5 hours. The reaction was allowed to cool to room temperature and the reaction was concentrated in vacuo. The compound was crystallised from the gum residue by the addition of ether/methanol solution. The crystalline solid was filtered and washed with ether/methanol (1:1) to give a white crystalline solid. Yield (2.0 g, 47%) 1H NMR (D6-DMSO) 2.35 (s, 3H); 3.18 (br s, 8H); 6.68 (d, 2H); 7.02 (m, 1H); 7.18 (m, 1H); 7.3-7.5 (m, 4H); MS (MH+) 285.
The following compounds were prepared in an analogous fashion:
2b, 1-[2-(4-chlorophenylsulfanyl)phenyl]piperazine LC-MS (m/z) 305.1 (MH+) RT=2.46 purity (UV, ELSD) 71%, 91% yield 0.096 g, 100%
2c, 1-[2-(4-methoxyphenylsulfanyl)-4-chlorophenyl]piperazine LC-MS (m/z) (MH+) 335.2 RT=2.38 purity (UV, ELSD) 98%, 100% yield 0.22 g, 62%
2d, 1-[2-(4-methoxyphenylsulfanyl)-4-methylphenyl]piperazine LC-MS (m/z) (MH+) 315.1 RT=2.33 purity (UV, ELSD) 97%, 100% yield 0.21 g, 56%
2e, 1-[2-(4-methoxyphenylsulfanyl)-5-methylphenyl]piperazine LC-MS (m/z) (MH+) 315.2 RT=2.38 (UV, ELSD) 98%, 100% yield 2.3 g, 58%
2f, 1-[2-(4-fluorophenylsulfanyl)-5-methylphenyl]piperazine LC-MS (m/z) (MH+) 303.2 RT=2.46 (UV) 98% yield 2.1 g, 62%
2g, 1-[2-(4-Methoxyphenylsulfanyl)-5-trfluoromethylphenyphenyl]piperazine LC-MS (m/z) (MH+) 369 RT=2.50 (UV, ELSD) 96%, 100% yield 0.54 g, 31%
Example 3 3a, 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3-methylpiperazine
2-(3-Methylpiperazin-1-yl)phenylamine (0.96 g, 5 mmol) was dissolved in 30 mL water containing sulfuric acid (0.28 mL, 5.2 mmol) and the solution was cooled to 0° C. and sodium nitrite (0.36 g, 5.2 mmol) was added. The reaction was stirred for 30 minutes before the pH of the reaction was adjusted to pH 7 with sodium acetate. The diazonium salt solution was then added dropwise to a solution of 4-chlorothiophenol in a suspension of copper (0.3 g, 5 mmol) in 2 M NaOH (4 mL). After addition, the reaction mixture was heated to 60° C. for 30 minutes before being allowed to cool to room temperature and ethyl acetate (10 mL) was added. The reaction mixture was filtered and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic phases were dried (MgSO4) and volatile solvents evaporated in vacuo. The crude product was purified by flash chromatography using silica gel, eluting with ethyl acetate/methanol/ammonia 96:3:1. The pure product was isolated as a colourless oil. Yield (0.18 g, 11%) 1H NMR (CDCl3, 500 MHz) 1.12 (d, 3H); 2.6-2.72 (br m, 2H); 3.0-3.15 (m, 5H); 6.9 (m, 2H); 7.08 (d, 1H); 7.15 (m, 1H); 7.25-7.35 (m, 4H); MS (MH+) 319.1.
The following compound was prepared in an analogous fashion:
3b, 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3,5-dimethylpiperazine LC-MS (m/z) (MH+)+333.1 RT=2.29 (UV, ELSD) 83%, 100% yield 0.54 g, 31%.
Example 4 4a, 4-[2-(4-Methylphenylsulfanyl)phenyl]-3,6-dihydro-2H-pyridine
Concentrated aq hydrochloric acid (10 ml) was added to a stirred solution of 1-tert-butoxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]piperidin-4-ol (0.84 g, 2.1 mmol) in acetic acid (30 mL). The solution was boiled under reflux overnight, cooled to room temperature and then stirred in an ice bath. An aqueous solution of NaOH (9.1 M, 40 mL) was slowly added and the unclear solution was extracted with ethyl acetate (2×40 ml). The combined organic phases were dried (MgSO4) and the solvents evaporated in vacuo. The crude material (0.48 g) was dissolved in ethyl acetate (3.2 mL) at 50° C. and a solution of oxalic acid (0.11 g) in EtOH (3.2 mL) was slowly added. The target compound was collected as a white oxalic salt. 1H (DMSO-d6) δ 7.3-7.2 (m, 7H); 7.15 (m, 1H); 7.00 (m, 1H); 5.6 (d, 1H); 3.7 (d, 2H); 3.25 (t, 2H); 2.6 (m, 2H); 2.3 (s, 3H). LC/MS (m/z) 282.2 (MH+); RT=2.24; purity (UV, ELSD): 99%, 100%; yield: 0.31 g (40%).
The following derivative was prepared analogously:
4b, 4-[2-(4-Methoxyphenylsulfanyl)phenyl]-3,6-dihydro-2H-pyridine LC/MS (m/z) 298 (MH+); RT=2.00; purity (UV, ELSD): 97%, 100%; yield: 0.28 g (30%).
Example 5 5a, 4-[2-(4-Methylphenylsulfanyl)phenyl]piperidine
Methyl Chloro-oxo-acetate (1.37 g, 11.25 mmol) was added to a stirred solution of 1-tert-butoxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]piperidin-4-ol (3.00 g, 7.5 mmol) and 4-(dimethylamino)pyridine (1.65 g, 13.5 mmol) in a mixture of dry CH3CN (24 ml) and CHCl3 (12 mL) at 0° C. under argon. The reaction mixture was allowed to reach room temperature and then stirred 2 h. Ethyl acetate (140 mL) was added and some salts were removed by filtration through celite. The organic phase was washed with sat. NaHCO3(140 ml), brine (140 mL) and dried (MgSO4). The solvents were evaporated in vacuo and the crude material was dried in vacuo. This material was dissolved in dry toluene (48 mL) under argon. Bu3SnH (3.27 g, 11.25 mmol) and AIBN (0.31 g, 1.88 mmol) were added. The solution was stirred under argon at 90° C. for 2.5 h. The solvent was evaporated in vacuo, and the crude material was purified by flash chromatography on silica gel (eluent: a stepwise gradient of ethyl acetate in heptane from 10:90 to 20:80) to produce 4-(2-(4-methylphenylsulfanyl)phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a clear oil (1.94 g, 67%). This oil was dissolved in MeOH (9.2 mL) and HCl in diethylether (2.0 M) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The target compound was collected as its hydrochloride. M.p 229-231° C. Calculated for C18H21NS.HCl: C, 67.58; H, 6.63; N, 4.38. Found: C, 67.33; H, 6.97; N, 4.31. LC/MS (m/z) 284 (MH+); RT=2.12; purity (UV, ELSD): 96%, 100%; yield: 0.26 g (46%).
Inhibition of the Uptake of [3H]Serotonin into Whole Rat Brain Synaptosomes
The compounds were tested with respect to their 5-HT reuptake inhibiting effect by measuring their ability to inhibit the uptake of [3H]serotonin into whole rat brain synaptosomes in vitro. The assay was performed as described by Hyttel Psychopharmacology 1978, 60, 13.
5-HT2C Receptor Efficacy as Determined by Fluorometry
The compounds were tested with respect to their efficacy on 5-HT2C receptor-expressing CHO cells (Euroscreen) as determined by fluorometric imaging plate reader (FLIPR) analysis. This assay was carried out according to Molecular Devices Inc. instructions for their FLIPR Calcium Assay Kit and as modified from Porter et al. British Journal of Pharmacology 1999, 128, 13.
Preferred compounds of the present invention exhibit serotonin reuptake inhibition below 200 nM (IC50) in the assay above. More preferred are the compounds which exhibit inhibition below 100 nM and most preferably below 50 nM. Compounds of particular interest exhibit serotonin reuptake inhibition below 10 nm.
1. A compound represented by the formula I wherein
Y is N;
X is S;
m is 1;
each R1 is independently C1-6-alkyl, or two R1 attached to the same carbon atom form a 3-6-membered spiro-attached cycloalkyl;
each R2 is independently halogen, cyano, nitro, C1-6-alkyl, C1-6-alkyloxy, C1-6-alkylsulfanyl, hydroxy, hydroxy-C1-6-alkyl, halo-C1-6-alkyl, halo-C1-6-alkyloxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, acyl, C1-6-alkyloxycarbonyl, or C1-6-alkylsulfonyl;
each R3 is independently halogen;
2. The compound according claim 1, wherein p is 0, 1 or 2.
3. The compound according to claim 1, wherein R1 is C1-6-alkyl.
4. The compound according to claim 1, wherein q is 0, 1 or 2.
5. The compound according to claim 1, wherein R2 is trifluoromethyl, or C1-6-alkyl.
6. The compound according to claim 1, wherein s is 1 or 2.
7. The compound according to claim 1, wherein R3 is fluoro.
8. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.
9. A method for the treatment of an affective disorder in a living animal, comprising administering to the living animal in need thereof a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof.
10. The method of claim 9, wherein the affective disorder is depression or an anxiety disorder.
11. The method of claim 10, wherein the anxiety disorder is general anxiety disorder, panic disorder, or obsessive compulsive disorder.
12. The method of claim 9, wherein the living animal is a human.
4064245 December 20, 1977 Beregi et al.
4198417 April 15, 1980 Ong et al.
4241071 December 23, 1980 Martin et al.
4859675 August 22, 1989 Foguet et al.
6407099 June 18, 2002 Annoura et al.
6699864 March 2, 2004 Ruhland
7138407 November 21, 2006 Ruhland et al.
7144884 December 5, 2006 Ruhland et al.
7148238 December 12, 2006 Ruhland et al.
7291619 November 6, 2007 Biggers
7683053 March 23, 2010 Ruhland et al.
8110567 February 7, 2012 Ruhland et al.
8476279 July 2, 2013 Bang-Anderson
8722684 May 13, 2014 Bang-Anderson et al.
9095588 August 4, 2015 Faldt
9101626 August 11, 2015 Faldt
20050171061 August 4, 2005 Smith et al.
20060100242 May 11, 2006 Puschl et al.
20140163043 June 12, 2014 Ruhland et al.
20140256943 September 11, 2014 Faldt et al.
20140315921 October 23, 2014 Bang-Anderson et al.
151751 January 1974 CZ
0 301 549 February 1989 EP
0 755 923 January 1997 EP
1 489 711 October 1977 GB
WO 1993/012080 June 1993 WO
WO 1997/017325 May 1997 WO
WO 1999/017777 April 1999 WO
WO 2000/059878 October 2000 WO
WO 2001/010842 February 2001 WO
WO 2001/049678 July 2001 WO
WO 2002/059108 August 2002 WO
WO 2005/000309 January 2005 WO
Libbs' Post-Grant Review Petition in Application No. PI0212733-4, dated Nov. 10, 2014, 29 pages.
Braso et al., "Comparative Study on the Minimum Lethal Dose and Cardiotoxic Effects of Sifaprazine, Delfaprazine, Imipramine and Amitriptyline in Three Animal Species," Behavioural Pharmacology, 1992, vol. 3, Suppll, p. 42 Abstract 66.
Kopicova et al., "Neurotropic and psychotropic compounds. L. Derivatives of 1-(2-phenylthiobenzyl)piperazine and 1- (2-benzylbenzyl)piperazine," Collect. Czechoslov. Chem. Commun., 1972, 37:1371-1380.
Korolkovas et al., "Desenvolvimento de Farmacos," In: Quimica Farmaceutica, 1998, Guanabara Koogan Rio de Janeiro, p. 70.
Martin et al., "Synthesis of Spiro[isobenzofur4an-1 (3 H), 4′-piperidines] as Potential Central Nervous System Agents, 5. Conformationally Mobile Analogues Derived by Furan Ring Opening," J Med Chem., 1979, 22(11):1347-1354.
Oh et al., "Serotonin Receptor and Transporter Ligand—Current Status," Curr Med Chem., 2001, 8:999-1034.
Planas et al., "New derivatives of arylpiperazines showing antidepressive activities in animal models," Eur J Pharmacol, 1990, 183:1468.
Planas et al., "Pharmacological Profile of FI-4303, A Novel Antidepressive," Naunyn-Schied Arch Pharmacol, 1991, vol. 343 (suppl 1), p. R111 Abstract 441.
Planas et al., "Pharmacological Profile of the Potential New Antidepressant, Sifaprazine," Behavioural Pharmacology, 1992, vol. 3, Suppl 1 p. 48 Abstract 67.
Ruhland et al., Chemical Abstract, vol. 135, No. 107345, Abstract for WO 2001/049678 (Jul. 12, 2001), 2 pages.
Schatz, "Isosterism and Bio-isosterism as Guides to Structural Variations," Med Chem., 1960, pp. 72-78.
Technical Examination Report (dated Oct. 27, 2011) and Search Report (dated Oct. 25, 2011) for counterpart Brazilian national stage application No. P10212733-4 and English translations thereof (11 pages total).
Van Steen et al., "Structure-Affinity Relationship Studies on 5-HT1A Receptor Ligands. 1. Heterobicyclic Phenylpiperazines with N4-Alkyl Substituents," J Med Chem., 1993, 36:2751-2760.
Verdonk et al., "Structure and Serotinin 5-HT2C Receptor Activity of ortho- and meta-Substituted Phenylpiperazines," Acta Cryst., 1997, B53:976-983.
Filed: Jun 15, 2017
Assignee: H. Lundbeck A/S (Valby)
Inventors: Thomas Ruhland (Roskilde), Garrick Paul Smith (Valby), Benny Bang-Andersen (Copenhagen), Ask Puschl (Frederiksberg), Ejner Knud Moltzen (Gentofte), Kim Andersen (Ridgewood, NJ)
Primary Examiner: Brenda L Coleman
Current U.S. Class: Plural Ring Hetero Atoms In The Additional Hetero Ring (514/217.05)
International Classification: A61K 31/495 (20060101); A61P 25/22 (20060101); C07D 295/096 (20060101); C07D 295/033 (20060101); C07D 295/145 (20060101); C07D 211/20 (20060101); C07D 211/70 (20060101); C07D 243/08 (20060101);


The Premier Development League revealed the 2010 league schedule, and Ocean City FC will open its 14th season on Saturday, May 15 against the Hampton Roads Piranhas at Carey Stadium.
The Premier Development League (PDL) revealed the 2010 league schedule, and Ocean City FC will open its 14th season on Saturday, May 15 against the Hampton Roads Piranhas at Carey Stadium in Ocean City, NJ.
For 2010, Ocean City FC will move back to the Mid-Atlantic Division, which features only two teams that were in the their division last year. The first and second place teams will qualify for the PDL playoffs.
The two teams making the move from the Northeast to the 10-team Mid-Atlantic Division are in-state rivals Ironbound Express and the New Jersey Rangers. Both teams enter their third season in the PDL and while New Jersey has struggled in their first two campaigns, Newark hit the ground running, qualifying for the playoffs in their inaugural season, but finished in fifth place last year.
The rest of the division features an expansion team, a professional club who has made the move down to the PDL and five familiar faces that OC has played against at one time or another over the years.
The Bermuda Hogges were a USL Second Division expansion team in 2007, but after three years they have moved down to the PDL level. Ocean City will fly to Bermuda (1,100 miles northeast of Miami) for a pair of games on June 4 and 6.
Another new face in 2010 will be a fourth New Jersey-based team. The Central Jersey Spartans expansion franchise will begin play in 2010.
"Up until a couple of years ago, Ocean City FC was the sole PDL representative in the state of New Jersey," said general manager Neil Holloway. "Now we have three teams to battle with to establish who is the best team in the Garden State."
The rest of the division is highlighted by long-time Ocean City rival, and last year's PDL regular season champion, Reading United. OC fans know them better as the Reading Rage, but they re-branded themselves this past offseason. Also on the schedule this year is the West Virginia Chaos, the Northern Virginia Royals and one of the best franchises in USL history, the Carolina Dynamo.
"We are excited about returning to the Mid-Atlantic Division, but we will miss our battles with the New York-based teams," said Holloway. "At the same time, we're looking forward to re-establishing our rivalry with Reading United and definitely our trip to Bermuda in June."
While, the format has not yet been made official, the first four games of the 2010 schedule are expected to double as qualifying games for the Lamar Hunt US Open Cup. Ocean City will attempt to qualify for the tournament for the second year in a row and the fifth time in the last seven competitions. No amateur club in the PDL or the USASA has competed in more Open Cups during that span. Last year, the club defeated two professional teams (Crystal Palace Baltimore, Real Maryland Monarchs) but eventually were eliminated in the Third Round by DC United of Major League Soccer.
Ticket prices for the 2010 season will remain the same from last year. Season tickets are $40 for adults, $20 for kids and single-game tickets are $6 for adults and $4 for kids. Season and single-game tickets can be purchased at the Carey Stadium front gate on any gameday, or by calling the Ocean City FC ticket office at 609-525-9999. Single-game tickets can also be purchased online at the City of Ocean City's website, OCNJ.us..
Bermuda Hogges: Founded in 2007 as a professional side in the USL Second Division and struggled in their three seasons in the league. They failed to make the playoffs all three years.
Carolina Dynamo: One of the great franchises in USL history, with 16 seasons under their belt. Last year, they finished with an impressive 10-4-2 record and lost in the opening round of the PDL playoffs to the Cary Clarets. The Dynamo have only missed the playoffs three times in 16 seasons competing in the professional and PDL levels of the USL. Carolina ended the Barons' unbeaten season in 2004 with a 3-2 win in the Conference Finals.
Central Jersey Spartans: An expansion team that will begin play in 2010.
Hampton Roads Piranhas: The Piranhas will enter their fifth season in the PDL after beginning in 2006 as the Virginia Beach Submariners. They were division champions in their first two years, but their last two years, they have fallen short of the postseason.
Ironbound Express: The Express have had success in their first two seasons in the PDL, including a second place Northeast Division finish and a playoff appearance in their inaugural season in 2008. Last year, they struggled, finishing in fifth place in the division with a 6-8-2 record. Originally based in Newark, NJ, the club has dropped the city from their name for the 2010 season.
New Jersey Rangers: The Rangers entered the PDL the same year as the Ironbound Express, but have not enjoyed the same success. Last year, they finished in last place with a 2-12-2 record.
Northern Virginia Royals: The Royals began as a professional club (USL-2) in 1998 but have found little success over the years. They joined the PDL in 2006 and have not made the postseason since 1999. Last year, they finished with a 2-10-4 record. One of their notable former players is goalkeeper Troy Perkins who spent time with DC United of Major League Soccer and is playing professionally in Europe. Fun fact: In 2004, due to a unique scheduling situation, the Barons defeated the Royals 3-1 in a regular season game, despite the fact that Northern Virginia was a professional team in the Pro Soccer League (now known as the USL Second Division).
Reading United AC: The Reading Rage, a long-time rival of Ocean City, will enter the 2010 season with a new name and a new logo. Reading and Ocean City have been playing each other since they were professional teams in the late 90s and the early 2000s. Last year, Reading won their second straight division championship and won their first PDL regular season title. Their 13-1-2 earned them 41 points, the most of any team in the league.
West Virginia Chaos: The PDL side from West Virginia has yet to qualify for the playoffs since they began play in 2003. The Chaos finished in fifth place in the Northeast Division last year with a 5-8-3 mark.


text:
Use Registration Permit
Zoning Variances
Housing Rental License
Commercial Activity License
Not In My Back Yard: Homeless Veterans Home
by Philly Zoning Team
in RCO, RCO Rants, Zoning
This post is a featured post for our #RCORants series. #RCORants showcases stories about the often harmful actions that take place among RCO's (Registered Community Organizations) in Philadelphia. The goal is to raise awareness about what goes on, stimulate a conversation, and ultimately improve the RCO system to create more accountability, equality, and fairness. "Not in my backyard." That might as well have been the answer that...
By-Right Development
in Additional Information, All, Architects, Building Permits, Business, Design, Engineers, Philadelphia Licenses, RCO, Zoning, Zoning Permits, Zoning Process, Zoning Projects
By Right Development Projects which are allowed by the zoning code are known as by-right developments. Every parcel and property in the city of Philadelphia falls into a distinct category of the zoning code which can be found by searching the address in the City Atlas. This tool allows users to see the zoning classification, relevant overlays, registered neighborhood associations, past appeals, and more. The value...
Where's My Permit?
in Additional Information, Building Permits, Business, Philadelphia Licenses, RCO, Zoning, Zoning Permits, Zoning Process, Zoning Projects
When we started out at Philly Zoning, we got a version the same question every week: Where's my permit? Once someone gets started on a permitting project, they want to know how far along the permit is, and how they can check its progress. We give our clients weekly updates to answer that question, but we also think it might be helpful to provide an overview...
City Links Under the Tree
in Architects, Building Permits, Business, Design, Engineers, Floor Plans, Philadelphia Licenses, RCO, Zoning, Zoning Permits, Zoning Process, Zoning Projects
Happy holidays from Philadelphia Zoning! We've had quite a year here, thanks to our clients, legal partners, and design partners. To thank everyone, we're offering this present: A handy reference guide for our most common permitting projects. Enjoy! General Zoning and Permitting Information The source: The Philadelphia Zoning Code The Philadelphia Code can be found here. Title 14 (what those of us not in the legal profession would simply...
RCO Fever!
in Architects, Design, Engineers, Philadelphia Licenses, RCO, Zoning, Zoning Permits, Zoning Process, Zoning Projects
One of the most sensible and also counter-intuitive parts of the zoning process in Philly is the community review. Any time you want to use your property for something that the zoning code doesn't allow, you must seek a variance from the City of Philadelphia (as we've discussed). When you seek a variance, a community organization in Philadelphia gets to review the proposal before the City...
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How to Submit Additional Information
An additional information request is sent by Licenses and Inspections whenever one of their plans examiners wants to know more about......
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Our Plans Requirements Cheat Code We here at Philadelphia Zoning told you a while back about how important plans are......
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We here at Philadelphia Zoning like to think we have answers for you. We tell you we can saw through forests......
Email: info@philadelphiazoning.com
Navigating the clouded waters of Philadelphia's procedures and regulations for all things permits and zoning can be tough. And that's why we are here: To navigate those waters for you. We love our city and the people like you who contribute to its eclectic and unique vibe. We want to help you make your dreams become a reality; whether that's opening a coffee shop, turning an abandoned building into condos, or starting your dream business. Let's develop your dreams together!
Philadelphia Zoning is managed by Console Matison LLP, a law firm specializing in real estate and zoning needs in Philadelphia and the surrounding Pennsylvania and New Jersey suburbs.
Website Designed by Philadelphia Zoning Copyright © 2021, All rights reserved.

redpajama_set_name: RedPajamaCommonCrawl


text:
Almost Blue è un romanzo scritto da Carlo Lucarelli e pubblicato la prima volta nel 1997.

Trama
Tra musica, delitti e una Bologna quanto mai vitale, un giovane uomo cieco ascolta attraverso il suo scanner-radio le voci della città. E, chiuso nella sua stanza, si trova al centro di una vicenda sanguinosa ed incredibile, mentre dall'altro lato della città una poliziotta indaga sul caso di una serie di delitti commessi da un killer con seri problemi mentali, chiamato anche Iguana.

Film
Nel 2000 dal libro è stato tratto un film omonimo, diretto da Alex Infascelli.

Edizioni

Altri progetti

Collegamenti esterni

Romanzi di Carlo Lucarelli
Romanzi thriller
Romanzi ambientati a Bologna

redpajama_set_name: RedPajamaWikipedia


Chaince have received the info from KARMA that KARMA adjusted the ratio of airdrop, and adjusted 1:6 to 1:9 at July,1st,2018. Chaince has updated the page of 【Wool Hat】.
KARMA token airdrop has completed, we will promptly issue the KARMA token to the Chaince platform's EOS holding account.
More info about airdrops are updating, please looking forward !
What is RAM reference price?


My last order took exactly ONE week! Mr snuff truly is the greatest place to buy snuff from. I've never had any problems receiving my order and the delivery is the always quick. The selection is amazing and im glad that there's always new product coming in to try. Thanks Mr snuff!


We make the world everybody´s business.
committed to contribute to the creation of sustainable cities.
To link citizenship, social enterprises, companies, universities and government with social and environmental impact projects in Mexico, through the design and implementation of methodologies, workshops and events.
They inspire people about the challenges that big cities are facing, connect citizens with sustainable cities projects, incubate projects that offer solutions to critical problems, and scale collaborations.
More than 70,000 active volunteers trained in the MakeSense methodologies have been able to expand the community in more than 18 countries in Latin America. SenseCube, MakeSense acceleration platform, has succeeded in driving 14 social enterprises that offer solutions to the most pressing challenges of Mexico City.
"Thanks to the support of CO_Plataforma we managed to create the first international office of MakeSense in Mexico".


BEECH CREEK – Theresa Lee Stirsman, 55, of Beech Creek, died Friday, January 24, 2014 at her residence after a short, but burdensome battle with cancer. She was born March 13, 1958 in Gary, IN. She was the daughter of Oscar Knight and Margie Ray and the faithful wife of Stanley Stirsman.
Survivors include her husband of 36 years, Stanley Stirsman, daughters, Amanda (Joshua) Mimbs, Alana Stirsman and a son, Kyle Stirsman, mother, Margie Ray and a sister, Sharon Knight.
Services will be held at 11:00 AM, Tuesday, January 28, 2014 at Second Baptist Church in Greenville, conducted by Rev. Bob Thurman and Dr. Ray England with burial to follow in Forest Grove Cemetery in Browder. Visitation will be after 5:00 PM Monday and after 8:00 AM Tuesday at the Second Baptist Church in Greenville.
Second Baptist Church Building Fund, 217 West Depot St. Greenville, KY42345 or Vanderbilt Ingram Cancer Center, 691 Preston Building, Nashville, TN 37232.
Tucker Funeral Home in Charge of arrangements.
I Loved her and will miss that beautiful smile and those beautiful eyes. She was a precious, precious person.
Theresa was a member of one of the first youth groups I ever lead in Acteens at church. Even at that young age, she was a reflection of God's love. She grew into an outstanding christian wife and mother. She freely allowed me as a student in education to test her young children , so I could learn better to serve others. Her life brought light and laughter that only comes from a heart that is filled with the love of God.
Margie & Sharon; and all of her extended family.
Theresa was a great woman. I thought a lot of her. She was everything a great mother and wife could be. I will miss her as many others will. My thoughts and prayers go out to her son and daughters. May she rest forever more and walk in the everlasting paradise of the kingdom of heaven. A truly beautiful spirit. I hope to see you again one day. God bless.
I never saw Theresa without a smile. Your day would brighten up just by talking to her. Praying for all of you that God will give you Peace and Comfort during your time of sorrow.
We are so very sorry to hear of Theresa's passing. She was always such a sweet person. Our hearts go out to your family. Kirk and Vicki Strader.
Sharon and family, I am so sorry for your loss. I have nothing but nice memories of Theresa in school,.I know your wonderful memories will be a comfort for you.Love and Prayers for the family.
May God comfort the entire Stirsman family during this difficult time. Theresa was an outstanding lady and employee for the school system. I always enjoyed her smile when visiting the lunchroom at South High School. Take comfort in knowing she is in Heaven and resting with her eternal God.
I remember seeing her at school thinking how pretty she was, and she never changed!!
Sharon and family, Phillip and I are so sorry for your loss. You are all in our prayers.
We are so sorry for your loss, Theresa was a blessing to know and was loved by all. Will be praying for the family that God will give you comfort and peace during this difficult time.


With footage from our 25th Anniversary celebrations we have put together a video and hardcovered book.
3. A copy of the 11x11 Hardcover photobook, 42 pages with well over 300 photos!
To order your copies please fill out the form below!
Orders will be place once money has been recieved. Please mail cheque to Club Address.


text:
Edward Snowden: The Biggest Revelations Are Yet to Come
Edward Snowden made an unscheduled appearance at TED 2014 in Vancouver on March 18.
Image: Amanda Wills, Mashable
By Amanda Wills 2014-03-18 17:48:26 UTC
VANCOUVER, Canada — Edward Snowden on Tuesday said the biggest revelations have yet to come out of the estimated 1.7 million documents he acquired from the National Security Agency.
In a surprise appearance via satellite robot at the 2014 TED conference in Vancouver, Snowden said there is still a lot of reporting to be done, including diving deeper into the accusation that the NSA tricks companies into building backdoors into their systems that make data vulnerable to hackers across the world.
See also: Edward Snowden: If I Could Do It All Again, I Would
"Is it really terrorism that we're stopping? I say no," Snowden said. "The bottom line is that terrorism [...] has always been a cover for actions. Terrorism evokes an emotional response."
Snowden, who is still in hiding somewhere in Russia, maintained that his act wasn't reckless and that he did it all for the American people. He also said he would love to return to the United States — if granted immunity.
Snowden gets his badge. #TEDActive #TED pic.twitter.com/16cA6FXKuU
— Grant W. Graves (@GrantWGraves) March 18, 2014
"I don't want to harm my government" he said. "The fact that they're willing to ignore due process and declare guilt without a trial [...] these are things we need to work against as a society."
Snowden remains a controversial figure throughout the world, but he was speaking to the right crowd at TED. When Anderson asked the audience who disagreed with Snowden's actions, only a few hands shot into the air. When he asked if the room felt Snowden was right in handing over the NSA's secret, the audience erupted with applause. Tim Berners-Lee, a man widely credited with inventing the World Wide Web, then stepped on stage to talk with Snowden.
He called him a "hero."
After Snowden exposed NSA programs like PRISM, many Americans wanted to know why they should care about this surveillance if they're not guilty of doing anything wrong. Snowden said it comes down to protecting rights.
"Rights matter because you never know when you're going to need them," Snowden said, adding that people should be able to pick up the phone and call their family, send a text to their loved ones and travel by train without worrying about how these events will look to a government years in the future.
The former NSA contractor has been on a public relations tour over the past few weeks, embracing the public debate that has erupted over his actions. He recently made an appearance at the SXSW festival in Austin, Texas via satellite, in which he touched on similar talking points that he did on Tuesday.
"I am living proof that an individual can go head to head with the most powerful intelligence agencies around the world — and win," Snowden said.
Snowden: "I'm living proof that an individual can go head to head with the most powerful intelligence agencies around the world — and win"
— Amanda Wills (@AmandaWills) March 18, 2014
Topics: edward snowden, TED, U.S., World


text:
Sophie Turner Reveals Her Wedding Planning Secret Weapon and How She Met Joe Jonas
TOPICS:celebrity weddingsJoe JonasSophie Turner
Joe Jonas and Sophie Turner attend 2019 Roc Nation THE BRUNCH on February 9, 2019 in Los Angeles, California. (Photo by Kevin Mazur/Getty Images for Roc Nation )
Wedding planning advice is readily available to those who seek it, but a tip from Sophie Turner is a rare treat. The Game of Thrones actress revealed how she's currently faring with the wedding planning process ahead of her destination nuptials in France to Joe Jonas this summer.
With Turner prepping for the final season of HBO's wildly popular fantasy series, as well as with the impending release of the Dark Phoenix—which stars the actress as a younger version X-Men's Jean Grey—the future bride is stretched thin especially with figuring out the details for her destination wedding.
Her secret weapon?
"Wedding planners are key," Turner revealed to Extra this week. "That means you don't have to do anything." (Along with help from a planner, Jonas previously shared with James Corden that he's figured out what not to do on his wedding day after watching his brothers make a few mistakes.)
The two are planning to keep their nuptials relatively under-the-radar in relation to the weddings of Jonas's brothers Nick and Kevin. "We're trying to keep the wedding low-key, so it's more intimate," Turner told Harper's Bazaar UK in its May cover story.
Turner and Jonas announced their engagement in April 2017 after the singer had popped the question with a pear-shaped diamond ring. The couple's love story started, interestingly enough, in a rather relatable way. Mutual friends had attempted to set the pair up together for a while, leading the two to become social media friends first.
"We were following each other on Instagram," Turner added in the same interview. "And he direct-messaged me one fine day, out of the blue."
Secure your ideal wedding vision by starting with The Knot's Style Quiz, here.


text:
Q: Flutter Recipient: null Tried call (getTranslated method) I have added a new page to my application. But I can't use the getTranslated method. I'm getting this error The 'getTranslate' method was called null. Recipient: null Tried call. how can i fix this problem?
I called the files needed for the getTranslate method in this image.

redpajama_set_name: RedPajamaStackExchange


text:
Q: Old WiFi SSID is displayed on ESP8266 I'm working on an Arduino project using the RemoteXY library and online app maker. My problem occurs when I try to log into the wifi with my phone. I go to WiFi settings and instead of seeing "Ant-Man's Van" as the network name I see "Inkognitic  Arduinoitic" - the name of a project I did with the same esp8266 module.
The phone used for  testing: Samsung Galaxy J3 2017
Picture: https://imgur.com/CIivh4f
// RemoteXY select connection mode and include library
#define REMOTEXY_MODE__ESP8266_SOFTSERIAL_POINT
#include <SoftwareSerial.h>
#include <RemoteXY.h>

// RemoteXY connection settings
#define REMOTEXY_SERIAL_RX 2
#define REMOTEXY_SERIAL_TX 3
#define REMOTEXY_SERIAL_SPEED 9600
#define REMOTEXY_WIFI_SSID "Ant-Man's Van"
#define REMOTEXY_WIFI_PASSWORD "12345678"
#define REMOTEXY_SERVER_PORT 6377

// RemoteXY configurate
#pragma pack(push, 1)
uint8_t RemoteXY_CONF[] =
    { 255,5,0,0,0,63,0,8,13,0,
    2,1,53,1,46,13,2,26,31,31,
    79,78,0,79,70,70,0,1,4,55,
    16,26,26,2,31,84,73,77,69,32,
    77,65,67,72,73,78,69,0,5,0,
    3,8,50,50,2,26,31,1,4,75,
    38,24,24,2,31,72,79,82,78,0 };

// this structure defines all the variables of your control interface
struct {
    uint8_t switch_; // =1 if switch ON and =0 if OFF
    uint8_t machine; // =1 if button pressed, else =0
    int8_t joystick_x; // =-100..100 x-coordinate joystick position
    int8_t joystick_y; // =-100..100 y-coordinate joystick position
    uint8_t horn; // =1 if button pressed, else =0

    uint8_t connect_flag;  // =1 if wire connected, else =0
} RemoteXY;
#pragma pack(pop)

void setup(void)
{
    pinMode(8, OUTPUT);//buzzer
    pinMode(13, OUTPUT);
    pinMode(12, OUTPUT);//led indicators when singing a note
    RemoteXY_Init();
    for(int i=0;i<2;i++){
        digitalWrite(8, HIGH);
        delay(100);
        digitalWrite(8,LOW);
        delay(500);
    }
}

void loop()
{
    RemoteXY_Handler();
    if(RemoteXY.horn){
        sing(1);
        sing(2);
        sing(3);
    }

    if(RemoteXY.switch_){
        digitalWrite(13,HIGH);
        digitalWrite(12, HIGH);
    }else{
        digitalWrite(13,HIGH);
        digitalWrite(12, HIGH);
    }
}

A: Before flashing new firmware from Arduino IDE erase the flash memory using esptool.py.

*

*install esptool on you machine by pip install esptool.

*Erase the flash memory by esptool.py --port <serial-port> erase_flash.

More details of the tool can be found here.
To know more about this behavior, read these:

*

*https://arduino.stackexchange.com/questions/52059/does-the-esp8266-somehow-remember-wifi-access-data

*https://github.com/esp8266/Arduino/issues/2843


My hunt for a good natural deodorant started around the fresh age of 14, when I began to notice I was developing a…scent…upon perspiring, and having my mother reprimand me immediately when I asked her to buy me an aerosol can of dove, or Rexona, or whatever everyone was using back then. She told me how awful chemical deodorants are for me, and banned them from the house, instead buying me a (TBH) really gross natural deodorant which made me smell 10x worse especially after P.E class. I bought the dove spray anyway, and hid it out of sight, but after a few months of using, I couldn't get her words that my body wasn't detoxing properly if I used deodorants which prevented me from sweating, out of my head.
To preface, before I begin this article properly, I'm not an overly smelly person, nor overly sweaty, so for me, my deodorant M.O is a bit more relaxed than maybe someone who sweats profusely or smells profusely. I just want something that is going to keep any bad smells away for as long as possible. Using natural deodorants is a bit of a switch, in case you're curious about the transition. A lot of people say that they smell worse when switching to natural deodorants as your body is finally getting rid of all the toxins that your chemical deodorant was preventing from escaping (yuck and yikes), however, I have been on the natural deodorant band wagon for some years now, and actually prefer applying them. I'm no longer powdery, I can feel my body ~breathing~, and I really don't smell that bad unless I've completed a particularly strenuous workout in hot weather (rare).
Moving on, here are 3 natural, aluminum free deodorants that I put to the test, and encourage you to make the switch too because it ain't health unless ya pits are breathing (sorry).
The claim: A vegan, natural, hypoallergenic deodorant stick that really works.
The Scent: Powdery yet clean, reminiscent of dove, kind of a nice break from sandalwood scented natural deodorants.
Scent repelling power: tried this for a week, sadly it was an uneventful week, so didn't get a good workout, but held up while I was at my desk or power walking to get lunch.
Side note: Claims to be Hypo-allergenic but my girlfriend used it and said it irritated her underarms, so if you're super sensitive, it's maybe a no-go.
Rating: 6/10, not terrible, not blown away! Pretty nice for chill days.
The Claim: A natural, luxury deodorant which actually works, non-GMO and non-toxic, baking soda free.
The Scent: This one is a bit more ~natural~ but pleasant, notes of Jasmine, bergamot, and sandalwood. The scent makes it feel like you are really taking the natural plunge, but in a luxe way.
Texture: Formulated with Coconut and Avocado oils, this one is a little more emollient and buttery, goes on smoothly.
Sweat repelling power: No dice. But as I mentioned, not a realistic expectation of the natural deodorants, so all g.
Rating: 4/10, sadly, this wasn't a winner for me, but the redeeming factors such as scent and application and packaging, mean I will still use if I'm having a bare minimum day.
The Claim: Made from 100% natural mineral salts which eliminate odor by leaving an invisible protective barrier against odor-causing bacteria. Body odour is apparently caused by bacteria that forms on the body, and natural mineral salts form a barrier on the skin that provides an unfriendly environment for odor-causing bacteria, even under the sweatiest of conditions.
The Scent: This deodorant comes in a few different scent ways, but I stuck to the original, unscented, as I do find that scented deodorants can be irritating or a bit gross.
Texture: Literally feels like you are rolling slightly thicker water on your pits, quite refreshing.
Scent repelling power: Ok, straight off the bat, this deodorant is NOT f*king around. Literally lasts for hours, I never smell when I use this, it's my OG go-to natural deodorant because it ACTUALLY works due to the science behind it. I want to be their hype man because it is cheap and effective (basically me in deodorant form).
Sweat repelling power: Again, in my natural deodorant world, this does not exist, but hit me up if you find one that does.
Rating: 9/10, this stuff is the sh*t. If you are planning on embarking on a natural deodorant journey, start here, because it's cheap, and you won't hate yourself for spending money if it somehow doesn't work for you.
Great post, thanks for sharing. I'm currently using Forever Living deodorant which is working well so far. It lasts most of the day, but also calms down any irritation. Thanks again for sharing the products.


text:
Dancehall / News / Trending
Koffee Plans To Finish What Bob Marley Started With Reggae Music
By Kady Anglin On: August 7, 2019 3:10 PM
Kady Anglin Author
Koffee wants to follow in Bob Marley's footsteps with Reggae music.
TV personality Simone Clarke-Cooper interviewed Koffee after her performance at the Independence Grand Gala at the National Stadium on August 6th. The 'Lyrical Docta' expressed how thankful she was to Jamaica for embracing her and for the opportunity to perform at a national celebration for her home country.
Koffee does genuinely seem grateful for her accomplishments and fans, and most of all, her country. When asked what she would like to say to Jamaica on Independence Day, she responded by expressing her gratitude being able to travel the globe and perform for other people who love her "small country" with "big culture."
Koffee's answer to how she stays grounded is her mother, who has also been traveling with her.
In just a few short years, Koffee has achieved rapid growth and tremendous success. She might have even surpassed some of her personal goals. In her post-gala performance interview, she shared that one of her long term goals is to finish what Bob Marley started by spreading Reggae music and its message throughout the globe.
The Reggae singer told Simone that she had been away for the last month on the European leg of a tour. Her talent was showcased on stages in Germany, Denmark, France, Belgium, Switzerland, and more. Don't worry the always modest and tasteful Koffee didn't brag; we're doing it for her.
On what's next, she said she has a tour coming up in the United States with Daniel Caesar. Just before arriving in Jamaica for this grand event, Koffee performed at the Osheaga Music and Arts in Quebec on a lineup that also featured acts like Childish Gambino and Young Thug.
Not many Reggae artistes have successfully tapped into the US market even at the apex of their careers. Koffee is breaking ground on a multi-continental basis at just 19-years-old. The "Toast" singer had already made her US national television debut when she performed on Late Night with Jimmy Kimmel. She is also one of the songwriters on Rihanna's upcoming Reggae album.
Koffee has the potential to attain unprecedented stardom and bring attention to Reggae Music that it undoubtedly deserves.
Bob Marley, Koffee
More Bob Marley News
Ziggy Marley Tributes Jo Mersa Marley Ahead Of Tuesday's Funeral
Bob Marley, Barrington Levy Among Jamaicans On Rolling Stone Greatest Singers List
Jo Mersa Marley Cause Of Death, Tributes Pour In For Reggae Singer
Boosie Badazz Reacts To Yung Miami Statement On 'Pee Diddy'
Anthony B Celebrating Black History Month With First 'Black & Proud' Concert In NY


Classic earthy Indonesian flavor exploding with a cherry, black currant, and golden raisin throughout.
Full-bodied, syrupy mouthfeel; snappy with a sweet well-rounded finish.
Honduran: Delicious nut tones, smooth creamy body, and a spice finish.
Honduran: Delicious nut tones. Smooth, creamy body and a spice finish.
Peruvian:Light and bright, easy drinking with a cinnamon spice finish.
Peruvian: Light, bright, easy drinking with a cinnamon spice finish.
Full body. Long, oaky finish.
Big body. Long, oaky finish.


text:
Facebook Leaked Oculus Quest 2: Features Qualcomm XR2
In the Oculus Quest 2 VR headset, the entirety of the leak is provided by means of a pair of promotional videos that are posted to a content hub run by the parent company Facebook. There are also a couple of live headset workshops on the platform which are planned for 16 and 17 September. The launch date for Quest 2 on 15 September is well-matched with the speculated launch date. The new Headset is operated by the Snapdragon XR2 platform of Qualcomm and is built particularly for AR and VR hardware (unlike the Snapdragon 835 general purpose that operated the original Quest). One of the videos has a "nearly 4 K monitor," which means that the second video says it's around 50% more of the pixels than the first.
The headset now has 6 GB of RAM (up from 4 GB) and up to 256 GB of storage (up from up to 128 GB) and 3D dimensional audio, with hand-tracking returned without controllers. Although the videos contain plenty of new material concerning the OculusQuest2, a few recurring concerns emerge.
For the start, it is not known what refresh rate the show would have, which previous sources suggested might grow from 72Hz to 90Hz or even 120Hz for smoother moving. No note of the size or weight of the headset is also made.
Previous sources have indicated that Quest 2 is less unpredictable than the original Quest, but the Videos are clearly named "streamlined" and "light." The current hardware. Since its contentious decision to make Oculus users have a Facebook account, the Oculus Quest 2 appears to have been the first headset Facebook released.
Although owners of the current headsets could have an Oculus account independently before 2023, Facebook announced that potential devices will need Facebook authentication, whether or not you already have a separate Oculus account. The cost of the headset is uncertain but a Walmart page now deleted indicates that the 256 GB of its version will sell for $399.
Little More About Oculus Quest:
With the production conference on Facebook Connect planned for 16 September, a formal announcement could not be too far away. It is not a surprise that many leaks such as the photos that emerged in July have revealed themselves. This is somewhat distinct as these are public videos that were presumably used throughout the keynote on Wednesday. The content not only provides the greatest insight into the new product, but it also offers a lot of hardware knowledge. Another important aspect listed here is that each title of Oculus Quest will work with Oculus Quest 2, perhaps with the updated hardware, they will look much better. The XR2 framework of Qualcomm is used for a host of potential products such as Neal Light (AR) and XR Monitor Augments, from companies such as Panasonic. The platform could then encourage developers to create even better VR gaming experiences. There is still a lot of information about Oculus Quest 2, such as the availability, usability, and what is going on with IPD change, so you will have to watch Facebook Link. VR App Venues and Facebook Live encourage you to watch the action. This large hardware ad will not have the same effect. There is also a virtually 4 K screen for players with a native 2 K per eye. The accompanying video clip 'Within The Headset' shows that the search screen has 50 percent more pixels. The video also states that there will be 256 GB Quest 2 and presents us with "modified ergonomics" on the new controllers. The headset will still play your old Quest names, but no new games or encounters have only been announced to us. The video below shows that support for Oculus Connect is still included.
Tags: Facebook, OculusQuest2, QualcommXR2
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