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methylenedioxy

Joined: 29 Mar 2005
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Wed Mar 30, 2005 12:33 am
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My discovery of Edward Khaus’ works was by accident. This guy has a special gift to discover potent opiates, so I desided to present him to your attention.

The most simple idea was the discovery of the cmpnd which I would call pyfentanyl. You take fentanyl and replace the terminal phenyl with pyridyl. Here is the abstract.

Drug Des Discov. 1992 Jul; 8(4):301-12.
Synthesis and antinociceptive activity of 1-[2-(pyridyl)ethyl] and 1-[2-(dihydropyridyl)ethyl] analogues of fentanyl.
Buolamwini JK, Knaus EE.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
The syntheses and antinociceptive activities of all three isomeric 1-[2-(pyridyl)ethyl]-4-(propionanilido)-piperidine isosteres (11a-c) of fentanyl (1) are described. The 2- (11a), 3- (11b) and 4-pyridyl (11c) isomers exhibited 10, 2 and 0.2 times the antinociceptive activity of fentanyl, respectively. The ED50 values for 11a, 11b, 11c and fentanyl in the rat 4% NaCl-induced writhing test were 0.00023, 0.00085, 0.0087 and 0.0021 mg/kg sc, respectively. The 3-pyridyl (11b) and 4-pyridyl (11c) compounds were further elaborated to the 6-phenyl-1,6-dihydropyridine (12), C-2 H, Me, n-Bu and Ph 1,2-dihydropyridine (13a-d) analogues having a phenoxycarbonyl substituent on the dihydropyridine ring nitrogen. The most active compound in this series was 1-(2-[3-(1-phenoxycarbonyl-6-phenyl-1,6-dihydropyridyl)ethyl ])-4- (propionanilido)piperidine (12), which provided a 58% inhibition of writhing at a dose of 0.4 mg/kg sc. 1-(2-[4-(1-phenoxycarbonyl-1,2-dihydropyridyl)ethyl])-4-(propionanilido)piperidine (13a) exhibited an ED50 of 1.3 mg/kg sc, indicating a decrease in antinociceptive activity of about a 100 fold relative to the parent 4-pyridyl compound (11c). The dihydropyridine analogues 12 and 13 exhibit substantial antinociceptive activity relative to meperidine (ED50 = 0.6 mg/kg sc). The muscular rigidity effect induced by the pyridine compounds (11a-c) at a dose of 4 mg/kg sc, was not illicited by the dihydropyridine analogues at the same dose, or at a high dose of 40 mg/kg sc (13a). Compounds 12 and 13 may therefore be useful lead compounds for the development of more useful 4-anilidopiperidines if the antinociceptive activity can be dissociated from the muscular rigidity effect.

Since 2-pyridyl is the best, I suppose that the e-pair of pyridine forms a H-bond with the receptor like the a-hydroxyl in ohfentanyls and the carboxyl in remifentanyl. Pyfentanyl has no optic isomers, it is 10 times more potent than fentanyl, and the pyridylethyl can be attached by Mannich condensation of a-picoline (or better its oxide) with formaldehyde to the piperidone nitrogen. I will not dare to imagine potential monsters like pycarfentanyl or pymefentanyl.

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However, the most interesting achievement of Knaus is the discovery of a new class of potent opioids – piperilidenesulfonamides – which do not contain a single protonated nitrogen. A friend of mine made some Hyperchem calculations and all nitrogens were with a negative charge.

These cmpnds are easily synthesized by the reaction of sulfonylazides with the corresponding 1,2,3,4-tetrahydropyridines (see the patent description below). 1,2- and 1,4-dihydropuridines can be used also, with subsequent Pd/H2 reduction of the remaining double bond. I dot not know, and I have never surched for, a simple method for making tetrahydropyridines. Knaus, as I remember, starts with 1,2,5,6-tetrahidropyridines, which readily can be made by NaBH4 reduction of pyridinium salts, and which are then isomerized to 1,2,3,4-tetrahydropyridines with KOtBu in DMSO.

The most impressive cmpnd is 1-(4-nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide (W-1Cool which is some 10000 times more potent than morphine! I learned for the first time about W-18 in a russian book on chemical weapons, but it was just mentioned among other superpotent opiods. They are naloxone inhibited, but it means only that they are opioids. But what kind – mu, delta, or kappa? I personally would prefer kappa. Unfortunately, I have no more data on this class of opioids. They are, however, interesting, since their SAR seems strange – a simple change of Me for Cl in the sulfonamide phenyl leads to an almost 1000 times drop in activity. Or maybe they are already explored in some military lab, and the russians are wright that they are most suitable as a non-lethal weapon, like the not so non-lethal Moscow gas.

Here are the papers and patents of Knaus relevant to this class of cmpnds:
1. Some reactions of 1-methyl-1,2,3,4-tetrahydropyridine with organic azides. Synthesis of 1-methylpiperidylidene-2-sulfon(cyan)amides, B. K. Warren and E. E. Knaus, J. Heterocycl. Chem., 19, 1259 (1982)
2. Some reactions of 1-methyl-1,2-dihydropyridines with organic azides. Synthesis and reactions of 1,2,5,6-tetrahydropyridylidene-2-cyan(sulfon)amides and piperidylidene-2-cyan(sulfon)amides, T. A. Ondrus, P. R. Pednekar and E. E. Knaus, Can. J. Chem., 63, 2362 (1985)
3. Some reactions of 1-methyl(2-phenylethyl)-1,2,3,4-tetrahydropyridines with organic azides. Synthesis of 1-methyl(2-phenylethyl)piperidylidene-2-sulfonamides, B. K. Warren and E. E. Knaus, J. Heterocyclic Chem., 24, 1413 (1987)
4. Some reactions of 1-alkyl-1,2,3,4-tetrahydropyridines with organic azides. Synthesis of 1-alkylpiperidylidene-2-sulfonamides, B. K. Warren and E. E. Knaus, J. Heterocycl. Chem., 25, 1379 (1988)
5. Synthesis and antinociceptive activity of 1-methylpiperidylidene-2-(pyridyl)sulfonamides and related dihydropyridyl analogs, J. K. Buolamwini and E. E. Knaus, Eur. J. Med. Chem., 28, 447-453 (1993)
6. Analgesic substituted piperidylidene-2-sulfon(cyan)amide derivatives. E. E. Knaus, B. K. Warren and T. A. Ondrus, United States Patent No. 4,468,403, Issued Aug. 28, 1984.
7. Analgesic substituted piperidylidene-2-sulfon(cyan)amide derivatives, E. E. Knaus, B. K. Warren and T. A. Ondrus, Canadian Patent No. 1,255,680, June 13, 1989

Some quotes from United States Patent 4,468,403 . The patent discusses cmpnds with antagonist activity too, but they are omitted. You can see the whole patent for more details.

PREPARATION

Example 1
1-methylpiperidylidene-2-methanesulfonamide (W-1)
A solution of methanesulfonyl azide (0.377 g, 3.14 mmol) in 10 ml of ether was added to a solution of 1-methyl-1,2,3,4-tetrahydropyridine (0.305 g, 3.4 mmol) in 10 ml of ether with stirring at 25.degree. C. Evolution of nitrogen gas was immediate. The reaction was allowed to proceed for one hour at room temperature. The solid which precipitated was removed by filtration and recrystallized from methylene chlorideether to give 1-methylpiperidylidene-2-methanesulfonamide (0.492 g, 82%) as a white solid with mp 129-131.degree. C., IR (KBr) 1590 cm.sup.-1 (C+N); NMR(CDCl3) 1.69-1.98 (m, 4H, H-4 and H-5), 2.9-3.25 (m, 2H, H-3), 3.02 (s, 3H, Me), 3.06 (s, 3H, Me), 3.24-3.53 (m,2H, H-6).
Analysis found: C, 44.04; H, 7.19; N, 14.86.
C7 H14 N2 O2 S requires: C 44.19; H, 7.42; N, 14.72.

Example 2
Related 1-alkyl(arylalkyl, cycloalkylalkyl, alkenyl)piperidylidene-2-sulfon(cyan)amide derivatives have been prepared as shown in the schematic representation below using equivalent quantities of other azides of formula (2) using a procedure similar to that outlined in Example 1. The melting point for each product is set out in Table 1.

Example 3
1-methylpiperidylidene-2-(3-aminophenyl)sulfonamide (W-10)
(see schematic representation following example)
10% Palladium on charcoal (30 mg) was added at once and then 0.5 ml of 85% hydrazine hydrate was added dropwise to a suspension of 1-methylpiperidylidene-2-(3-nitrophenyl)-sulfonamide (0.20 g, 0.67 mmol) in 30 ml 95% ethyl alcohol with stirring at 0.degree. C. The temperature of the reaction mixture was allowed to return to 25.degree. C. and the reaction mixture was stirred for a further 16 hours. The solid material was removed by filtration. Water (50 ml) was added to the filtrate which was then extracted with methylene chloride (5.times.50 ml). Drying (Na2 SO4) and removal of the solvent in vacuo gave 1-methylpiperidylidene-2-(3-amino-phenyl)sulfonamide as a pale yellow solid which was then recrystallized from carbon tetrachloride-acetone to give yellow crystals with mp 164-165.degree. (0.137 g, 76%); IR (KBr) 3480 and 3370 (NH2) and 1590 cm.sup.-1 (C.dbd.N).
A similar reduction of 1-methylpiperidylidene-2-(2-nitrophenyl)sulfonamide gave 1-methylpiperidylidene-2-(2-aminophenyl)sulfonamide, mp 113-114.degree. (Compound W-11).

Example 4
3-bromo-1-methylpiperidylidene-2-cyanamide (0-1)
n-butyllithium (2.03 mmol) in hexane (0.83 ml) was added to a suspension of 1-methylpiperidylidene-2-cyanamide (0.274 g) W-13 in 50 ml dry tetrahydrofuran at -77.degree. C. under an atmosphere of nitrogen with stirring. The resulting solution was allowed to stir for 10 minutes at -77.degree. C. This solution of 3-lithio-1-methylpiperidylidene-2-cyanamide was then added dropwise over 20 min. to a solution of N-bromosuccinimide (0.356 g, 2.0 mmol) in 50 ml dry tetrahydrofuran at -77.degree. C. with stirring under a nitrogen atmosphere. The reaction mixture was allowed to return to 25.degree. C. slowly and water (50 ml) was added. Extraction with methylene chloride (3.times.75 ml), drying the extract (Na2 SO4) and removal of the solvent in vacuo gave 0.364 g of a pale yellow solid. Purification was effected on six 8.times.8 in silica gel G plates, 0.75 mm in thickness, using methylene chloride-methanol (15:1 v/v) as development solvent. Extraction of the band having Rf 0.67 using warm methanol gave 3-bromo-1-methylpiperidylidene-2-cyanamide as a white solid with mp 116-118.degree. (0.215 g, 66%); IR (KBr) 2160 (C.dbd.N) and 1600 cm.sup.-1 (C.dbd.N); NMR (CDCl3) 1.72-2.38 (m, 4H, H-4 and H-5), 3.12 (s, 3H, Me), 3.56 (m, 2H, H-6) and 5.11 (m, 1H, H-3).
Mass spectrum (70 ev): Mass calc'd for C7 H10 N3 .sup.81 Br: 217.0039.
Found: 217.0023.

Example 6
1-methylpiperidylidene-2-(4-aminophenyl)sulfonamide (W-9)
A solution of 4-aminobenzenesulfonyl azide (0.63 g, 3.2 mmol) in 75 ml ether was added slowly to a solution of 1-methyl-1,4-dihydropyridine (0.30 g, 3.2 mmol) in 75 ml ether with stirring at 25.degree. C. Evolution of nitrogen gas was immediate. The reaction was allowed to proceed for 2 hours and the solvent was removed in vacuo to give 2-methyl-7-[(4-aminophenyl)sulfonyl]-2,7-diazabicyclo[4.1.0]hept-3-ene (0.82 g, 97%) with mp 188-190.degree. Hydrogenation of 2-methyl-7-[(4-aminophenyl)sulfonyl]-2,7-diazbicyclo[4.1.0]hept-3-ene (33 mg, 0.117 mmol) in 15 ml ethanol was effected using 10% palladium on charcoal (15 mg) and hydrogen gas at 30 psi for 4 hours. Removal of the catalyst by filtration and evaporation of the solvent in vacuo gave 1-methylpiperidylidene-2-(4-aminophenyl)sulfonamide (31 mg, 93%) with mp 186-188.degree. ; IR (KBr) 3480 and 3380 cm.sup.-1 (NH2) and 1590 cm.sup.-1 (C.dbd.N).
Analysis found: C, 53.49; H, 6.24; N, 15.64. C12 H15 N3 O2 S requires:
C, 53.91; H, 6.42; N, 15.72.

Example 7
1-(4-nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide (W-1Cool
A mixture of 1-phenylethylpiperdylidene-2-(4-chlorophenyl)sulfonamide (1.17 g, 3.11 mmol) W-15, 90% fuming nitric acid (3.0 ml) and concentrated nitric acid (2.0 ml) were stirred vigorously for 4 hours at 25.degree. C. This mixture was poured onto 50 ml water and the pH adjusted to 10 using 1 N sodium hydroxide. Extraction with methylene chloride (4.times.50 ml), drying (Na2 SO4) and removal of the solvent in vacuo gave a yellow gum which was purified by preparative tlc using 0.75 mm silica gel G plates with acetone: ether (1:1 v/v) as development solvent. Extraction of the band having Rf 0.88 gave 1-(4-nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide as a pale yellow solid (0.734 g, 61%) having mp 157.degree.-158.degree.; IR (KBr) 1350 and 1540 cm.sup.-1 (NO2).

EXAMPLE 8
1-(4-aminophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide (W-19)
10% palladium on charcoal (30mg) and then 85% hydrazine hydrate (0.5 ml) was added to a rapidly stirred suspension of 1-(4-nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide (0.15 g, 0.355 mmol) W-18 in 95% ethanol (30 ml). The reaction was allowed to proceed for 4 hours at 25.degree. C., the reaction mixture was filtered to remove the palladium on charcoal and water (30 ml) was added. Extraction with methylene chloride (3.times.30 ml), drying (Na2 SO4) and removal of the solvent in vacuo gave a solid which on recrystallization from acetone/hexane gave 1-(4-aminophenylethyl)piperidylidene-2-(4 -chlorophenyl)sulfonamide (0.095 g, 68%) having mp 129.degree.-130.degree., IR (KBr) 3370 and 3440 cm.sup.-1 (NH2).

ANALGESIC AGONIST TESTING
Analgesic activity was evaluated by the phenylquinone writhing test (H.O. Collier, L.C. Dineen, C. A. Johnson and C. Schneider, Br. J. Pharmacol. Chermotherap., 32, 295, 1968. Five male Swiss albino mice weighing 18-22 g were used in each group. The test compound, suspended in a solution of physiological saline and Tween 80 (TM) surfactant, was administered subcutaneously, and 30 min. later each mouse received a 0.03% phenyl-p-benzoquinone solution in a volume of 0.1 mL/10 g of body weight intraperitoneally. The total number of writhes exhibited by each animal in the test group was recorded and compared to that of a vehicle treated control group. The percent change is calculated according to the following equation: % change=100- (no. of writhes in treated group/no. of writhes in control group).times.100. A compound causing a 30-50% reduction is considered to be slightly active, whereas one causing a greater than 50% reduction in the number of writhes is an active analgesic agent. The test results are shown in Table 2 and Table 3, the compounds tested being compared to Aspirin (TM), Dextropropoxyphene (TM), and morphine sulfate.
Compounds W-20 to W-32, inclusive, exhibited analgesic antagonist activity toward compounds W-1 to W-19, inclusive, 0-1 to 0-3, inclusive, as well as toward morphine sulfate. Naloxone (TM) also acted as an antagonist toward W-3.
Spectroscopic and Chromatographic Identification of Dimethoxyamphetamines

Name Designation dose(mg/kg) % inhibition
1-Methylpiperidylidene-2-methanesulfonamide W-1 108.0 50
1-Methylpiperidylidene-2-benzenesulfonamide W-2 68.0 50
1-Methylpiperidylidene-2-(4-chlorophenyl)sulfonamide W-3 0.0038 50
1-Methylpiperidylidene-2-(4-methoxyphenyl)sulfonamide W-4 0.002 50
1-Methylpiperidylidene-2-(4-methylphenyl)sulfonamide W-5 2.4 50
1-Methylpiperidylidene-2-(4-nitrophenyl)sulfonamide W-6 0.0028 50
1-Methylpiperidylidene-2-(3-nitrophenyl)sulfonamide W-7 0.0028 50
1-Methylpiperidylidene-2-(2-nitrophenyl)sulfonamide W-8 0.0018 50
1-Methylpiperidylidene-2-(4-aminophenyl)sulfonamide W-9 0.007 50
1-Methylpiperidylidene-2-(3-aminophenyl)sulfonamide W-10 0.0017 50
1-Methylpiperidylidene-2-(2-aminophenyl)sulfonamide W-11 0.00024 50
1-Methylpiperidylidene-2-(4-acetamidophenyl)sulfonamide W-12 1.2 50
1-Methylpiperidylidene-2-cyanamide W-13 6.0 50
1-Methylpiperidylidene-2-(3-pyridyl)sulfonamide W-14 0.00038 50
1-Phenylethylpiperidylidene-2-(4-chlorophenyl)sulfonamide W-15 0.007 50
1-Phenylethylpiperidylidene-2-(4-aminophenyl)sulfonamide W-16 0.20 56
1-Phenylethylpiperidylidene-2-(3-pyridyl)sulfonamide W-17 0.20 65
1-(4-Nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide W-18 0.0000037 50
1-(4-Aminophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide W-19 0.000034 50
Standards:
Aspirin (TM) 50.0 50
Dextropropoxyphene (TM) 56.0 50
Morphine Sulfate 0.038 50
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Sun Apr 03, 2005 7:48 am
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This is a great find,

Pyridinium salts
So a reduction of say Pyridine Chl, with Nabh4?
Maybee a poor man amalgum?

A very novel route,
I wonderwahat theraputic and addictory behaviuors these compunds may have,,



Syn

" One day i will build a solvent that will solvate anything"
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