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I Like to Draw Pictures of Random Molecules

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oxymorphone analogue
 
Sekio, I don't know about the ketone on that, but I'm pretty sure molecules based on that design were active opioids and quite potent.
 
Hammilton, after posting here I did some scouring and all I could find was syntheses - no actual tests of the compound. The dehydro analog has been made (double-bond a la morphine & no tertiary OH) as well as a dimethoxyphenyl variant (to simulate the epoxy bridge) but I haven't actually found any data on tests in vivo.

Definitely interesting compounds. I bet they would have activity as SNRI's or maybe even NMDA antagonists.
 
This one has piqued my curiosity for an extensive period of time. I welcome thoughts from the more chemically literate individuals on bluelight as to the expected activity of this compound. Like, the 2c series, if this one has interesting activity, other similar substituted compounds exist, that may also have interesting profiles. I give you :: d-thio-LSD! Edit: New here so I still can't upload images. Also, attached image in web link does not show. Follow link for visual clarification. http://imgur.com/D8Y69
 
sekio said:
Hammilton, after posting here I did some scouring and all I could find was syntheses - no actual tests of the compound. The dehydro analog has been made (double-bond a la morphine & no tertiary OH) as well as a dimethoxyphenyl variant (to simulate the epoxy bridge) but I haven't actually found any data on tests in vivo.

Definitely interesting compounds. I bet they would have activity as SNRI's or maybe even NMDA antagonists.
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Sorry, it took me a while to see this. I found these two pretty quickly. I'm sure there's more, but I've got two kids bugging me. First one isn't too promising. Well, actually, they're pretty potent. I'm thinking that either that 8a-methyl substitution is the problem or maybe the trans isomers are agonists. Not sure

N-Substituted cis-4a-(3-Hydroxyphenyl)- 8a-methyloctahydroisoquin olines Are Opioid Receptor Pure Antagonists
Authors: F. Ivy Carroll, Sachin Chaudhari, James B. Thomas, S. Wayne Mascarella, Kenneth M. Gigstad, Jeffrey Deschamps, and Hernán A. Navarro
J. Med. Chem. 48(26), 8182-8193 (2005)
ISSN: 0022-2623 00222623 DOI: 10.1021/jm058261c
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N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahy-droisoquinolines 6a-g can exist in conformations where the 3-hydroxyphenyl substituent iseither axial or equatorial, similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenylequatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single-crystal X-ray analysis of 6a shows that the3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modelingstudies also suggest that the equatorial conformation has lower potential energy relative tothat of the axial conformation. Evaluation of 6a-g in the [35S]GTP-γ-S in vitro functional assayshowed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a Ki of 0.27 nM at the κ opioid receptor with 154- and 46-fold selectivity relative to those of the µ and δ receptors, respectively, possessed the best combination of κ potency and selectivity.
http://www.scribd.com/doc/43821646/...ntagonists-J-Med-Chem-48-2005-8182-8193-J-Med


Slightly more promising, but of significantly less value. I hope the NSFW tag works...


If might be worthwhile for someone to pull the following refs:
Boekelheide et al., JACS 72, 712 (1950)
Eddy, "J. of the Am. Pharm. Assoc.", May 1950, pp. 245ff
Finch et al., "J. Org. Chem" 39, No. 8, 1118-1124, Apr. 19, 1974

These are all real old, obviously!

Patent 4150135
4A-Aryl-cis-decahydroisoquinolines, such as N-phenethyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline, useful as analgesics.
NSFW:
BACKGROUND

This invention concerns the discovery that a selected group of 4a-aryl-cis-decahydroisoquinolines are useful as analgesics, many with little or no addictive properties.

Boekelheide and Schilling, J. Am. Chem. Soc. 72, 712 (1950), disclosed the compound N-methyl-4a-phenyl-cis decahydroisoquinoline, (naming it "N-methyl-10-phenyldecahydroisoquinoline") and indicated that it had low analgesic activity.

The present invention results from efforts to develop new compounds with high analgesic potency and low abuse liability.

SUMMARY

According to this invention there is provided novel compounds of formula I and their suitable pharmaceutical salts, processes for their manufacture, pharmaceutical compositions containing them, and methods of using them to produce analgesia inmammals. ##STR1## where R1 is hydrogen; C1 -C6 alkyl; --CH2 Y where Y is C2 -C6 alkenyl or C2 -C6 alkynyl;

--(CH2)m ##STR2## WHERE M IS 1 TO 4, X is Cl, Br, F, CF3, OCH3, CH3, isopropyl, --NH2, or --N(CH3)2, a=0, 1 or 2;

--(CH2)m ##STR3## --(CH2)m ##STR4## or cycloalkylmethyl of the formula --CH2 CH<(CH2)n, where n is 2-5;

R2 is divalent oxygen (=O), ##STR5## R3 is --OH, --OCH3, ##STR6## or F; R4 is --H, --OH, --OCH3, ##STR7## with the proviso that when R3 is --F, R4 must be --H.

DETAILED DESCRIPTION

Representative R1 groups are methyl, ethyl, propyl, butyl, hexyl, allyl (--CH2 CH=CH2), 2-butenyl, 3-butenyl, 4-heptenyl, 3,3-dimethylallyl [--CH2 CH=C(CH3)2 ], propargyl (--CH2 .tbd.CH), phenylpropargyl, heptynyl, benzyl, phenethyl, 4-phenyl-n-butyl[--CH2 (C2)3 C6 H5 ], cyclopropylmethyl [--CH2 CH<(CH2)2 ], cyclobutylmethyl [--CH2 CH<(CH2)3 ], cyclohexylmethyl [--CH2CH<(CH2)5 ], furylmethyl ##STR8## 2-furylethyl ##STR9## 2-thienylethyl ##STR10## p-methylphenethyl ##STR11## p-fluorophenethyl, ##STR12## p-methoxyphenethyl ##STR13## p-chlorophenethyl ##STR14## p-aminophenethyl ##STR15##p-dimethylaminophenethyl, and cinnamyl (--CH2 CH=CHC6 H5).

Representative Ar groups are 3-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-acetoxyphenyl, 2,3-dihydroxyphenyl, 3,4-dimethoxyphenyl, 3,4-diacetoxyphenyl, 3-hydroxy-4-methoxyphenyl, 2-methoxy-3-acetoxyphenyl, 3-fluorophenyl and4-fluorophenyl.

The 4a-aryl-cis-decahydroisoquinolines of formula I include various stereochemical isomers stemming from substitution at position 6, and from optical asymmetry of the whole structure. When monovalent R2 substituents at position 6 aredifferent (e.g., when ##STR16## spatial considerations require the existence of axial and equatorial isomers. In the molecule as a whole, spatial considerations require the existence of d and l optical isomers. These are normally present as racemicmixtures which can be resolved by known methods (Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, 1962, p. 31).

Pharmaceutically suitable acid addition salts of these compounds include those made with physiologically acceptable acids that are known in the art; such salts include hydrochloride, sulfate, phosphate, nitrate, citrate, maleate and the like.

PREFERRED COMPOUNDS

The analgesic compounds preferred because of their high level of activity are those where

R1 is ##STR17## X=H or CH3 with CH3 being more preferred; R2 is ##STR18## being more preferred; R3 is m-OH or m-OCH3 ; and

R4 is H.

Most preferred because of their activity are N-(p-tolylethyl)-4a-m-hydroxyphenyl-6β-cis-decahydroisoquinoline and N-(phenethyl)-4a-m-methoxyphenyl-cis-decahydroisoquinoline.

Synthesis

The multi-step processes of the invention start with 2-cyano-3-aryl-3-carbalkoxymethylcyclohexenes which can be obtained according to procedures disclosed by Boekelheide and Schilling (loc. cit.) with respect to2-cyano-3-phenyl-3-carbethoxymethylcyclohexene (cf, Example 1, Part A). Reaction of a 2-cyano-3-aryl-3-carbalkoxymethylcyclohexene with hydrogen chloride in a lower alkanol such as ethanol forms a4a-aryl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (cf, Example 1, Part B). These 1,3-diketo-octahydroisoquinolines possess a conformational arrangement of the fused rings which requires formation of trans-decahydroisoquinoline structures whenthe 8,8a- double bond is converted to a single bond (cf, Example 1, Part D; Example 6, Part A). A key step in the invention is the novel isomerization of a 1,3-diketo-trans-decahydroisoquinoline to the cis isomer in the presence of a relatively strongbase (cf, Example 1, Part E; Example 4, Part A).

The selection of specific preparational steps following the initial formation of a 1,3-diketo-1,2,3,4,4a,-5,6,7-octahydroisoquinoline depends upon the specific 4a-aryl-cis-decahydroisoquinoline derivative that is desired. The sequence involvesat least three steps, A, B, and C, which are illustrated below. Compounds having no unsaturated carbon to carbon bonds in R1 (R1a in process steps) are prepared by steps A, B-1, and C. Compounds having saturated or unsaturated carbon to carbonbonds in R1 are prepared by steps A, B-2, and C. ##STR19##

R1a in path B-1 is the same as R1 except that it does not include unsaturated groups such as alkenyl or alkynyl. These groups appear to undergo reduction to alkyl, simultaneously with the reduction of the 8,8a bond, in going fromcompound (3) to compound (4). Thus to obtain compounds of formula I where R1 has alkenyl or alkynyl bonds, path B-2is followed. In this path the 8,8a bond of compound (2) is first reduced and then the resulting trans product (6) is reacted withR1 Br, R1 I or mesylates to form the cis product (5) in which R1 has alkenyl or alkynyl groups. Path B-2 includes the possibility of isolating the N-unsubstituted cis imide followed by normal N-alkylation with either a saturated orunsaturated R1 group. ##STR20##

In the foregoing formulas (1) through (8), the groups R1 have the values given previously. R5 is ##STR21## R6 is C1 to C4 alkyl. Ar1 is ##STR22## in which R7 is hydrogen, F or methoxyl;

R8 is H or methoxyl; provided when R7 is F, R8 is H.

In Step A reactant R6 OH, which is also the reaction medium, is generally used in excess, but to insure maximum yield it should be used in an amount of at least one mole per mole of cyanoester. Likewise, the HCl reactant can be used inexcess but to insure maximum yield it should be present in an amount of at least one mole per mole of cyanoester. The reaction is run in the liquid phase under anhydrous conditions. The reaction temperature should be in the range of about 50° to about 120° C. The reaction pressure is not critical, ordinarily being atmospheric for convenience, but should be consistent with achievement of the stated reaction temperature.

In step B-1 for the conversion of (2) to (3), or in step B-2 for converting (6) to (5), any reactive alkylating agent can be used, such as hydrocarbyl iodide, bromide, mesylate, tosylate, azide, and the like. Alkyl iodides, bromides, mesylates,tosylates, and azides are included and the hydrocarbyl group corresponds to R1 in general formula I. Any base capable of extracting a proton from the imide is satisfactory. Exemplary are alkali metal hydrides (sodium hydride or potassium hydride)in aprotic media (dimethylformamide, hexamethyl phosphoramide, dimethylsulfoxide); alkoxides in aprotic or alcoholic solvents, as, for example, sodium ethoxide in ethanol and potassium t-butoxide in ethanol. Mesylates (Ms=mesyl group=methanesulfonylgroup) are described in Fieser and Fieser, Advanced Organic Chemistry, 1961, pp. 292, 293 and 319. Hydrocarbyl bromides, iodides or mesylates are readily available, as indicated in the following table (Table I).

In paths B-1 (4) to (5a) and B-2 (6) to (7) a relatively strong base, with or without an inert solvent, is used. Representative strong bases include alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, and lithium hydroxide;alkali metal alkoxides in which the alkoxide group contains 1-4 carbon atoms, such as sodium methoxide, potassium ethoxide, lithium propoxide, and the like. An inert solvent can be used if desired; included are lower alkanols, e.g., methanol, ethanol,t-butanol and the like. The reaction temperature can range from room temperature to reflux temperature of the reaction mixture.
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Oops, I had to read this one really carefully because I think they're using a different numbering scheme. Today, I'm pretty sure that where the phenyl group is attached it's called 4a-phenyl-decahydroisoquinoline. This patent talks about 3a-phenyl-decahydroisoquinolines, which made me think they were a bit like methopholine but when I read the abstract, it says, "[the structure can be described] as a decahydroisoquinoline with an hydroxyphenyl group substituted on a ring junction carbon atom para to the isoquinoline nitrogen." Based on that it seems we're talking about the same structure, especially considering that he references the same Boekelheide paper from 1950.

http://www.patentgenius.com/patent/4001247.html
BACKGROUND OF THE INVENTION

It has long been known that slight chemical modifications of the morphine molecule lead to analgesic agonists of widely differing potency and addictive properties. For example, codeine, the methyl ether of morphine, is a relatively mildanalgesic agonist having slight dependance (addiction) liability. On the other hand, heroin, the diacetyl derivative of morphine, is a powerful agonist with extremely high addiction potential. In addition, as long ago as 1915, Pohl found that when theN-methyl group of codeine was replaced with an allyl group, the resulting compound, N-allylnorcodeine, was an opiate antagonist. In 1940, N-allylnormorphine or nalorphine was synthesized and was shown to have a highly specific ability to reverse thedepressant effects of morphine. Other simple chemical modifications of the morphine molecule have yielded many interesting drugs. Thus, one fruitful research area in the search for improved analgesics of high potency and/or lower dependence (addiction)liability has been the chemical modification of the morphine molecule.

In addition to modifying the morphine ring structure by chemical means, chemists have developed a second related field of research--the preparation of certain morphine partstructures--with the same end in mind as above; i.e., the synthesis ofimproved analgesic agonists and/or analgensic antagonists of improved properties. For example, meperidine, a widely used analgesic, can be written as a morphine part-structure. Many other morphine part-structures have been prepared, some of which haveimproved analgesic agonist properties and others, particularly those with an allyl group attached to a ring nitrogen, have opiate antagonist properties. It had been hoped that morphine part-structure research would produce a compound having both opiateagonist and antagonist properties since the opiate antagonist property would assure a user that the compound would have a greatly reduced dependence liability. Two recently marketed analgesics, pentazocine and phenazocine, have been found to be bothantagonists and agonists although they still retain a certain degree of opiate dependance liability.

One potential morphine part-structure can be written as a decahydroisoquinoline with an hydroxyphenyl group substituted on a ring junction carbon atom para to the isoquinoline nitrogen. An attempt to prepare such a compound was described by Boekelheide in a paper appearing in J. Am. Chem. Soc., 69, 790 (1947). This paper set forth the preparation of what, according to the numbering system then in vogue, were 10-phenyldecahydroisoquinolines. It was the author's conclusion, however, thatthe compound (IX) had a cis configuration and (footnote 5) showed low analgesic activity. The synthesis itself is cumbersome and not free from ambiguity. Sugimotp et. al., J. Pharm. Soc. Japan, 75 177 (1955), C.A. 1956 1814b described the synthesisof 8 or 10-alkylated decahydroquinolines. The reference also shows the morphine part-structure, 10-(m-hydroxyphenyl)-3-methylisoquinoline [presently named as 1-methyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a, 8-decahydroisoquinoline] but withoutfurnishing a synthesis for it. These authors do not, in fact, describe the preparation of any decahydroisoquinoline, but describe only the preparation of the decahydroquinoline analogs.

Belgian Pat. No. 802,557 issued Jan. 19, 1974, discloses a general method of preparing N-substituted 3a-phenyldecahydroisoquinolines and specifically discloses 3a, phenyl-3a-(m-methoxy phenyl) and3a-(m-hydroxyphenyl)-1-methyldecahydroisoquinolines, 3a-(m-methyoxyphenyl) and 3a-(m-hydroxyphenyl)-1-phenethyldecahydroisoquinolines. and 1-cyclohexylmethyl-3a-phenyldecahydroisoquinoline.
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edit, again: actually he's citing a Boekelheide paper from three years earlier. Based on the description, though, I'm still pretty sure these are from the same family. Someone better at reading chemistry patents should give it closer look.

Personally, I still think that 4a-(3-hydroxyphenyl)-2-(2-phenylethyl)-decahydroisoquinolin-6-one will be a potent opioid, whether an agonist or an antagonist. I dunno about the ketone, though. It serves a purpose on true morphinans, but these more stripped down fellas don't necessarily follow that closely.

Don't think it's an analogue of anything scheduled, so these could be a fruitful place to work.
 
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^ ah! for whatever reason i kept seeing 11 carbons. my monitor is probably totally broken or something. anyway, thank you muchly!
 
Fluorinated analogues of existing drugs offer a great way to circumvent legislation while retaining a very similar effects profile to the originals. With the exception of things like those above, I think as fluorine chemistry becomes easier and more accessible, we will hopefully start seeing some pretty brilliant analogues.
 
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Even the haloamines that aren't explosive are not things I would want to put in my body - they are freakishly similar to nitrogen mustards (alkylating agents)

See also chloramine
 
2-benzylpyrrolidine

basically methamphetamine with the n methyl wrapped around to join the alpha methyl carbon, forming a terminal pyrrolidine ring.
I'm having difficulty with my chemsketch program at the moment.
similar terminal structure to the highly active lucigenol tryptamine.
Any thoughts on theoretical activity of these 2 compounds?
 
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You mean this?

I can't find any info about 2-benzylpyrrolidine (the compound above), but the structurally similar 2-benzylpiperidine is a shitty stimulant with mainly noradrenergic effects, which doesn't sound promising...
 
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