Synthesis of New Functionalized Derivatives of Six-Membered Heterocycles as

Synthons for Creation of Potential Analgesics and their Antagonists

or
Thirty Seven Years in a Lab

Dr. Ruben S.Vardanyan

Chemistry Department Colloquim, University of Arizona

August 24, 2006

The main chemical results of my research 1974-2002 is possible to summarize as the

following:

1. A simple and common method for the synthesis of alkyl-propargyl ethers had
been proposed.
2. A simple method for the synthesis of alkyl ethers of hydroxyacetone had been
proposed.
3. A simple and common method for the synthesis of 2-alkoxymethylpiperidine-4-
ones had been proposed.
4. A homoanomeric effect (a significant increase of the quantity of an isomer with
axially oriented bulky alkoxymethyl group depending on size of alkoxy group) in
series of 2-alkoxymethylpiperidine-4-ones had been observed.
5. Several simple and common methods for the synthesis of bifunctionalized
derivatives of tetrahydropyrans, tetrahydrothiopyrans and piperidines, such as β-
ketoesters, β-diketones, β-dinitriles and others had been observed.
6. Simple and common methods for the synthesis of amino-, hydrazino- derivatives
of tetrahydropyrans, tetrahydrothiopyrans and piperidines had been proposed.

7. Simple heterocylization methods for the synthesis of non-condensed

biheterocycles with C-C and C-N coupling of heterocycles based on above
mentioned functionalized derivatives of tetrahydropyrans, tetrahydrothiopyrans
and piperidines had been proposed.

8. A new rearrangement of 2-amino-(hydroxy-, mercapto-)-4-methyl-5-

ethoxycarbonyl- pyrimidines to 2-amino-(hydroxy-, mercapto-)-5-acetyl-4-
hydroxy pyrimidines (ANRORC rearrangement) had been obtained.

9. A new rearrangement of 1,3-disubstituted-5-(α-alkylthio)benzylaminopyrazoles

into 1,3-disubstituted-4-(α-alkylthio)benzyl-5-aminopyrazoles had been obtained.

10. Several conclusions concerning structure-activity relationships among synthesized

compounds had been done and a concept of substrat-receptor interaction of
opioids with receptor system had been proposed.
11. As a result of the cited investigations a new powerful analgesic Phenaridine,
which had been passed through all necessary preclinical and all stages of clinical
trials, had been proposed for clinical use.
 12. As a result of the cited investigations a new powerful antagonist of opioid
analgesics Phenetam had been proposed for preclinical trials.

13. As a result of the cited investigations a new antiarrhytmic compound with

fibrinolytic properties Dipifen had been proposed for preclinical trials.

14. A new direction in the field of saturated 6-membered heterocycles – chemistry of

functionalized hexahydropyridazines had been established and developed. It
includes proposition of methods for preparation of previously not described
functionalized hexahydropyridazines, such as 4-keto-, 5-halogen-4-keto-,4-
hydroxy-, 4-amino-, 4,5-epoxyhexahydropyridazinesnes, as well as, a series of
their transformations into biologically active compounds. It is necessary to
mention, that all described compounds are of a very low toxicity, and could serve
as excellent carriers for known pharmacophore groups.

The main pharmacological directions of my research work 1974-2002 concerned creation

of new analgesics, drugs acting on CNS and cardio-vascular system based on mentioned
saturated heterocycles.
As a result of my investigations three new potential drugs have been created in my
laboratory under my guidance.
The clinical trials of one of them, the opioid analgesic Phenaridine, were finished with
positive results and it is permitted for wide use in medicine in the former USSR.
The two others were on different stages of preclinical trials.

As I have mentioned, among them - a very simple piperidine derivative, which represents
unique narcotic analgesics antagonist properties and has no structural analogues in
literature. At the same time this compound elicits anti-shock and anti-alcohol activities.
This direction of investigations is far to be finished and need to be developed in a very
intensive manner.
The third compound proposed for medicinal use in my laboratory is a new antiarrhytmic
drug possessing at the same time fibrinolytic activity.

These achievements have been published in ~ 80 scientific articles and reviews in the
peer-reviewed Chemical and Chemical-Pharmaceutical Journals of the former USSR and
18 Authorship Certificates (Patents) of USSR and reported on multiple peer-reviewed
Soviet Scientific Symposiums.

Now, with Regent Prof. V.Hruby we have published a book “Synthesis of Essential
Drugs” It contains 38 Chapters, which include ~350 schemes for drug synthesis, written
on 650 pages and contains more than 2350 references.

Statement of Current Research

The main direction of my work:

from pharmacological point:
- Creation of new analgesics and their antagonists.
- Design of new drugs to relieve chronic and pathological pain, especially
rheumatoid and osteoarthritis, neuropathic and cancer pain.

from chemical point:

– synthesis of analgesics and their antagonists chemically related to Fentanyl.
– synthesis and utilization of functionalized piperidines as starting material for
achieving above mentioned goal.

Class of compounds, known as 4-anilinopiperidines, or the Fentanyl series is the most

powerful of existing known analgesics, which includes - Fentanyl, Sufentanyl,
Alfentanyl, Carfentanyl, Lofentanyl, Mefentanyl, Ohmefentanyl, Brifentanyl,
Remifentanyl, Ocfentanyl, Trefentanyl, Phenaridine).

These are the most powerful drugs for severe acute and chronic pain, but their
widespread use is hampered by side effects such as depression of breathing, nausea,
clouding of consciousness, constipation, addiction and tolerance.
Three most popular compounds in medicinal practice are Fentanyl, Sufentanyl,
Alfentanyl.

The analgesic potency of Fentanyl had been enhanced up to 10000 times than that of
Morphine(Carfentanyl) by the introduction of appropriate substituents the structure of
Fentanil.
A huge amount of work had been done and published.

The main changes of practical meaning the in structures of compounds of these series
include the replacement of phenyl group in phenethyl- part of molecule for some
aromatic heterocyles (changes of practical meaning are replacemenys of phenyl group for
thiophene (Sufentanyl) and tetrazole rings (Alfentanyl, Brifentanyl, Trefentanyl), or
carbomethoxy- group as in Remifentanil.
Another sensible change was done via attaching additional methoxymethyl (Alfentanyl,
Sufentanyl) or metoxycarbonyl group (Lofentanyl, Carfentanyl) into the forth position of
piperidine ring.
Changes of practical meaning had been done and in aniline part of molecule of Fentanil
via introduction of fluorine atom into the ortho- position of aniline- part of molecule
(Ocfentanyl. Brifentanyl, Trefentanyl).
Additional methyl group (Lofentanyl, Brifentanyl), as well as two methyl groups
(Phenaridine) had been introduced into the third position or second and fifth positions of
piperidine ring.

Among other changes a lot of work had been done on replacement of propionyl group in
the 4-anilido-phragment for several other acyl groups. But propionyl group remains
preferable.
The single successful case of replacement of propionyl group is the replacement for
methoxyacetyl- group (Ocfentanyl).
The peak of activity more than 10000 times higher than that of morphine (Carfentanyl) is
achieved and practical medicine do not need more potent analgesic.

But there remain three great problems on Fentanyl Series, as well as for all opioids:
1. Respiratory depression.
2. Physical dependence. Addiction
3. Absence on the pharmaceutical market and even in the literature information of
antagonist from the same chemical row of 4-anilinopiperidines.

What remains to do in Pain area in general, without respect to any concrete chemical row
of compounds? (Evident white gaps in pain relief.)

The evaluation of new drugs with new mechanisms of action to treat chronic and
pathological pain, especially rheumatoid and osteoarthritis, neuropathic pain and cancer
pain. The remaining compounds are opioids and COX-2 inhibitors”.

The evaluation of new drugs with new mechanisms of action to treat chronic and
pathological pain, especially rheumatoid and osteoarthritis, neuropathic pain and cancer
pain is one of the most intense areas of development of new analgesics today.

There is no any theoretical scientific substantiation for how to do it. This is obviously a
complex question.

Today we can only present some empirical approach.

So, I would like to present my vision, of that what is not done and what is possible to do
in this area.

What is known from medical practice?

The analysis of the literature allows to conclude that “simultaneous administration of

morphine with some of nonsteroidal anti-inflammatory drug (NSAID) demonstrates the
existence of a supra-additive interaction (synergy).”

Conclusion:
Combination of morphine with NSAIDs in a single molecule could be that chemical entity
that is able to modulate multiple nociceptive targets simultaneously. The same is possible
to say about morphine with adjuvant analgesic combinations.

But morphine have enough cumbersome and complicated structure and its further
enlargement and complications, as it is evident from the literature unlikely will give
significant result for practical medicine.
What simple molecule can replace, substitute morphine and to act by the same
mechanism?
So, the fentanyl molecule itself, or its precursors or derivatives, such as additionally
functionalized piperidines could serve as an excellent basement for creation of new
molecules with potential to combine different opioid and nonopioid analgesics
pharmacophore elements as well as different types of opioids opiods (μ−μ, μ−δ, μ−κ, μ-
substance P antagonists, μ-CCK antagonists etc.)

The general strategy of my research is:

1. To develop a single chemical entity that is able to modulate multiple nociceptive

targets simultaneously. The basic part will remain constantly as a fentanyl derivative.
Taking into account the evident fact of the lack of toxicity of amino acids and peptides,
we decided to start a series of work on replacing the propionyl- fragment of Fentanil
series for aminoacid and short peptides fragments

a. To synthesize combinations of fentanyl with aminoacids and peptides an the basis of

“amino”- and “carboxyfentanyls” . with possible creation of “Fentefallins”.

O O O
OH
N NH2 N N
O

N N N

Aminofentanil Fentanil Carboxyfentanil S9

O O

N (CH2)n NH2 N (CH2)nNHAA1AA2AA3....

N N

O O

N (CH2)nCOOH N (CH2)nCONHAA1AA2AA3...

N N

S9

b. To synthesize combinations of fentanyl with different NSAID, and adjuvant analgesics

pharmacophores.
 O O
NH2 OH N
NH2 N N
NH
O

N N N N
N H
β-C-Terminal !-N-Terminal
4-N-Terminal 4-N-Terminal Hydrazine-Lincor

I7

To synthesize new functionalized 4-piperidones for creation of novel fentanyl analogs,

containing elements of the min class of adjuvant analgesics – substance P antagonists.

COOC2H5 COOC2H5
COOC2H5
+ Br COOC2H5
NH N
R R

O O
COOC2H5

N N
R R

R = CH3, C6H5CH2, C6H5CH2CH2

HN N O
COOC2H5 N N HN N
COOH
COOC2H5 COOC2H5 N
N O
N
R N N
or R
R R

O
O O
O
COOC2H5 N COOC2H5
H N
N
O
N N O
N
R R
R
and other secondary amines

CH3NH2
XH

O O R N N
C2H5OOC COOC2H5 N N
N O N OH
CH3 N O
N N O N
R R N R
R

R = CH3, C6H5CH2, C6H5CH2CH2

R1 = CH3
 COOC2H5 COOC2H5 COOC2H5 COOC2H5
+
NH2 COOC2H5 COOC2H5
N N
H R

O
O
COOC2H5

N
N
R
R

R = C6H5CH2- C6H5CH2CH2-, CH3-

COOC2H5 COOC2H5 COOC2H5 COOC2H5

+
COOC2H5 COOC2H5
NH2 N N
H R

O
O N
COOC2H5

N
N N
R
R R

R = C6H5CH2- C6H5CH2CH2-, CH3-

COOC2H5

NH2
N S

2.To develop an antagonist of narcotics in Fentanyl series.

To use new functionalized 4-piperidones for creation of novel antagonist analogs, as well
as to conduct above mentioned aminoacid synthesis with them.
O O
O
HN HN
HN

N N
N

Detailed schemes of the done work are attached.