U.S. patent application number 15/709394 was filed with the patent office on 2018-01-25 for 1-arylalkyl-4-acylaminopiperidine compounds.
This patent application is currently assigned to ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIVERSITY OF ARIZONA. The applicant listed for this patent is ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIVERSITY OF ARIZONA. Invention is credited to Victor J. Hruby, Ruben S. Vardanyan.
Application Number | 20180021322 15/709394 |
Document ID | / |
Family ID | 55347719 |
Filed Date | 2018-01-25 |
United States Patent
Application |
20180021322 |
Kind Code |
A1 |
Vardanyan; Ruben S. ; et
al. |
January 25, 2018 |
1-ARYLALKYL-4-ACYLAMINOPIPERIDINE COMPOUNDS
Abstract
The present invention provides a compound of the formula:
##STR00001## wherein ring Z is a 5-, 6- or 7-membered ring; R.sup.1
is C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, optionally substituted
aralkyl, optionally substituted aryl, optionally substituted
heteroaryl or optionally substituted heteroaralkyl; R.sup.2 is
C.sub.1-10 alkylene; and Y is optionally substituted aryl,
optionally substituted heteroaryl, or a moiety of the formula
--C(.dbd.O)-X.sup.1, wherein X.sup.1 is --OR.sup.3 or
--NR.sup.4R.sup.5, where each of R.sup.3, R.sup.4 and R.sup.5 is H
or C.sub.1-10 alkyl. The present invention also provides a method
for using compound of Formula I to treat a wide variety of clinical
conditions.
Inventors: |
Vardanyan; Ruben S.;
(Tucson, AZ) ; Hruby; Victor J.; (Tucson,
AZ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIVERSITY OF
ARIZONA |
Tucson |
AZ |
US |
|
|
Assignee: |
ARIZONA BOARD OF REGENTS ON BEHALF
OF THE UNIVERSITY OF ARIZONA
Tucson
AZ
|
Family ID: |
55347719 |
Appl. No.: |
15/709394 |
Filed: |
September 19, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14834185 |
Aug 24, 2015 |
9765027 |
|
|
15709394 |
|
|
|
|
62040886 |
Aug 22, 2014 |
|
|
|
Current U.S.
Class: |
514/315 |
Current CPC
Class: |
C07D 407/12 20130101;
C07D 409/12 20130101; A61K 31/16 20130101; C07D 409/06 20130101;
A61K 31/4465 20130101; C07D 211/58 20130101; C07D 405/12 20130101;
A61K 31/451 20130101; A61P 25/00 20180101; A61K 31/4468
20130101 |
International
Class: |
A61K 31/4465 20060101
A61K031/4465; A61K 31/451 20060101 A61K031/451; A61K 31/16 20060101
A61K031/16 |
Goverment Interests
STATEMENT REGARDING FEDERALLY FUNDED RESEARCH
[0002] This invention was made with government support under grant
number R01 DK017420, R01 GM108040 and P01 DA006284 awarded by the
National Institutes of Health. The government has certain rights in
the invention.
Claims
1. A compound of the formula: ##STR00008## wherein ring Z is a 5-,
6- or 7-membered ring; R.sup.1 is C.sub.1-10 alkyl, C.sub.1-10
haloalkyl, optionally substituted aralkyl, optionally substituted
aryl, optionally substituted heteroaryl or optionally substituted
heteroaralkyl; R.sup.2 is C.sub.1-10 alkylene; and Y is optionally
substituted aryl, optionally substituted heteroaryl, or a moiety of
the formula --C(.dbd.O)-X.sup.1, wherein X.sup.1 is --OR.sup.3 or
--NR.sup.4R.sup.5, where each of R.sup.3, R.sup.4 and R.sup.5 is H
or C.sub.1-10 alkyl.
2. The compound according to claim 1, wherein R.sup.1 is selected
from the group consisting of ethyl, 7-bromoheptyl, optionally
substituted fur-2-yl, optionally substituted fur-3-yl, optionally
substituted thiophen-2-yl, optionally substituted thiophen-3-yl,
and optionally substituted phenyl.
3. The compound according to claim 2, wherein R.sup.1 is optionally
substituted fur-2-yl, optionally substituted fur-3-yl, optionally
substituted thiophen-2-yl, optionally substituted thiophen-3-yl or
optionally substituted phenyl.
4. The compound according to claim 1, wherein R.sup.2 is
C.sub.1-C.sub.4 alkylene.
5. The compound according to claim 1, wherein Y is selected from
the group consisting of optionally substituted phenyl, optionally
substituted thiophen-2-yl, optionally substituted thiophen-3-yl,
optionally substituted fur-2-yl, optionally substituted fur-3-yl, a
moiety of the formula --C(.dbd.O)--OR.sup.3, where R.sup.3 is
C.sub.1-C.sub.10 alkyl, and a moiety of the formula
--C(.dbd.O)NR.sup.aR.sup.b, where each of R.sup.a and R.sup.b is
independently H or C.sub.1-C.sub.10 alkyl.
6. The compound according to claim 5, wherein Y is optionally
substituted phenyl, optionally substituted thiophen-2-yl,
optionally substituted thiophen-3-yl, optionally substituted
fur-2-yl or optionally substituted fur-3-yl.
7. The compound according to claim 1 of the formula: ##STR00009##
wherein R.sup.1, R.sup.2 and Y are those defined in claim 1.
8. The compound according to claim 1 of the formula: ##STR00010##
wherein R.sup.1, R.sup.2 and Y are those defined in claim 1.
9. A method for treating hemorrhagic shock, nicotine withdrawal
symptoms, gastrointestinal side effects of opioids, cancer therapy,
epithelial wounds, herpes zoster infection, or opioid-induced
pruritus in a subject, said method comprising administering a
therapeutically effective amount of a compound of claim 1.
10. A method for treating a subject suffering from Raynaud's
disease, hypertension, scleroderma, anxiety and panic disorders, or
dyskinesia associated with Parkinson's disease, said method
comprising administering a therapeutically effective amount of a
compound of claim 1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is continuation-in-part of U.S. patent
application Ser. No. 14/834,185, filed Aug. 24, 2015, which claims
the priority benefit of U.S. Provisional Application No.
62/040,886, filed Aug. 22, 2014, all of which are incorporated
herein by reference in its entirety.
FIELD OF THE INVENTION
[0003] The invention relates to novel pharmacological compounds,
and more specifically to the creation of a new class of small
molecules which simultaneously exhibit high binding affinities to
the .mu.-, .delta.-, and .kappa.-opioid receptors and the
.alpha..sub.2-adrenoreceptor. The binding activity is believed to
be antagonistic at least with respect to the .mu.-opioid receptors.
In addition to providing these compounds with novel pharmacological
binding properties, the invention also describes detailed novel
methods for the preparation of representative compounds and a
scheme for the synthesis of related compounds that bind to the
opioid receptors and/or .alpha..sub.2-adrenoreceptor.
BACKGROUND OF THE INVENTION
[0004] Opioid antagonists are drugs which bind to the opioid
receptors with higher affinity than opioid agonists but do not
activate the opioid receptors. Commonly known opioid antagonists
include drugs such as, for example, naltrexone, naloxone,
nelmefene, nalorphine, and nalbuphine. Opioid antagonists
effectively block the receptor from the action of both naturally
occurring agonists (e.g., morphine, codeine, thebaine) and
synthetic agonists (e.g., fentanyl, pethidine, levorphanol,
methadone, tramadol, dextropropoxyphene) and uses include
counteracting life-threatening depression of the central nervous
and respiratory systems and thus are used for emergency overdose
and dependence treatment (e.g., naloxone). There are many excellent
reviews dedicated to different aspects of opioid antagonists
[28-46].
[0005] Opioid receptor antagonists are known to modulate numerous
central and peripheral effects including those associated with
opioid abuse, the development of opioid tolerance and dependence,
opioid-induced constipation, alcohol and cocaine abuse, depression,
and immune responses. The diverse therapeutic applications of
.mu.-opioid antagonists include opioid-overdose-induced respiratory
depression, opioid and cocaine abuse, alcohol dependence, smoking
cessation, obesity, psychosis and for the treatment of dyskinesia
associated with Parkinson's disease.
[0006] The few opioid antagonists currently on the market are
represented by very few drugs (e.g., naloxone, naltrexone, and
nalorphine (a partial agonist)) that have been shown to have
therapeutic utility in a variety of indications. During last two
decades only Alvimopan--a peripherally acting .mu.-opioid
antagonist for the treatment of postoperative ileus--has received
approval as new drug. In addition, some azabicyclohexane
derivatives and series of bi(hetero)aryl ethers as biological tools
have been proposed as new chemical entities in this class of
compounds.
[0007] Every chemical class of compounds with opioid-agonist
activity has a structurally similar opioid-antagonist pair.
Agonist-antagonist transformation in any of these cases takes place
as a result of a small change in the structure of the agonist. The
only exceptions, where the corresponding change for
agonist-antagonist transformations has not been found, are the
compounds of the fentanyl series.
[0008] Since the discovery of the "army" of opioid agonists of the
fentanyl series (sufentanyl, alfentanyl, carfentanyl, remifentanyl,
etc.) beginning in the 1960s, a structurally corresponding
antagonist has not been found for any of these compounds. Thus, for
decades there has been an evident gap in the art with respect to a
possible specific structural change that could make possible the
transformation of powerful opioid agonist properties of compounds
of fentanyl series into powerful antagonists.
[0009] Similar to the general action of the opioid antagonists,
antagonists of the adrenoreceptors (adrenergic receptors) bind to
the adrenoreceptors and act to inhibit the action of those
receptors. Alpha antagonists, or alpha-blockers, may selectively
act at the .alpha..sub.1-adrenoreceptors or at the
.alpha..sub.2-adrenoreceptors, or they may non-selectively act at
both receptors. Commonly known .alpha.-blockers include, for
example, phenoxybenzamine and phentolamine (non-selective);
alfuzosin and prazosin (.alpha..sub.1-blockers); and atipamezole,
idazoxan, mirtazapine and yohimbine (.alpha..sub.2-blockers).
Generally, .alpha.-blockers have shown to be effective in the
treatment of various medical conditions, including Raynaud's
disease, hypertension, scleroderma, anxiety and panic disorders,
and in the treatment of dyskinesia associated with Parkinson's
disease.
SUMMARY OF THE INVENTION
[0010] The present invention provides a compound of the
formula:
##STR00002## [0011] where [0012] ring Z is a 5-, 6- or 7-membered
ring; [0013] R.sup.1 is C.sub.1-10 alkyl, C.sub.1-10 haloalkyl,
optionally substituted aralkyl, optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heteroaralkyl; [0014] R.sup.2 is C.sub.1-10 alkylene; and [0015] Y
is optionally substituted aryl, optionally substituted heteroaryl,
or a moiety of the formula --C(.dbd.O)-X.sup.1, wherein X.sup.1 is
--OR.sup.3 or --NR.sup.4R.sup.5, where each of R.sup.3, R.sup.4 and
R.sup.5 is H or C.sub.1-10 alkyl.
[0016] In some embodiments, compounds of the invention are of the
formula:
##STR00003##
where R.sup.1, R.sup.2 and Y are those defined herein.
[0017] The present invention also provides a method for treating a
subject suffering from a wide variety of clinical conditions by
administering a therapeutically effective amount of a compound of
the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0018] Definitions: Unless the context requires otherwise, the
following definitions are used.
[0019] "Alkyl" refers to a saturated linear monovalent hydrocarbon
moiety or a saturated branched monovalent hydrocarbon moiety.
Exemplary alkyl group include, but are not limited to, methyl,
ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, and the like.
[0020] "Alkylene" refers to a saturated linear saturated divalent
hydrocarbon moiety or a branched saturated divalent hydrocarbon
moiety. Exemplary alkylene groups include, but are not limited to,
methylene, ethylene, propylene, butylene, iso-butylene, pentylene,
and the like.
[0021] "Aryl" refers to a monovalent mono-, bi- or tricyclic
aromatic hydrocarbon moiety of 6 to 15 ring atoms which is
optionally substituted with one or more substituents. More
specifically the term aryl includes, but is not limited to, phenyl,
1-naphthyl, and 2-naphthyl, and the derivatives thereof. When
substituted, the aryl group typically contains one, two or three
substituents within the ring structure. Moreover, when two or more
substituents are present in an aryl group, each substituent is
independently selected. Exemplary substituents for the aryl group
include, but are not limited to, alkyl, haloalkyl, heteroalkyl,
halo, nitro, cyano, optionally substituted phenyl, heteroaryl,
haloalkoxy, --OR' (where R' is H, alkyl or a phenol protecting
group) and carboxyl (i.e., a moiety of the formula --COX, where X
is --OR.sup.a or --NR.sup.bR.sup.c, where each of R.sup.a, R.sup.b,
R.sup.c is independently H, alkyl, or a corresponding protecting
group.
[0022] "Aralkyl" refers to a moiety of the formula --R.sup.bR.sup.c
where R.sup.b is an alkylene group and R.sup.c is an optionally
substituted aryl group as defined herein. Exemplary aralkyl groups
include, but are not limited to, benzyl, phenylethyl,
(halo-substituted phenyl)ethyl, and the like.
[0023] The terms "halo," "halogen" and "halide" are used
interchangeably herein and refer to fluoro, chloro, bromo, or
iodo.
[0024] "Haloalkyl" refers to an alkyl group as defined herein in
which one or more hydrogen atom is replaced by same or different
halo atoms. The term "haloalkyl" also includes perhalogenated alkyl
groups in which all alkyl hydrogen atoms are replaced by halogen
atoms. Exemplary haloalkyl groups include, but are not limited to,
--CH.sub.2Cl, --CF.sub.3, --CH.sub.2CF.sub.3, --CH.sub.2CCl.sub.3,
and the like.
[0025] The term "heteroaryl" means a monovalent monocyclic or
bicyclic aromatic moiety of 5 to 12 ring atoms containing one, two,
or three ring heteroatoms selected from N, O, or S, the remaining
ring atoms being C. Exemplary heteroaryl includes, but is not
limited to, pyridyl, furanyl, thiophenyl, thiazolyl, isothiazolyl,
triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl,
pyrimidinyl, benzofuranyl, isobenzofuranyl, benzothiazolyl,
benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl,
benzoxazolyl, quinolyl, isoquinolyl, benzimidazolyl,
benzisoxazolyl, benzothiophenyl, dibenzofuran, and
benzodiazepin-2-one-5-yl, and the like. The heteroaryl ring can
optionally be substituted with one or more substituents, typically
one or two substituents. When two or more substituents are present
in heteroaryl, each substituent is independently selected.
Exemplary substituents for heteroaryl include, but are not limited
to, substituents described for aryl group above.
[0026] "Pharmaceutically acceptable excipient" refers to an
excipient that is useful in preparing a pharmaceutical composition
that is generally safe, non-toxic and neither biologically nor
otherwise undesirable, and includes excipient that is acceptable
for veterinary use as well as human pharmaceutical use.
[0027] "Pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. Such salts
include: (1) acid addition salts, formed with inorganic acids such
as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic
acid, glycolic acid, pyruvic acid, lactic acid, malonic acid,
succinic acid, malic acid, maleic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
acid, 4-methylbicyclo[2,2,2]-oct-2-ene-1carboxylic acid,
glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid,
tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid,
glutamic acid, hydroxynaphthoic acid, oxalic acid, salicylic acid,
stearic acid, muconic acid, and the like; or (2) salts formed when
an acidic proton present in the parent compound either is replaced
by a metal ion, e.g., an alkali metal ion, an alkaline earth ion,
or an aluminum ion; or coordinates with an organic base such as
ethanolamine, diethanolamine, triethanolamine, tromethamine,
N-methylglucamine, and the like.
[0028] The terms "pro-drug" and "prodrug" are used interchangeably
herein and refer to any compound which releases an active parent
drug according to Formula I in vivo when such prodrug is
administered to a mammalian subject. Prodrugs of a compound of
Formula I are prepared by modifying one or more functional group(s)
present in the compound of Formula I in such a way that the
modification(s) may be cleaved in vivo to release the parent
compound. Prodrugs include compounds of Formula I wherein a
hydroxy, amino, or sulfhydryl group in a compound of Formula I is
bonded to any group that may be cleaved in vivo to regenerate the
free hydroxyl, amino, or sulfhydryl group, respectively. Examples
of prodrugs include, but are not limited to, esters (e.g., acetate,
formate, and benzoate derivatives), carbamates (e.g.,
N,N-dimethylaminocarbonyl) of hydroxy functional groups in
compounds of Formula I, and the like.
[0029] "Protecting group" refers to a moiety, except alkyl groups,
that when attached to a reactive group in a molecule masks, reduces
or prevents that reactivity. Examples of protecting groups can be
found in T. W. Greene and P. G. M. Wuts, Protective Groups in
Organic Synthesis, 3.sup.rd edition, John Wiley & Sons, New
York, 1999, and Harrison and Harrison et al., Compendium of
Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons,
1971-1996), which are incorporated herein by reference in their
entirety. Representative hydroxy protecting groups include acyl
groups, benzyl and trityl ethers, tetrahydropyranyl ethers,
trialkylsilyl ethers and allyl ethers. Representative amino
protecting groups include, formyl, acetyl, trifluoroacetyl, benzyl,
benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl
(TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and
substituted trityl groups, allyloxycarbonyl,
9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl
(NVOC), and the like.
[0030] "Corresponding protecting group" means an appropriate
protecting group corresponding to the heteroatom (i.e., N, O, P or
S) to which it is attached.
[0031] "A therapeutically effective amount" means the amount of a
compound that, when administered to a mammal for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, etc.,
of the mammal to be treated.
[0032] "Treating" or "treatment" of a disease includes: (1)
preventing the disease, i.e., causing the clinical symptoms of the
disease not to develop in a mammal that may be exposed to or
predisposed to the disease but does not yet experience or display
symptoms of the disease; (2) inhibiting the disease, i.e.,
arresting or reducing the development of the disease or its
clinical symptoms; or (3) relieving the disease, i.e., causing
regression of the disease or its clinical symptoms.
[0033] As used herein, the term "treating", "contacting" or
"reacting" refers to adding or mixing two or more reagents under
appropriate conditions to produce the indicated and/or the desired
product. It should be appreciated that the reaction which produces
the indicated and/or the desired product may not necessarily result
directly from the combination of two reagents which were initially
added, i.e., there may be one or more intermediates which are
produced in the mixture which ultimately leads to the formation of
the indicated and/or the desired product.
[0034] As used herein, the terms "those defined above" and "those
defined herein" when referring to a variable incorporates by
reference the broad definition of the variable as well as narrower
definitions, if any.
[0035] Compounds of the Invention: One aspect of the invention
provides compounds that can simultaneously bind with high affinity
to opioid .mu.-, .delta.-, .kappa.-receptors and also to
.alpha.-adrenoreceptors, thereby exhibiting modulation-type
interactions with those receptors. The interaction of the molecules
with .mu.-receptors is believed to have the character of antagonist
action, based at least in part on the observed high affinity
binding of the molecules with respect to the m-receptors.
[0036] Without being bound by any theory, it is believed that the
principal structural change for agonist-antagonist transformation
is the removal of a phenyl group from an N-phenylpropionamide
moiety of fentanyl as illustrated below, where
N-(1-phenethylpiperidin-4-yl)-N-phenylpropionamide (A) is
transformed to N-(1-phenethylpiperidin-4-yl)-N-propionamide (B).
The present inventors have found that while compound (A) exhibits
.mu.-agonist property, compound (B), which lacks the phenyl moiety
on the amide nitrogen, exhibits .mu.-antagonist property in some
instances with simultaneous modulation of delta-, kappa- and
alpha-receptors:
##STR00004##
[0037] Accordingly, some aspects of the invention provide
N-substituted piperidin-4-yl compounds of Formula I:
##STR00005##
where the phenyl group on the amide nitrogen of has been replaced
with hydrogen. With regards to Compound of Formula I, in some
embodiments Z is a 5-, 6- or 7-membered ring, typically
unsbustituted; R.sup.1 is C.sub.1-10 alkyl, C.sub.1-10 haloalkyl,
optionally substituted aralkyl, optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heteroaralkyl; R.sup.2 is C.sub.1-6 alkylene; Y is optionally
substituted aryl, optionally substituted heteroaryl, or a moiety of
the formula --C(.dbd.O)-X.sup.1, wherein X.sup.1 is --OR.sup.3 or
--NR.sup.4R.sup.5, where each of R.sup.3, R.sup.4 and R.sup.5 is H
or C.sub.1-10 alkyl. In some aspects of the invention, when R.sup.1
is optionally substituted aryl, then Y is a substituted heteroaryl,
or a moiety of the formula --C(.dbd.O)-X.sup.1. Still in another
aspect of the invention, when Y is heteroaryl or aryl, then R.sup.1
is C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, or optionally
substituted heteroaryl.
[0038] In some embodiments, compounds of the invention include
compounds of the formulas:
##STR00006##
where R.sup.1, R.sup.2 and Y are those defined herein.
[0039] Yet still in another aspect of the invention, compounds of
invention are those of Formula I as broadly disclosed above
provided when Y is heteroaryl, R.sup.1 is not optionally
substituted phenyl, in particular R.sup.1 is not phenyl.
[0040] Still in another aspect of the invention, compounds of
invention are those of Formula I as broadly disclosed above
provided when Y is phenyl, R.sup.1 is not substituted phenyl.
[0041] In some embodiments, R.sup.1 is selected from the group
consisting of C.sub.1-8 alkyl, C.sub.1-8 haloalkyl, optionally
substituted phenyl, and optionally substituted furyl. In some
instances, R1 is selected from the group consisting of ethyl,
7-bromoheptyl, fur-2-yl, fur-3-yl, and phenyl.
[0042] Yet in other embodiments, R.sup.2 is C.sub.1-4 alkylene. In
one particular embodiment, R.sup.2 is ethylene.
[0043] Still in other embodiments, Y is selected from the group
consisting of optionally substituted phenyl, optionally substituted
furyl, optionally substituted thiophenyl and a moiety of the
formula --C(.dbd.O)-X.sup.1, where X.sup.1 is those defined herein.
Within these embodiments, in some instances Y is selected from the
group consisting of phenyl, thiophenyl (typically thiophen-2-yl),
and a moiety of the formula --C(.dbd.O)--OR.sup.3, where R.sup.3 is
C.sub.1-10 alkyl.
[0044] Still further, combinations of the various embodiments of
different variables described herein form other embodiments. For
example, in one particularly preferred embodiment R.sup.1 is ethyl,
R.sup.2 is ethylene, Y is phenyl. In this manner, a variety of
specific compounds are embodied within the present invention
including, but not limited to,
N-(1-phenethylpiperidin-4-yl)propionamide ("HCV-3"), methyl
3-(4-propionamidopiperidin-1-yl)propanoate,
N-(1-phenethylpiperidin-4-yl)furan-2-carboxamide,
N-(1-phenethylpiperidin-4-yl)furan-3-carboxamide,
N-(1-(2-(thiophen-2-yl)ethyl)piperidin-4-yl)propionamide,
8-bromo-N-(1-phenethylpiperidin-4-yl)octanamide, and
N-(1-phenethylpiperidin-4-yl)benzamide.
[0045] Synthesis: Compound of the invention can be readily prepared
by one skilled in the art having read the present disclosure. It
should be appreciated that although the following schemes for
producing compounds of Formula I often indicate exact structures,
methods of the present invention apply widely to analogous
compounds of Formula I, given an appropriate consideration to
protection and deprotection of reactive functional groups by
methods standard to the art of organic chemistry. For example,
hydroxyl groups, in order to prevent unwanted side reactions,
sometimes need to be converted to ethers or esters during chemical
reactions at other sites in the molecule. The hydroxyl protecting
group is then removed to provide the free hydroxyl group.
Similarly, amino groups and carboxylic acid groups can be
derivatized to protect them against unwanted side reactions.
Typical protecting groups, and methods for attaching and cleaving
them, are described fully in the above incorporated references by
T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3.sup.rd edition, John Wiley & Sons, New York, 1999,
and Harrison and Harrison et al., Compendium of Synthetic Organic
Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996).
[0046] One particular method of producing compounds of the
invention is illustrated in Scheme I below:
##STR00007##
[0047] Briefly, compound I-1 is reduced to alcohol, via Reformatsky
reaction or a simple reduction using, for example, a reducing agent
such as NaBH.sub.4, NaB(CN)H.sub.3, LiAlH.sub.4, etc. Compound I-2
is then subject to a Ritter type reaction (using R.sup.1-CN
compound in the presence of a strong base, such as sulfuric acid)
to produce compound I-3. Alternatively, compound I-2 can be
subjected to a substitution reaction (e.g., an S.sub.N1 or
S.sub.N2-type reaction by converting the hydroxyl group into a
leaving group and displacing with an amine group. The amine group
can then be acylated to produce compound I-3. A wide variety of
acylating agent can be used to acylate the amine compound.
Exemplary acylating agents include, acetic anhydride, acetyl
chloride, butyric anhydride, 2-furoyl chloride, methoxy 2-furoyl
chloride, chloro 2-furoyl chloride, fluoro 2-furoyl chloride,
3-furoyl chloride, methoxy 3-furoyl chloride, chloro 3-furoyl
chloride, fluoro 3-furoyl chloride, 2-thiophenoyl chloride, methoxy
2-thiophenoyl chloride, chloro 3-thiophenoyl chloride,
3-thiophenoyl chloride, methoxy 3-thiophenoyl chloride, chloro
3-thiophenoyl chloride, fluoro 3-thiophenoyl chloride, benzoyl
chloride, methoxy benzoyl chloride, chloro benzoyl chloride, fluoro
benzoyl chloride, trifluoromethyl benzoyl chloride, as well as
Cl--C(.dbd.O)--(CH.sub.2)n-Ar, where n is 1-10 and Ar is optionally
substituted phenyl, including but not limited to, phenyl, methoxy
phenyl, chlorophenyl, trifluoromethylphenyl, etc.
[0048] Compound 1-3 is deprotected to remove the protection group
(PG) and alkylated to yield compound of Formula I. A wide variety
of alkylating agents can be used to introduce the moiety
"-R.sup.2-Y". such alkylating agents include a compound of the
formula X-R.sup.2-Y, where X is a leaving group and R.sup.2 and Y
are those defined herein. Suitable leaving groups include halides,
such as bromide, chloride, or iodide, mesylates (e.g.,
methanesulfonate), tosylate, etc.
[0049] It should also be apparent to those skilled in the art that
the reaction need not be carried out in the sequence outlined in
Scheme I. For example, "-R.sup.2-Y" group can be introduced prior
to introducing "R.sup.1-C(.dbd.O)--NH--" moiety to compound I-1.
Thus, the compounds of the invention can be prepared by a variety
of methods.
[0050] Utility: The compounds of the invention have a variety of
physiological properties. In particular, the present inventors have
discovered that compounds of the invention can modulate a variety
of receptors including, but not limited to, .mu.-, .delta.-, and
.kappa.-opioid receptors and .alpha..sub.2-adrenoreceptor, in
particular .alpha..sub.2B-adrenoreceptor. In particular, the
compounds of the invention are found to be antagonists of these
receptors. Accordingly, any clinical conditions that are due or
associated with at least in part to abnormal activation of one or
more of these receptors can be treated by the compounds of the
invention.
[0051] In some embodiments, compounds of the invention are found to
be opioid antagonists. As such, compounds of the invention bind to
the opioid receptors with higher affinity than opioid agonists but
do not activate the opioid receptors. Thus, compounds of the
invention can be used to effectively block the receptor from the
action of both naturally occurring opioid agonists (e.g., morphine,
codeine, thebaine) and synthetic opioid agonists (e.g., fentanyl,
pethidine, levorphanol, methadone, tramadol, dextropropoxyphene).
Accordingly, compounds of the invention can be used in a variety of
clinical conditions associated with opioid use including, but not
limited to, counteracting life-threatening depression of the
central nervous and respiratory systems. Therefore, compounds of
the invention can be used for emergency overdose and dependence
treatment.
[0052] Compounds of the invention can modulate numerous central and
peripheral effects including those associated with opioid abuse,
the development of opioid tolerance and dependence, opioid-induced
constipation, alcohol and cocaine abuse, depression, and immune
responses. The diverse therapeutic applications of compounds of the
invention include opioid-overdose-induced respiratory depression,
opioid and cocaine abuse, alcohol dependence, smoking cessation,
obesity, psychosis and for the treatment of dyskinesia associated
with Parkinson's disease.
[0053] In another aspect of the invention, the present inventors
have discovered that compounds of the invention are antagonists of
adrenoreceptors. Thus, compounds of the invention bind to the
adrenoreceptors and inhibit the action of these receptors.
.alpha.-Adrenoreceptor antagonists (commonly known as
.alpha.-blockers) may selectively bind to the
.alpha..sub.1-adrenoreceptors or the .alpha..sub.2-adrenoreceptors,
or they may bind non-selectively to both adrenoreceptor types. In
some embodiments, compounds of the invention are found to be
selective .alpha..sub.2B-adrenoreceptor antagonists. As used
herein, the term "selective .alpha..sub.2B-adrenoreceptor
antagonist" means that the ratio of binding to
.alpha..sub.2B-adrenoreceptor compared to other adrenoreceptor is
at great than 1:1, typically, at least about 1.5:1, often at least
about 2:1, more often at least about 5:1, and most often at least
about 10:1. Compounds of the invention can be used to treat various
clinical conditions that are related to or associated with abnormal
activation of adrenoreceptors including, but not limited to,
Raynaud's disease, hypertension, scleroderma, anxiety and panic
disorders, and in the treatment of dyskinesia associated with
Parkinson's disease.
[0054] Utility for compounds of various receptor antagonists are
known. See, for example, Singleton et al., Cancer, 2015, 121(16),
2681-2688 (use of .mu.-opioid receptor antagonists in cancer
treatment); Jackson et al., Neuropharmacology, 2015, 97, 270-274
(use of .kappa.-opioid receptor antagonist for nicotine
withdrawal); Bear et al., U.S. Pat. Appl. Publication No. US
20150202199 A1 (treatments for depression and other diseases using
dopaminergic agents); Noble et al., British Journal of
Pharmacology, 2015, 172(16), 3964-3979 (opioid receptor antagonists
for drug abuse and/or the prevention of relapse treatment);
Brokjaer et al., Neurogastroenterology & Motility, 2015, 27(5),
693-704 (opioid antagonists for treatment of gastrointestinal side
effects such as pain); Labuzek et al., Pharmacological Reports,
2014, 66(5), 811-820 (opioid antagonists for pharmacotherapy for
gambling disorder); Soyka et al., Current Drug Abuse Reviews,
2008,1(3), 280-291 (opioid antagonists for pharmacological
treatment of alcohol dependence); Nutt et al., Psychopharmacology,
(London, United Kingdom), 2014, 28(1), 8-22 (treatment of alcohol
dependence); Tek et al., Journal of Clinical Psychopharmacology,
2014, 34(5), 608-612 (use of opioid antagonists in arresting
antipsychotic-associated weight gain); Shi et al., Guoji Yaoxue
Yanjiu Zazhi, 2013, 40(4), 439-442 (combinations of opioid agonists
and opioid antagonists to treat side effects of opioid agonists and
decrease risk of drug abuse); Wang et al., Expert Opinion on
Investigational Drugs, 2013, 22(10), 1225-1227 (use of opioid
antagonists for treatment of opioid-induced constipation); Taylor
et al., Expert Opinion on Investigational Drugs, 2013, 22(4),
517-525 (use of opioid antagonists as analgesics); Zagon et al.,
PCT patent application publication number WO 2013016480 A1 (use of
opioid antagonists for treatment of epithelial wounds); Pisak et
al., PCT Patent Application Publication No. WO 2012134410 A1 (use
of opioid antagonists for treating scleroderma including systemic
sclerosis); Hopp et al., PCT Patent Application Publication No. WO
2012089738 A1 (use of a combination of opioid agonists and opioid
antagonists for the treatment of Parkinson's disease and associated
symptoms); Tenhola et al., J. Endocrinological Investigation, 2012,
35(2), 227-230 (effect of opioid antagonists on sex hormone
secretion, e.g., using an opioid antagonists to increase the
secretion of GnRH in the hypothalamus which then causes a pulsatile
release of LH in the pituitary and secretion of testosterone);
Miller et al., Amer. J. Health-System Pharmacy, 2011, 68(15),
1419-1425 (use of opioid antagonists for management of
opioid-induced pruritus); Toledano et al., U.S. Pat. Appl. Publ.
No. 20110269727 A1 (using opioid antagonists and direct-acting
.alpha..sub.2-adrenergic agonists to reduce allodynic back pain);
Pisak et al., PCT Patent Application Publication No. WO 2011123084
A1 (using an opioid receptor antagonist to treat herpes zoster
disease); Ockert et al., J. Addiction Med., 2011, 5(2), 110-114
(using an opioid antagonist for outpatient opioid detoxification
and/or the treatment of opioid withdrawal); Moss et al., U.S. Pat.
Appl. Publ. No. 20100286059 A1 (use of opioid antagonists for
inhibiting or reducing, cellular proliferation and migration, such
as endothelial cell proliferation and migration, including that
associated with angiogenesis, as well as attenuating cancerous
tumor growth and metastasis); Zagon et al., U.S. Pat. Appl. Publ.
No. US 20100273821 A1 (using opioid antagonists to treat dry eye);
Lobmaier et al., Eur. J. Clin. Pharm., 2010, 66(6), 537-545 (use of
the opioid antagonists for the treatment of intoxication and
overdose); Stotts et al., Expert Opinion on Pharmacotherapy, 2009,
10(11), 1727-1740 (using opioid antagonists for treating opioid
dependency); Hopp et al., PCT Patent Application Publication No. WO
2010003963 A1 (using opioid antagonists for treating urinary
retention); and Hayward et al., PCT Patent Application Publication
No. WO 2009156889 A1 (using opioid antagonists for treating
obesity, obesity-related co-morbidities, and CNS disorders).
Accordingly, compounds of the invention can be used treat all of
these clinical conditions. In addition, compounds of the invention
can be used in the treatment of various forms of depression and/or
mood disorders, including, for example, breakthrough depression and
treatment-refractory depression, and other mood disorders.
[0055] Some of the more specific exemplary clinical conditions that
can be treated by compounds of the invention include, but are not
limited to, hemorrhagic shock, nicotine withdrawal symptoms,
gastrointestinal side effects of opioids, cancer therapy,
epithelial wounds, herpes zoster infection, and opioid-induced
pruritus.
[0056] Administration and Pharmaceutical Composition: The present
invention includes pharmaceutical compositions comprising at least
one compound of the invention or a pharmaceutically acceptable salt
or solvate thereof, together with at least one pharmaceutically
acceptable carrier, and optionally other therapeutic and/or
prophylactic ingredients.
[0057] In general, the compounds of the invention are administered
in a therapeutically effective amount by any of the accepted modes
of administration for agents that serve similar utilities. Suitable
dosage ranges are typically 1-500 mg daily, typically 1-100 mg
daily, and often 1-30 mg daily, depending on numerous factors such
as the severity of the disease to be treated, the age and relative
health of the subject, the potency of the compound used, the route
and form of administration, the indication towards which the
administration is directed, and the preferences and experience of
the medical practitioner involved. One of ordinary skill in the art
of treating such diseases is typically able, without undue
experimentation and in reliance upon personal knowledge and the
disclosure of this application, to ascertain a therapeutically
effective amount of the compounds of the invention.
[0058] Typically, compounds of the invention are administered as
pharmaceutical formulations including those suitable for oral
(including buccal and sub-lingual), rectal, nasal, topical,
pulmonary, vaginal, or parenteral (including intramuscular,
intraarterial, intrathecal, subcutaneous and intravenous)
administration or in a form suitable for administration by
inhalation or insufflation. Typical manner of administration is
generally oral using a convenient daily dosage regimen which can be
adjusted according to the degree of affliction.
[0059] A compound or compounds of the invention, together with one
or more conventional adjuvants, carriers, or diluents, can be
placed into the form of pharmaceutical compositions and unit
dosages. The pharmaceutical compositions and unit dosage forms can
be comprised of conventional ingredients in conventional
proportions, with or without additional active compounds or
principles, and the unit dosage forms can contain any suitable
effective amount of the active ingredient commensurate with the
intended daily dosage range to be employed. The pharmaceutical
compositions can be employed as solids, such as tablets or filled
capsules, semisolids, powders, sustained release formulations, or
liquids such as solutions, suspensions, emulsions, elixirs, or
filled capsules for oral use; or in the form of suppositories for
rectal or vaginal administration; or in the form of sterile
injectable solutions for parenteral use. Formulations containing
about one (1) milligram of active ingredient or, more broadly,
about 0.01 to about one hundred (100) milligrams, per tablet, are
accordingly suitable representative unit dosage forms.
[0060] The compounds of the invention can be formulated in a wide
variety of oral administration dosage forms. The pharmaceutical
compositions and dosage forms can comprise a compound or compounds
of the invention or pharmaceutically acceptable salts thereof as
the active component. The pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispersible
granules. A solid carrier can be one or more substances which can
also act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, preservatives, tablet disintegrating
agents, or an encapsulating material. In powders, the carrier
generally is a finely divided solid which is a mixture with the
finely divided active component. In tablets, the active component
generally is mixed with the carrier having the necessary binding
capacity in suitable proportions and compacted in the shape and
size desired. The powders and tablets preferably contain from about
one (1) to about seventy (70) percent of the active compound.
Suitable carriers include but are not limited to magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatine, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. The term "preparation" is intended to include the formulation
of the active compound with encapsulating material as carrier,
providing a capsule in which the active component, with or without
carriers, is surrounded by a carrier, which is in association with
it. Similarly, cachets and lozenges are included. Tablets, powders,
capsules, pills, cachets, and lozenges can be as solid forms
suitable for oral administration.
[0061] Other forms suitable for oral administration include liquid
form preparations including emulsions, syrups, elixirs, aqueous
solutions, aqueous suspensions, or solid form preparations which
are intended to be converted shortly before use to liquid form
preparations. Emulsions can be prepared in solutions, for example,
in aqueous propylene glycol solutions or may contain emulsifying
agents, for example, such as lecithin, sorbitan monooleate, or
acacia. Aqueous solutions can be prepared by dissolving the active
component in water and adding suitable colorants, flavors,
stabilizers, and thickening agents. Aqueous suspensions can be
prepared by dispersing the finely divided active component in water
with viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other well
known suspending agents. Solid form preparations include solutions,
suspensions, and emulsions, and can contain, in addition to the
active component, colorants, flavors, stabilizers, buffers,
artificial and natural sweeteners, dispersants, thickeners,
solubilizing agents, and the like.
[0062] The compounds of the invention can also be formulated for
parenteral administration (e.g., by injection, for example bolus
injection or continuous infusion) and can be presented in unit dose
form in ampoules, pre-filled syringes, small volume infusion or in
multi-dose containers with an added preservative. The compositions
can take such forms as suspensions, solutions, or emulsions in oily
or aqueous vehicles, for example solutions in aqueous polyethylene
glycol. Examples of oily or nonaqueous carriers, diluents, solvents
or vehicles include propylene glycol, polyethylene glycol,
vegetable oils (e.g., olive oil), and injectable organic esters
(e.g., ethyl oleate), and can contain formulatory agents such as
preserving, wetting, emulsifying or suspending, stabilizing and/or
dispersing agents. Alternatively, the active ingredient can be in
powder form, obtained by aseptic isolation of sterile solid or by
lyophilization from solution for constitution before use with a
suitable vehicle, e.g., sterile, pyrogen-free water.
[0063] The compounds of the invention can be formulated for topical
administration to the epidermis as ointments, creams or lotions, or
as a transdermal patch. Ointments and creams can, for example, be
formulated with an aqueous or oily base with the addition of
suitable thickening and/or gelling agents. Lotions can be
formulated with an aqueous or oily base and will in general also
contain one or more emulsifying agents, stabilizing agents,
dispersing agents, suspending agents, thickening agents, or
coloring agents. Formulations suitable for topical administration
in the mouth include lozenges comprising active agents in a
flavored base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert base such as gelatine
and glycerine or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0064] The compounds of the invention can be formulated for
administration as suppositories. A low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter is first melted
and the active component is dispersed homogeneously, for example,
by stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool, and to solidify.
[0065] The compounds of the invention can also be formulated for
vaginal administration. Pessaries, tampons, creams, gels, pastes,
foams or sprays containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0066] The compounds of the invention can be formulated for nasal
administration. The solutions or suspensions are applied directly
to the nasal cavity by conventional means, for example, with a
dropper, pipette or spray. The formulations can be provided in a
single or multidose form. In the latter case of a dropper or
pipette, this can be achieved by the patient administering an
appropriate, predetermined volume of the solution or suspension. In
the case of a spray, this can be achieved for example by means of a
metering atomizing spray pump.
[0067] The compounds of the invention can be formulated for aerosol
administration, particularly to the respiratory tract and including
intranasal administration. The compound will generally have a small
particle size for example of the order of five (5) microns or less.
Such a particle size can be obtained by means known in the art, for
example by micronization. The active ingredient is provided in a
pressurized pack with a suitable propellant such as a
chlorofluorocarbon (CFC), for example, dichlorodifluoromethane,
trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon
dioxide or other suitable gas. The aerosol can conveniently also
contain a surfactant such as lecithin. The dose of drug can be
controlled by a metered valve. Alternatively the active ingredients
can be provided in a form of a dry powder, for example, a powder
mix of the compound in a suitable powder base such as lactose,
starch, starch derivatives such as hydroxypropylmethyl cellulose
and polyvinylpyrrolidine (PVP). The powder carrier typically forms
a gel in the nasal cavity. The powder composition can be presented
in unit dose form, for example, in capsules or cartridges of e.g.,
gelatine or blister packs from which the powder can be administered
by means of an inhaler.
[0068] When desired, formulations can be prepared with enteric
coatings adapted for sustained or controlled release administration
of the active ingredient. For example, the compounds of the
invention can be formulated in transdermal or subcutaneous drug
delivery devices. These delivery systems are advantageous when
sustained release of the compound is necessary or desired and when
patient compliance with a treatment regimen is crucial. Compounds
in transdermal delivery systems are frequently attached to a
skin-adhesive solid support. The compound of interest can also be
combined with a penetration enhancer, e.g., Azone
(1-dodecylazacycloheptan-2-one). Sustained release delivery systems
can be inserted subcutaneously into the subdermal layer by surgery
or injection. The subdermal implants encapsulate the compound in a
lipid soluble membrane, e.g., silicone rubber, or a biodegradable
polymer, e.g., polylactic acid.
[0069] The pharmaceutical preparations are typically in unit dosage
forms. In such form, the preparation is often subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packeted
tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0070] Other suitable pharmaceutical carriers and their
formulations are described in Remington: The Science and Practice
of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company,
19th edition, Easton, Pa.
[0071] When it is possible that, for use in therapy,
therapeutically effective amounts of a compound of Formula I, as
well as pharmaceutically acceptable salts thereof, can be
administered as the raw chemical, it is possible to present the
active ingredient as a pharmaceutical composition. Accordingly, the
disclosure further provides pharmaceutical compositions, which
include therapeutically effective mounts of compounds of Formula I
or pharmaceutically acceptable salts thereof or a prodrug thereof,
and one or more pharmaceutically acceptable carriers, diluents, or
excipients. When applied to a combination, the term refers to
combined amounts of the active ingredients that result in the
therapeutic effect, whether administered in combination, serially,
or simultaneously. The compounds of Formula I and pharmaceutically
acceptable salts thereof, are as described above. The carrier(s),
diluent(s), or excipient(s) must be acceptable in the sense of
being compatible with the other ingredients of the formulation and
not deleterious to the recipient thereof. In accordance with
another aspect of the disclosure there is also provided a process
for the preparation of a pharmaceutical formulation including
admixing a compound of Formula I, or a pharmaceutically acceptable
salt thereof or a prodrug thereof, with one or more
pharmaceutically acceptable carriers, diluents, or excipients.
[0072] When the compositions of this disclosure comprise a
combination of a compound of the present disclosure and one or more
additional therapeutic or prophylactic agent, both the compound and
the additional agent are usually present at dosage levels of
between about 10 to 150%, and more typically between about 10 and
80% of the dosage normally administered in a monotherapy
regimen.
[0073] Additional objects, advantages, and novel features of this
invention will become apparent to those skilled in the art upon
examination of the following examples thereof, which are not
intended to be limiting. In the Examples, procedures that are
constructively reduced to practice are described in the present
tense, and procedures that have been carried out in the laboratory
are set forth in the past tense.
EXAMPLES
[0074] 1-Phenethylpiperidin-4-one oxime (Compound V):
1-Phenethylpiperidin-4-one (10.15 g (0.05 mol) dissolved in 60 mL
of ethanol) was added drop-wise at 0.degree. C. to a solution of
hydroxylamine in water. The water solution of hydroxylamine was
preliminarily prepared by adding at 0.degree. C. in portions 13.8 g
(0.1 mol) of K.sub.2CO.sub.3 to the solution of 6.95 g (0.1 mol)
hydroxylamine hydrochloride in 50 mL of water. The mixture was set
aside for a night. Ethanol was evaporated under slight vacuum.
Water (.about.100 mL) was added, and the mixture was stirred on ice
bath for an hour. The separated solid product was filtered, washed
with water and allowed to air-dry. The crude oxime (10.71 g
(98.25%), m.p. 132-134.degree. C.) was reserved for use in the next
reaction without further purification. Analysis with electrospray
ionization mass spectrometry (MS (ESI)) resulted in a peak at 219.1
(MH+).
[0075] 1-Phenethylpiperidin-4-amine (Compound VI):
1-Phenethylpiperidin-4-one oxime (6.54 g (0.03 mol)) was dissolved
in 100 mL of dry i-AmOH on heating. A ten-fold excess of sodium
(6.9 g (0.3 mol)) was slowly (1 hour) added to the stirred solution
in small pieces, while the temperature was maintained around
110.degree.. The solution was stirred on heating at 110.degree. for
two hours and left to cool to room temperature. 150 mL of ether,
followed by 75 mL of water, was then added to the solution. The
organic layer was separated and dried on MgSO.sub.4. After
evaporation of solvents under slight vacuum, the product was
distilled to give 4.3 g (70%) of 1-phenethylpiperidin-4-amine (VI)
with a boiling point of 138-142.degree./1.5 mm. MS (ESI): 205.0
(MH+).
[0076] N-(1-Phenethylpiperidin-4-yl)propionamide (Compound I):
Propionyl chloride (2.775 g (0.03 mol)) in 5.55 mL of CHCl.sub.3
was added drop-wise on stirring to the cooled (0.degree. C.)
solution of 4.08 g (0.02 mol) 1-phenethylpiperidin-4-amine and 3.03
g (0.03 mol) of Et.sub.3N in 30 mL of CHCl.sub.3. The mixture was
left to come to room temperature and stirred overnight. After
working up with 5% solution of NaHCO.sub.3 (2.52 g (0.03 mol)) in
47.88 H.sub.2O, the organic layer was separated, washed with water
and dried on MgSO.sub.4. After evaporation of solvents under slight
vacuum, the residue was crystallized from hexane to give 4.9 g
(94%) of N-(1-phenethylpiperidin-4-yl)propionamide (I) with m.p.
134-135.degree.. MS (ESI): 261.2 (MH+). .sup.1H NMR (600 MHz,
CDCl.sub.3): .delta. 7.27 (t, J=7.4 Hz, 2H), 7.19 (m, 3H), 5.32 (d,
J=7.4 Hz, 1H), 3.82 (qt, J=7.8, 4.2 Hz, 1H), 2.92 (dt, J=11.8, 3.4
Hz, 2H), 2.79 (m*, 2H), 2.59 (m*, 2H), 2.19 (q, J=7.5 Hz, 2H), 2.18
(m, 2H), 1.95 (dtd, J=12.4, 4.4, 1.7 Hz, 2H), 1.46 (qd, J=11.7, 3.8
Hz, 2H), 1.15 (t, J=7.5 Hz, 3H). .sup.13C NMR (150 MHz,
CDCl.sub.3): .delta. 173.0, 140.2, 128.6, 128.4, 126.0, 60.4, 52.3,
46.3, 33.7, 32.3, 29.8, 9.9.
[0077] N-(1-Phenethylpiperidin-4-yl)propionamide oxalate (Compound
VII): Oxalic acid (1 g (0.011 mol)) in 10 mL of ethanol was added
drop-wise to the solution of 2.93 g (0.011 mol) of
N-(1-phenethylpiperidin-4-yl)propionamide (I) in 29.3 mL of
ethanol. The mixture was set aside overnight. The obtained crystals
were then separated and dried in a desiccator over P.sub.2O.sub.5
to give 3.5 g of N-(1-phenethylpiperidin-4-yl)propionamide oxalate
(VII) with m.p. 216-218 (MS (ESI): 261.2 ([M+H]).
[0078] The compound designated as HCV-3 was then subject to
cellular functional assay and results reported below:
Cellular functional assays
TABLE-US-00001 Catalog Ref Reference Experimental Client Com
Compound Test Conce % of EC.sub.50 Assay Batch Contro % of Agonist
Response 1.sup.st 2.sup.nd Mean Ref(M) 27/07/201 .alpha. HCV-3 1
1000233221.0E-05 7.1 9.2 5.1 7.1 dexmedetc 2B(h1813 1.3E-08
27/07/201 .kappa. HCV-3 1 1000233221.0E-05 -4.2 -10.3 1.8 -4.2 U
50488 (KO 2071 1.6E-09 27/07/201 .mu. HCV-3 1 1000233221.0E-05 33.5
28.1 38.9 33.5 DAMGO (MOP) 1392 4.2E-09
Cellular functional assays
TABLE-US-00002 Catalog Ref Compound Test Conce % Reference
Experimental Client Com Inhibition Agonist Response IC50Ref(N Assay
Batch (% of Control) 1.sup.st 2.sup.nd Mean KbRef(M) 27/07/201
HCV-3 1 1000233221.0E-05 -28 116.8 138.7 127.8 yohimine
.alpha.2B(h1814 3.7E-07 4.8E-08 27/07/201 .kappa. HCV-3 1
1000233221.0E-05 6 112.4 76.5 94.4 nor-BNI (KO 2072 4.3E-10 7.2E-11
27/07/201 .mu. HCV-3 1 1000233221.0E-05 -1 100.1 101.8 101.0 CTOP
(MOP) 1393 2.1E-07 2.3E-08
[0079] Compound HCV-3 also was tested for hERG inhibition. Over the
concentration range tested (up to 25 micromolar) no dose-response
was obtained. Therefore the inhibition IC.sub.50 was considered as
>25 micromolar. There was a hint of some inhibition at the top
concentration of 25 micromolar, with 32.5% inhibition observed
(insufficient to generate an IC.sub.50 value). As such, this
compound is categorised as having weak or no hERG inhibition. The
control compounds behaved as expected in the assay.
[0080] Compound HCV-3 also was tested for CYP inhibition, and was
found to inhibit CYP2D6, and to weakly inhibit CYP2C19. However,
with CYP2C19 the inhibition was too weak to generate an IC.sub.50
value, and we observed just 36.4% inhibition at the top
concentration of 25 micromolar. With CYP2D6, an IC.sub.50 of 4.2
micromolar was observed. Thus, this compound was considered to be a
moderate CYP2D6 inhibitor, and a weak CYP2C19 inhibitor. No
inhibition was observed at CYP2B6, CYP2C9, CYP3A4 (with either
substrate), CYP2C8 or CYP1A2. The significance of this CYP2D6
inhibition will depend on the levels of the compound in vivo.
Compound HCV-3 also was tested in cellular and nuclear receptor
functional assays and was also subjected to AMES testing.
[0081] Compound HCV-3 was negative for genotoxicity against both
strains used in this assay (TA98 and TA 100) up to a maximum tested
concentration of 1 mg/mL, in both the absence and presence of S9
metabolic activation. The assay controls behaved as expected.
[0082] Compound HCV-3 also was subjected to in vitro metabolic
disposition in mouse, rat, monkey and human microsomes. The test
compound was incubated with pooled liver microsomes, since drip
stability in liver microsomes can be predictive of drug stability
in vivo. Aliquots were taken at 0, 5, 15, 30 and 45 minutes and
quenched immediately. The samples were extracted and analyzed by
LC-MS/MS. Compound HCV-3 was observed to have low clearance in
human, monkey and mouse microsomes, and moderate clearance in
rat.
[0083] Compound HCV-3 also was subjected to MDCK permeability
assay. The compound was observed to be highly permeable in the MDCK
assay. There was a slight difference between the plus and minus
inhibitor data in terms of the efflux ratio obtained (1.48 minus
inhibitor, versus 0.929 plus inhibitor). A ratio of greater than 2
generally indicates that efflux, i.e., blood brain barrier
permeability, is occurring. The control compounds behaved as
expected, with prazosin (a P-gp substrate) showing efflux in the
absence of Cyclosporin A, which was inhibited in its presence.
[0084] Various derivatives of the above compounds with potential
opiod and alpha antagonist activity were prepared using Scheme I as
well as procedures describe herein.
[0085] Synthesis of 1-benzylpiperidin-4-one oxime: 28.35 g (1
equiv., 0.15 mol) of 1-benzylpiperidin-4-one was dissolved in 60 mL
of EtOH and then cooled to 0.degree. C. using an ice bath. A
solution containing 20.85 g (2 equiv., 0.30 mol) of hydroxylamine
hydrochloride dissolved in 75 mL of H.sub.2O was prepared and then
added dropwise to the reaction mixture followed by dropwise
addition of a solution containing 20.7 g (1 equiv., 0.15 mol) of
K.sub.2CO.sub.3 dissolved in 75 mL of H.sub.2O. The reaction
mixture was then brought to room temperature and stirred overnight.
The EtOH was then removed via rotary evaporation and the reaction
mixture was then cooled in an ice bath to allow the product to
crystallize out of solution. The product was filtered and washed
several times with H.sub.2O and recrystallized in EtOH. Yield:
27.78 g (70.17%).
[0086] Synthesis of 1-benzylpiperidin-4-amine: A solution
containing 6.12 g (1 equiv., 0.03 mol) of 1-benzylpiperidin-4-one
oxime dissolved in 90 mL of iso-amyl alcohol was prepared and
heated to approximately 110.degree. C. 6.9 g (10 equiv., 0.3 mol)
of Na metal was then added slowly to the reaction mixture. After
addition of Na, the reaction mixture was allowed to cool to room
temperature and stirred until the reaction mixture turned into a
thick slurry. The slurry was dissolved in 50 mL of ethyl acetate
and 25 mL of H.sub.2O. The organic layer was separated and washed
with H.sub.2O (2.times.20 mL) followed by drying over anhydrous
magnesium sulfate. The solvent was removed via rotary evaporation,
resulting in a yellow oil. The crude product was purified via
column chromatography utilizing silica gel and a DCM:MeOH solvent
system in a ratio of 4:1 with an additional 1% of Et.sub.3N. Yield:
3.7 g (64%).
[0087] Synthesis of N-(1-benzylpiperidin-4-yl)propionamide: A
solution of 3.7 g of 1-benzylpiperidin-4-amine (1 equiv., 0.019
mol) dissolved in 45 mL of dry dichloromethane was prepared
followed by the addition of 5 mL of Et.sub.3N (2.6 equiv., 0.05
mol). The reaction mixture was then cooled to 0.degree. C. using an
ice bath, and then 2.17 mL (1.3 equiv., 0.025 mol) of propionyl
chloride dissolved in 10 mL of dry dichloromethane was added
dropwise to the reaction mixture. The reaction mixture was then
warmed to room temperature and stirred overnight. Once the reaction
was complete, 4 mL of NH.sub.4OH and 45 mL of H.sub.2O were added
to the reaction mixture. The organic layer was separated, and the
aqueous layer was washed with dichloromethane (3.times.20 mL)
followed by NaHCO.sub.3 solution and brine. The organic extracts
were dried over anhydrous magnesium sulfate and the solvent was
removed via rotary evaporation, resulting in a white solid. The
product was washed with hexanes to obtain an analytically pure
sample. Yield: 2.8 g (72%).
[0088] Synthesis of N-(piperidin-4-yl)propionamide: About 0.7 g of
N-(1-benzylpiperidin-4-yl)propionamide (1 equivalent, 0.003 moles)
were added to a parr hydrogenation flask and dissolved in 30 mL of
EtOH. The solution was then degassed with argon for 30 min followed
by the addition of 0.07 g of 10% Pd/C (0.2 equiv.,
6.58.times.10.sup.-4 mol) and 0.07 g of 20% Pd(OH).sub.2 (0.17
equiv., 4.98.times.10.sup.-4 mol). The black solution was then
degassed with argon for an additional 15 min. The reaction mixture
was then charged with 50 psi of H.sub.2 gas and shaken for 24 h.
The product was filtered through celite and the solvent was removed
via rotary evaporation. No further purification was required.
Yield: 0.467 g (99%).
[0089] Synthesis of methyl
3-(4-propionamidopiperidin-1-yl)propanoate (CRA5): About 0.1 g of
N-(piperidin-4-yl)propionamide (1 equiv., 5.26.times.10.sup.-4
moles) was dissolved in 2 mL of dry acetonitrile followed by the
addition of 0.071 mL of methyl acrylate (1.5 equiv.,
7.89.times.10.sup.-4 mol). The reaction mixture was refluxed
overnight. The solvent was removed via rotary evaporation. The
crude product was purified by washing with hexanes followed by
drying under high vacuum. Yield: 0.90 g (71%).
[0090] Synthesis of
N-(1-(2-(thiophen-2-yl)ethyl)piperidin-4-yl)propionamide (CRAS1):
About 0.1 g of N-(piperidin-4-yl)propionamide (1 equiv.,
6.40.times.10.sup.-4 mol), 0.145 g of 2-(thiophen-2-yl)ethyl
methanesulfonate (1.1 equiv., 7.04.times.10.sup.-4 moles), 0.097 g
of K.sub.2CO.sub.3 (1.1 equiv., 7.04.times.10.sup.-4 mol), 0.032 g
of KI (1.92.times.10.sup.-4 mol), and 0.178 mL of Et.sub.3N (2
equiv., 1.28.times.10.sup.-3 mol) were added to a round bottom
flask and dissolved in 5 mL of dry acetonitrile. The reaction
mixture was stirred and refluxed overnight. The solvent was then
removed via rotary evaporation followed by the addition of
H.sub.2O. The mixture was extracted with ethyl acetate (3.times.5
mL), and the organic extracts were combined and dried over
anhydrous magnesium sulfate. The solvent was removed via rotary
evaporation. The crude product was washed with hexanes to obtain an
analytically pure sample. Yield: 0.101 g (60%).
[0091] Synthesis of 1-phenethylpiperidin-4-one oxime: 28.35 g (1
equivalent, 0.14 mol) of 1-benzylpiperidin-4-one were dissolved in
60 mL of EtOH and then cooled to 0.degree. C. using an ice bath. A
solution containing 19.46 g (2 equivalents, 0.28 mol) of
hydroxylamine hydrochloride dissolved in 75 mL of H.sub.2O was
prepared and then added dropwise to the reaction mixture followed
by dropwise addition of a solution containing 19.35 g (1
equivalent, 0.14 mol) of K.sub.2CO.sub.3 dissolved in 75 mL of
H.sub.2O. The reaction mixture was then brought to room temperature
and stirred overnight. The EtOH was then removed via rotary
evaporation and the reaction mixture was then cooled in an ice bath
to allow the product to crystallize out of solution. The product
was filtered and washed several times with H.sub.2O and
recrystallized in EtOH. Yield: 25.60 g (83.77%).
[0092] Synthesis of 1-phenethylpiperidin-4-amine: A solution
containing 6.00 g (1 equiv., 0.027 mol) of
1-phenethylpiperidin-4-one oxime dissolved in 90 mL of iso-amyl
alcohol was prepared and heated to approximately 110.degree. C.
6.21 g (10 equiv., 0.27 mol) of Na metal was then added slowly to
the reaction mixture. After addition of Na, the reaction mixture
was allowed to cool to room temperature and stirred until the
reaction mixture turned into a thick slurry. The slurry was
dissolved in 50 mL of ethyl acetate and 25 mL of H.sub.2O. The
organic layer was separated and washed with H.sub.2O (2.times.20
mL) followed by drying over anhydrous magnesium sulfate. The
solvent was removed via rotary evaporation, resulting in a yellow
oil. The crude product was purified via column chromatography
utilizing silica gel and a DCM:MeOH solvent system in a ratio of
4:1 containing an additional 1% of Et.sub.3N.
[0093] Synthesis of
N-(1-phenethylpiperidin-4-yl)furan-2-carboxamide (CRA8): A solution
of 0.1 g of 1-phenethylpiperidin-4-amine (1 equiv.,
4.89.times.10.sup.-4 mol) dissolved in 2 mL of dry dichloromethane
was prepared followed by the addition of 0.178 mL (2.6 equiv.,
1.27.times.10.sup.-3 moles) of Et.sub.3N. The reaction mixture was
then cooled to 0.degree. C. using an ice bath, and then 0.063 mL
(1.3 equiv., 6.36.times.10.sup.-4 mol) of 2-furoyl chloride
dissolved in 0.25 mL of dry dichloromethane was added dropwise to
the reaction mixture. The reaction mixture was then warmed to room
temperature and stirred overnight. Once the reaction was complete,
4 mL of NH.sub.4OH and 45 mL of H.sub.2O were added to the reaction
mixture. The organic layer was separated, and the aqueous layer was
washed with dichloromethane (3.times.5 mL) followed by NaHCO.sub.3
solution and brine. The organic extracts were dried over anhydrous
magnesium sulfate and the solvent was removed via rotary
evaporation, resulting in a white solid. The product was washed
with hexanes to obtain an analytically pure sample. Yield: 0.0845 g
(58.3%).
[0094] Synthesis of
N-(1-phenethylpiperidin-4-yl)furan-3-carboxamide (CRA9): A solution
of 0.1 g of 1-phenethylpiperidin-4-amine (1 equiv.,
4.89.times.10.sup.-4 mol) dissolved in 2 mL of dry dichloromethane
was prepared followed by the addition of 0.178 mL (2.6 equiv.,
1.27.times.10.sup.-3 mol) of Et.sub.3N. The reaction mixture was
then cooled to 0.degree. C. using an ice bath, and then 0.063 mL
(1.3 equiv., 6.36.times.10.sup.-4 mol) of 3-furoyl chloride
dissolved in 0.25 mL of dry dichloromethane was added dropwise to
the reaction mixture. The reaction mixture was then warmed to room
temperature and stirred overnight. Once the reaction was complete,
4 mL of NH.sub.4OH and 45 mL of H.sub.2O were added to the reaction
mixture. The organic layer was separated, and the aqueous layer was
washed with dichloromethane (3.times.5 mL) followed by NaHCO.sub.3
solution and brine. The organic extracts were dried over anhydrous
magnesium sulfate and the solvent was removed via rotary
evaporation, resulting in a white solid. The product was washed
with hexanes to obtain an analytically pure sample. Yield: 0.104 g
(72%).
[0095] Synthesis of 8-bromo-N-(1-phenethylpiperidin-4-yl)octanamide
(CRA10): A solution of 0.101 g of 1-phenethylpiperidin-4-amine (1.1
equiv., 4.93.times.10.sup.-4 mol), 0.1 g of 8-bromooctanoic acid
(1.0 equiv., 4.48.times.10.sup.-4 mol), 0.170 g of HATU (1.0
equiv., 4.48.times.10.sup.-4 mol), 0.061 g of HOAt (1.0 equiv.,
4.48.times.10.sup.-4 mol), and 0.314 mL of DIEPA (4.0 equiv.,
0.0018 mol) in dry DMF was prepared. The reaction mixture was
stirred at room temperature overnight. The reaction mixture was
then quenched with 0.5 M KHSO.sub.4 solution followed by the
addition of dichloromethane. The organic and aqueous layers were
separated, and the aqueous layer was extracted with dichloromethane
(3.times.5 mL) followed by washing with NaHCO.sub.3 solution and
Brine. The organic extracts were then dried over anhydrous
magnesium sulfate.
[0096] Synthesis of 2-(thiophen-2-yl)ethyl methanesulfonate: 2.6 mL
of 2-(thiophen-2-yl)ethanol (1 equiv., 0.023 mol) was dissolved in
45 mL of dry dichloromethane followed by the addition of 3.63 mL of
Et.sub.3N (1.13 equiv., 0.026 mol). The reaction mixture was
stirred at room temperature for 1 h. It was then cooled to
-5.degree. C. using an ice bath and solid NaCl. Once cooled, 1.92
mL of methanesulfonyl chloride was added dropwise over the course
of 10 min. The reaction mixture was then warmed to room temperature
and stirred for 1 h. Once the reaction was complete, 30 mL of
NaHCO.sub.3 solution was added followed by separation of the
organic and aqueous layers. The aqueous layer was extracted with
dichloromethane (3.times.30 mL). The combined organic extracts were
dried over anhydrous magnesium sulfate and the solvent was removed
via rotary evaporation, resulting in a brown oil. No further
purification was required.
[0097] Synthesis of N-(1-Phenethylpiperidin-4-yl)propionamide:
Propionyl chloride 2.775 g (0.03 mol) in 5.55 mL of CHCl.sub.3 was
added dropwise to a cooled (0.degree. C.) solution of 4.08 g (0.02
mol) 1-phenethylpiperidin-4-amine and 3.03 g (0.03 mol) of
Et.sub.3N in 30 mL of CHCl.sub.3. The mixture was allowed to reach
room temperature and stirred overnight. After work-up with 5%
aqueous solution of NaHCO.sub.3, organic layer was separated,
washed with water, dried over MgSO.sub.4, and filtered. Filtrate
was concentrated and crystallized from hexane to give 4.9 g (94%)
of N-(1-phenethylpiperidin-4-yl)propionamide. M.p. 134-135.degree.
C. MS (ESI): 261.2 (MH+). .sup.1H NMR (600 MHz, CDCl.sub.3):
.delta. 7.27 (t, J=7.4 Hz, 2H), 7.19 (m, 3H), 5.32 (d, J=7.4 Hz,
1H), 3.82 (qt, J=7.8, 4.2 Hz, 1H), 2.92 (dt, J=11.8, 3.4 Hz, 2H),
2.79 (m*, 2H), 2.59 (m*, 2H), 2.19 (q, J=7.5 Hz, 2H), 2.18 (m, 2H),
1.95 (dtd, J=12.4, 4.4, 1.7 Hz, 2H), 1.46 (qd, J=11.7, 3.8 Hz, 2H),
1.15 (t, J=7.5 Hz, 3H). .sup.13C NMR (150 MHz, CDCl.sub.3): .delta.
173.0, 140.2, 128.6, 128.4, 126.0, 60.4, 52.3, 46.3, 33.7, 32.3,
29.8, 9.9.
[0098] Synthesis of N-(1-Phenethylpiperidin-4-yl)propionamide
oxalate. Oxalic acid 1 g (0.011 mol) in 10 mL of ethanol was added
dropwise to the solution of 2.93 g (0.011 mol) of
N-(1-phenethylpiperidin-4-yl)propionamide in 29.3 mL of ethanol.
The mixture was left overnight. Obtained crystals were separated
and dried in dessicator over P.sub.2O.sub.5 to give 3.5 g of
N-(1-phenethylpiperidin-4-yl)propionamide oxalate. M.P.
216-218.degree. C. MS (ESI): 261.2 (M+). X-ray crystallography data
for a representative compound of the invention,
N-(1-phenethyl-piperidin-4-yl)propionamide oxalate confirmed the
structure.
[0099] Synthesis of N-(1-phenethylpiperidin-4-yl)benzamide. A
solution of benzoyl chloride 0.89 g, (0.00636 mol) in 0.25 mL of
dry dichloromethane was added dropwise to a cooled (0.degree. C.)
solution of 1.08 g (0.00468 mol) 1-phenethylpiperidin-4-amine and
0.178 mL of Et.sub.3N in 2 mL of CHCl.sub.3. The mixture was
allowed to reach to room temperature and stirred for a night. After
work-up with 5% solution of NaHCO.sub.3, organic layer was
separated, washed with water, dried over MgSO.sub.4, and filtered.
Concentration of the filtrate gave a white solid. The product was
washed with hexanes to obtain an analytically pure sample. Yield:
0.132 g (87%). MS (ESI): 309.2 (MH+). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.35 (t, J=7.29, 7.29 Hz, 2H), 1.64 (qd,
J=3.80, 11.29, 11.29, 11.35 Hz, 2H), 2.08 (m, 2H), 2.27 (td,
J=2.57, 11.61, 11.65 Hz, 2H), 2.64 (m, 2H), 2.83 (m, 2H), 3.00 (m,
3H), 4.04 (dddd, J=4.28, 8.29, 10.85, 15.24 Hz, 1H), 6.04 (d,
J=7.94 Hz, 1H), 7.25 (m, 5H), 7.44 (m, 3H), 7.75 (m, 2H). .sup.13C
NMR (100 MHz, CDCl.sub.3): .delta. 32.22, 33.71, 45.83, 46.97,
52.38, 60.42, 114.25, 126.12, 126.86, 128.42, 128.56, 128.68,
131.42, 134.75, 140.11, 166.88. Obtained compound was transformed
to oxalate salt as described above.
[0100] Synthesis of 1-Benzylpiperidin-4-one oxime: A solution of
1-benzylpiperidin-4-one (28.35 g, 0.15 mol) in 60 mL of EtOH was
added to the cooled to 0.degree. C. solution of hydroxylamine
hydrochloride (20.85 g, 0.30 mol) in 75 mL of H.sub.2O. To the
resulting mixture was added a solution of K.sub.2CO.sub.3 (20.7 g,
0.15 mol) in 75 mL of H.sub.2O. The reaction mixture was then
allowed to reach room temperature and stirred overnight. The EtOH
was removed and the reaction mixture was cooled in an ice bath to
allow the product to crystallize out of solution. The product was
filtered and washed several times with H.sub.2O and recrystallized
in EtOH. Yield: 27.78 g (70.17%).
[0101] Synthesis of 1-Benzylpiperidin-4-amine: Na metal (6.9 g, 0.3
mol) was added to a 110.degree. C. solution of
1-benzylpiperidin-4-one oxime (6.12 g, 0.03 mol) in 90 mL of
iso-amyl alcohol. The reaction mixture was allowed to cool to room
temperature and stirred until the reaction mixture became a thick
slurry. The slurry was dissolved in 50 mL of diethyl ether and 25
mL of H.sub.2O. The organic layer was separated, washed with
H.sub.2O, dried over anhydrous magnesium sulfate, and filtered. The
filtrate was concentrated to yield a yellow oil. The crude product
was purified via column chromatography using silica gel and a
DCM:MeOH solvent in a ratio of 4:1 with an additional 1% of
Et.sub.3N. Yield: 3.7 g (64%).
[0102] Synthesis of N-(1-Benzylpiperidin-4-yl)propionamide. To a
0.degree. C. solution of 1-benzylpiperidin-4-amine (3.7 g, 0.019
mol) and 5 mL of Et.sub.3N (0.05 mol) in 45 mL of dry
dichloromethane was added a solution of propionyl chloride (2.17
mL, 0.025 mol) in 10 mL of dichloromethane. The reaction mixture
was allowed to reach room temperature and stirred overnight. To the
reaction mixture was added 4 mL of NH.sub.4OH and 45 mL of
H.sub.2O. The aqueous layer was separated and extracted with
dichloromethane. The combined organic layers were washed with
NaHCO.sub.3 solution and brine, dried over anhydrous magnesium
sulfate, filtered and concentrated to yield a white solid. The
product was washed with hexanes to obtain an analytically pure
sample. Yield: 2.8 g (72%)
[0103] Synthesis of N-(Piperidin-4-yl)propionamide: A solution of
N-(1-benzylpi-peridin-4-yl)propionamide (0.7 g, 0.003 mol) in 30 mL
of EtOH was hydrogenated for 24 hours under 50 psi of H.sub.2 in
the presence of 10% Pd/C (0.07 g) and 20% Pd(OH).sub.2 (0.07 g).
The solution was filtered through celite and the solvent was
evaporated to yield 0.467 g (99%) of the product.
[0104] Synthesis of methyl
3-(4-propionamidopiperidin-1-yl)propanoate. A solution of
N-(piperidin-4-yl)propionamide (0.1 g, 0.0052 mol) in 2 mL of dry
acetonitrile and methyl acrylate (0.071 mL, 0.00789 mol) was
refluxed overnight. The solvent was removed and the crude product
was purified by washing with hexanes to yield 0.90 g (71%) of the
product. MS (ESI): 243.3 (MH+). .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 1.14 (t, J=7.59, 7.59 Hz, 3H), 1.41 (dtd, J=3.70, 11.10,
11.13, 12.61 Hz, 2H), 1.91 (m, 2H), 2.17 (m, 4 H), 2.49 (m, 2H),
2.68 (m, 2H), 2.81 (m, 2H), 3.67 (s, 3H), 3.78 (dddd, J=4.29, 4.36,
11.92, 15.26, 1H), 5.25 (d, J=7.96 Hz, 1H). .sup.13C NMR (100 MHz,
CDCl.sub.3): .delta. 10.02, 29.99, 32.41, 46.40, 51.76, 52.25,
55.63, 173.14, 174.05. Obtained compound was transformed to oxalate
salt as described above.
[0105] Synthesis of
N-(1-(2-(Thiophen-2-yl)ethyl)piperidin-4-yl)propionamide. A
solution of N-(piperidin-4-yl)propionamide (0.1 g, 0.0064 mol),
2-(thiophen-2-yl)ethyl methanesulfonate (0.145 g, 0.704 mol),
K.sub.2CO.sub.3 (0.097 g, 0.00704 mol), KI (0.032 g, 0.00192 mol),
Et.sub.3N (0.178 mL, 0.00128 mol) in 5 mL of dry acetonitrile was
stirred overnight under refluxing conditions. The mixture was
concentrated, and the residue was diluted with H.sub.2O and
extracted with ethyl acetate. The organic extracts were combined,
dried over anhydrous magnesium sulfate, filtered and concentrated.
The crude product was washed with hexanes to obtain an analytically
pure sample. Yield: 0.101 g (60%). MS (ESI): 267.7 (MH+). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 1.15 (t, J=7.58, 7.58 Hz, 3H),
1.47 (m, 2H), 1.95 (m, 2H), 2.18 (m, 4H), 2.64 (dd, J=6.87, 8.62
Hz, 2H), 2.90 (m, 2H), 3.00 (m, 2H), 3.82 (dddd, J=4.20, 8.31,
10.86, 15.17 Hz, 1H), 5.32 (d, J=7.95 Hz, 1H), 6.81 (dq, J=1.02,
1.02, 1.02, 3.20 Hz, 1H), 6.91 (dd, J=3.39, 5.14 Hz, 1H), 7.11 (dd,
J=1.21, 5.13 Hz, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
10.04, 28.06, 30.03, 32.15, 46.52, 52.42, 59.98, 123.62, 124.71,
126.69, 142.87, 173.15. Obtained compound was transformed to
oxalate salt as described above.
[0106] The foregoing discussion of the invention has been presented
for purposes of illustration and description. The foregoing is not
intended to limit the invention to the form or forms disclosed
herein. Although the description of the invention has included
description of one or more embodiments and certain variations and
modifications, other variations and modifications are within the
scope of the invention, e.g., as may be within the skill and
knowledge of those in the art, after understanding the present
disclosure. It is intended to obtain rights which include
alternative embodiments to the extent permitted, including
alternate, interchangeable and/or equivalent structures, functions,
ranges or steps to those claimed, whether or not such alternate,
interchangeable and/or equivalent structures, functions, ranges or
steps are disclosed herein, and without intending to publicly
dedicate any patentable subject matter. All references cited herein
are incorporated by reference in their entirety.
* * * * *