U.S. patent application number 13/542821 was filed with the patent office on 2012-11-08 for novel processes for the preparation of cyclopropyl-amide derivatives.
Invention is credited to Sergio Cesco-Cancian, Neelakandha S. Mani, David C. Palmer, Chennagiri R. Pandit, Mayra B. Reyes, Tong Xiao.
Application Number | 20120283433 13/542821 |
Document ID | / |
Family ID | 38119600 |
Filed Date | 2012-11-08 |
United States Patent
Application |
20120283433 |
Kind Code |
A1 |
Mani; Neelakandha S. ; et
al. |
November 8, 2012 |
NOVEL PROCESSES FOR THE PREPARATION OF CYCLOPROPYL-AMIDE
DERIVATIVES
Abstract
The present invention is directed to novel processes for the
preparation of cyclopropyl-amide derivatives, useful for the
treatment of disorders and conditions mediated by the histamine
receptor.
Inventors: |
Mani; Neelakandha S.; (San
Diego, CA) ; Palmer; David C.; (Doylestown, PA)
; Pandit; Chennagiri R.; (San Diego, CA) ; Reyes;
Mayra B.; (Somerset, NJ) ; Xiao; Tong;
(Edison, NJ) ; Cesco-Cancian; Sergio; (Bethlehem,
PA) |
Family ID: |
38119600 |
Appl. No.: |
13/542821 |
Filed: |
July 6, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13270924 |
Oct 11, 2011 |
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13542821 |
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11553154 |
Oct 26, 2006 |
7795426 |
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13270924 |
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60731725 |
Oct 31, 2005 |
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Current U.S.
Class: |
544/121 |
Current CPC
Class: |
C07D 295/192
20130101 |
Class at
Publication: |
544/121 |
International
Class: |
C07D 413/10 20060101
C07D413/10 |
Claims
1-18. (canceled)
19. A process for the preparation of a compound of formula (II)
##STR00079## and enantiomers, diastereomers, hydrates, solvates,
and pharmaceutically acceptable salts, esters and amides thereof;
wherein p is an integer selected from 1 or 2; R.sup.14 is selected
from the group consisting of --H and --C.sub.1-6alkyl; q is an
integer selected from 0, 1 or 2; each R.sup.13 is independently
selected from the group consisting of --C.sub.1-6alkyl,
--OC.sub.1-6alkyl, and halo; R.sup.11 is --H or is independently
selected from the group consisting of --C.sub.1-6alkyl,
--C.sub.3-8cycloalkyl, and 4- to 8-membered heterocycloalkyl ring;
wherein each alkyl, cycloalkyl, and heterocycloalkyl is optionally
substituted with one, two, or three substituents R.sup.a; each
R.sup.a substituent is independently selected from the group
consisting of --C.sub.1-6alkyl, fluoro, --OH, --OC.sub.1-6alkyl,
and --NR.sup.bR.sup.c; R.sup.b and R.sup.c are each independently
--H or --C.sub.1-6alkyl, or R.sup.b and R.sup.c taken together with
their nitrogen of attachment form a 5- to 7-membered
heterocycloalkyl ring, said ring optionally substituted with halo,
--C.sub.1-4alkyl, --OH, or --OC.sub.1-6alkyl; R.sup.12 is
independently selected from the group consisting of
--C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, and 4- to 8-membered
heterocycloalkyl ring; wherein each alkyl, cycloalkyl, and
heterocycloalkyl is optionally substituted with one, two, or three
substituents R.sup.a; alternatively, R.sup.11 and R.sup.12 taken
together with their nitrogen of attachment form a 5- to 7-membered
heterocycloalkyl ring; wherein the heterocycloalkyl ring is
optionally substituted with one, two, or three substituents
R.sup.d; each R.sup.d substituent is independently selected from
the group consisting of --C.sub.1-4alkyl, halo, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --OH, --OC.sub.1-6alkyl,
--C.sub.1-4alkylOH, and --NR.sup.eR.sup.f; wherein R.sup.e and
R.sup.f are independently --H or --C.sub.1-6alkyl; comprising
##STR00080## reacting a compound of formula (XXIII) with source of
bisulfite; in a polar organic solvent; to yield the corresponding
bisulfite, the compound of formula (XXVII); ##STR00081## reacting
the compound of formula (XXVII) with an organic or inorganic base;
in an organic solvent; to yield the corresponding compound of
formula (XXIII); ##STR00082## and reacting the compound of formula
(XXIII) with a compound of formula (XXIV); in the presence of a
reducing agent; in an organic solvent; to yield the corresponding
compound of formula (II).
20. A process as in claim 19, wherein the organic or inorganic base
is present in an amount greater than or equal to about 1
equivalent.
21. A process as in claim 19, wherein the compound of formula
(XXIV) is present in an amount greater than or equal to about one
equivalent; and wherein the reducing agent is present in an amount
in the range of from about 1 to abut 2 equivalents.
22. A process as in claim 19, wherein the compound of formula
(XXVII) is isolated by filtration.
23. A process as in claim 19, further comprising reacting the
compound of formula (II) to yield the corresponding
pharmaceutically acceptable salt of the compound of formula
(II).
24-29. (canceled)
30. A process for the preparation of a compound of formula (IIs)
##STR00083## or an enantiomer, diastereomer, hydrate, solvate, or
pharmaceutically acceptable salt, ester or amide thereof;
comprising ##STR00084## reacting a compound of formula (XXIIIs)
with source of bisulfite; in a polar organic solvent; to yield the
corresponding bisulfite, the compound of formula (XXVIIs);
##STR00085## reacting the compound of formula (XXVIIs) with an
organic or inorganic base; in an organic solvent; to yield the
corresponding compound of formula (XXIIIs); ##STR00086## and
reacting the compound of formula (XXIII) with a compound of formula
(XXIV); in the presence of a reducing agent; in an organic solvent;
to yield the corresponding compound of formula (II).
31. A process as in claim 30, wherein the organic or inorganic base
is present in an amount greater than or equal to about 1
equivalent.
32. A process as in claim 30, wherein the compound of formula
(XXIVs) is present in an amount greater than or equal to about one
equivalent; and wherein the reducing agent is present in an amount
in the range of from about 1 to abut 2 equivalents.
33. A process as in claim 30, wherein the compound of formula
(XXVIIs) is isolated by filtration.
34. A process as in claim 30, further comprising reacting the
compound of formula (IIs) to yield the corresponding
pharmaceutically acceptable salt of the compound of formula (IIs).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application 60/731,725 filed on Oct. 31, 2005, which is
incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to processes for the
preparation of cyclopropyl-amine derivatives, useful for the
treatment of disorders and conditions mediated by the histamine
receptor.
BACKGROUND OF THE INVENTION
[0003] US Patent Application Publication 2004-0110746 A1, published
Apr. 21, 2005 (also published as PCT Publication WO 04/037801, May
6, 2004), which is hereby incorporated by reference, discloses
novel piperazinyl and diazepanyl benzamide derivatives useful for
the treatment of histamine receptor mediated disorders. More
specifically, the compounds are useful for the treatment of
disorders and conditions mediated by the H.sub.3 receptor. More
particularly, the compounds are useful for treating or preventing
neurologic disorders including sleep/wake and arousal/vigilance
disorders (e.g. insomnia and jet lag), attention deficit
hyperactivity disorders (ADHD), learning and memory disorders,
cognitive dysfunction, migraine, neurogenic inflammation, dementia,
mild cognitive impairment (pre-dementia), Alzheimer's disease,
epilepsy, narcolepsy, eating disorders, obesity, motion sickness,
vertigo, schizophrenia, substance abuse, bipolar disorders, manic
disorders and depression, as well as other histamine H.sub.3
receptor mediated disorders such as upper airway allergic response,
asthma, itch, nasal congestion and allergic rhinitis in a subject
in need thereof. For example, methods for preventing, inhibiting
the progression of, or treating upper airway allergic response,
asthma, itch, nasal congestion and allergic rhinitis.
[0004] US Patent Application Publication 2004-0110746 A1, published
Apr. 21, 2005 (also published as PCT Publication WO 04/037801, May
6, 2004) discloses a process for the preparation of the piperazinyl
and diazepanyl benzamides. There remains a need for processes for
the preparation of piperazinyl and diazepanyl benzamide derivatives
that are suitable for large scale/commercial applications.
SUMMARY OF THE INVENTION
[0005] The present invention is further directed to a process for
the preparation of compounds of formula (II)
##STR00001##
[0006] and enantiomers, diastereomers, hydrates, solvates, and
pharmaceutically acceptable salts, esters and amides thereof;
[0007] wherein
[0008] p is an integer selected from 1 or 2;
[0009] R.sup.14 is selected from the group consisting of --H and
--C.sub.1-6alkyl;
[0010] q is an integer selected from 0, 1 or 2;
[0011] each R.sup.13 is independently selected from the group
consisting of --C.sub.1-6alkyl, --OC.sub.1-6alkyl, and halo;
[0012] R.sup.11 is --H or is independently selected from the group
consisting of --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, and 4- to
8-membered heterocycloalkyl ring; wherein each alkyl, cycloalkyl,
and heterocycloalkyl is optionally substituted with one, two, or
three substituents R.sup.a;
[0013] each R.sup.a substituent is independently selected from the
group consisting of --C.sub.1-6alkyl, fluoro, --OH,
--OC.sub.1-6alkyl, and --NR.sup.bR.sup.c;
[0014] R.sup.b and R.sup.c are each independently --H or
--C.sub.1-6alkyl, or R.sup.b and R.sup.c taken together with their
nitrogen of attachment form a 5- to 7-membered heterocycloalkyl
ring, said ring optionally substituted with halo, --C.sub.1-4alkyl,
--OH, or --OC.sub.1-6alkyl;
[0015] R.sup.12 is independently selected from the group consisting
of --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, and 4- to 8-membered
heterocycloalkyl ring; wherein each alkyl, cycloalkyl, and
heterocycloalkyl is optionally substituted with one, two, or three
substituents R.sup.a;
[0016] alternatively, R.sup.11 and R.sup.12 taken together with
their nitrogen of attachment form a 5- to 7-membered
heterocycloalkyl ring; wherein the heterocycloalkyl ring is
optionally substituted with one, two, or three substituents
R.sup.d;
[0017] each R.sup.d substituent is independently selected from the
group consisting of --C.sub.1-4alkyl, halo, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --OH, --OC.sub.1-6alkyl,
--C.sub.1-4alkylOH, and --NR.sup.eR.sup.f; wherein R.sup.e and
R.sup.f are independently --H or --C.sub.1-6alkyl;
[0018] comprising
##STR00002##
[0019] reacting a compound of formula (XX); in a first organic
solvent; to yield the corresponding compound of formula (XXI),
wherein L is a leaving group; and wherein the compound of formula
(XXI) is not isolated;
##STR00003##
[0020] reacting the compound of formula (XXI) with a compound of
formula (XXII); in the presence of an organic or inorganic base; in
a second organic solvent; to yield the corresponding compound of
formula (XXIII); wherein the compound of formula (XXIII) is not
isolated;
##STR00004##
[0021] and reacting the compound of formula (XXIII) with a compound
of formula (XXIV); in the presence of a reducing agent; in a third
organic solvent; to yield the corresponding compound of formula
(II).
[0022] The present invention is further to an alternate process for
the preparation of compounds of formula (II)
##STR00005##
[0023] and enantiomers, diastereomers, hydrates, solvates, and
pharmaceutically acceptable salts, esters and amides thereof;
[0024] wherein
[0025] p is an integer selected from 1 or 2;
[0026] R.sup.14 is selected from the group consisting of --H and
--C.sub.1-6alkyl;
[0027] q is an integer selected from 0, 1 or 2;
[0028] each R.sup.13 is independently selected from the group
consisting of --C.sub.1-6alkyl, --OC.sub.1-6alkyl, and halo;
[0029] R.sup.11 is --H or is independently selected from the group
consisting of --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, and 4- to
8-membered heterocycloalkyl ring; wherein each alkyl, cycloalkyl,
and heterocycloalkyl is optionally substituted with one, two, or
three substituents R.sup.a;
[0030] each R.sup.a substituent is independently selected from the
group consisting of --C.sub.1-6alkyl, fluoro, --OH,
--OC.sub.1-6alkyl, and --NR.sup.bR.sup.c;
[0031] R.sup.b and R.sup.c are each independently --H or
--C.sub.1-6alkyl, or R.sup.b and R.sup.c taken together with their
nitrogen of attachment form a 5- to 7-membered heterocycloalkyl
ring, said ring optionally substituted with halo, --C.sub.1-4alkyl,
--OH, or --OC.sub.1-6alkyl;
[0032] R.sup.12 is independently selected from the group consisting
of --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, and 4- to 8-membered
heterocycloalkyl ring; wherein each alkyl, cycloalkyl, and
heterocycloalkyl is optionally substituted with one, two, or three
substituents R.sup.a;
[0033] alternatively, R.sup.11 and R.sup.12 taken together with
their nitrogen of attachment form a 5- to 7-membered
heterocycloalkyl ring; wherein the heterocycloalkyl ring is
optionally substituted with one, two, or three substituents
R.sup.d;
[0034] each R.sup.d substituent is independently selected from the
group consisting of --C.sub.1-4alkyl, halo, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --OH, --OC.sub.1-6alkyl,
--C.sub.1-4alkylOH, and --NR.sup.eR.sup.f; wherein R.sup.e and
R.sup.f are independently --H or --C.sub.1-6alkyl;
[0035] comprising
##STR00006##
[0036] reacting a compound of formula (XXIII) with source of
bisulfite; in a polar organic solvent; to yield the corresponding
bisulfite, the compound of formula (XXVII);
##STR00007##
[0037] and reacting the compound of formula (XXVII) with a compound
of formula (XXIV); in the presence of a reducing agent; in the
presence of an organic or inorganic base; in an organic solvent; to
yield the corresponding compound of formula (II).
[0038] The present invention is further directed to an alternate
process for the preparation of compounds of formula (II)
##STR00008##
[0039] and enantiomers, diastereomers, hydrates, solvates, and
pharmaceutically acceptable salts, esters and amides thereof;
[0040] wherein
[0041] p is an integer selected from 1 or 2;
[0042] R.sup.14 is selected from the group consisting of --H and
--C.sub.1-6alkyl;
[0043] q is an integer selected from 0, 1 or 2;
[0044] each R.sup.13 is independently selected from the group
consisting of --C.sub.1-6alkyl, --OC.sub.1-6alkyl, and halo;
[0045] R.sup.11 is --H or is independently selected from the group
consisting of --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, and 4- to
8-membered heterocycloalkyl ring; wherein each alkyl, cycloalkyl,
and heterocycloalkyl is optionally substituted with one, two, or
three substituents R.sup.a;
[0046] each R.sup.a substituent is independently selected from the
group consisting of --C.sub.1-6alkyl, fluoro, --OH,
--OC.sub.1-6alkyl, and --NR.sup.bR.sup.c;
[0047] R.sup.b and R.sup.c are each independently --H or
--C.sub.1-6alkyl, or R.sup.b and R.sup.c taken together with their
nitrogen of attachment form a 5- to 7-membered heterocycloalkyl
ring, said ring optionally substituted with halo, --C.sub.1-4alkyl,
--OH, or --OC.sub.1-6alkyl;
[0048] R.sup.12 is independently selected from the group consisting
of --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, and 4- to 8-membered
heterocycloalkyl ring; wherein each alkyl, cycloalkyl, and
heterocycloalkyl is optionally substituted with one, two, or three
substituents R.sup.a;
[0049] alternatively, R.sup.11 and R.sup.12 taken together with
their nitrogen of attachment form a 5- to 7-membered
heterocycloalkyl ring; wherein the heterocycloalkyl ring is
optionally substituted with one, two, or three substituents
R.sup.d;
[0050] each R.sup.d substituent is independently selected from the
group consisting of --C.sub.1-4alkyl, halo, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --OH, --OC.sub.1-6alkyl,
--C.sub.1-4alkylOH, and --NR.sup.eR.sup.f; wherein R.sup.e and
R.sup.f are independently --H or --C.sub.1-6alkyl;
[0051] comprising
##STR00009##
[0052] reacting a compound of formula (XXIII) with source of
bisulfite; in a polar organic solvent; to yield the corresponding
bisulfite, the compound of formula (XXVII);
##STR00010##
[0053] reacting the compound of formula (XXVII) with an organic or
inorganic base; in an organic solvent; to yield the corresponding
compound of formula (XXIII);
##STR00011##
[0054] and reacting the compound of formula (XXIII) with a compound
of formula (XXIV); in the presence of a reducing agent; in an
organic solvent; to yield the corresponding compound of formula
(II).
[0055] In an embodiment, the present invention is directed to
processes for the preparation of a compound of formula (IIs)
##STR00012##
[0056] also known as
(4-cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,
or its pharmaceutically acceptable salt thereof, preferably the
di-hydrochloride salt.
[0057] The present invention is further directed to a product
prepared according to any of the processed described herein.
[0058] Illustrative of the invention is a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and a
product prepared according to any of the processes described
herein. An illustration of the invention is a pharmaceutical
composition made by mixing a product prepared according to any of
the processes described herein and a pharmaceutically acceptable
carrier. Illustrating the invention is a process for making a
pharmaceutical composition comprising mixing a product prepared
according to any of the processes described herein and a
pharmaceutically acceptable carrier.
[0059] Exemplifying the invention are methods of treating a
disorder mediated by histamine, preferably, the H.sub.3 histamine
receptor, (selected from the group consisting of neurologic
disorders including sleep/wake and arousal/vigilance disorders
(e.g. insomnia and jet lag), attention deficit hyperactivity
disorders (ADHD), learning and memory disorders, cognitive
dysfunction, migraine, neurogenic inflammation, dementia, mild
cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy,
narcolepsy, eating disorders, obesity, motion sickness, vertigo,
schizophrenia, substance abuse, bipolar disorders, manic disorders
and depression, as well as other histamine H.sub.3 receptor
mediated disorders such as upper airway allergic response, asthma,
itch, nasal congestion and allergic rhinitis) comprising
administering to a subject in need thereof, a therapeutically
effective amount of a products prepared according to any of the
processes described herein or a pharmaceutical composition as
described above.
[0060] Another example of the invention is the use of a product
prepared according to any of the processes described herein in the
preparation of a medicament for treating: (a) a sleep/wake
disorder, (b) an arousal/vigilance disorders, (c) insomnia, (d) jet
lag, (e) attention deficit hyperactivity disorders (ADHD), (f) a
learning disorder, (g) a memory disorder, (h) cognitive
dysfunction, (i) migraine, (j) neurogenic inflammation, (k)
dementia, (l) mild cognitive impairment (pre-dementia), (m)
Alzheimer's disease, (n) epilepsy, (o) narcolepsy, (p) an eating
disorder, (q) obesity, (r) motion sickness, (s) vertigo, (t)
schizophrenia, (u) substance abuse, (v) bipolar disorder, (w) manic
disorder, (x) depression, (y) upper airway allergic response, (z)
asthma, (aa) itch, (bb) nasal congestion or (cc) allergic rhinitis,
in a subject in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0061] The present invention is directed to processes for the
preparation of compounds of formula (II)
##STR00013##
[0062] wherein p, R.sup.14, q, R.sup.13, R.sup.11 and R.sup.12 are
as herein defined, useful for the treatment of disorders and
conditions modulated by a histamine receptor.
[0063] As used herein, the terms "including", "containing" and
"comprising" are used herein in their open, non-limiting sense.
[0064] The term "alkyl" refers to a straight- or branched-chain
alkyl group having from 1 to 12 carbon atoms in the chain.
Exemplary alkyl groups include methyl (Me, which also may be
structurally depicted by "/"), ethyl (Et), n-propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl,
tert-pentyl, hexyl, isohexyl, and the like.
[0065] The term "alkylene" refers to a divalent straight- or
branched-chain alkyl group having from 1 to 12 carbon atoms in the
chain. Exemplary alkylene groups include methylene, ethylene,
propylene, and the like.
[0066] The term "alkenyl" refers to a straight- or branched-chain
alkenyl group having from 2 to 12 carbon atoms in the chain. (The
double bond of the alkenyl group is formed by two sp.sup.2
hybridized carbon atoms.) Illustrative alkenyl groups include
prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl,
hex-2-enyl, and the like.
[0067] The term "alkynyl" refers to a straight- or branched-chain
alkynyl group having from 2 to 12 carbon atoms in the chain. (The
triple bond of the alkynyl group is formed by two sp hybridized
carbon atoms.) Illustrative alkynyl groups include prop-2-ynyl,
but-2-ynyl, but-3-ynyl, 2-methylbut-2-ynyl, hex-2-ynyl, and the
like.
[0068] The term "aryl" refers to a monocyclic, or fused or spiro
polycyclic, aromatic carbocycle (ring structure having ring atoms
that are all carbon) having from 3 to 12 ring atoms per ring.
(Carbon atoms in aryl groups are sp.sup.2 hybridized.) Illustrative
examples of aryl groups include phenyl, naphthyl, anthracenyl,
phenanthrenyl, and the like.
[0069] The term "heteroaryl" refers to a monocyclic, or fused
bicyclic or polycyclic, aromatic heterocycle (ring structure having
ring atoms selected from carbon atoms as well as nitrogen, oxygen,
and sulfur heteroatoms) having from 3 to 12 ring atoms per ring.
Illustrative examples of heteroaryl groups include the following
moieties:
##STR00014##
and the like.
[0070] The term "cycloalkyl" refers to a saturated or partially
saturated, monocyclic or fused or spiro polycyclic, carbocycle
having from 3 to 12 ring atoms per ring. Illustrative examples of
cycloalkyl groups include the following moieties:
##STR00015##
and the like.
[0071] A "heterocycloalkyl" refers to a monocyclic, or fused or
spiro polycyclic, ring structure that is saturated or partially
saturated and has from 3 to 12 ring atoms per ring selected from C
atoms and N, O, and S heteroatoms. Illustrative examples of
heterocycloalkyl groups include:
##STR00016##
and the like.
[0072] The term "halogen" represents chlorine, fluorine, bromine or
iodine. The term "halo" represents chloro, fluoro, bromo or
iodo.
[0073] The term "substituted" means that the specified group or
moiety bears one or more substituents. The term "unsubstituted"
means that the specified group bears no substituents. The term
"optionally substituted" means that the specified group is
unsubstituted or substituted by one or more substituents. Where the
term "substituted" is used to describe a structural system, the
substitution is meant to occur at any valency-allowed position on
the system.
[0074] Abbreviations used in the specification, particularly in the
Schemes and Examples, are as follows: [0075]
CDI=N,N'-Carbonyldiimidazole [0076] DCM=Dichloromethane [0077]
DIPEA=Diisopropyl ethyl amine [0078] DMF=Dimethylformamide [0079]
DSC Differential Scanning calorimetry [0080] DVS=Dynamic Vapour
Sorption [0081] EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride [0082] Et.sub.2O=Diethyl Ether [0083] EtOAc=Ethyl
Acetate [0084] EtOH=Ethanol [0085] HOBt=1-Hydroxybenzotriazole
[0086] HPLC=High Performance Liquid Chromatography [0087]
MeOH=Methanol [0088] MTBE=Methyl t-Butyl Ether [0089]
NaBH(OAc).sub.3=Sodium triacetoxyborohydride [0090] NMR=Nuclear
Magnetic Resonance [0091] OBt=--O-(1-benzotriazolyl) [0092]
RH=Relative Humidity [0093] TEA or Et.sub.3N=Triethylamine [0094]
THF=Tetrahydrofuran [0095] TLC=Thin Layer Chromatography [0096] XRD
X-Ray Diffraction
[0097] With reference to substituents, the term "independently"
means that when more than one of such substituents is possible,
such substituents may be the same or different from each other.
[0098] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who has been the
object of treatment, observation or experiment.
[0099] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of
the symptoms of the disease or disorder being treated.
[0100] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0101] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation to such given value that would reasonably be
inferred based on the ordinary skill in the art, including
approximations due to the experimental and/or measurement
conditions for such given value.
[0102] As used herein, unless otherwise noted, the term "leaving
group" shall mean a charged or uncharged atom or group which
departs during a substitution or displacement reaction. Suitable
examples include, but are not limited to, Br, Cl, imidazolyl, and
the like.
[0103] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Preferably, wherein the compound is
present as an enantiomer, the enantiomer is present at an
enantiomeric excess of greater than or equal to about 80%, more
preferably, at an enantiomeric excess of greater than or equal to
about 90%, more preferably still, at an enantiomeric excess of
greater than or equal to about 95%, more preferably still, at an
enantiomeric excess of greater than or equal to about 98%, most
preferably, at an enantiomeric excess of greater than or equal to
about 99%. Similarly, wherein the compound is present as a
diastereomer, the diastereomer is present at an diastereomeric
excess of greater than or equal to about 80%, more preferably, at
an diastereomeric excess of greater than or equal to about 90%,
more preferably still, at an diastereomeric excess of greater than
or equal to about 95%, more preferably still, at an diastereomeric
excess of greater than or equal to about 98%, most preferably, at
an diastereomeric excess of greater than or equal to about 99%.
[0104] Furthermore, some of the crystalline forms for the compounds
of the present invention may exist as polymorphs and as such are
intended to be included in the present invention. In addition, some
of the compounds of the present invention may form solvates with
water (i.e., hydrates) or common organic solvents, and such
solvates are also intended to be encompassed within the scope of
this invention.
[0105] One skilled in the art will recognize that wherein a
reaction step of the present invention may be carried out in a
variety of solvents or solvent systems, said reaction step may also
be carried out in a mixture of the suitable solvents or solvent
systems.
[0106] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography. The compounds may be prepared in
racemic form, or individual enantiomers may be prepared either by
enantiospecific synthesis or by resolution. The compounds may, for
example, be resolved into their component enantiomers by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as
(-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric
acid followed by fractional crystallization and regeneration of the
free base. The compounds may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column.
[0107] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known from the art.
For example, one skilled in the art will recognize that in the
processes of the present invention, it may be necessary and/or
desirable to protect substituent groups such as
(C.sub.1-8alkylcarbonyl)C.sub.1-8alkyl.
[0108] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds which are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0109] For use in medicine, the salts of the compounds of this
invention refer to non-toxic "pharmaceutically acceptable salts."
Other salts may, however, be useful in the preparation of compounds
according to this invention or of their pharmaceutically acceptable
salts. Suitable pharmaceutically acceptable salts of the compounds
include acid addition salts which may, for example, be formed by
mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid,
sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, benzoic acid, citric acid, tartaric acid, carbonic acid or
phosphoric acid. Furthermore, where the compounds of the invention
carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may include alkali metal salts, e.g., sodium or potassium
salts; alkaline earth metal salts, e.g., calcium or magnesium
salts; and salts formed with suitable organic ligands, e.g.,
quaternary ammonium salts. Thus, representative pharmaceutically
acceptable salts include the following:
[0110] acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,
chloride, clavulanate, citrate, dihydrochloride, edetate,
edisylate, estolate, esylate, fumarate, gluceptate, gluconate,
glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,
hydrobromide, hydrochloride, hydroxynaphthoate, iodide,
isothionate, lactate, lactobionate, laurate, malate, maleate,
mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,
mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
oleate, pamoate (embonate), palmitate, pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate,
sulfate, subacetate, succinate, tannate, tartrate, teoclate,
tosylate, triethiodide and valerate.
[0111] Representative acids and bases which may be used in the
preparation of pharmaceutically acceptable salts include the
following:
[0112] acids including acetic acid, 2,2-dichloroactic acid,
acylated amino acids, adipic acid, alginic acid, ascorbic acid,
L-aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucoronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hipuric acid, hydrobromic acid, hydrochloric
acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid, lactobionic acid,
maleic acid, (-)-L-malic acid, malonic acid, (.+-.)-DL-mandelic
acid, methanesulfonic acid, naphthalene-2-sulfonic acid,
naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,
nicotinc acid, nitric acid, oleic acid, orotic acid, oxalic acid,
palmitric acid, pamoic acid, phosphoric acid, L-pyroglutamic acid,
salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid,
succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid,
thiocyanic acid, p-toluenesulfonic acid and undecylenic acid;
and
[0113] bases including ammonia, L-arginine, benethamine,
benzathine, calcium hydroxide, choline, deanol, diethanolamine,
diethylamine, 2-(diethylamino)-ethanol, ethanolamine,
ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole,
L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine,
piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine,
secondary amine, sodium hydroxide, triethanolamine, tromethamine
and zinc hydroxide.
[0114] In an embodiment, the present invention is directed to
processes for the preparation of compounds of formula (II), or an
enantiomer, diastereomer, hydrate, solvate thereof, or a
pharmaceutically acceptable salt, amide or ester thereof, wherein
R.sup.11, R.sup.12, R.sup.13, R.sup.14, p and q have any of the
meanings defined hereinabove and equivalents thereof, or at least
one of the following assignments and equivalents thereof. Such
assignments may be used where appropriate with any of the
definitions, claims or embodiments defined herein:
[0115] In an embodiment, the present invention is directed to
processes for the preparation of compounds of formula (II) wherein
p is 1.
[0116] In an embodiment, the present invention is directed to
processes for the preparation of compounds of formula (II) wherein
R.sup.11 and R.sup.12 are each independently selected from the
group consisting of methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and
thiomorpholinyl, each optionally substituted as described
above.
[0117] In an embodiment, the present invention is directed to
processes for the preparation of compounds of formula (II) wherein
R.sup.11 and R.sup.12 taken together with the nitrogen to which
they are attached form 2-methylpyrrolidinyl, 3-hydroxypyrrolidinyl,
3-dimethylaminopyrrolidinyl, 2,5-dimethylpyrrolidinyl,
2-trifluoromethylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl,
piperidinyl, 4-fluoropiperidinyl, 3,3-difluoropiperidinyl,
4,4-difluoropiperidinyl, 3-trifluoromethylpiperidinyl,
4-trifluoromethylpiperidinyl, morpholinyl, 3-hydroxypiperidinyl,
4-hydroxypiperidinyl, 2-hydroxymethylpiperidinyl,
3-hydroxymethylpiperidinyl, 4-hydroxymethylpiperidinyl,
4-hydroxyethylpiperidinyl, 3-methylmorpholin-4-yl,
3-hydroxymethylmorpholin-4-yl, 2-hydroxymethylmorpholin-4-yl,
2,6-dimethylmorpholin-4-yl, thiomorpholinyl,
1,1-dioxo-thiomorpholin-4-yl, or 2-methylmorpholin-4-yl.
[0118] In another embodiment, the present invention is directed to
processes for the preparation of compounds of formula (II) wherein,
R.sup.11 and R.sup.12 taken together with the nitrogen to which
they are attached form piperidinyl, 4-fluoropiperidinyl,
4,4-difluoropiperidinyl, morpholinyl, or 3-methylmorpholin-4-yl. In
another embodiment, the present invention is directed to processes
for the preparation of compounds of formula (II) wherein R.sup.11
and R.sup.12 taken together with the nitrogen to which they are
attached form morpholinyl.
[0119] In an embodiment, the present invention is directed to
processes for the preparation of compounds of formula (II) wherein
each R.sup.13 is independently selected from the group consisting
of methyl, methoxy, and fluoro.
[0120] In an embodiment, the present invention is directed to
processes for the preparation of compounds of formula (II) wherein
q is 0.
[0121] In an embodiment, the present invention is directed to
processes for the preparation of compounds of formula (II) wherein
R.sup.14 is --H or methyl.
[0122] In an embodiment, the present invention is directed to
processes for the preparation of compounds of formula (II) that
satisfy any one of the combinations of definitions given herein and
equivalents thereof.
[0123] In an embodiment, the present invention is directed to
processes for the preparation of compounds of formula (II) selected
from the group consisting of
(4-cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
and
(4-cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methan-
one dihydrochloride.
[0124] The compounds of the present invention are modulators of the
histamine H.sub.3 receptor, and as such, the compounds are useful
in the treatment of disease states in which the histamine H.sub.3
receptor is involved. Particularly, the compounds may be used in
methods for treating or preventing neurologic or neuropsychiatric
disorders including sleep/wake and arousal/vigilance disorders
(e.g. insomnia and jet lag), attention deficit hyperactivity
disorders (ADHD), learning and memory disorders, cognitive
dysfunction, migraine, neurogenic inflammation, dementia, mild
cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy,
narcolepsy with or without associated cataplexy, cataplexy,
disorders of sleep/wake homeostasis, idiopathic somnolence,
excessive daytime sleepiness (EDS), circadian rhythm disorders,
sleep/fatigue disorders, fatigue, drowsiness associated with sleep
apnea, sleep impairment due to perimenopausal hormonal shifts,
Parkinson's-related fatigue, MS-related fatigue, depression-related
fatigue, chemotherapy-induced fatigue, eating disorders, obesity,
motion sickness, vertigo, schizophrenia, substance abuse, bipolar
disorders, manic disorders and depression, as well as other
disorders in which the histamine H.sub.3 receptor is involved, such
as upper airway allergic response, asthma, itch, nasal congestion
and allergic rhinitis in a subject in need thereof. For example,
the invention features methods for preventing, inhibiting the
progression of, or treating upper airway allergic response, asthma,
itch, nasal congestion and allergic rhinitis. Excessive daytime
sleepiness (EDS) may occur with or without associated sleep apnea,
shift work, fibromyalgia, MS, and the like.
[0125] The present invention is directed to a process for the
preparation of compounds of formula (II). The process of the
present invention is advantageous for large scale and/or commercial
purposes because it does not require isolation and/or purification
of oily intermediates; and does not require column chromatography
which is impractical and highly cost prohibitive on a large and/or
commercial scale. Additionally, the process of the present
invention may be completed in a single solvent system, whereas a
similar process, disclosed in US Patent Application Publication
2004-0010746 A1, published Apr. 21, 2005 (also published as PCT
Publication WO 2004/037801, May 6, 2004) would requires multiple
solvents (including reaction and extractive work-up solvents) if
applied to the compounds of formula (II).
[0126] The present invention is directed to a process for the
preparation of compounds of formula (II), as described in more
detail in Scheme 1, below.
##STR00017##
[0127] Accordingly, a suitably substituted compound of formula
(XX), a known compound or compound prepared by known methods, is
activated according to known methods, in a first organic solvent;
to yield the corresponding compound of formula (XXI), wherein Lisa
suitable leaving group such as chloro, bromo,
--OC(O)O--C.sub.1-4alkyl, OBt (wherein the activating agent is
HOBt), -imidazolide (wherein the activating agent is CDI), and the
like; preferably chloro.
[0128] For example, wherein L is chloro, the compound of formula
(XX) is reacted with a suitable chlorinating agent such as oxalyl
chloride, thionyl chloride, phosphorus oxychloride, and the like,
preferably about 1.05 equivalents of oxalyl chloride in the
presence of a catalytic amount of DMF; in an organic solvent such
as THF, toluene, dichloromethane, dichloroethane, acetonitrile, and
the like, preferably THF. Alternatively, the compound of formula
(XX) is reacted with Vilsmeier's reagent
(chloromethylene-dimethyl-ammonium chloride) in an organic solvent
such as DCM; at a temperature in the range of from about 0.degree.
C. to about room temperature.
[0129] The compound of formula (XXI) is not isolated.
[0130] The compound of formula (XXI) is reacted with a suitably
substituted compound of formula (XXII), a known compound or
compound prepared by known methods, wherein the compound of formula
(XXII) is preferably present in an amount equal to about one
equivalent, more preferably about 0.95 equivalents; in the presence
of an organic or inorganic base (solid or aqueous) such as TEA,
DIPEA, pyridine, NaOH, KOH, sodium carbonate, potassium carbonate,
and the like, preferably 50% aqueous NaOH; wherein the base is
organic, preferably in the absence of water; in a second organic
solvent such as THF, toluene, acetonitrile, and the like,
preferably THF; to yield the corresponding compound of formula
(XXIII).
[0131] The compound of formula (XXIII) is not isolated.
[0132] The compound of formula (XXIII) is reacted with a suitably
substituted compound of formula (XXIV), a known compound or
compound prepared by known methods, wherein the compound of formula
(XXIV) is preferably present in an amount greater than about one
equivalent, more preferably in an amount in the range of from about
1 to about 5 equivalents, more preferably still in an amount in the
range of from about 1.5 to about 2.5 equivalents, most preferably
in an amount in the range of from about 1.5 to about 2 equivalents;
in the presence of a reducing agent such as NaBH(OAc).sub.3,
NaBH.sub.4, sodium cyanoborohydride, and the like, preferably,
NaBH(OAc).sub.3; wherein the reducing agent is preferably present
in an amount in the range of from about 1 to about 2 equivalents,
more preferably in an amount in the range of from about 1.25 to
about 1.5 equivalents; in a third organic solvent such as THF,
toluene, acetonitrile, and the like, preferably, THF; to yield the
corresponding compound of formula (II).
[0133] The compound of formula (II) is further, optionally isolated
and/or purified according to known methods. Alternatively, the
compound of formula (II) is not isolated and/or purified, rather,
the compound of formula (II) is reacted according to known methods,
to yield a corresponding pharmaceutically acceptable salt of the
compound of formula (II).
[0134] Preferably, the first organic solvent, the second organic
solvent and the third organic solvent are the same. Preferably, the
conversion of the compound of formula (XX) to the corresponding
compound of formula (II) is completed in a single solvent
system.
[0135] In an embodiment of the present invention, the compound of
formula (II) is further reacted with a suitably selected
pharmaceutically acceptable acid to yield the corresponding
pharmaceutically acceptable salt of the compound of formula (II).
In an embodiment of the present invention, the compound of formula
(II) is not isolated and is reacted with a suitably selected
pharmaceutically acceptable acid to yield the corresponding
pharmaceutically acceptable salt of the compound of formula
(II).
[0136] In an embodiment, the present invention is directed to a
process for the preparation of the compound of formula (IIs), also
known as also known as
(4-cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-m-
ethanone, as described in more detail in Scheme 2, below.
##STR00018##
[0137] Accordingly, a suitably substituted compound of formula
(XXs), also known as 4-formyl-benzaldehyde, a known compound, is
activated according to known methods, in a first organic solvent,
to yield the corresponding compound of formula (XXIs), wherein L is
a suitable leaving group such as chloro, bromo,
--OC(O)O--C.sub.1-4alkyl, OBt (wherein the activating agent is
HOBt), -imidazolide (wherein the activating agent is CDI), and the
like; preferably chloro.
[0138] For example, wherein L is chloro, the compound of formula
(XXs) is reacted with a suitable chlorinating agent such as oxalyl
chloride, thionyl chloride, phosphorus oxychloride, and the like,
preferably about 1.05 equivalents of oxalyl chloride in the
presence of a catalytic amount of DM F; in an organic solvent such
as THF, toluene, dichloromethane, dichloroethane, acetonitrile, and
the like, preferably THF. Alternatively, the compound of formula
(XXs) is reacted with Vilsmeier's reagent
(chloromethylene-dimethyl-ammonium chloride) in an organic solvent
such as DCM; at a temperature in the range of from about 0.degree.
C. to about room temperature.
[0139] The compound of formula (XXIs) is not isolated.
[0140] The compound of formula (XXIs) is reacted with a suitably
substituted compound of formula (XXIIs), also known as
N-cyclopropyl-piperazine, a known compound, wherein the compound of
formula (XXIIs) is preferably present in an amount equal to about
one equivalent, more preferably about 0.95 equivalents; in the
presence of an organic or inorganic base (solid or aqueous) such as
TEA, DIPEA, pyridine, NaOH, KOH, sodium carbonate, potassium
carbonate, and the like, preferably 50% aqueous NaOH; wherein the
base is organic, preferably in the absence of water; in a second
organic solvent such as THF, toluene, acetonitrile, and the like,
preferably THF; to yield the corresponding compound of formula
(XXIIIs), also known as
4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde.
[0141] The compound of formula (XXIIIs) is not isolated.
[0142] The compound of formula (XXIIIs) is reacted with a suitably
substituted compound of formula (XXIVs), also known as morpholine,
a known compound, wherein the compound of formula (XXIVs) is
preferably present in an amount greater than about one equivalent,
more preferably in an amount in the range of from about 1 to about
5 equivalents, more preferably still in an amount in the range of
from about 1.5 to about 2.5 equivalents, most preferably in an
amount in the range of from about 1.5 to about 2 equivalents; in
the presence of a reducing agent such as NaBH(OAc).sub.3,
NaBH.sub.4, sodium cyanoborohydride, and the like, preferably,
NaBH(OAc).sub.3; wherein the reducing agent is preferably present
in an amount in the range of from about 1 to about 2 equivalents,
more preferably in an amount in the range of from about 1.25 to
about 1.5 equivalents; in a third organic solvent such as THF,
toluene, acetonitrile, and the like, preferably, THF; to yield the
corresponding compound of formula (IIs), also known as
(4-cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone.
[0143] The compound of formula (IIs) is further, optionally
isolated and/or purified according to known methods. Alternatively,
the compound of formula (IIs) is not isolated and/or purified,
rather, the compound of formula (IIs) is reacted according to known
methods, to yield a corresponding pharmaceutically acceptable salt
of the compound of formula (IIs).
[0144] In an embodiment of the present invention, the compound of
formula (IIs) is further reacted with a suitably selected
pharmaceutically acceptable acid to yield the corresponding
pharmaceutically acceptable salt of the compound of formula (IIs).
In an embodiment of the present invention, the compound of formula
(IIs) is not isolated and is reacted with a suitably selected
pharmaceutically acceptable acid to yield the corresponding
pharmaceutically acceptable salt of the compound of formula
(IIs).
[0145] The present invention is further directed to a process for
the preparation of compounds of formula (II) comprising preparation
of a bisulfite intermediate (a compound of formula (XXVII)) in the
Schemes which follow herein) which may be isolated as a solid,
thereby providing an advantageous means of purification and/or
improved stability and shelf-life relative to the aldehyde
intermediate (a compound of formula (XXIII) in the Schemes which
follow herein).
[0146] In an embodiment, the present invention is directed to a
process for the purification of the aldehyde intermediate, a
compound of formula (XXIII), comprising preparation of its
corresponding bisulfite derivative, isolation of said bisulfite
derivative as a solid, and optionally purification according to
known methods, for example recrystallization from a suitable
solvent such as methanol, ethanol, isopropanol, acetonitrile, and
the like, preferably ethanol. The bisulfite derivative may then be
further reacted as described herein to yield the desired compound
of formula (II) or alternatively, may be reacted to re-form the
compound of formula (XXIII), which is then reacted according to the
processes as described herein, to yield the desired compound of
formula (II).
[0147] Compounds of formula (II) may alternatively be prepared
according to the process as described in more detail in Scheme 3,
below.
##STR00019##
[0148] Accordingly, a suitably substituted compound of formula
(XX), a known compound or compound prepared by known methods, is
activated according to known methods, to yield the corresponding
compound of formula (XXI), wherein L is a suitable leaving group
such as chloro, bromo, --OC(O)O--C.sub.1-4alkyl, OBt (wherein the
activating agent is HOBt), -imidazolide (wherein the activating
agent is CDI), and the like; preferably chloro.
[0149] For example, wherein L is chloro, the compound of formula
(XX) is reacted with a suitable chlorinating agent such as oxalyl
chloride, thionyl chloride, phosphorus oxychloride, and the like,
preferably about 1.05 equivalents of thionyl chloride in the
presence of a catalytic amount of DM F; in an organic solvent such
as THF, toluene, dichloromethane, dichloroethane, acetonitrile, and
the like, preferably THF. Alternatively, the compound of formula
(XX) is reacted with Vilsmeier's reagent
(chloromethylene-dimethyl-ammonium chloride) in an organic solvent
such as DCM; at a temperature in the range of from about 0.degree.
C. to about room temperature.
[0150] Preferably, the compound of formula (XXI) is not
isolated.
[0151] The compound of formula (XXI) is reacted with a suitably
substituted compound of formula (XXII), a known compound or
compound prepared by known methods, wherein the compound of formula
(XXII) is preferably present in an amount equal to about one
equivalent, more preferably about 0.95 equivalents; in the presence
of an organic or inorganic base (solid or aqueous) such as TEA,
DIPEA, pyridine, NaOH, KOH, sodium carbonate, potassium carbonate,
and the like, preferably TEA; wherein the base is organic,
preferably in the absence of water; in an organic solvent such as
THF, toluene, acetonitrile, and the like, preferably THF; to yield
the corresponding compound of formula (XXIII).
[0152] Preferably, the compound of formula (XXIII) is not
isolated.
[0153] The compound of formula (XXIII) is reacted with a suitable
source of bisulfite such as NaHSO.sub.3, KHSO.sub.3, and the like,
preferably aqueous NaHSO.sub.3; wherein the source of bisulfite is
preferably present in an amount greater than or equal to about one
equivalent, more preferably in an amount in range of from about 1
to about 2 equivalents, more preferably still in an amount equal to
about 1.2 equivalents; in a polar organic solvent such as methanol,
ethanol, THF, DMF, acetonitrile, and the like, preferably ethanol;
to yield the corresponding bisulfite, the compound of formula
(XXVII).
[0154] Preferably, the compound of formula (XXVII) is isolated by
known methods, for example by filtration and washing with a
suitable organic solvent such ethanol, hexane, and the like; and
then further, optionally purified, by known methods, for example by
recrystallization from a suitable solvent such as methanol,
ethanol, isopropanol, acetonitrile, and the like, preferably
ethanol.
[0155] The compound of formula (XXVII) is reacted in a 2-step or
1-step process, wherein the bisulfite is reacted to liberate the
corresponding aldehyde, the compound of formula (XXIII) and the
aldehyde compound of formula (XXIII) is reacted with the compound
of formula (XXIV) to yield the corresponding compound of formula
(II).
[0156] More specifically, the compound of formula (XXVII) is
reacted with a suitably substituted compound of formula (XXIV), a
known compound or compound prepared by known methods, wherein the
compound of formula (XXIV) is preferably present in an amount
greater than about one equivalent, more preferably in an amount in
the range of from about 1 to about 2 equivalents; more preferably
still, about 2 equivalents; in the presence of a reducing agent
such as NaBH(OAc).sub.3, NaBH.sub.4, sodium cyanoborohydride, and
the like, preferably, NaBH(OAc).sub.3; wherein the reducing agent
is preferably present in an amount in the range of from about 1 to
about 2 equivalents, more preferably in an amount in the range of
from about 1.25 to about 1.5 equivalents; in the presence of an
organic or inorganic base such as TEA, DIPEA, pyridine, NaOH, KOH,
and the like, preferably 10% aqueous NaOH; in an organic solvent
such as dichloroethane, THF, toluene, acetonitrile, and the like,
preferably, dichloroethane; optionally in the presence of a source
of acid such as the acid clay Montmorillonite K-10 (available from
Aldrich), Nafion-H (CA Reg. No. 63937-00-8), and the like; to yield
the corresponding compound of formula (II).
[0157] One skilled in the art will recognize that wherein the
amount of the compound of formula (XXIV) is greater than or equal
to about 2 equivalents, then one equivalent of the compound of
formula (XXIV) acts as the organic or inorganic base to liberate
the aldehyde, the compound of formula (XXIII) and therefore,
additional organic or inorganic base is not necessary.
[0158] Alternatively, the compound of formula (XXVII) is reacted
with an organic or inorganic base such as TEA, DIPEA, pyridine,
NaOH, KOH, and the like, preferably 10% aqueous NaOH; wherein the
base is preferably present in an amount greater than or equal to
about 1 equivalent, more preferably in an amount in the range of
from about 1 to about 2 equivalents; according to known methods to
remove the bisulfite and liberate the corresponding compound of
formula (XXIII).
[0159] The compound of formula (XXIII) is then reacted with a
suitably substituted compound of formula (XXIV), wherein the
compound of formula (XXIV) is preferably present in an amount
greater than or equal to about 1 equivalent, preferably in an
amount in the range of form about 1 equivalent to about 2
equivalents; in the presence of a reducing agent such as
NaBH(OAc).sub.3, NaBH.sub.4, sodium cyanoborohydride, and the like,
preferably, NaBH(OAc).sub.3; wherein the reducing agent is
preferably present in an amount in the range of from about 1 to
about 2 equivalents, more preferably in an amount in the range of
from about 1.25 to about 1.5 equivalents; optionally in the
presence of a source of acid such as the acid clay Montmorillonite
K-10 (available from Aldrich), Nafion-H (CA Reg. No. 63937-00-8)
and the like; in an organic solvent such as THF, toluene,
acetonitrile, and the like, preferably, THF; to yield the
corresponding compound of formula (II).
[0160] Preferably, the compound of formula (II) is isolated
according to known methods, for example by solvent evaporation. The
compound of formula (II) may be further, optionally, reacted
according to known methods, to yield its corresponding
pharmaceutically acceptable salt.
[0161] In an embodiment, the present invention is directed to a
process for the preparation of the compound of formula (IIs), also
known as
(4-cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,
as described in more detail in Scheme 4 below.
##STR00020##
[0162] Accordingly, a suitably substituted compound of formula
(XXs), also known as 4-formyl-benzaldehyde, a known compound, is
activated according to known methods, to yield the corresponding
compound of formula (XXIs), wherein L is a suitable leaving group
such as chloro, bromo, --OC(O)O--C.sub.1-4alkyl, OBt (wherein the
activating agent is HOBt), -imidazolide (wherein the activating
agent is CDI), and the like; preferably chloro.
[0163] For example, wherein L is chloro, the compound of formula
(XXs) is reacted with a suitable chlorinating agent such as oxalyl
chloride, thionyl chloride, phosphorus oxychloride, and the like,
preferably about 1.05 equivalents of thionyl chloride in the
presence of a catalytic amount of DMF; in an organic solvent such
as THF, toluene, dichloromethane, dichloroethane, acetonitrile, and
the like, preferably THF. Alternatively, the compound of formula
(XXs) is reacted with Vilsmeier's reagent
(chloromethylene-dimethyl-ammonium chloride) in an organic solvent
such as DCM; at a temperature in the range of from about 0.degree.
C. to about room temperature.
[0164] Preferably, the compound of formula (XXIs) is not
isolated.
[0165] The compound of formula (XXIs) is reacted with a suitably
substituted compound of formula (XXIIs), also known as
N-cyclopropyl-piperazine, a known compound, wherein the compound of
formula (XXIIs) is preferably present in an amount equal to about
one equivalent, more preferably about 0.95 equivalents; in the
presence of an organic or inorganic base (solid or aqueous) such as
TEA, DIPEA, pyridine, NaOH, KOH, sodium carbonate, potassium
carbonate, and the like, preferably TEA; wherein the base is
organic, preferably in the absence of water; in an organic solvent
such as THF, toluene, acetonitrile, and the like, preferably THF;
to yield the corresponding compound of formula (XXIIIs).
[0166] Preferably, the compound of formula (XXIIIs) is not
isolated.
[0167] The compound of formula (XXIIIs) is reacted with a suitable
source of bisulfite such as NaHSO.sub.3, KHSO.sub.3, and the like,
preferably aqueous NaHSO.sub.3; wherein the source of bisulfite is
preferably present in an amount greater than or equal to about one
equivalent, more preferably in an amount in range of from about 1
to about 2 equivalents, more preferably still in an amount equal to
about 1.2 equivalents; in a polar organic solvent such as methanol,
ethanol, THF, DMF, acetonitrile, and the like, preferably ethanol;
to yield the corresponding bisulfite, the compound of formula
(XXVIIs).
[0168] Preferably, the compound of formula (XXVIIs) is isolated by
known methods, for example by filtration and washing with a
suitable organic solvent such ethanol, hexane, and the like; and
then further, optionally purified, by known methods, for example by
recrystallization from a suitable solvent such as methanol,
ethanol, isopropanol, acetonitrile, and the like, preferably
ethanol.
[0169] The compound of formula (XXVIIs) is reacted in a 2-step or
1-step process, wherein the bisulfite is reacted to liberate the
corresponding aldehyde, the compound of formula (XXIIIs) and the
aldehyde compound of formula (XXIIIs) is reacted with the compound
of formula (XXIVs) to yield the corresponding compound of formula
(IIs).
[0170] More specifically, the compound of formula (XXVIIs) is
reacted with a suitably substituted compound of formula (XXIVs),
also known as morpholine, a known compound, wherein the compound of
formula (XXIVs) is preferably present in an amount greater than
about one equivalent, more preferably in an amount in the range of
from about 1 to about 2 equivalents; more preferably still, about 2
equivalents; in the presence of a reducing agent such as
NaBH(OAc).sub.3, NaBH.sub.4, sodium cyanoborohydride, and the like,
preferably, NaBH(OAc).sub.3; wherein the reducing agent is
preferably present in an amount in the range of from about 1 to
about 2 equivalents, more preferably in an amount in the range of
from about 1.25 to about 1.5 equivalents; in the presence of an
organic or inorganic base such as TEA, DIPEA, pyridine, NaOH, KOH,
and the like, preferably 10% aqueous NaOH; in an organic solvent
such as dichloroethane, THF, toluene, acetonitrile, and the like,
preferably, dichloroethane; optionally in the presence of a source
of acid such as the acid clay Montmorillonite K-10 (available from
Aldrich), Nafion-H (CA Reg. No. 63937-00-8), and the like; to yield
the corresponding compound of formula (IIs).
[0171] One skilled in the art will recognize that wherein the
amount of the compound of formula (XXIVs) is greater than or equal
to about 2 equivalents, then one equivalent of the compound of
formula (XXIVs) acts as the organic or inorganic base to liberate
the aldehyde, the compound of formula (XXIIIs) and therefore,
additional organic or inorganic base is not necessary.
[0172] Alternatively, the compound of formula (XXVIIs) is reacted
with an organic or inorganic base such as TEA, DIPEA, pyridine,
NaOH, KOH, and the like, preferably 10% aqueous NaOH; wherein the
base is preferably present in an amount greater than or equal to
about 1 equivalent, more preferably in an amount in the range of
from about 1 to about 2 equivalents; according to known methods to
remove the bisulfite and liberate the corresponding compound of
formula (XXIIIs).
[0173] The compound of formula (XXIIIs) is then reacted with a
suitably substituted compound of formula (XXIVs), also known as
morpholine, a known compound, wherein the compound of formula
(XXIVs) is preferably present in an amount greater than or equal to
about 1 equivalent, preferably in an amount in the range of form
about 1 equivalent to about 2 equivalents; in the presence of a
reducing agent such as NaBH(OAc).sub.3, NaBH.sub.4, sodium
cyanoborohydride, and the like, preferably, NaBH(OAc).sub.3;
wherein the reducing agent is preferably present in an amount in
the range of from about 1 to about 2 equivalents, more preferably
in an amount in the range of from about 1.25 to about 1.5
equivalents; optionally in the presence of a source of acid such as
the acid clay Montmorillonite K-10 (available from Aldrich),
Nafion-H (CA Reg. No. 63937-00-8), and the like; in an organic
solvent such as THF, toluene, acetonitrile, and the like,
preferably, THF; to yield the corresponding compound of formula
(IIs).
[0174] Preferably, the compound of formula (IIs) is isolated
according to known methods, for example by solvent evaporation. The
compound of formula (IIs) may be further, optionally, reacted
according to known methods, to yield its corresponding
pharmaceutically acceptable salt, preferably its corresponding
di-hydrochloride salt.
[0175] The compounds or compositions of the invention may be
formulated and administered to a subject by any conventional route
of administration, including, but not limited to, intravenous,
oral, subcutaneous, intramuscular, intradermal and parenteral
administration. The quantity of the compound which is effective for
treating each condition may vary, and can be determined by one of
ordinary skill in the art.
[0176] The present invention also provides pharmaceutical
compositions comprising one or more compounds of this invention in
association with a pharmaceutically acceptable carrier and
optionally additional pharmaceutical agents such as H.sub.1
antagonists or SSRIs (Selective Serotonin Reuptake Inhibitors).
Preferably these compositions are in unit dosage forms such as
pills, tablets, caplets, capsules (each including immediate
release, timed release and sustained release formulations),
powders, granules, sterile parenteral solutions or suspensions
(including syrups and emulsions), metered aerosol or liquid sprays,
drops, ampoules, autoinjector devices or suppositories; for oral,
parenteral, intranasal, sublingual or rectal administration, or for
administration by inhalation or insufflation. Alternatively, the
composition may be presented in a form suitable for once-weekly or
once-monthly administration; for example, an insoluble salt of the
active compound, such as the decanoate salt, may be adapted to
provide a depot preparation for intramuscular injection. For
preparing solid compositions such as tablets, the principal active
ingredient is mixed with a pharmaceutical carrier, e.g.
conventional tableting ingredients such as corn starch, lactose,
sucrose, sorbitol, talc, stearic acid, magnesium stearate,
dicalcium phosphate or gums, and other pharmaceutical diluents,
e.g. water, to form a solid pre-formulation composition containing
a homogeneous mixture of a compound of the present invention, or a
pharmaceutically acceptable salt thereof. When referring to these
pre-formulation compositions as homogeneous, it is meant that the
active ingredient is dispersed evenly throughout the composition so
that the composition may be readily subdivided into equally
effective dosage forms such as tablets, pills and capsules. This
solid pre-formulation composition is then subdivided into unit
dosage forms of the type described above containing from 5 to about
1000 mg of the active ingredient of the present invention. Examples
include 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, 35 mg, 50 mg, 75 mg, 100
mg, 120 mg, 150 mg, and so on. The tablets or pills of the
disclosed compositions can be coated or otherwise compounded to
provide a dosage form affording the advantage of prolonged action.
For example, the tablet or pill can comprise an inner dosage and an
outer dosage component, the latter being in the form of an envelope
over the former. The two components can be separated by an enteric
layer, which serves to resist disintegration in the stomach and
permits the inner component to pass intact into the duodenum or to
be delayed in release. A variety of material can be used for such
enteric layers or coatings, such materials including a number of
polymeric acids with such materials as shellac, cetyl alcohol and
cellulose acetate.
[0177] The liquid forms in which the compounds and compositions of
the present invention may be incorporated for administration orally
or by injection include, aqueous solutions, suitably flavored
syrups, aqueous or oil suspensions, and flavored emulsions with
edible oils such as cottonseed oil, sesame oil, coconut oil or
peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Suitable dispersing or suspending agents for aqueous suspensions,
include synthetic and natural gums such as tragacanth, acacia,
alginate, dextran, sodium carboxymethylcellulose, methylcellulose,
polyvinyl-pyrrolidone or gelatin.
[0178] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times daily.
Furthermore, compounds for the present invention can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to
those of ordinary skill in that art. To be administered in the form
of a transdermal delivery system, the dosage administration will,
of course, be continuous rather than intermittent throughout the
dosage regimen.
[0179] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. Moreover, when desired or
necessary, suitable binders, lubricants, disintegrating agents and
coloring agents can also be incorporated into the mixture. Suitable
binders include, without limitation, starch, gelatin, natural
sugars such as glucose or beta-lactose, corn sweeteners, natural
and synthetic gums such as acacia, tragacanth or sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite,
xanthan gum and the like.
[0180] The compound of the present invention can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine or
phophatidylcholines.
[0181] Compounds of the present invention may also be delivered by
the use of monoclonal antibodies as individual carriers to which
the compound molecules are coupled. The compounds of the present
invention may also be coupled with soluble polymers as targetable
drug carriers. Such polymers can include polyvinylpyrrolidone,
pyran copolymer, polyhydroxypropylmethacrylamidephenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residue. Furthermore, the compounds of
the present invention may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for
example, polylactic acid, polyepsilon caprolactone, polyhydroxy
butyric acid, polyoesters, polyacetals, polydihydropyrans,
polycyanoacrylates and cross-linked or amphipathic block copolymers
of hydrogels.
[0182] Compounds of this invention may be administered in any of
the foregoing compositions and according to dosage regimens
established in the art whenever treatment is required.
[0183] The daily dosage of the products may be varied over a wide
range from 1 to 1,000 mg per adult human per day. For oral
administration, the compositions are preferably provided in the
form of tablets containing 1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100,
250 and 500 milligrams of the active ingredient for the symptomatic
adjustment of the dosage to the subject to be treated. An effective
amount of the drug is ordinarily supplied at a dosage level of from
about 0.01 mg/kg to about 20 mg/kg of body weight per day.
Preferably, the range is from about 0.02 mg/kg to about 10 mg/kg of
body weight per day, and especially from about 0.05 mg/kg to about
10 mg/kg of body weight per day. The compounds may be administered
on a regimen of 1 to 4 times per day.
[0184] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound used, the mode of administration, the strength of the
preparation, the mode of administration, and the advancement of the
disease condition. In addition, factors associated with the
particular patient being treated, including patient age, weight,
diet and time of administration, will result in the need to adjust
dosages.
[0185] The following Examples are set forth to aid in the
understanding of the invention, and are not intended and should not
be construed to limit in any way the invention set forth in the
claims which follow thereafter.
[0186] In the Examples which follow, some synthesis products are
listed as having been isolated as a residue. It will be understood
by one of ordinary skill in the art that the term "residue" does
not limit the physical state in which the product was isolated and
may include, for example, a solid, an oil, a foam, a gum, a syrup,
and the like.
Example 1
4-Formyl-benzoyl chloride
##STR00021##
[0188] To a thin suspension of 4-carboxybenzaldehyde (600 g, 3.92
mol) in tetrahydrofuran (2664 g, 36.57 mol) was added
dimethylformadehyde (11.48 g, 0.16 mol) and the reaction mixture
was cooled to 0-5.degree. C. with an ice bath. The reaction mixture
was then stirred at 0.degree. C. while oxalyl chloride (608.69 g,
4.70 mol) was added slowly. The reaction mixture was stirred until
it was deemed complete by .sup.1HNMR to yield the title compound.
The reaction mixture was used in the next step without further
manipulation.
[0189] .sup.1HNMR (CDCl3): 10.15 (s, 1H), 8.35 (d, 2H), 8.05 (d,
2H)
Example 2
4-(4-Isopropyl-piperazine-1-carbonyl)-benzaldehyde
##STR00022##
[0191] A solution of 4-formyl-benzoyl chloride (2.80, 16.65 mol)
(prepared as in Example 1 above) in toluene (43.3 g, 469.39 mmol)
was added slowly to a solution of NaHCO.sub.3 (0.8 g, 9.52 mmol)
and 4-isopropylpiperazine (2.50 g, 18.35 mmol) in water (5 g, 277
mmol) at 0.degree. C. The reaction mixture was vigorously stirred
until the reaction was deemed complete. The layers were split and
the toluene phase was concentrated to yield the title compound as a
yellow oil.
[0192] .sup.1HNMR (CDCl3): 10.15 (s, 1H), 7.95 (d, 2H), 7.55 (d,
2H), 3.75 (br s, 2H), 3.40 (br s, 2H), 2.75 (m, 1H), 2.55 (br s,
2H), 2.41 (br s, 2H), 1.09 (d, 6H)
Example 3
4-(4-Isopropyl-piperazine-1-carbonyl)-benzaldehyde
##STR00023##
[0194] 4-Isopropyl-piperazine (79.53 g, 0.620 mol), THF (444 g,
5.04 mol), water (36 g, 2 mol) and a 50% solution of sodium
hydroxide (130.6 g, 1.63 mol) were charged to a reaction vessel and
cooled to 0-5.degree. C. 4-Formyl-benzoyl chloride in THF (110.08
g, 0.630 mol) was added to the 4-isopropyl-piperazine reaction
mixture while maintaining the temperature below about 10.degree. C.
The resulting white suspension was stirred at room temperature
until the reaction was deemed complete. Water was added to the
reaction slurry and the resulting hazy solution was filtered over
Celite to remove insolubles. The filtered reaction solution was
settled and the water layer was removed. The product/THF layer was
dried sequentially with magnesium sulfate and molecular sieves. The
product solution (KF 0.5%) was stored at 5.degree. C. for use
without further manipulations.
Example 4
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
##STR00024##
[0196] To a solution of
4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (4.0 g, 15.38
mmol) in THF (40 mL) was added morpholine (2.9 g, 33.83 mmol), and
the resulting mixture was stirred at room temperature for 1 h
before it was cooled to 0.degree. C. with an ice bath. The reaction
mixture was then treated with NaBH(OAc).sub.3 (4.56 g, 21.53 mmol)
in portions over 15 min. The resulting suspension was stirred at
room temperature until it was deemed complete by HPLC. After
completion, 10% NaOH (25 mL) was added and the reaction was
vigorously agitated for 15 min. The phases were separated and the
aqueous layer was extracted with THF (20 mL). The organic layers
were combined, dried (MgSO.sub.4), filtered and concentrated to
yield the title compound as a yellow oil.
[0197] .sup.1H NMR (CDCl.sub.3): 7.36 (s, 4H), 3.79 (br s, 2H),
3.71 (t, 4H), 3.51 (s, 2H), 3.44 (br s, 2H), 2.76-2.69 (m, 1H),
2.59 (br s, 2H), 2.44 (t, 6H), 1.05 (d, 6H).
Example 5
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
##STR00025##
[0199] A THF solution of 1-(4-formylbenzoyl)-4-isopropylpiperazine
(containing 945 g of 1-(4-formylbenzoyl)-4-isopropylpiperazine and
3879 g of THF) was charged to a reaction vessel followed by the
addition of morpholine (576.3 g, 6.55 mol). After 20 min, the
reaction was cooled to about 0-10.degree. C. and sodium
triacetoxyborohydride (1167.3 g, 5.23 mol) was added in portions.
Upon reaction completion, 10% sodium hydroxide solution (3623.2 mL,
9.06 mol) was added slowly and the reaction mixture was stirred for
20 min. The layers were separated, and the aqueous layer was washed
with THF. The combined organic layers were dried over magnesium
sulfate. The dried THF solution of
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
was used without further manipulations.
Example 6
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
Mono-succinate Salt
##STR00026##
[0201] A THF solution (278.0 g) of crude
(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
(59.4 g, 0.179 mol) was heated to 40.degree. C. and succinic acid
(27.53 g, 0.233 mol) was added. The reaction mixture was heated to
60.degree. C. and filtered into a clean flask. The resulting
solution was re-heated to 60.degree. C. and then cooled slowly,
first to room temperature and then to -7.degree. C. The resulting
suspension was held at -7.degree. C. and filtered. The filter cake
was washed with THF (60 mL) and the solid was dried overnight at
50.degree. C. under full vacuum to yield crude mono-succinate salt
as a white solid.
[0202] A suspension of the crude mono-succinate salt (701.3 g, 1.56
mol) in ethanol (7.01 L) was heated to 60-65.degree. C. Any
insoluble material was removed by filtration. The resulting clear
solution was cooled slowly to -7.degree. C. The slurry was filtered
and washed with ethanol (700 mL). The filter cake was dried
overnight at 50.degree. C. under full vacuum to yield the
mono-succinate salt as a white crystalline solid.
[0203] M.P.: 154-156.degree. C.
[0204] Elemental Analysis For
C.sub.16H.sub.29N.sub.3O.sub.2.times.C.sub.4H.sub.6O.sub.2:
[0205] Calculated: C, 61.45; H, 7.85; N, 9.35; H.sub.2O,
<0.1%.
[0206] Found: C, 61.42; H, 7.84; N, 9.29; H.sub.2O, <0.1%.
[0207] MS: [M+H].sup.+=332; [2M+H].sup.+=685.
Example 7
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
Mono-fumarate Salt
##STR00027##
[0209] To a THF solution (40 mL) of
(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
(3.0 g, 9.0 mmol) were added THF (40 mL) and fumaric acid (3.3 g,
28.4 mmol). The resulting mixture was heated to 60.degree. C. and
stirred for 0.5 h. The resulting suspension was cooled to 0.degree.
C. and the resulting precipitate was collected by filtration,
washed with THF (20 mL), and dried in a vacuum oven at 65.degree.
C. for 20 h to yield crude title compound as a white solid.
[0210] A suspension of crude
(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,
mono-fumarate (5.7 g, 12.7 mmol) in absolute EtOH (110 mL) was
heated to 70.degree. C. Any insoluble material was removed by
filtration through a Celite pad. The filtrate was reheated to
65.degree. C. and then cooled to 0.degree. C. The precipitate was
collected by filtration and washed with MTBE (20 mL). The solids
were dried in a vacuum oven at 65.degree. C. for 20 h to yield the
title compound as a white solid.
[0211] M.P.: 196-198.degree. C.
[0212] Elemental Analysis for
C.sub.19H.sub.29N.sub.3O.sub.2.times.C.sub.4H.sub.4O.sub.4:
[0213] Calculated: C, 61.73; H, 7.43; N, 9.39.
[0214] Found: C, 61.44; H, 7.50; N, 9.30.
Example 8
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,
dihydrochloride monohydrate salt
##STR00028##
[0216] A solution of
(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
(2.0 g, 6.0 mmol) in absolute EtOH (20 mL) was treated with
HCl.sub.(g) (0.5 g, 13.7 mmol) at room temperature. The resulting
suspension was stirred for 1 h, and then MTBE (5 mL) was added. The
suspension was cooled to 0.degree. C. and filtered. The filter cake
was washed with MTBE (20 mL), and the solid was dried in a vacuum
oven at 60.degree. C. for 20 h to yield crude title compound as a
white solid.
[0217] A suspension of crude
(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,
dihydrochloride (2.1 g, 5.2 mmol) in absolute EtOH (30 mL) was
heated to 78.degree. C. and H.sub.2O (2.2 mL) was added. The
resulting solution was cooled to room temperature and MTBE (5 mL)
was added. The resulting suspension was cooled to 0.degree. C. and
filtered. The filter cake was washed with MeOH (15 mL). The solids
were dried in a vacuum oven at 105.degree. C. for 20 h to yield the
title compound as a white solid.
[0218] M.P.: decomp >220.degree. C.
[0219] Elemental Analysis for
C.sub.19H.sub.29N.sub.3O.sub.2.times.2HCl.times.H.sub.2O:
[0220] Calculated: C, 53.97; H, 7.81; N, 9.94; Cl, 16.81.
[0221] Found: C, 54.13; H, 7.50; N, 9.90; Cl, 16.68; KF: 4.02%.
Example 9
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,
dihydrobromide semi-hydrate salt
##STR00029##
[0223] To a THF solution (40 mL) of
(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
(3.0 g, 9.0 mmol) were added THF (40 mL) and 30% hydrogen bromide
solution in acetic acid (3.7 mL, 18.6 mmol) while maintaining the
temperature between 15.degree. C. and 20.degree. C. The resulting
suspension was stirred for 1 h, and then cooled to 0.degree. C. The
precipitate was collected by filtration, washed with THF (20 mL),
and dried in a vacuum oven at 65.degree. C. for 20 h to yield crude
title compound as a white solid.
[0224] A suspension of crude
(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,
dihydrobromide (4.9 g, 9.9 mmol) in MeOH (50 mL) was heated to
65.degree. C. The resulting solution was cooled to 0.degree. C. and
the precipitate was collected by filtration and washed with MeOH
(15 mL). The solids were dried in a vacuum oven at 65.degree. C.
for 20 h to yield the title compound as a white solid.
[0225] M.P.: >290.degree. C. decomp
[0226] Elemental Analysis for
C.sub.19H.sub.29N.sub.3O.sub.2.times.2HBr.times.0.5H.sub.2O:
[0227] Calculated: C, 45.39; H, 6.37; N, 8.36; Br, 31.85.
[0228] Found: C, 45.60; H, 6.32; N, 8.36; Br, 33.41.
[0229] KF: 2.02%
Example 10
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
Bis-maleate Salt
##STR00030##
[0231] To a solution of
(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
(3.0 g, 9.05 mmol) in absolute EtOH (20 mL) was added, via an
addition funnel, a solution of maleic acid (3.3 g, 19.8 mmol) in
absolute EtOH (20 mL) over 10 min. The resulting suspension was
stirred at room temperature for 15 min, at 75.degree. C. for 30
min, and was then allowed to cool to room temperature for 15 h. The
reaction mixture was cooled further to 0.degree. C. and was then
stirred for 2 h. The resulting precipitate was collected by suction
filtration and washed with cold EtOH (20 mL). The wet solid was
dried in a vacuum oven at 40.degree. C. for 6 h to yield the title
compound as crude material, as a white solid.
[0232] A suspension of the crude
(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,
bis-maleate salt (3.0 g) in absolute EtOH (30 mL) was heated at
75.degree. C. for 1 h, and the resulting solution was filtered
through a fine porosity glass frit. The filtrate was heated at
75.degree. C. and then cooled to room temperature over 2 h, with
stirring, and Et.sub.2O (10 mL) was added. The resulting suspension
was cooled to 0.degree. C. for 2 h, the precipitate was collected
by suction filtration and washed with Et.sub.2O (20 mL) under
nitrogen protection. The solids were dried in a vacuum oven at
45.degree. C. for 20 h to yield the title compound as a white
crystalline solid.
[0233] MP: 154.1.degree. C.
[0234] Elemental Analysis for C.sub.27H.sub.37N.sub.3O.sub.10:
[0235] Calculated: C, 57.54; H, 6.62; N, 7.46.
[0236] Found: C, 57.44; H, 6.66; N, 7.33.
Example 11
Analysis Protocol for Compounds Prepared as in Examples 12-29
[0237] Hewlett Packard HPLC, Zorbax Eclipse XDB-C8, 5 uM,
4.6.times.150 mm column; Solvents used were
H.sub.2O/CH.sub.3CN/0.05% Trifluoroacetic Acid; Gradient conditions
were 1%-99% CH.sub.3CN gradient over 8 min, 99% CH.sub.3CN for 2
min.
[0238] All reactions were carried out under a nitrogen
atmosphere.
[0239] Mass spectra were obtained on an Agilent series 1100 MSD
using electrospray ionization (ESI) in either positive or negative
modes as indicated.
[0240] Thin-layer chromatography was performed using Merck silica
gel 60 F.sub.254 2.5 cm.times.7.5 cm 250 .mu.m or 5.0 cm.times.10.0
cm 250 .mu.m pre-coated silica gel plates. Preparative thin-layer
chromatography was performed using EM Science silica gel 60
F.sub.254 20 cm.times.20 cm 0.5 mm pre-coated plates with a 20
cm.times.4 cm concentrating zone.
[0241] NMR spectra were obtained on either a Bruker model DPX400
(400 MHz) or DPX500 (500 MHz) spectrometer. The format of the
.sup.1H NMR data below is: chemical shift in ppm down field of the
tetramethylsilane reference (multiplicity, coupling constant J in
Hz, integration).
Example 12
1-Isopropyl piperazine dihydrochloride
##STR00031##
[0243] To a solution of tert-butyl piperazine-1-carboxylate (100 g)
and acetone (48 mL) in CH.sub.2Cl.sub.2 (1 L) was added acetic acid
(31 mL) and NaBH(OAc).sub.3 (170 g). The reaction mixture was
stirred for 18 h, then was diluted with 1 N NaOH (500 mL), and
extracted with CH.sub.2Cl.sub.2 (500 mL.times.2). The combined
organic layers were dried (Na.sub.2SO.sub.4) and concentrated to a
residue. The residue was dissolved in MeOH (200 mL) and 4 M HCl in
1,4-dioxane (700 mL) was added to the reaction mixture over a
period of several hours. After 18 h, the reaction mixture was
concentrated to yield a solid, which was washed with Et.sub.2O (500
mL.times.2) and dried overnight to yield the title compound as a
white solid.
[0244] .sup.1H NMR (CD.sub.3OD): 3.76-3.51 (m, 9H), 1.44 (d, J=6.7
Hz, 6H).
Example 13
4-Formyl-benzoyl chloride
##STR00032##
[0246] A suspension of (chloromethylene)dimethylammonium chloride
(Vilsmeier Reagent; 37.7 g, 0.280 mol) in CH.sub.2Cl.sub.2 (300 mL)
at 0.degree. C. was treated with 4-carboxybenzaldehyde (40.0 g, 267
mmol) in one portion. The reaction mixture was stirred at 0.degree.
C. for 30 min, then at room temperature for 2 h. HPLC analysis of
an aliquot of the reaction mixture quenched into MeOH indicated
consumption of 4-carboxybenzaldehyde. The reaction mixture was
filtered through a medium porosity glass frit. The filtrate,
containing the title compound, was stored at 0.degree. C., and used
in the next step without further manipulation.
Example 14
4-(4-Isopropyl-piperazine-1-carbonyl)-benzaldehyde
##STR00033##
[0248] To a suspension of isopropyl piperazine dihydrochloride salt
(52.5 g, 262 mmol) (prepared as in Example 12 above) in
CH.sub.2Cl.sub.2 was added Et.sub.3N (83.5 g, 827 mmol) and the
resulting slurry was stirred at room temperature for 1 h, then at
0.degree. C. for 30 min. The reaction mixture was filtered through
a medium porosity glass frit and the filtrate was cooled to
0.degree. C. A solution of 4-formyl benzoyl chloride in
CH.sub.2Cl.sub.2 was added via an addition funnel in a slow stream
over 30 min. The resulting mixture was stirred at 0.degree. C. for
30 min, then at room temperature for 2 h. The reaction mixture was
cooled to 0.degree. C. and filtered through a medium porosity glass
frit. The filtrate was washed with H.sub.2O, 0.5 N NaOH, and brine
(1.times.400 mL each). The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated to yield an oil (59.8 g).
Trituration of the oil with anhydrous Et.sub.2O (275 mL), followed
by removal of the solvent on a rotary evaporator yielded the title
compound as a pale yellow-brown oil.
[0249] HPLC: R.sub.T=5.43 min.
Example 15
Hydroxy-[4-(4-isopropyl-piperazine-1-carbonyl)-phenyl]-methanesulfonic
acid sodium salt
##STR00034##
[0251] A solution of
4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (20.0 g, 76.9
mmol) in EtOH (200 mL) was stirred at room temperature for 15 min.
To the resulting solution was added a solution of NaHSO.sub.3 (9.6
g) in H.sub.2O (25 mL), dropwise over 30 min. The resulting
suspension was stirred at room temperature for 2 h, then cooled to
0.degree. C. and stirred for 3 h, adding EtOH periodically (total
200 mL) to aid stirring. A precipitate formed and was collected by
suction filtration through a glass frit lined with filter paper.
The filter cake was washed with hexane (1.times.50 mL), and dried
under vacuum for 16 h to yield the title compound as a white
solid.
[0252] MP: 275.degree. C. (dec.)
[0253] The purity of the compound was determined by dissolution of
the bisulfite adduct in 1:1 1 N NaOH/MeOH and analysis by HPLC. In
addition, the liberated product was extracted into EtOAc and the
organic layer analyzed by TLC (MeOH/CH.sub.2Cl.sub.2, 1:9).
Prolonged exposure in an iodine chamber indicated a single spot
(R.sub.f=0.71).
Example 16
4-(4-Isopropyl-piperazine-1-carbonyl)-benzaldehyde
##STR00035##
[0255] To a suspension of
hydroxy-[4-(4-isopropyl-piperazine-1-carbonyl)-phenyl]-methanesulfonic
acid sodium salt (49.0 g, 135 mmol) in de-ionized H.sub.2O (490 mL)
at 0.degree. C. was added 1 N NaOH (100 mL) in 10 mL portions with
vigorous stirring. A clear solution resulted (pH 12), which was
stirred at 0.degree. C. for 1 h, then at room temperature for 30
min. The aqueous solution was extracted with EtOAc (3.times.200
mL), followed by CH.sub.2Cl.sub.2 (3.times.200 mL). The organic
layers were combined, washed with brine (1.times.300 mL), dried
(Na.sub.2SO.sub.4) and concentrated to yield the title compound as
a pale yellow oil.
[0256] HPLC: R.sub.T=5.43 min
[0257] MS (ESI): calcd. for C.sub.15H.sub.20N.sub.2O.sub.2, 260.33;
m/z found, 261.1 (M+1)
[0258] .sup.1H NMR (CDCl.sub.3): 10.1 (s, 1H), 7.96 (d, J=8.4 Hz,
2H), 7.45 (d, J=8.3 Hz, 2H), 3.83 (br s, 2H), 3.41 (br s, 2H), 2.78
(m, 1H), 2.64 (br s, 2H), 2.48 (br s, 2H), 1.08 (d, J=6.5 Hz,
6H).
Example 17
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
##STR00036##
[0260] To a solution of
4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (32.0 g, 123
mmol) in THF (650 mL) was added morpholine (21.4 g, 246 mmol), in a
slow stream via an addition funnel over 15 min, and the resulting
mixture was stirred at room temperature for 40 min. The reaction
mixture was treated with NaBH(OAc).sub.3 (38.4 g, 172 mmol) in
portions over 40 min, was stirred at room temperature for 16 h, and
then concentrated to a residue. The residue was diluted with EtOAc
(400 mL), cooled to 0.degree. C., and treated with 1 N NaOH (250
mL). The biphasic solution stirred at 0.degree. C. for 30 min. The
phases were separated and the aqueous layer was extracted with
EtOAc (2.times.200 mL) and CH.sub.2Cl.sub.2 (2.times.100 mL). The
organic layers were combined, washed with brine (1.times.300 mL),
dried (Na.sub.2SO.sub.4), and concentrated to yield the title
compound as a pale yellow oil.
[0261] HPLC: R.sub.T=4.69 min
[0262] MS (ESI): calcd. for C.sub.19H.sub.29N.sub.3O.sub.2, 331.23.
m/z found, 332.2 (M+1).
[0263] .sup.1H NMR (CDCl.sub.3): 7.36 (s, 4H), 3.79 (br s, 2H),
3.71 (t, J=4.7 Hz, 4H), 3.51 (s, 2H), 3.44 (br s, 2H), 2.76-2.69
(m, 1H), 2.59 (br s, 2H), 2.44 (t, J=4.4 Hz, 6H), 1.05 (d, J=6.5
Hz, 6H).
Example 18
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,
bis-maleate salt
##STR00037##
[0265] To a solution of
(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
(34.0 g, 102.7 mmol) in absolute EtOH (200 mL) was added, via an
addition funnel, a solution of maleic acid (23.9 g, 206 mmol) in
absolute EtOH (200 mL) over 15 min. The resulting suspension was
stirred at room temperature for 30 min, at 75.degree. C. for 1 h,
and was then allowed to cool to room temperature over 16 h. The
reaction mixture was cooled further to 0.degree. C. and was stirred
for 2 h. The reaction mixture was diluted with Et.sub.2O (50 mL)
and stirred for 30 min. The resulting precipitate was collected by
suction filtration, washed with cold EtOH/Et.sub.2O (4:1, 100
mL.times.2), and dried in a vacuum oven at 40.degree. C. for 20 h
to yield the title compound as crude material, as a white
solid.
[0266] A suspension of the crude
(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,
bis-maleate salt (90.5 g) in absolute EtOH (905 mL) was heated at
75.degree. C. for 1 h, and the resulting solution was filtered
through a fine porosity glass frit. The filtrate was cooled to room
temperature over 20 h, with stirring. The resulting suspension was
cooled to 0.degree. C. for 2 h, and the precipitate was collected
by suction filtration and washed with Et.sub.2O (2.times.200 mL).
The solids were dried in a vacuum oven at 40.degree. C. for 20 h to
yield the title compound as a white crystalline solid.
[0267] MP: 148-150.degree. C.
[0268] MS (ESI): calcd. for C.sub.19H.sub.29N.sub.3O.sub.2, 331.23.
m/z found, 332.2 (M+1)
[0269] .sup.1H NMR (CD.sub.3OD): 7.54-7.48 (m, 4H), 6.26 (s, 4H),
4.23 (s, 2H), 3.85 (br m, 8H), 3.56 (br s, 1H), 3.42-3.32 (br s,
4H), 3.13 (br s, 4H), 1.38 (d, J=6.6 Hz, 6H). Anal. calcd. for
C.sub.27H.sub.37N.sub.3O.sub.10: C, 57.54; H, 6.62; N, 7.46. Found:
C, 57.52; H, 6.73; N, 7.54.
Example 19
4-Formyl-benzoyl chloride
##STR00038##
[0271] A solution of 4-carboxybenzaldehyde (30.0 g, 0.200 mol) in
toluene (300 mL) was treated with thionyl chloride (28.6 g, 0.240
mol) and DMF (1.0 mL). The reaction mixture was heated at
100.degree. C. for 2 h, during which time the solids dissolved to
yield a pale yellow colored solution. The reaction mixture was
cooled to 0.degree. C. to yield a solution of the title compound in
toluene, which was used without further manipulation.
Example 20
Hydroxy-[4-(4-isopropyl-piperazine-1-carbonyl)-phenyl]-methanesulfonic
acid sodium salt
##STR00039##
[0273] A solution of NaOH (24.0 g, 0.600 mol) in de-ionized
H.sub.2O (240 mL) and toluene (60 mL) at 0.degree. C. was treated
with isopropyl piperazine dihydrochloride salt (39.0 g, 194 mmol).
The resulting biphasic solution was stirred at 0.degree. C. for 30
min. A solution of 4-formyl-benzoyl chloride in toluene was added
in a slow stream via an addition funnel over 1 h, with vigorous
mechanical agitation. The mixture was allowed to warm to room
temperature over 16 h, then cooled to 0.degree. C., and the pH
adjusted to 10 with 1 N NaOH. The phases were separated and the
aqueous layer was extracted with toluene (2.times.200 mL). The
organic layers were combined, washed with brine (200 mL), and
concentrated to yield
4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (52.5 g, mass
balance 101%) as a pale, yellow-brown oil. The oil was dissolved in
EtOH (600 mL) and, with vigorous mechanical agitation, was treated
with a solution of NaHSO.sub.3 (23.1 g, 222 mmol) in de-ionized
H.sub.2O (50 mL) which was added via an addition funnel over 30
min. The resulting mixture was stirred at room temperature for 48
h, and then cooled to 0.degree. C. Methyl-tert-butyl ether (500 mL)
was added and the resulting the slurry was stirred for 30 min. The
precipitate was collected by suction filtration through a medium
porosity glass frit, washed with cold EtOH/EtOAc (5:1, 3.times.60
mL). The solids were dried under vacuum for 2 h, then at 40.degree.
C. in a vacuum oven for 16 h to yield the title compound as a white
solid.
[0274] HPLC: R.sub.T=5.43 min
[0275] MP: 275.degree. C. (dec.)
Example 21
(4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone
##STR00040##
[0277] A mixture of
hydroxy-[4-(4-isopropyl-piperazine-1-carbonyl)-phenyl]-methanesulfonic
acid sodium salt (54.6 g, 0.150 mol), piperidine (28.0 g, 0.330
mol), and Montmorillonite-K10 (10.9 g, 20% by wt. relative to
starting material) in dichloroethane (820 mL) was stirred at room
temperature for 16 h. NaBH(OAc).sub.3 (44.5 g, 210.0 mmol) was
added in portions over 1 h, and the resulting suspension was
stirred at room temperature for 5 h. Diatomaceous earth (5.4 g) was
added and the suspension was stirred for an additional 30 min. The
reaction mixture was filtered through a pad of diatomaceous earth,
rinsing with dichloroethane (2.times.100 mL). The filtrate was
washed with 1 N NaOH (2.times.200 mL). The aqueous layers were
combined and back-extracted with dichloroethane (2.times.100 mL).
The organic layers were combined, dried (Na.sub.2SO.sub.4), and
concentrated to yield the title compound as its corresponding free
base, as a pale yellow oil.
[0278] HPLC: R.sub.T=4.76 min
[0279] MS (ESI): calcd. for C.sub.20H.sub.31N.sub.3O, 329.25. m/z
found, 330.2 (M+1).
[0280] .sup.1H NMR (CDCl.sub.3): 7.35 (s, 4H), 3.79 (br s, 2H),
3.48 (br s, 2H), 3.45 (br s, 2H), 2.72 (m, 1H), 2.59 (br s, 2H),
2.45 (br s, 2H), 2.38 (br s, 4H), 1.60-1.55 (m, 4H), 1.48-1.40 (m,
2H), 1.06 (d, J=6.3 Hz, 6H).
Example 22
(4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone,
bis-maleate salt
##STR00041##
[0282] To a mechanically agitated solution of
(4-isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone
(40.0 g, 122 mmol) in absolute EtOH (800 mL) was added, via an
addition funnel, a solution of maleic acid (28.2 g, 243 mmol) in
absolute EtOH (200 mL) over 30 min. The resulting suspension was
stirred at room temperature for 16 h, then diluted with Et.sub.2O
(200 mL), cooled to 0.degree. C., and stirred for 2 h. The
precipitate was collected by suction filtration, washed with cold
EtOH/Et.sub.2O (4:1, 3.times.100 mL). The solids were dried under
vacuum to yield crude title compound as a white solid.
[0283] A mechanically agitated suspension of the crude material
(4-isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone,
bis-maleate salt) (89.0 g) in absolute EtOH (1780 mL) was heated at
75.degree. C. for 1 h. The resulting pale yellow solution was
allowed to cool to room temperature with stirring over 36 h, then
diluted with Et.sub.2O (220 mL), cooled to 0.degree. C., and
stirred for 3 h. The precipitate was collected by suction
filtration, washed with Et.sub.2O (2.times.100 mL). The solids were
dried under vacuum for 16 h to yield the title compound as a white
crystalline solid.
[0284] MP: 165-167.degree. C.
[0285] MS (ESI): calcd. for C.sub.20H.sub.31N.sub.3O, 329.25. m/z
found, 330.2 (M+1).
[0286] Anal. calcd. for C.sub.28H.sub.39N.sub.3O.sub.9: C, 59.88;
H, 7.00; N, 7.48.
[0287] Found: C, 59.56; H, 7.29; N, 7.40.
Example 23
Representative Examples of Reductive Amination of Bisulfite
Adducts
Method A
[0288] A suspension of benzaldehyde bisulfite adduct as listed in
Table 3 below (5.0 mmol), Montmorillonite-K10 (0.21 g), and
morpholine (10.0 mmol) in dichloroethane (20 mL) was stirred at
room temperature for 45 min. NaBH(OAc).sub.3 (7.0 mmol) was added
portion-wise over approximately 30 min. After 4 h, the reaction
mixture was diluted with EtOAc (80 mL), filtered, and washed with 1
N NaOH (25 mL) followed by brine (25 mL). The organic layer was
dried (MgSO.sub.4) and concentrated to yield 4-benzyl-morpholine as
an oil. In cases where Montmorillonite K-10 was not used, the
filtration step after completion of reaction was not necessary.
General Purification Method
[0289] The crude product from Method A was dissolved in EtOAc (50
mL) and the organic layer was extracted with 1.5 N HCl (25 mL). The
aqueous layer was basified to ca. pH 12 with 1 N NaOH, and
extracted with EtOAc (3.times.50 mL). The combined organic layers
were dried (MgSO.sub.4) and concentrated to yield the desired
product (HPLC Purity >97%).
Method B
[0290] A suspension of cyclohexanecarboxaldehyde bisulfite adduct
(5.0 mmol) and Et.sub.3N (5.5 mmol) in dichloroethane (20 mL) was
stirred at room temperature for 15 min. The suspension was treated
with N-methylbenzylamine (5.5 mmol) and was stirred for 45 min.
NaBH(OAc).sub.3 (7.0 mmol) was added portion-wise over
approximately 30 min. After 16 h, the reaction mixture was diluted
with EtOAc (80 mL), and was washed with 1 N NaOH (25 mL) followed
by brine (25 mL). The organic layer was dried (MgSO.sub.4) and
concentrated to yield benzyl-cyclohexylmethyl-methyl-amine as an
oil. The crude material was purified by the General Purification
Method as described above.
[0291] Table 9 below lists reductive amination reactions which were
completed on representative bisulfite compounds. The column
entitled "Reagents" list the reagents or reagent combination used
in the reaction to yielded the desired product as listed.
TABLE-US-00001 TABLE 9 Representative Examples of Reductive
Amination ##STR00042## Bisulfite Reagent Method Reagents Product
##STR00043## A Morpholine (2.0 equiv.) ##STR00044## ##STR00045## A
Montmorillonite K-10 + Morpholine (2.0 equiv.) ##STR00046##
##STR00047## A Piperidine (2.0 equiv.) ##STR00048## ##STR00049## A
Montmorillonite K-10 + Piperidine (2.0 equiv.) ##STR00050##
##STR00051## B TEA (1.1 equiv.) + Piperidine (1.1 equiv.)
##STR00052## ##STR00053## A Pyrrolidine (2.0 equiv.) ##STR00054##
##STR00055## B TEA (1.1 equiv.) + Pyrrolidine (1.1 equiv.)
##STR00056## ##STR00057## B TEA (1.1 equiv.) + Pyrrolidine (1.1
equiv.) ##STR00058## ##STR00059## B TEA (1.1 equiv.) + Diethylamine
(1.1 equiv.) ##STR00060## ##STR00061## B TEA (1.1 equiv.) +
Pyrrolidine (1.1 equiv.) ##STR00062## ##STR00063## B TEA (1.1
equiv.) + Morpholine (1.1 Equiv.) ##STR00064## ##STR00065## B TEA
(1.1 equiv.) + N-Methylbenzyl- amine ##STR00066## ##STR00067## B
TEA (1.2 equiv.) + 3-[4-(1-Acetyl- 2,3-dihydro-1H-
idol-6-yl)-3-oxo- 4-piperidin-4-yl- butyl]-benzonitrile (0.8
Equiv.) ##STR00068## ##STR00069## A Morpholine (2.0 equiv.)
##STR00070## ##STR00071## B TEA (1.1 equiv.); Morpholine (1.1
equiv.) ##STR00072##
Example 24
(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
##STR00073##
[0292] Step A. 4-(4-Formyl-benzoyl)-piperazine-1-carboxylic acid
tert-butyl ester
[0293] A suspension of 4-carboxybenzaldehyde (3.10 g) in
CH.sub.2Cl.sub.2 was treated sequentially with
piperazine-1-carboxylic acid tert-butyl ester (3.6 g), EDCI (3.86
g), HOBt (2.68 g), and 4-dimethylaminopyridine (0.020 g). After 18
h, the mixture was extracted with 1 N NaOH and then with 1 N HCl.
The organic layer was dried (Na.sub.2SO.sub.4) and concentrated to
yield the title compound.
[0294] MS (ESI): mass calcd. for C.sub.17H.sub.22N.sub.2O.sub.4,
318.16. m/z found, 219.3 [M-100)+H].sup.+.
[0295] .sup.1H NMR (CDCl.sub.3): 10.04 (s, 1H), 7.93 (d, J=8.2,
2H), 7.54 (d, J=8.1, 2H), 3.82-3.67 (m, 2H), 3.58-3.30 (m, 6H),
1.46 (s, 9H).
Step B. 4-(4-Morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylic
acid tert-butyl ester
[0296] A solution of 4-(4-formyl-benzoyl)-piperazine-1-carboxylic
acid tert-butyl ester (2.06 g) in methanol (100 mL) was treated
with morpholine (4 mL) and NaBH(OAc).sub.3 (6.98 g, in portions
over 1 h). After 3 h, the mixture was diluted with saturated
aqueous NaHCO.sub.3 and extracted with CH.sub.2Cl.sub.2. The
organic layer was dried (Na.sub.2SO.sub.4) and concentrated. The
residue was purified by column chromatography (SiO.sub.2) to yield
the title compound.
[0297] MS (ESI): mass calcd. for C.sub.21H.sub.31N.sub.3O.sub.4,
389.23. m/z found, 390.4 [M+H].sup.+.
[0298] .sup.1H NMR (CDCl.sub.3): 7.39-7.33 (m, 4H), 3.75-3.66 (m,
6H), 3.50 (s, 2H), 3.51-3.33 (m, 6H), 2.45-2.41 (m, 4H), 1.46 (s,
9H).
Step C.
(4-Morpholin-4-ylmethyl-phenyl)-piperazin-1-yl-methanone
[0299] A solution of
4-(4-morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylic acid
tert-butyl ester (1.163 g) in CH.sub.2Cl.sub.2 (10 mL) was treated
with trifluoroacetic acid (.about.4 mL). After 30 min, additional
trifluoroacetic acid (5 mL) was added, and the mixture was stirred
for a further 2 h. The mixture was diluted with diluted with
saturated aqueous NaHCO.sub.3 and extracted with CH.sub.2Cl.sub.2.
The organic layer was dried (Na.sub.2SO.sub.4) and concentrated.
The residue was purified by column chromatography (SiO.sub.2) to
yield the title compound.
[0300] MS (ESI): mass calcd. for C.sub.16H.sub.23N.sub.3O.sub.2,
289.18. m/z found, 290.4 [M+H].sup.+.
[0301] 1H NMR (CDCl.sub.3): 7.41-7.35 (m, 4H), 3.95-3.70 (m, 6H),
3.52 (s, 2H), 3.09-2.80 (m, 6H), 2.49-2.42 (m, 4H).
Step D.
(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-met-
hanone
[0302] A solution of
(4-morpholin-4-ylmethyl-phenyl)-piperazin-1-yl-methanone (0.128 g)
in methanol (7.5 mL) was treated with
(1-ethoxy-cyclopropoxy)-trimethyl-silane (1.5 mL), acetic acid (0.2
mL), and NaBH.sub.3CN (.about.400 mg). The mixture was heated at
60.degree. C. for 18 h, and then was cooled to room temperature and
concentrated. The residue was diluted with 1 N NaOH and extracted
with CH.sub.2Cl.sub.2. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated. The residue was purified by
column chromatography (SiO.sub.2) to yield the title compound.
[0303] MS (ESI): mass calcd. for C.sub.19H.sub.27N.sub.3O.sub.2,
329.21. m/z found, 330.4 [M+H].sup.+.
[0304] .sup.1H NMR (CDCl.sub.3): 7.36 (s, 4H), 3.79-3.68 (m, 6H),
3.50 (s, 2H), 3.44-3.32 (m, 2H), 2.74-2.61 (m, 2H), 2.60-2.50 (s,
2H), 2.45-2.40 (m, 4H), 1.66-1.62 (m, 1H), 0.49-0.44 (m, 2H),
0.44-0.39 (m, 2H).
Example 25
(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
##STR00074##
[0305] Step A. tert-Butyl 4-cyclopropylpiperazine-1-carboxylate
[0306] A mixture of tert-butyl piperazine-1-carboxylate (75.0 g),
THF (500 mL), methanol (500 mL),
[(1-ethoxycyclopropyl)oxy]trimethylsilane (161 mL), NaBH.sub.3CN
(38.0 g), and acetic acid (37 mL) was heated at 60.degree. C. for 5
h. The mixture was cooled to room temperature, treated with water
(30 mL) and stirred for 5 min. The mixture was then treated with 1
N NaOH (130 mL) and was further stirred for 15 min. The mixture was
concentrated, and the remaining aqueous solution was extracted with
CH.sub.2Cl.sub.2 (500 mL). The organic layer was washed with 1 N
NaOH (500 mL). The combined aqueous layers were extracted with
CH.sub.2Cl.sub.2 (150 mL). The combined organic layers were washed
with brine (400 mL), dried (Na.sub.2SO.sub.4), and concentrated to
yield the title compound as a white solid.
[0307] MS (ESI): mass calcd. for C.sub.12H.sub.22N.sub.2O.sub.2,
226.17. m/z found, 227.2 [M+H.sup.+].
[0308] .sup.1H NMR (400 MHz, CDCl.sub.3): 3.39 (t, J=5.0 Hz, 4H),
2.55 (t, J=4.9 Hz, 4H), 1.60 (ddd, J=10.3, 6.5, 3.8 Hz, 1H), 1.46
(s, 9H), 0.49-0.38 (m, 4H).
Step B. 1-Cyclopropylpiperazine dihydrochloride
[0309] A solution of tert-butyl
4-cyclopropylpiperazine-1-carboxylate (92 g) in 1,4-dioxane (200
mL) was treated with HCl (4 M in 1,4-dioxane, 500 mL) over 10 min
while maintaining the temperature below 40.degree. C. After the
addition was complete, the mixture was heated at 45.degree. C. for
9 h and then was cooled to room temperature. The thick suspension
was diluted with hexanes (400 mL) and was cooled to 10.degree. C.
The resulting solid was collected by filtration, washed with
hexanes, and dried to yield the title compound as a white
solid.
[0310] MS (ESI): mass calcd. for C.sub.7H.sub.14N.sub.2, 126.12.
m/z found, 127.0 [M+H.sup.+].
[0311] .sup.1H NMR (400 MHz, D.sub.2O): 3.65 (br t, J=4.7 Hz, 4H),
3.47 (br t, J=5.5 Hz, 4H), 2.85 (br quintet, J=5.8 Hz, 1H), 0.94
(br s, 2H), 0.92 (br s, 2H).
Step C. 4-(4-Cyclopropyl-piperazine-1-carbonyl)-benzaldehyde
[0312] A mixture of 4-formyl-benzoic acid (54.4 g), toluene (500
mL), DMF (3.6 mL), and thionyl chloride (30.4 mL) was heated at
60.degree. C. for 2 h and then was cooled to 5.degree. C. In a
separate flask, a 5.degree. C. mixture of NaOH (50.7 g), water (550
mL), and toluene (150 mL) was treated with 1-cyclopropyl-piperazine
dihydrochloride (70.0 g) in portions while the temperature was
maintained below 10.degree. C. After the addition was complete, the
mixture was cooled to 5.degree. C. and treated with the crude acyl
chloride solution prepared as above at a rate such that the
temperature did not exceed 10.degree. C. After the addition was
complete, the mixture was allowed to warm to room temperature and
was stirred overnight. The biphasic mixture was basified to pH
.about.10 with 1 N NaOH (300 mL). The layers were separated and the
aqueous layer was extracted with toluene (100 mL.times.2). The
combined organic layers were washed with brine (200 mL), dried
(Na.sub.2SO.sub.4), and concentrated to yield the title compound as
pale yellow viscous oil.
[0313] HPLC: R.sub.T=5.19 min
[0314] MS (ESI): mass calcd. for C.sub.15H.sub.18N.sub.2O.sub.2,
258.14. m/z found, 258.9 [M+H.sup.+].
[0315] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.1 (s, 1H), 7.94
(pseudo d, J=8.2 Hz, 2H), 7.56 (pseudo d, J=8.1 Hz, 2H), 3.77 (br
s, 2H), 3.33 (br s, 2H), 2.71 (br s, 2H), 2.55 (br s, 2H), 1.66
(ddd, J=10.2, 6.6, 3.7 Hz, 1H), 0.52-0.46 (m, 2H), 0.45-0.40 (br s,
2H).
Step D.
(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-met-
hanone
[0316] To a solution of
4-(4-cyclopropyl-piperazine-1-carbonyl)-benzaldehyde (56.0 g) in
1,2-dichloroethane (550 mL) was added morpholine (37.8 mL) dropwise
over 5 min. The mixture was cooled to 10.degree. C. and was treated
with NaBH(OAc).sub.3 (64.3 g) in portions over 1 h. After a further
2 h, the mixture was warmed to room temperature, and a water bath
was used to keep the temperature below 20.degree. C. After 18 h,
water (60 mL) was added while the temperature was kept under
20.degree. C. by the addition of small amounts of ice. After 20
min, the mixture was basified to pH .about.10 with 1 N NaOH (450
mL) and the mixture was stirred for 10 min. The layers were
separated, and the organic layer was washed with 1 N NaOH (150 mL).
The combined aqueous layers were extracted with CH.sub.2Cl.sub.2
(200 mL). The combined organic layers were washed with brine (200
mL), dried (Na.sub.2SO.sub.4), and concentrated to yield the title
compound as pale yellow viscous oil.
[0317] HPLC: R.sub.T=4.39 min
[0318] MS (ESI): mass calcd. for C.sub.19H.sub.27N.sub.3O.sub.2,
329.21. m/z found, 330.2 [M+H.sup.+].
[0319] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.35 (br s, 4H), 3.73 (br
s, 2H), 3.69 (t, J=4.6 Hz, 4H), 3.50 (s, 2H), 3.37 (br s, 2H), 2.67
(br s, 2H), 2.53 (br s, 2H), 2.43 (t, J=4.2 Hz, 4H), 1.63 (ddd,
J=10.3, 6.7, 3.7 Hz, 1H), 0.49-0.43 (m, 2H), 0.42-0.39 (br s,
2H).
[0320] .sup.13C NMR (101 MHz, CDCl.sub.3): 170.6, 140.0, 135.1,
129.5, 127.5, 67.4, 63.4, 54.0, 38.7, 6.3.
Example 26
(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
dihydrochloride salt
##STR00075##
[0322] A solution of
(4-cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
(68.0 g) in ethanol (400 mL) was heated to 60.degree. C. and
treated with concentrated HCl (37.8 mL) dropwise over 40 min. A
precipitate started to form after .about.20 mL of HCl had been
added. After the addition was complete, the thick suspension was
slowly cooled to 20.degree. C. over 3 h. The solid was collected by
filtration, washed with ethanol, and dried at 50.degree. C.
overnight in a vacuum oven to provide the title compound as a white
solid.
[0323] HPLC: R.sub.T=4.30 min
[0324] MS (ESI): mass calcd. for C.sub.19H.sub.27N.sub.3O.sub.2,
329.21. m/z found, 330.0 [M+H.sup.+].
[0325] .sup.1H NMR (400 MHz, D.sub.2O): 7.64 (pseudo d, J=8.3 Hz,
2H), 7.58 (pseudo d, J=8.3 Hz, 2H), 4.44 (br s, 2H), 4.20-3.10 (m,
16H), 2.88 (ddd, J=11.2, 6.6, 4.8 Hz, 1H), 1.03-0.98 (m, 4H)
[0326] .sup.13C NMR (101 MHz, D.sub.2O): 172.1, 135.3, 132.2,
130.9, 128.0, 64.0, 60.5, 52.6, 52.4, 51.7, 44.8, 39.7, 39.5,
3.9.
Example 27
(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
##STR00076##
[0328] Preparation and analytical data for the title compound was
presented in U.S. Patent Application Publication 2004-0110746 A1,
published Apr. 21, 2005.
Example 28
(4-Cyclobutyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone
##STR00077##
[0330] The title compound was prepared according to the methods
described in Example 23 above.
Example 29
Sodium
[4-(4-Cyclopropyl-piperazine-1-carbonyl)-phenyl]-hydroxy-methanesul-
fonate
##STR00078##
[0332] A 100 mL flask was charged with
4-(4-cyclopropyl-piperazine-1-carbonyl)-benzaldehyde (2.58 g, 10.0
mmol, 1.0 eq), acetonitrile (30 mL), and water (1.0 mL) under
nitrogen atmosphere. The reaction mixture was heated to 50.degree.
C. A solution of NaHSO.sub.3 (1.14 g, 11.0 mol, 1.1 eq) in water
(2.0 mL) was added dropwise over 5 min. The reaction mixture was
then cooled to 17.degree. C. The product was collected by
filtration as a white solid.
[0333] .sup.1H-NMR (400 MHz, D.sub.2O): .delta. 7.66 (pseudo d, 2H,
J=8.1 Hz), 7.47 (pseudo d, 2H, J=8.2 Hz), 5.58 (s, 1H), 3.74 (br s,
2H), 3.47 (br s, 2H), 2.84 (br s, 2H), 2.69 (br s, 2H), 1.85 (tt,
1H, J=7.0, 3.8 Hz), 0.60-0.54 (m, 2H), 0.49-0.44 (m, 2H)
[0334] MS (ESI-): mass calculated for
C.sub.15H.sub.19N.sub.2O.sub.5S, 339.1. m/z found, 339.0
[M-Na].sup.-.
Example 30
[0335] As a specific embodiment of an oral composition, 100 mg of
the compound prepared as in Example 26 is formulated with
sufficient finely divided lactose to provide a total amount of 580
to 590 mg to fill a size 0 hard gel capsule.
[0336] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *