U.S. patent application number 09/862171 was filed with the patent office on 2002-03-14 for 2-cyclohexyl quinazoline nmda/nr2b antagonists.
Invention is credited to Claremon, David A., McCauley, John A., Munson, Peter M., Thompson, Wayne.
Application Number | 20020032207 09/862171 |
Document ID | / |
Family ID | 46149971 |
Filed Date | 2002-03-14 |
United States Patent
Application |
20020032207 |
Kind Code |
A1 |
Thompson, Wayne ; et
al. |
March 14, 2002 |
2-Cyclohexyl quinazoline NMDA/NR2B antagonists
Abstract
4-substituted cyclohexanes substituted in the 1-position with
quinazoline either directly or through a C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, amino, aminoC.sub.1-C.sub.4alkyl,
hydroxyC.sub.1-C.sub.4alkyl, carbonyl, cycloC.sub.3-C.sub.6alkyl or
aminocarbonyl chain are effective as NMDA NR2B antagonists useful
for relieving pain.
Inventors: |
Thompson, Wayne; (Lansdale,
PA) ; Claremon, David A.; (Maple Glen, PA) ;
Munson, Peter M.; (Harleysville, PA) ; McCauley, John
A.; (Maple Glen, PA) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Family ID: |
46149971 |
Appl. No.: |
09/862171 |
Filed: |
May 21, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09862171 |
May 21, 2001 |
|
|
|
09696612 |
Oct 25, 2000 |
|
|
|
6291499 |
|
|
|
|
60162714 |
Oct 29, 1999 |
|
|
|
Current U.S.
Class: |
514/266.3 ;
544/287 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 417/12 20130101; A61P 25/06 20180101; C07D 235/10 20130101;
A61P 25/28 20180101; C07D 235/08 20130101; C07D 235/12 20130101;
C07D 405/12 20130101; C07D 235/16 20130101; C07D 235/30 20130101;
C07D 403/12 20130101; C07D 235/14 20130101 |
Class at
Publication: |
514/259 ;
544/287 |
International
Class: |
A61K 031/517; C07D
239/72 |
Claims
What is claimed is:
1. A compound having the formula: 158or a pharmaceutically
acceptable salt thereof, wherein R.sub.1 is 2-quinazoline;
optionally substituted with fluoro, amino, or hydroxy; R.sub.2 is
phenyl, optionally substituted with one to five substituents, each
substituent independently being chloro, fluoro, bromo,
C.sub.1-C.sub.4alkyl, trifluoromethyl, hydroxy, or carboxy; L.sub.1
and L.sub.2 are independently C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, amrino, aminoC.sub.1-C.sub.4alkyl,
hydroxyC.sub.1-C.sub.4alkyl, carbonyl, cycloC.sub.3-C.sub.6alkyl or
aminocarbonyl; A.sub.1, A.sub.2, and A.sub.3 are each hydrogen or
i) A.sub.1 and A.sub.2 form a two carbon bridge or ii) A.sub.1 and
A.sub.3 form a two carbon bridge; and optionally substituted with
X, wherein X is hydroxy, amino, C.sub.1-C.sub.4alkylamin- o,
di(C.sub.1-C.sub.4)alkylamino, C.sub.1-C.sub.4alkyl, ester,
carbamate, carbonate, or ether.
2. The compound according to claim 1, wherein said compound is
159or a pharmaceutically acceptable salt thereof.
3. A pharmaceutical composition comprising an inert carrier and an
effective amount of a compound according to claim 1.
4. The pharmaceutical composition according to claim 3 useful for
the treatment of pain.
5. The pharmaceutical composition according to claim 3 useful for
the treatment of migraine, depression, anxiety, schizophrenia,
Parkinson's disease, or stroke.
6. A method of treating pain comprising a step of administering to
one in need of such treatment an effective amount of a compound
according to claim 1.
7. A method of treating migraine, depression, anxiety,
schizophrenia, Parkinson's disease, or stroke comprising a step of
administering to one in need of such treatment an effective amount
of a compound according to claim 1.
Description
[0001] This is a continuation-in-part of U.S. patent application
No. 09/696,612, filed Oct. 25, 2000, which claims the benefit of
U.S. patent application No. 60/162,714, filed Oct. 29, 1999.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] This invention relates to novel 2-cyclohexyl quinazolines.
In particular, this invention relates to novel 4-substituted
cyclohexanes substituted in the I-position with 2-benzimidazoles,
2-imidazopyridines, or 4-imidazoles either directly or through a
C.sub.1-C.sub.4alkyl, cycloalkyl, hydroxyalkyl, alkoxy or
aminoalkyl chain that are effective as NMDA NR2B antagonists useful
for relieving pain.
[0003] Ions such as glutamate play a key role in processes related
to chronic pain and pain-associated neurotoxicity--primarily by
acting through N-methyl-D-aspartate ("NMDA") receptors. Thus,
inhibition of such action--by employing ion channel antagonists,
particularly NMDA antagonists--can be beneficial in the treatment
and control of pain.
[0004] Known NMDA antagonists include ketamine, dextromorphan, and
3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ("CPP").
Although these compounds have been reported (J. D. Kristensen, et
al., Pain, 51:249-253 (1992); K. Eide, et al., Pain, 61:221-228
(1995); D. J. Knox, et al., Anaesth. Intensive Care 23:620-622
(1995); and M. B. Max, et al., Clin. Neuropharmacol. 18:360-368
(1995)) to produce symptomatic relief in a number of neuropathies
including postherpetic neuralgia, central pain from spinal cord
injury, and phantom limb pain, widespread use of these compounds is
precluded by their undesirable side effects. Such side effects at
analgesic doses include psychotomimetic effects such as dizziness,
headache, hallucinations, dysphoria, and disturbances of cognitive
and motor function. Additionally, more severe hallucinations,
sedation, and ataxia are produced at doses only marginally higher
than analgesic doses. Thus, it would be desirable to provide novel
NMDA antagonists that are absent of undesirable side effects or
that produce fewer and/or milder side effects.
[0005] NMDA receptors are heteromeric assemblies of subunits, of
which two major subunit families designated NR1 and NR2 have been
cloned. Without being bound by theory, it is generally believed
that the various functional NMDA receptors in the mammalian central
nervous system ("CNS") are only formed by combinations of NR1 and
NR2 subunits, which respectively express glycine and glutamate
recognition sites. The NR2 subunit family is in turn divided into
four individual subunit types: NR2A, NR2B, NR2C, and NR2D. I.
Ishii, et al., J. Biol. Chem., 268:2836-2843 (1993), A. Wenel, et
al., Neural Report, 7:45-48 (1995), and D. J. Laurie et al., Mol.
Brain Res., 51:23-32 (1997) describe how the various resulting
combinations produce a variety of NMDA receptors differing in
physiological and pharmacological properties such as ion gating
properties, magnesium sensitivity, pharmacological profile, as well
as in anatomical distribution.
[0006] For example, while NR1 is found throughout the brain, NR2
subunits are differentially distributed. In particular, it is
believed that the distribution map for NR2B lowers the probability
of side effects while producing pain relief. For example, S. Boyce,
et al., Neurophannacology, 38:611-623(1999) describes the effect of
selective NMDA NR2B antagonists on pain with reduced side-effects.
Thus, it would be desirable to provide novel NMDA antagonists that
target the NR2B receptor.
[0007] International Patent Publication WO94/21615 describes
benzimidazole-piperidine compounds utilized as dopamine D4
antagonists. Phenol compounds described as NMDA antagonists are
described in U.S. Pat. Nos. 5,306,723 and 5,436,255, and in
International Patent Publications WO91/17156, WO92/19502,
WO93/02052, WO94/29571, WO95/28057, WO96/37226, and EP 04422506.
Benzyl piperidines substituted with phenols or imidazoles are
described in Z.-L. Zhou, et al., J. Medicinal Chemistry,
42:2993-3000(1999); T. F. Gregory, et al., Poster #94, 218.sup.th
National Meeting American Chemical Society, New Orleans, La., Aug.
22-26, 1999. Other NMDA NR2B selective compounds are described in
European Patent Publication EP 787493 and British J. Pharnacol.,
123:463(1998). However, there continues to be a need for novel NMDA
antagonists that target the NR2B receptor.
SUMMARY OF THE INVENTION
[0008] The present invention relates to novel 2-cyclohexyl
quinazolines. The present invention also forms novel pharmaceutical
compositions utilizing these novel compounds. Further, this
invention includes novel methods to treat pain by utilizing the
novel compounds.
DETAILED DESCRIPTION OF THE INVENTION
[0009] In one aspect, the compounds of this invention are
represented by Formula (I): 1
[0010] or pharmaceutically acceptable salts thereof, wherein
[0011] R.sub.1 is 2-benzimidazole, 2-imidazopyridine, or
2-quinazoline; optionally substituted with fluoro, amino, or
hydroxy;
[0012] R.sub.2 is phenyl, optionally substituted with one to five
substituents, each substituent independently being chloro, fluoro,
bromo, C.sub.1-C.sub.4alkyl, trifluoromethyl, hydroxy, or
carboxy;
[0013] L.sub.1 and L.sub.2 are independently C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, amino, aminoC.sub.1-C.sub.4alkyl,
hydroxyC.sub.1-C.sub.4alkyl, carbonyl, cycloC.sub.3-C.sub.6alkyl or
aminocarbonyl;
[0014] A.sub.1, A.sub.2, and A.sub.3 are each hydrogen or i)
A.sub.1 and A.sub.2 form a two carbon bridge or ii) A.sub.1 and
A.sub.3 form a two carbon bridge; and
[0015] optionally substituted with X, wherein X is hydroxy, amino,
C.sub.1-C.sub.4alkylamino, di(C.sub.1-C.sub.4)alkylamino,
C.sub.1-C.sub.4alkyl, ester, carbamate, carbonate, or ether.
[0016] In an embodiment, the compound of this invention is
represented by Formula (I) or a pharmaceutically acceptable salt
thereof, wherein
[0017] R.sub.1 is 2-benzimidazole;
[0018] R.sub.2 is phenyl, optionally substituted with one to five
substituents, each substituent independently being chloro, fluoro,
bromo, Cl-C4alkyl, trifluoromethyl, hydroxy, or carboxy;
[0019] L.sub.1 and L.sub.2 are independently C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, amino, aminoC.sub.1-C.sub.4alkyl,
hydroxyC.sub.1-C.sub.4alkyl, carbonyl, cycloC.sub.3-C.sub.6alkyl or
aminocarbonyl;
[0020] A.sub.1, A.sub.2, and A.sub.3 are each hydrogen or i)
A.sub.1 and A.sub.2 form a two carbon bridge or ii) A.sub.1 and
A.sub.3 form a two carbon bridge; and
[0021] optionally substituted with X, wherein X is hydroxy, amino,
C.sub.1-C.sub.4alkylamino, di(C.sub.1-C.sub.4)alkylamino,
C.sub.1-C.sub.4alkyl, ester, carbamate, carbonate, or ether.
[0022] As used herein, "alkyl" as well as other groups having the
prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl,
alkynyl and the like, means carbon chains which may be linear or
branched or combinations thereof. Examples of alkyl groups include
methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl,
pentyl, hexyl, heptyl and the like. "Alkenyl", "alkynyl" and other
like terms include carbon chains containing at least one
unsaturated C--C bond.
[0023] The term "cycloalkyl" means carbocycles containing no
heteroatoms, and includes mono-, bi- and tricyclic saturated
carbocycles, as well as fused ring systems. Such fused ring systems
can include one ring that is partially or fully unsaturated such as
a benzene ring to form fused ring systems such as benzofused
carbocycles. Cycloalkyl includes such fused ring systems as
spirofused ring systems. Examples of cycloalkyl include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl,
1,2,3,4-tetrahydronaphalene and the like. Similarly, "cycloalkenyl"
means carbocycles containing no heteroatoms and at least one
non-aromatic C--C double bond, and include mono-, bi- and tricyclic
partially saturated carbocycles, as well as benzofused
cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,
indenyl, and the like.
[0024] Unless otherwise stated, the terms "carbonyl" and
"aminocarbonyl" include short C.sub.1--C.sub.2 termini. The terms
include, for example, --CO--, --CONH--, --CH.sub.2CO--,
--CH2CONH--, --C.sub.2H.sub.4CO--, --C.sub.2H.sub.4CONH--,
--COCH.sub.2--, --CONHCH.sub.2--, --COC.sub.2H.sub.4--,
--CONHC.sub.2H.sub.4--, --CH.sub.2COCH.sub.2--,
--CH.sub.2CONHCH.sub.2--, --CH.sub.2COC.sub.2H.sub.4--,
--CH.sub.2CONHC.sub.2H.sub.4--, --C.sub.2H.sub.4COC.sub.2H.sub.4--,
and --C.sub.2H.sub.4CONHC.sub.2H.sub.4--. Similarly, unless
otherwise stated, the term "aminoC.sub.1-C.sub.4alkyl" includes
short C.sub.1-C.sub.2 termini. The term includes, for example,
--CH.sub.2NH--, --C.sub.2H.sub.4NH--, --C.sub.3H.sub.6NH--,
--C.sub.4H.sub.8NH--, --CH.sub.2NHCH.sub.2--,
--C.sub.2H.sub.4NHCH.sub.2--, --C.sub.3H.sub.6NHCH.sub.2--,
--C.sub.4H.sub.8NHCH.sub.2--, --CH.sub.2NHC.sub.2H.sub.4--,
--C.sub.2H.sub.4NHC.sub.2H.sub.4--,
--C.sub.3H.sub.6NHC.sub.2H.sub.4--,
--C.sub.4H.sub.8NHC.sub.2H.sub.4--, --NHCH.sub.2--,
--NHC.sub.2H.sub.4--, --NHC.sub.3H.sub.6--, --NHC.sub.4H.sub.8--,
--CH.sub.2NHC.sub.2H.sub.4--, --CH.sub.2NHC.sub.3H.sub.6--,
--CH.sub.2NHC.sub.4H.sub.8--, --C.sub.2H.sub.4NHC.sub.3H.sub.6--,
and --C.sub.2H.sub.4NHC.sub.4H.sub.8-- -.
[0025] Unless otherwise stated, the term "carbamate" is used to
include --OCOOC.sub.1-C.sub.4alkyl, --NHCOOC.sub.1-C.sub.4alkyl,
and --OCONHC.sub.1-C.sub.4alkyl.
[0026] The term "halogen" includes fluorine, chlorine, bromine and
iodine atoms.
[0027] The term "SEM" is used to describe
--CH.sub.2--O--CH.sub.2CH.sub.2-- -Si(CH.sub.3).sub.3.
[0028] The term "C.sub.0" means that the carbon is not present.
Thus, "C.sub.0-C.sub.5" means that there are from none to five
carbons present--that is, five, four, three, two, one, or no
carbons present. Accordingly, "C.sub.0-C.sub.5alkyl" means a direct
bond for the case of "C.sub.0".
[0029] The term "optionally substituted" is intended to include
both substituted and unsubstituted. Thus, for example, optionally
substituted aryl could represent a pentafluorophenyl or a phenyl
ring.
[0030] Compounds described herein contain one or more asymmetric
centers and may thus give rise to diastereomers and optical
isomers. The present invention includes all such possible
diastereomers as well as their racemic mixtures, their
substantially pure resolved enantiomers, all possible geometric
isomers, and pharmaceutically acceptable salts thereof. The above
Formula I is shown without a definitive stereochemistry at certain
positions. The present invention includes all stereoisomers of
Formula I and pharmaceutically acceptable salts thereof. Further,
mixtures of stereoisomers as well as isolated specific
stereoisomers are also included. During the course of the synthetic
procedures used to prepare such compounds, or in using racemization
or epimerization procedures known to those skilled in the art, the
products of such procedures can be a mixture of stereoisomers.
[0031] The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids.
When the compound of the present invention is acidic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic bases, including inorganic
bases and organic bases. Salts derived from such inorganic bases
include aluminum, ammonium, calcium, copper (ic and ous), ferric,
ferrous, lithium, magnesium, manganese (ic and ous), potassium,
sodium, zinc and the like salts. Particularly preferred are the
amrnmonium, calcium, magnesium, potassium and sodium salts. Salts
derived from pharmaceutically acceptable organic non-toxic bases
include salts of primary, secondary, and tertiary amines, as well
as cyclic amines and substituted amines such as naturally occurring
and synthesized substituted amines. Other pharmaceutically
acceptable organic non-toxic bases from which salts can be formed
include ion exchange resins such as, for example, arginine,
betaine, caffeine, choline, N,N'-dibenzylethylenediamine,
diethylarnine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediaamine, N-ethylmorpholine,
N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine,
piperidine, polyamine resins, procaine, purines, theobromine,
triethylamine, trimethylamine, tripropylamine, tromethamine and the
like.
[0032] When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
and organic acids. Such acids include, for example, acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
and tartaric acids.
[0033] The pharmaceutical compositions of the present invention
comprise a compound represented by Formula I (or pharmaceutically
acceptable salts thereof) as an active ingredient, a
pharmaceutically acceptable carrier and optionally other
therapeutic ingredients or adjuvants. The compositions include
compositions suitable for oral, rectal, topical, and parenteral
(including subcutaneous, intramuscular, and intravenous)
administration, although the most suitable route in any given case
will depend on the particular host, and nature and severity of the
conditions for which the active ingredient is being administered.
The pharmaceutical compositions may be conveniently presented in
unit dosage form and prepared by any of the methods well known in
the art of pharmacy.
[0034] In practice, the compounds represented by Formula I, or
pharmaceutically acceptable salts thereof, of this invention can be
combined as the active ingredient in intimate admixture with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of
forms depending on the form of preparation desired for
administration, e.g., oral or parenteral (including intravenous).
Thus, the pharmaceutical compositions of the present invention can
be presented as discrete units suitable for oral administration
such as capsules, cachets or tablets each containing a
predetermined amount of the active ingredient. Further, the
compositions can be presented as a powder, as granules, as a
solution, as a suspension in an aqueous liquid, as a non-aqueous
liquid, as an oil-in-water emulsion or as a water-in-oil liquid
emulsion. In addition to the common dosage forms set out above, the
compound represented by Formula I, or pharmaceutically acceptable
salts thereof, may also be administered by controlled release means
and/or delivery devices. The compositions may be prepared by any of
the methods of pharmacy. In general, such methods include a step of
bringing into association the active ingredient with the carrier
that constitutes one or more necessary ingredients. In general, the
compositions are prepared by uniformly and intimately admixing the
active ingredient with liquid carriers or finely divided solid
carriers or both. The product can then be conveniently shaped into
the desired presentation.
[0035] Thus, the pharmaceutical compositions of this invention may
include a pharmaceutically acceptable carrier and a compound or a
pharmaceutically acceptable salt of Formula I. The compounds of
Formula I, or pharmaceutically acceptable salts thereof, can also
be included in pharmaceutical compositions in combination with one
or more other therapeutically active compounds.
[0036] The pharmaceutical carrier employed can be, for example, a
solid, liquid, or gas. Examples of solid carriers include lactose,
terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, and stearic acid. Examples of liquid carriers are sugar
syrup, peanut oil, olive oil, and water. Examples of gaseous
carriers include carbon dioxide and nitrogen.
[0037] In preparing the compositions for oral dosage form, any
convenient pharmaceutical media may be employed. For example,
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like may be used to form oral liquid
preparations such as suspensions, elixirs and solutions; while
carriers such as starches, sugars, microcrystalline cellulose,
diluents, granulating agents, lubricants, binders, disintegrating
agents, and the like may be used to form oral solid preparations
such as powders, capsules and tablets. Because of their ease of
administration, tablets and capsules are the preferred oral dosage
units whereby solid pharmaceutical carriers are employed.
Optionally, tablets may be coated by standard aqueous or nonaqueous
techniques
[0038] A tablet containing the composition of this invention may be
prepared by compression or molding, optionally with one or more
accessory ingredients or adjuvants. Compressed tablets may be
prepared by compressing, in a suitable machine, the active
ingredient in a free-flowing form such as powder or granules,
optionally mixed with a binder, lubricant, inert diluent, surface
active or dispersing agent. Molded tablets may be made by molding
in a suitable machine, a mixture of the powdered compound moistened
with an inert liquid diluent. Each tablet preferably contains from
about 1 mg to about 500mg of the active ingredient and each cachet
or capsule preferably containing from about 1 to about 500mg of the
active ingredient.
[0039] Pharmaceutical compositions of the present invention
suitable for parenteral administration may be prepared as solutions
or suspensions of the active compounds in water. A suitable
surfactant can be included such as, for example,
hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols, and mixtures thereof in
oils. Further, a preservative can be included to prevent the
detrimental growth of microorganisms.
[0040] Pharmaceutical compositions of the present invention
suitable for injectable use include sterile aqueous solutions or
dispersions. Furthermore, the compositions can be in the form of
sterile powders for the extemporaneous preparation of such sterile
injectable solutions or dispersions. In all cases, the final
injectable form must be sterile and must be effectively fluid for
easy syringability. The pharmaceutical compositions must be stable
under the conditions of manufacture and storage; thus, preferably
should be preserved against the contaminating action of
microorganisms such as bacteria and fungi. The carrier can be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (e.g. glycerol, propylene glycol and liquid
polyethylene glycol), vegetable oils, and suitable mixtures
thereof.
[0041] Pharmaceutical compositions of the present invention can be
in a form suitable for topical use such as, for example, an
aerosol, cream, ointment, lotion, dusting powder, or the like.
Further, the compositions can be in a form suitable for use in
transdermal devices. These formulations may be prepared, utilizing
a compound represented by Formula I of this invention, or
pharmaceutically acceptable salts thereof, via conventional
processing methods. As an example, a cream or ointment is prepared
by mixing hydrophilic material and water, together with about 5 wt
% to about 10 wt % of the compound, to produce a cream or ointment
having a desired consistency.
[0042] Pharmaceutical compositions of this invention can be in a
form suitable for rectal administration wherein the carrier is a
solid. It is preferable that the mixture forms unit dose
suppositories. Suitable carriers include cocoa butter and other
materials commonly used in the art. The suppositories may be
conveniently formed by first admixing the composition with the
softened or melted carrier(s) followed by chilling and shaping in
moulds.
[0043] In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above may include, as
appropriate, one or more additional carrier ingredients such as
diluents, buffers, flavoring agents, binders, surface-active
agents, thickeners, lubricants, preservatives (including
anti-oxidants) and the like. Furthermore, other adjuvants can be
included to render the formulation isotonic with the blood of the
intended recipient. Compositions containing a compound described by
Formula I, or pharmaceutically acceptable salts thereof, may also
be prepared in powder or liquid concentrate form.
[0044] Experimental Protocols
[0045] Assessing the Activity of Selected Compounds to Inhibit
NR1A2B NMDA Receptor Activation (FLIPR Assay)
[0046] The activity of selected compounds to inhibit NR1A/2B NMDA
receptor activation measured as NR1A/2B receptor-mediated Ca.sup.2+
influx is assessed by the following procedure:
[0047] NR1A/2B receptor transfected L(tk) cells are plated in
96-well format at 3.times.10.sup.6 cells per plate and grown for
one-two days in normal growth media (Dulbeccos MEM with Na
pyruvate, 4500 mgglucose, pen/strep, glutamine, 10% FCS and 0.5
mg/ml geneticin). NR1A/2B-expression in these cells is induced by
the addition of 4 nM dexamethasone in the presence of 500 .mu.M
ketamine for 16-24 hours. After receptor induction cells are washed
using a Labsystem Cellwasher two times with assay buffer (Hanks
balanced salt solution (HBSS-Mg.sup.++ free) containing 20 mnM
HEPES, 0.1% BSA, 2 mM CaCl.sub.2 and 250 .mu.M probenecid). The
cells of each 96 well cell plate are loaded with the Ca.sup.++
sensitive dye Fluo-3 (Molecular Probes, Inc.) at 4 .mu.M in assay
buffer containing 0.5% FBS, and 0.04% pluronic F-127 (Molecular
Probes, Inc.) for 1 h at 37.degree. C. avoiding light. The cells
are then washed with the Cellwasher four times with assay buffer
leaving them in 100 .mu.l buffer. Test compounds in solution are
pipetted by FLIPR (Fluorometric Imaging Plate Reader) into each
test well for a 2 min pretreatment. During this time the
fluorescence intensity is recorded (excitation at 488 nm and
emission at 530 nm). The glutamate/glycine 50 .mu.l agonist
solution (final concentration 1 .mu.M/1 .mu.M) is then added by
FLIPR into each well already containing 150 .mu.l of buffer
(containing the test compound or vehicle) and the fluorescence is
continuously monitored for 10 min. The endpoint fluorescence values
are used to determine an IC.sub.50 value comparing the
agonist-stimulated signal for the vehicle alone sample and that for
the cells incubated with each concentration of test compound.
[0048] Determining the Apparent Dissociation Constant (Ki) of
Compounds for Human NR1A/NR2B Receptors (Binding Assay):
[0049] The radioligand binding assay is performed at room
temperature in 96-well microtiter plates with a final assay volume
of 1.0 mL in 20 mM Hepes buffer (pH 7.4) containing 150 mM NaCl.
Solutions of test compounds were prepared in DMSO and serially
diluted with DMSO to yield 20 .mu.L of each of 10 solutions
differing by 3-fold in concentration. Non-specific binding (NSB)
using hot AMD-1 (10 .mu.M final concentration) and total binding
(TB) by using DMSO (2% final concentration). A solution of
NR1A/NR2B receptors (40 pM final concentration) and tritiated AMD-2
(1 nM final concentration) were added to the test compounds. After
3 h of incubation at room temperature, samples are filtered through
Packard GF/B filters (presoaked in 0.05% PEI, polyethyleninine
Sigma P-3143) and washed 10 times with 1 mL of cold 20 mM Hepes
buffer per wash. After vacuum drying of the filter plates, 40 .mu.L
of Packard Microscint-20 was added and bound radioactivity
determined in a Packard TopCount. The apparent dissociation
constant (Ki), the maximum percentage inhibition (%I.sub.max), the
minimum percentage inhibition (%I.sub.min) and the hill slope (nH)
were determined by a non-linear least squares fitting the bound CPM
data to Equation #1 below. Equation#1: 1 CPM Bound = ( SB ) ( % I
max - % I min ) ( 1 + ( [ Drug ] / ( Ki [ L - 844 , 345 ] / K D ) )
nH ) + NSB + ( SB ) ( 1 - % I max )
[0050] where, K.sub.D is the apparent dissociation constant for the
radioligand for the receptor as determined by hot saturation and SB
is the specifically bound CPM determined from the difference of TB
and NSB. 2
[0051] Compounds AMD-1 and AMD-2 can be synthesized in accordance
with the following general reaction schemes. 3
[0052] In accordance with scheme 1, hydrogen chloride is bubbled
through a solution of the appropriately substituted benzonitrile 1
in methanol at room temperature. The volatiles are removed under
reduced pressure and the resulting residue is triturated with ether
and filtered to yield the desired imidate 2. imidate 2 is dissolved
in methanol at ambient temperature, treated with amine 3 at ambient
temperature and stirred under argon. The volatiles are removed
under reduced pressure and the residue purified by preparative HPLC
or trituration with ether to afford amidine Ia. 4
[0053] In accordance with scheme 2, at room temperature under
argon, anine 3a is dissolved in ether and was treated with 1M
hydrogen chloride in ether (I equiv.) in a single portion. The
resulting precipitate is stirred vigorously for 10 minutes. The
volatiles are removed under reduced pressure. The residue is
suspended in toluene, cooled to 0.degree. C. under argon, treated
with 2.0-M trimethylaluminum (1.05 equiv.) in a dropwise manner,
and stirred for 45 minutes at room temperature to afford
intermediate 6 (not isolated). Compound 6 is added to a solution of
nitrile I in toluene. The reaction is heated to 80.degree. C.
without stirring in a sealed tube for 18h, cooled to ambient
temperature, poured onto a silica gel column and eluted with
methanol/dichloromethane to give the amidine 4. 5
[0054] Tritiated AMD-1 was prepared by the following procedure: A
mixture of AMD-1, hydrochloride salt, (5 mg, 0.012 mmol) in dioxane
(0.2 mL) containing triethylamine (4 .mu.L) was treated with
hexamethylditin (5 .mu.L), a catalytic amount of palladium catalyst
and heated at 100.degree. C. for 45 minutes. The reaction was
cooled to room temperature, filtered through a glass wool plug,
rinsed with methanol and concentrated in vacuo to give 10.7 mg of a
brown oil. The oil was dissolved in methylene chloride and passed
through a small silica column eluting with methylene chloride
followed by 5% methanol/methylene chloride. Fractions containing
the trimethylstannane (Rf 0.26 in 10% methanol/methylene chloride)
were pooled and concentrated in vacuo to give 4.5mg of the
trimethylstannane as a clear colorless oil. This material was
further purified by BPLC (C18 Econosil, 10.times.250 mm, 20 minute
linear gradient, 30% MeCN:70% H.sub.2O (0.1% TFA) to 90% MeCN, 3
ml/min, 254 nm, retention time 15 minutes) to give 3mg of the
trimethylstannane.
[0055] A Na.sup.125I shipping vial (10 mL, Amersham) was charged
with a stir bar, an iodobead, 50 .mu.L of methanol and stirred five
minutes at room temperature. A solution of the trimethylstannane
(0.1 mg) in 50 .mu.L of methanol containing 5 .mu.L of
trifluoroacetic acid was added and the reaction was stirred for
five minutes. The reaction was quenched with 50 .mu.L of ammonium
hydroxide and purified by BPLC (C18 Vydac protein and peptide
column, 4.6.times.250 mm, 20 minute linear gradient, 30% MeCN:70%
H.sub.20 (0.1% TFA) to 90% MeCN, 1 mL/min, retention time 11
minutes). Fractions containing the radioactive product were pooled
and concentrated in vacuo to give 989 .mu.Ci of [.sup.125I]AMD-1
with a specific activity of 898 Ci/mmol as measured by LW
absorbance at 272 nm.
[0056] Synthesis of Tritiated AMD-2
[0057] Tritiated AMD-2 was prepared by the following procedure: The
phenol of AMD-2 (2 mg, 0.008 mmol) dissolved in dimethylformamide
(0.6 mL) and potasium carbonate (1.2 mg) for 1 hr. High specific
activity tritiated methyl iodide (50 mCi, 0.0006 mmol, in toluene 1
mL, American Radiolabeled Chemicals) was added at room temperature
and stirred for 2 hours. The reaction mixture was filtered using a
Whatman PTFE 0.45 .mu.m syringeless filter device to remove any
insoluable potassium carbonate, washed with Abs. ethanol (2 mL,
Pharmco), and the combined filtrates were concentrated to dryness
at room temperature using a rotary evaporator; this also removed
any unreacted tritiated methyl iodide. The residue was purified by
HPLC chromatography on a Phenomenx Luna C8 semi-prep column (Luna 5
micro C8(2), 250.times.10.0 mm) using a gradient system of 20/80
acetonitrile/water with 0.1% trifluoroacetic acid to 100%
acetronitrile with 0.1% trifluoroacetic acid in 20 min. Total
activity of the product was 8 mCi. Further purification was
effected by absorption onto a Waters C-18 Sep-pak column (Waters
Sep-Pak PLUS C18) and elution with water followed by absolute
ethanol. The product was diluted with absolute ethanol (10 mL)
before submission for final analysis.
[0058] The compounds of this invention exhibit less than 50 .mu.M
in the FLIBR and binding assays. Thus, the compounds and
pharmaceutical compositions of this invention have been found to
exhibit biological activity as NMDA NR2B antagonists. Accordingly,
another aspect of the invention is the treatment of pain, migraine,
depression, anxiety, schizophrenia, Parkinson's disease, or
stroke--maladies that are amenable to amelioration through
inhibition of NMDA NR2B receptors--by the administration of an
effective amount of the compounds of this invention.
[0059] The following examples are provided to more fully illustrate
the present invention, and are not to be construed as limiting the
scope of the claims in any manner.
EXAMPLES
[0060] The compounds of this invention can be prepared according to
Scheme 1 shown below: 6
[0061] The compounds of this invention can be prepared according to
Scheme 2 shown below: 7
[0062] The compounds of this invention can be prepared according to
Scheme 3 shown below: 8
[0063] The compounds of this invention can be prepared according to
Scheme 4 shown below: 9
[0064] The compounds of this invention can be prepared according to
Scheme 5 shown below: 10
[0065] The compounds of this invention can be prepared according to
Scheme 6 shown below: 11
EXAMPLE 1
[0066] 12
[0067] 2-(4-Benzyl-cyclohexylidenemethyl)-1H-benzimidazole
[0068] Example 1 was prepared by the following procedure. 13
[0069] 8-Benzylidene-1,4-dioxa-spiro[4.5]decane:
[0070] To a stirred solution of 20g of
1,4-dioxa-spiro[4.5]decan-8-one and 35 g of diethyl
benzylphosphonate in 60 mL of 1,3-dimethyl-2-imidazolidin- one
dried over 4 .ANG. mol sieves was added 7 g of 60% NaH oil
dispersion. The mixture was allowed to stir overnight, diluted with
500 mL of water and extracted with 3.times.100 mL of ether.
Combined extracts were dried over magnesium sulfate and
concentrated under reduced pressure. Chromatography over silica gel
eluting with a gradient of 5:95 ethyl acetate:hexane to 1:3 ethyl
acetate:hexane gave 28 g of olefin as a colorless oil. 14
[0071] 8-Benzyl-1,4-dioxa-spiro[4.5]decane:
[0072] A solution of 28 g of
8-benzylidene-1,4-dioxa-spiro[4.5]decane and 1 g of 5% palladium on
carbon in 250 mL of ethanol was allowed to stir overnight under
latm of hydrogen. The catalyst was filtered off and the solution
concentrated to give 28 g of 8-benzyl-1,4-dioxa-spiro[4.5]decane as
an oil. 15
[0073] 4-Benzyl-cyclohexanone:
[0074] A mixture of 28g of 8-benzyl-1,4-dioxa-spiro[4.5]decane, 100
mL of water, 10 mL of methanol and 20 g of Amberlite.TM.
IR-120.sup.+ was heated to reflux for 5 h. After cooling, removal
of solvents under reduced pressure gave 24 g of
4-benzyl-cyclohexanone as an oil. 16
[0075] 2-(4-Benzyl-cyclohexylidenemethyl)-1H-benzimidazole:
[0076] A stirred solution of 0.5 g of 4-benzyl-cyclohexanone, 1.0 g
of 2-benzimidazolylmethyltriphenylphosphonium chloride and 15 mL of
anhydrous DMSO was heated gently until a clear solution was
obtained, then cooled to room temperature. To this solution was
added 90 mg of 60% sodium hydride oil dispersion. The resulting
orange solution was stirred for 48h at room temperature, then
quenched with 200 mL of water and extracted into 3.times.50 mL
portions of ethyl acetate. The combined extracts were dried over
magnesium sulfate and concentrated. Purification by preparative TLC
eluting with 25% ethyl acetate in hexane gave 220 mg of a white
solid: MS (m+1)=303.4; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.5 (m,
2H), 7.2-7.0 (3 x m, 7H), 6.2 (s, 1H), 3.75 (d, 1H), 2.45 (dd, 2H),
2.3 (d, 1H), 2.2 (t, 1 H), 2.05 (m, 1H), 1.8 (m, 4H), 1.05 (m,
2H).
EXAMPLE 2
[0077] 17
[0078] 2-(4-Benzyl-cyclohexylmethyl)-1H-benzimidazole:
[0079] Hydrogenation of 0.10 g of
2-(4-benzyl-cyclohexylidenemethyl)-1H-be- nzimidazole over 0.05 g
of 5% platinum on carbon in lOniL of ethanol at latm overnight gave
O.lg of 2-(4-benzyl-cyclohexylmethyl)-1H-benoimidazol- e as a 2:1
mixture of cis and trans isomers. Chromatography on a Chiralpak.TM.
column eluting with a gradient of 70:30 to 30:70 hexane and
2-propanol gave 2-(4-benzyl-cyclohexylmethyl)-1H-benoimidazole:
RT???min; MS (m+1)=; .sup.1H NMR (400 MHz, CDCl.sub.3) min; MS
(m+1)=; .sup.1H NMR (400 MHz, CDCl.sub.3)
[0080] Later fractions yielded
2-(4-benzyl-cyclohexylmethyl)-1H-benoimidaz- ole; MS (m+1)=;
.sup.1H NMR (400 MHz, CDCl.sub.3)
EXAMPLE 3
[0081] 18
[0082] (1H-Benzoimidazol-2-yl)-(4-benzyl-cyclohexyl)-methanol:
[0083] Example 3 was prepared by the following procedure. To a
stirred solution of 20 mg of
2-(4-benzyl-cyclohexylidenemethyl)-1H-benzimidazole in 10 mL of TMF
cooled in an ice bath was added 1 mL of 1 M borane.cndot.THF. After
stirring for 24 h warming to room temperature, 0.5 mL of water was
added followed by 0.5 mL of 6N sodium hydroxide and 0.5 mL of 30%
hydrogen peroxide. After 30min, the solution was diluted with lOOmL
of chloroform, washed 2.times.10 mL of water, dried over magnesium
sulfate and concentrated to dryness.
[0084] Preparative thin-layer chromatography eluting with 25% ethyl
acetate in hexane gave 11 mg of (.+-.)-cis and trans
(1H-benzimidazol-2-yl)-(4- benzyl-cyclohexyl)-methanol as a gummy
resin: MS (m+1)=321.4; .sup.1H NMR (400 MHz, CDC;.sub.3) 7.6 (m,
2H), 7.2 (m, 7H), 4.85 and 4.8 (2 x d, 1H), 2.6 and 2.42 (2 x d,
2H).
EXAMPLE 4
[0085] 19
[0086]
2-[3-(4--Chloro-benzyl)-bicyclo[3.2.1]oct-8-ylmethyl]-1H-benzimidaz-
ole
[0087] Example 4 was prepared by the following procedure. 20
[0088] Ethylene ketal of
3-(4-chloro-benzylidene)-bicyclo[3.2.1]octan-8-on- e:
[0089] To a stirred solution of lg of 3-mono-ethylene ketal of
bicyclo[3.2.1]octane-3,8-dione (prepared by Jones oxidation of the
mono-ethylene ketal of 3-endo-hydroxy-bicyclo[3.2.l]octan-8-one
which was prepared by the procedure described by M. Povarny, P.
Schreiber, G. Kraiss and K. Nador, Tetrahedron Letters,
25:1311-12(1984) and 2.4 g of diethyl 4-chlorobenzylphosphonate in
5 mL of 1 ,3-dimethyl-2-imidazolidin- one dried over 4 .ANG. mol
sieves was added 0.30 g of 60% NaH oil dispersion. The mixture was
allowed to stir overnight, diluted with 200 mL of water and
extracted with 3.times.100 mL of ethyl acetate. Combined extracts
were dried over magnesium sulfate and concentrated under reduced
pressure. Low pressure chromatography over silica gel eluting with
a gradient of 5:95 ethyl acetate:hexane to 1:3 ethyl acetate:hexane
gave 1.9 g of the ethylene ketal of
3-(4-chloro-benzylidene)-bicyclo[3.2.I]oct- an-8-one as a colorless
oil. 21
[0090] Ethylene ketal of
3-(4-chloro-benzyl)-bicyclo[3.2.1]octan-8-one:
[0091] Hydrogenation of 1.9 g of the ethylene ketal of
3-(4-chloro-benzylidene)-bicyclo[3.2.1]octan-8-one over 0.4 g of 5%
platinum on carbon in 50 mL of ethanol under 1 atm of hydrogen for
3 h gave 1.9 g the ethylene ketal of
3-(4-chloro-benzyl)-bicyclo[3.2.1]octan-- 8-one as a thick oil:
.sup.1H NMR (400 MHz, CDCl.sub.3): The crude product was a 3:1
mixture of exo:endo by peak integration of the exo benzylic protons
at 2.45 (d):endo benzylic protons at 2.78 (d). 22
[0092] 3-(4--Chloro-benzyl)-bicyclo[3.2.1]octan-8-one:
[0093] A stirred mixture of 1 .9 g of the ethylene ketal of
3-(4-chloro-benzyl)-bicyclo[3.2.1]octan-8-one, 10 mL of dioxane, 50
mL of water and 5 g of Amberlite.TM. IR-120+ was heated to reflux
for 8 h, cooled, fitered and extracted into 5.times.50 mL of ether.
Combined extracts were dried over magnesium sulfate and
concentrated. The crude 3:1 mixture of exo and endo
3-(4-chloro-benzyl)-bicyclo[3.2.1]octan-8-one- , 1.3 g, was an oi.
23
[0094]
2-[3-(4--Chloro-benzyl)-bicyclo[3.2.1]oct-8-ylidenemethyl]-1H-benzi-
midazole:
[0095] To a stirred solution of 0.25 g of 2-benzimidazolylmethyl
triphenyl phosphonium chloride and 0.1 g of
3-(4-chloro-benzyl)-bicyclo[3.2.1]octan- -8-one in 5 mL of DMSO
(heat to dissolve) at room temperature was added 60 mg of sodium
hydride 60% oil dispersion. After the orange-red mixture was
stirred for 24 h, conversion was complete and the solution was
diluted with 100 mL of water and extracted into 3.times.25 mL of
ethyl acetate. Combined extracts were dried over magnesium sulfate
and concentrated. Purification by chromatography, eluting with 50%
ethyl acetate in hexane gave 40 mg of
2-[3-(4-chloro-benzyl)-bicyclo[3.2.1]oct-8-ylidenemethyl]-1-
H-benzimidazole. 24
[0096] 2-[3
exo-(4--Chloro-benzyl)-bicyclo[3.2.1]oct-8-yl-exo-methyl]-1H-b-
enzimidazole:
[0097] Hydrogenation of 40 mg of the ethylene ketal of
3-(4-chloro-benzylidene)-bicyclo[3.2.1]octan-8-one over 0.05 g of
5% platinum on carbon in 10 mL of ethanol under latm of hydrogen
for 3 h gave 40 mg of
2-[3-(4-chloro-benzyl)-bicyclo[3.2.1]oct-8-ylmethyl]-1H-ben-
zimidazole as a mixture of 3-exo-8-exo and 3-exo-8-endo isomers.
Preparative TLC eluting with 50% ethyl acetate in hexane gave two
bands. The major upper band was the 3-exo-8-exo
2-[3-(4-chloro-benzyl)-bicyclo[3-
.2.1]oct-8-ylmethyl]-1H-benzimidazole: .sup.1H NMR (m+1)=321.4;
.sup.1H NMR (400 MHz, CDCl.sub.3) 7.6 (m, 2H), 7.2 (m, 7H), 4.85
and 4.8 (2 x d, 1H), 2.6 and 2.42 (2 x d, 2H).
EXAMPLE 5
[0098] 25
[0099]
(1H-Benzimiidazol-2-ylmethyl)-[3-(4-chloro-benzyl)-bicyclo[3.2.1]oc-
t-8-yl]-amine:
[0100] A mixture of 250 mg of 3:1 mixture of exo and endo
3-(4-chloro-benzyl)-bicyclo[3.2.1]octan-8-one, 400 mg of
2-aminomethylbenzimidazole dihydrochloride, 150 mg of anhydrous
sodium acetate, 10 mL of 1,2-dichloroethane and 400 mg of sodium
triacetoxyborohydride was stirred overnight in a stoppered flask.
The mixture was diluted with 50 mL of chloroform and washed with 20
mL of saturated sodium carbonate. The organic extract was dried
over magnesium sulfate and concentrated under reduced pressure.
Preparative TLC eluting with 225:25:5
chloroform:methanol:concentrated ammonium hydroxide gave in the
fastest band the product as a mixture of two isomers.
Crystallization and preparative TLC with 75:25:10
tetrahydrofuran:hexane:triethylamine or chromatography on
Chiralpak.TM. AD eluting with 90:10 0.1% diethylamine in hexane:
ethanol gave 150 mg of pure 3 -exo-8-exo
(1H-benzimidazol-2-ylmethyl)-[3-(4-chloro-benzyl)-bicyclo[3.2.1]oct-8-yl]-
-amine: RT=5.8 min; MS (m+1)=380.9; .sup.1H NMR (400 MHz,
CDCl.sub.3) 9.5 (br, 1H), 7.7 (br, 1H), 7.5 (br, 1H), 7.2 (m, 4H),
7.1 (d, 2H), 4.1 (s, 2H), 2.8 (m, 1H), 2.5 (d, 2H), 2.1 (s, 2H), 2-
1.2 (complex, 11H).
[0101] Later fractions gave 50 mg of pure 3-endo-8-exo
(1H-benzimidazol-2-ylmethyl)-[3-(4-chloro-benzyl)-bicyclo[3.2.1]oct-8-yl]-
-amine: RT=9 min; MS (m+1)=380.9; .sup.1H NMR (400 MHz, CDCl.sub.3)
9.5 (br, 1H), 7.7 (br, 1H), 7.5 (br, 1H), 7.2 (m, 4H), 7.1 (d, 2H),
4.18 (s, 2H), 2.82 (m, 1H), 2.78 (d, 2H), 2.06 (s, 2H), 2.1 - 1.2
(complex, 11H).
EXAMPLE 6
[0102] 26
[0103]
(1H-Benzimidazol-2-ylmethyl)-[5-(4-chloro-benzyl)-bicyclo[2.2.2]oct-
-2-yl]-amine:
[0104] Example 6 was prepared in a similar manner to Examples 4 and
5 above. A mixture of 250 mg of 3:1 mixture of exo and endo
5-(4-chloro-benzyl)-bicyclo[2.2.2]octan-2-one was prepared from
5-acetoxy-5-cyanobicyclo[2.2.2]octan-2-one in three sequential
steps without isolating intermediate products. The first two steps
were similar to those described in Steps 1 and 2 of Example 4
above, sequential treatment with sodium borohydride in ethanol,
sodium hydroxide, formed 5-hydroxy-bicyclo[2.2.2]octan-2-one.
Olefination, hydrogenation, and Swern oxidation of the product,
5-(4-chloro-benzyl)-bicyclo[2.2.2]octan-2- -ol followed. To the
resulting product was added 400 mg of 2-aminomethylbenzimidazole
dihydrochloride, 150 mg of anhydrous sodium acetate, 10 mL of
1,2-dichloroethane and 400 mg of sodium triacetoxyborohydride, and
stirred overnight in a stoppered flask. The mixture was diluted
with 50 mL of chloroform and washed with 20 mL of saturated sodium
carbonate. The organic extract was dried over magnesium sulfate and
concentrated under reduced pressure. Preparative TLC eluting with
95:5:5 ethyl acetate:methanol:triethyl amine gave
(1H-benzimidazol-2-ylmethyl)-[5-(4-chloro-benzyl)-bicyclo[2.2.2]oct-2-yl]-
-amine as a racemic mixture of four diastereomers: MS (m+1)=380.9;
.sup.1H NMR (400 MHz, CDCl.sub.3) 7.6 (br s, 1H), 7.2 (m, 4H), 7.05
(m, 2H), 4.04 and 4.06 (2 x s, 2H), 2.85 (m, 1H), 2.6-5 (m, 3H),
2.0-1.0 (complex, 12H).
EXAMPLE 7
[0105] 27
[0106] Cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic
acid 2-fluoro-benzylamnide
[0107] Example 7 was prepared by the following procedure, referring
to Scheme 4 above: 28
[0108] 4-tert-Butoxycarbonylmethylene-cyclohexanecarboxylic acid
ethyl ester (Compound B):
[0109] To a solution of ethyl 4-oxocyclohexanecarboxylate (Compound
A) (8.3 g, 48.8 mmol), tert-butyl diethylphosphonoacetate (13.5 g,
53.7 mmol), and activated 4A sieves (30 g) in anhydrous THF (250
mL) at reflux was added anhydrous LiOH (3.8 g, 161.0 mmol) in small
portions. After refluxing 6 h, the reaction was cooled and
partitioned between water and ethyl acetate. The organic layer was
dried with MgSO.sub.4 and concentrated to give 13 g of a colorless
oil. Flash chromatography on silica (10% EtOAc in hexane) yielded
(B) 4-tert-butoxycarbonylmethylene-c- yclohexanecarboxylic acid
tert-butyl ester (12.5 g, 95%) as a colorless oil. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 5.60 (s, 1 H), 4.15 (q, 2 H), 3.60 (m, 1
H), 2.55 (m, 1 H), 2.35 (m, 1 H), 2.21-2.02 (m, 4 H), 1.78-1.62 (m,
2 H), 1.48 (s, 9 H), 1.25 (t, 3 H); mass spectrum m/z 213
[(M--tBu).sup.+; calcd for C.sub.11H.sub.17O.sub.4: 213]. 29
[0110] 4--Carboxymethyl-cyclohexanecarboxylic acid ethyl ester
(C):
[0111] A solution of diester (B) (12.5 g, 46.3 mmol) and 10%
palladium on activated carbon (5 g) in absolute ethanol (200 mL)
was exposed to a hydrogen atmosphere (at balloon pressure) and
stirred vigorously for 1 h. After removal of catalyst by filtration
and concentration, the resultant colorless oil was dissolved in
methylene chloride (150 mL) and TFA (75 mL) and stirred for 15 min.
All volatiles were removed by rotary evaporation and the resultant
colorless oil placed under high vacuum to give (C)
4-carboxymethyl-cyclohexanecarboxylic acid ethyl ester (9.9 g, 99%)
as a white solid. Data for cis/trans mixture: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 4.13 (2q, 4 H), 2.58 (m, 1H), 2.30-2.20 (m, 1
H), 2.20 (2d, 4 H), 2.05-1.80 (m, 7 H), 1.80-1.55 (m, 5 H),
1.50-1.38 (m, 3 H), 1.32-1.25 (m, 1 H), 1.25 (2t, 6 H), 1.10-1.00
(m, 2 H); mass spectrum m/z 215 [(M+H).sup.+; calcd for
C.sub.11H.sub.19O.sub.4: 215]. 30
[0112] 4-(1H-Benzoimidazol-2-ylmethyl)-cyclohexanecarboxylic acid
ethyl ester (D):
[0113] To a solution of acid (C) (10.5 g, 49.0 mmol), EDC (9.4 g,
49.0 mmol) and HOAt (6.7 g, 49.0 mmol) in 80 mL anhydrous DMF was
added phenylenediamine (5.3 g, 49.0 mmol) and the reaction mixture
stirred for 1h. The reaction mixture was partitioned between
saturated aqueous NaHCO.sub.3 and EtOAc and the organic portion
washed 3.times. with water. The organic layer was dried with
MgSO.sub.4 and concentrated to yield 14 g of a yellow oil. The
crude material was dissolved in toluene/TFA (1:1 300 mL), heated to
90.degree. C. and stirred overnight. The reaction mixture was then
concentrated and purified by column chromatography on silica using
1:1 EtOAc/hexane followed by 90:10:1 CH.sub.2Cl.sub.2/MeOH/N-
H.sub.4OH to give (D)
4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid ethyl
ester (7.5 g, 53%) as a colorless oil. Data for cis/trans mixture:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.62 (2d, 4 H), 7.38 (2d,
4 H), 2.70 (2d, 4 H), 2.48 (m, 1 H), 2.10-1.90 (m, 5 H), 1.70-1.58
(m, 4 H), 1.60-1.53 (m, 3 H), 1.49-1.38 (m, 4 H), 1.63-1.50 (m, 1
H), 1.40 (2t, 6 H), 0.90-0.70 (m, 2 H); mass spectrum m/z 287
[(M+H).sup.+; calcd for C.sub.17H.sub.23N.sub.2O.sub.2: 287].
31
[0114] Cis-4-(lH-benzoimidazol-2-ylmethyl)-cyclohexanecarboxylic
acid (E):
[0115] The cis/trans mixture of
4-(1H-benzimidazol-2-ylmethyl)-cyclohexane- carboxylic acid ethyl
esters (D) (600 mg, 2.1 mmol) was dissolved in a minimal amount of
THF (5 mL) and mixed with concentrated aqueous LiOH (2 mL). The
reaction was stirred vigorously and heated at 65.degree. C. for 3
h. After cooling and concentration, the crude material was
dissolved in 1:1 water/CH.sub.3CN and subjected to preparative
reverse-phase HPLC to yield (E)
cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid (200
mg, 37%): .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.77 (m, 2 H),
7.60 (m, 2 H), 3.11 (d, 2 H), 2.62 (m, 1 H), 2.10 (m, 3 H), 1.65
(m, 4 H), 1.43 (m, 2 H); mass spectrum m/z 259 [(M+H).sup.+; calcd
for C.sub.15H.sub.19N.sub.2O.sub.2: 259].
[0116] Later fractions gave the trans isomer (F) (276 mg, 51 %):
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.77 (m, 2 H), 7.59 (m, 2
H), 3.08 (d, 2 H), 2.28 (m, 1 H), 2.05 (d, 2 H), 1.95 (m, 1 H),
1.84 (d, 2 H), 1.46 (dq, 2 H), 1.20 (dq, 2 H); mass spectrum m/z
259 [(M+H).sup.+; calcd for C.sub.15H.sub.19N.sub.2O.sub.2:
259].
EXAMPLE 7
[0117] 32
[0118] Cis-4-(1H-benzoimidazol-2-ylmethyl)-cyclohexanecarboxylic
acid 2-fluoro-benzylamide:
[0119] To a solution of (E)
cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexane- carboxylic acid
(271 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg, 1.05
mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine (131
mg, 1.05 mmol) and the reaction mixture was stirred for lh. The
reaction mixture was partitioned between saturated aqueous
NaHCO.sub.3 and EtOAc and the organic layer washed 2.times. with
water. The EtOAc was dried with MgSO.sub.4 and concentrated to give
a yellow solid. The crude material was triturated with 2:2:1
water/CH.sub.3CN/DMSO and the resultant white solid filtered off.
Repetitive concentration and trituration of the filtrate in the
same manner gave
cis-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid
2-fluoro-benzylamide (F) (230 mg, 60%) as a white solid. The (F)
compound was stirred in 1M HCl/ether (10mL) for 1 h and
concentrated to give the HCl salt of Ex. 7 (250 mg): .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 7.50 (br s 2 H), 7.35-7.25 (m, 2 H),
7.22-7.05 (m, 4 H), 4.43 (s, 2 H), 2.92 (d, 2 H), 2.41 (m, 1 H),
2.23 (m, 1 H), 1.93 (m, 2 H), 1.60 (m, 6 H); mass spectrum m/z 366
[(M+H).sup.+; calcd for C.sub.22H.sub.25N.sub.3- OF: 366].
EXAMPLE 8
[0120] 33
[0121] Trans-4-(1H-benzoimidazol-2-ylmethyl)-cyclohexanecarboxylic
acid 2-fluoro-benzylamide
[0122] Example 8 was prepared by the following procedure. To a
solution of
trans-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarboxylic acid (F)
(444 mg, 1.72 mmol), EDC (328 mg, 1.72 mmol) and HOAt (234 mg, 1.72
mmol) in anhydrous DMF (4 mL) was added benzylamine (184 mg, 1.72
mmol). The resulting reaction mixture was stirred for 15 h. The
reaction mixture was partitioned between saturated aqueous
NaHCO.sub.3 and EtOAc and the organic layer washed 2.times. with
water, and dried with MgSO.sub.4. Concentration gave
trans-4-(1H-benzimidazol-2-ylmethyl)-cyclohexanecarbox- ylic acid
benzylamide (400 mg, 67%) as a white solid. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.49 (br s, 2 H), 7.30-7.17 (m, 7 H), 4.34 (s,
2 H), 2.78 (d, 2 H), 2.21 (m, 1 H), 1.84 (m, 5 H), 1.55 (q, 2 H),
1.16 (q, 2 H); mass spectrum m/z 348 [(M+H).sup.+; calcd for
C.sub.22H.sub.26N.sub.3O: 348].
[0123] All compounds analogous to Example 8 were prepared from
carboxylic acid (F) via the above procedure using the appropriate
amine and purified by reverse-phase BPLC.
[0124] Compounds of the present invention can be prepared according
to Scheme 7 shown below: 34
EXAMPLE 9
[0125] 35
[0126] Trans-4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic
acid benzylamide
[0127] Referring to Scheme 7 above, Example 9 was prepared by the
following procedure. 36
[0128] 4-Amino-cyclohexanecarboxylic acid ethyl ester (H):
[0129] To a suspension of 4-amino-cyclohexanecarboxylic acid (G) (5
g, 35 mmol) in EtOH (175 mL) at 0.degree. C. was added SOCl.sub.2
(12.6 mL, 174 mmol) dropwise via a syringe. The reaction mixture
was warmed to room temperature and stirred for 16 h. After
concentration of the reaction mixture, ether was added and the
suspension was filtered to give 4-amino-cyclohexanecarboxylic acid
ethyl ester (H) (mixture of cis/trans) as a white solid (4.8 g):
.sup.1H NMR (300 MHz, CDCl.sub.3) 6 8.35 (br s, 3 H), 4.18 (m, 2
H), 3.36-3.15 (m, 1 H), 2.54 (m, 1 H), 2.30-1.45 (series of m, 8
H), 1.13 (t, 3 H); mass spectrum m/z 172 [(M+H).sup.+; calcd for
C.sub.9H.sub.18NO.sub.2: 172]. 37
[0130] Cis-4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid
ethyl ester (J) and
Trans-4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid
ethyl ester (K):
[0131] A mixture of 2--Chlorobenzimidazole (I) (0.9 g, 5.9 mmol)
and ethyl-4-amino-cyclohexane carboxylate (1.1 g, 5.4 mmol) were
placed in a glass high pressure tube. Diisopropylethylamine (2.8
mL, 16.2 mmol) was added, the reaction vessel was sealed and heated
to 200.degree. C. for 4 h and allowed to cool to room temperature.
Next was added 5 mL EtOH and heated to dissolve the reaction
mixture. The reaction mixture was partitioned between aqueous
NaHCO.sub.3 and EtOAc, and the organic layer was washed with water
and brine, dried over MgSO.sub.4, filtered and concentrated.
Purification of the crude product on silica gel (gradient, 1:1
hexanes:EtOAc to EtOAc) gave the cis
4-(1H-benzimidazol-2-ylamino)-cy- clohexanecarboxylic acid ethyl
ester (J) (0.5 g) and the trans
4-(1H-benzirnidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl
ester (K) (0.5 g). Data for (J): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.28 (br s, 2 H), 7.02 (m, 2 H), 5.16 (br s, 1 H), 4.15 (q,
2 H), 3.97 (br s, 1 H), 2.40 (br s, 1 H), 1.80-1.54 (m, 8 H), 1.22
(t, 3 H); mass spectrum m/z 288 [(M+H).sup.+; calcd for
C.sub.16H.sub.22N.sub.3O.sub.2: 288]. Later fractions gave the
trans isomer (K) (0.5 g): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.28 (br s, 2 H), 7.02 (m, 2 H), 4.82 (br s, 1 H), 4.15 (q, 2 H),
3.64 (m, 1 H), 2.20 (br d, 3 H), 1.96 (br d, 2 H), 1.42 (m, 2 H),
1.22 (t, 3 H), 1.20 (m, 2 H); mass spectrum m/z 288 [(M+H).sup.+;
calcd for C.sub.16H.sub.22N.sub.3O.sub.2: 288]. 38
[0132] Trans-4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic
acid (M):
[0133] A solution of trans
4-(1H-benzimidazol-2-ylamino)-cyclohexanecarbox- ylic acid ethyl
ester (K) (SOOmg, 1.7 mmol) in dioxane (4 mL) and HCl (6 N, 8 mL)
was heated to 60.degree. C. for 16 h. After cooling, concentration
of the reaction mixture gave trans 4-(1H-benzimidazol-2-yla-
mino)-cyclohexanecarboxylic acid as a white solid (M) (420 mg):
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.39 (m, 2 H), 7.28 (m, 2
H), 3.57 (m, 1 H), 2.35 (m, 1 H), 2.18 (br t, 4 H), 1.65-1.40 (m, 4
H); mass spectrum m/z 260 [(M+H).sup.+; calcd for
C.sub.14H.sub.18N.sub.3O.sub.2: 260]. 39
[0134] Example 9,
Trans-4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxyli- c acid
benzylamide:
[0135] To a solution of trans
4-(1H-benzimidazol-2-ylamino)-cyclohexanecar- boxylic acid (M) (20
mg, 0.07 mmol) in DMF (0.2 mL) was added EDC (26 mg, 0.14 mmol),
HOBt (18 mg, 0.14 mmol), triethylamine (0.019mL, 0.14 mmol) and
benzyl amine (0.007 mL, 0.7 mmol). The reaction mixture was stirred
at room temperature for lh followed by quenching with aqueous
NaHCO.sub.3 and EtOAc. The layers were separated and the organic
was washed twice with water, dried over Na.sub.2SO.sub.4, filtered
and concentrated. Purification of the crude oil by preparative
reverse-phase HPLC gave trans
4-(1H-benzimidazol-2-ylarino)-cyclohexanecarboxylic acid
benzylamide (Example 9) (14 mg): .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 7.40-7.20 (m, 9 H), 4.39 (s, 2 H), 3.55 (m, 1 H), 2.31 (m,
1 H), 2.20 (br d, 2 H), 1.98 (br d, 2 H), 1.77 (m, 2 H), 1.50 (m, 2
H); mass spectrum m/z 349 [(M+H).sup.+; calcd for
C.sub.21H.sub.25N.sub.4O: 349].
EXAMPLE 10
[0136] 40
[0137] Example 10,
Cis-4-(1H-benzoimidazol-2-ylamino)-cyclohexanecarboxyli- c acid
benzylamide: Referring to Scheme 7, Example 10 was prepared by the
following procedure. 41
[0138] Cis-4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid
(L):
[0139] In a similar manner to Example 9 above, cis
4-(1H-benzimidazol-2-yl- amino)-cyclohexanecarboxylic acid ethyl
ester (J) was saponified and gave the cis
4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid (L):
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.39 (m, 2 H), 7.28 (m, 2
H), 3.64 (m, 1 H), 2.60 (m, 1 H), 2.10 m, 2 H), 1.95 (m, 2 H),
1.81-1.65 (m, 4 H); mass spectrum Jn/z 260 [(M+H).sup.+; calcd for
C.sub.14H.sub.18N.sub.3O.sub.2: 260]. 42
[0140] Example 10,
Cis-4-(1H-benzoimidazol-2-ylamino)-cyclohexanecarboxyli- c acid
benzylamide:
[0141] To a solution of cis
4-(1H-benzimidazol-2-ylamino)-cyclohexanecarbo- xylic acid (L) (20
mg, 0.07 mmol) in DMF (0.2 mL) was added EDC (26 mg, 0.14 mmol),
HOBt (18 mg, 0.14 mmol), triethylamine (0.019 mL, 0.14 mmol) and
benzyl amine (0.007 mL, 0.7 mmol). The reaction mixture was stirred
at room temperature for 1 h followed by quenching with aqueous
NaHCO.sub.3 and EtOAc. The layers were separated and the organic
was washed twice with water, dried over Na.sub.2SO.sub.4, filtered
and concentrated. Purification of the crude oil by preparative
reverse-phase BPLC gave cis
4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid
benzylamide (Example 10) (12 mg): .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 7.40-7.20 (m, 9 H), 4.39 (s, 2 H), 3.81 (m, 1 H), 2.45 (m,
1 H), 2.02-1.77 (m, 8 H); mass spectrum m/z 349 [(M+H).sup.+; calcd
for C.sub.21H.sub.25N.sub.4O: 349].
[0142] All compounds analogous to Example 10 were prepared from
carboxylic acid (M) via the above procedure using the appropriate
amine and purified by reverse-phase HPLC.
EXAMPLE 11
[0143] 43
[0144] (1H-Benzimidazol-2-ylmethyl)-(4-benzyl-cyclohexyl)-amine
[0145] Example 11 was prepared in a manner similar to Example 5,
but substituting 4-benzyl-cyclohexanone, the product of Example 1,
Step 3, for exo and endo 3-(4-chloro-benzyl)-bicyclo[3.2.
1]octan-8-one. The procedure gave a 1:1 mixture of cis and trans
(1H-benzoimidazol-2-ylmethy- l)-(4-benzyl-cyclohexyl)-amine.
Chromatography on ChiralpakTM OD eluting with 60:40 of 0.1%
diethylamine in hexane:2-propanol gave first
(1H-benzoimidazol-2-ylmethyl)-(4-cis-benzyl-cyclohexyl)-amine:
RT=4.69 min; MS (m+1)=320; 1H NMR (400 MHz, CDCl.sub.3) .delta. 7.6
(m, 2H), 7.35 -7.25 (m, 5H), 7.18 (m, 2H), 4.2 (s, 2H), 2.85 (m,
1H), 2.55 (d, 2H), 1.75 (m, 3H), 1.7-1.55 (m, 2H), 1.5 (m, 2H), 1.4
(m, 3H).
[0146] Later fractions gave
(1H-benzoimidazol-2-ylmethyl)-(4-trans-benzyl-- cyclohexyl)-amine:
RT=5.67 min; MS (m+1)=320; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.6 (m, 2H), 7.35 -7.25 (m, 5H), 7.18 (m, 2H), 4.2 (s, 2H),
2.5 (d, 2H), 1.95 (d, 2H), 1.72 (d, 2H), 1.7-1.55 (m, 2H), 1.5 (m,
2H), 1.4 (m, 3H).
EXAMPLE 12
[0147] 44
[0148] (1H-Benzimidazol-2-yl)-(4-benzyl-cyclohexyl)-amnine
[0149] Example 12 was prepared by the following procedure. 45
[0150] 4-Benzyl-cyclohexylamine:
[0151] A mixture of 2 g of 4-benzylcyclohexanone, the product of
Example 1, Step 3, 16 g of ammonium acetate, 100 mL of methanol and
2.5 g of sodium cyanoborohydride was stirred for 5 days at room
temperature. After cooling in an ice bath, the reaction was
carefully quenched in an efficient fume hood by dropwise addition
of 25 mL of 1N HCl. After stirring for 10 min, sodium hydroxide
pellets were added to the cold solution until the pH (indicator
paper) was about 10. The mixture was concentrated under reduced
pressure, diluted with 100 mL of water, made basic by addition of
more sodium hydroxide pellets and extracted into 4.times.100 mL
portions of chloroform. After drying over magnesium sulfate, the
extracts were concentrated under reduced pressure and then dried
under vacuum overnight. Analysis by TLC (silica gel, elution with
90:10:1 chloroform:methanol:conc. ammonium hydroxide) indicated no
4-benzylcyclohexanone or 4-benzylcyclohexanol was present, only 2
new bands which correspond to a mixture of cis- and trans
4-benzyl-cyclohexylamine, which was an oil. 46
[0152] (1H-Benzimidazol-2-yl)-(4-benzyl-cyclohexyl)-amine:
[0153] Following the sample experimental procedure described by J.
J. Perkins, A. E. Zartman, and R. S. Meissner, Tetrahedron Letters,
40:1103-1106(1999), but substituting a mixture of cis- and trans
4-benzyl-cyclohexylamine for cyclohexylamine, gave a mixture of cis
and trans (1H-benziimidazol-2-yl)-(4-benzyl-cyclohexyl)-amine.
Chromatography on silica gel eluting with 90:10 chloroform:methanol
gave (1H-benziimidazol-2-yl)-(4-cis -benzyl-cyclohexyl)-amine: MS
(m+1)=306; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.42 (d, 2H),
2.10 (d, 2H), 1.70 (d, 2H).
[0154] Later fractions gave (1H-benziimidazol-2-yl)-(4-trans
-benzyl-cyclohexyl)-amine: MS (m+1)=306; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 2.55 (m, 2H), 2.15 (d, 2H), 1.70 (d, 2H).
EXAMPLE 13
[0155] 47
[0156] Example 13 was prepared by following the above procedure for
Example 7 except using N-methylbenzylamine instead of
2-fluorobenzylamine: mass spectrum m/z 361 [(M+H).sup.+; calcd for
C.sub.23H.sub.28N.sub.3O: 362]. 48
[0157] Compound (N)
[0158] Olefin (B) (0.3 g, 1.18 mmol) was dissolved in EtOAc (5 mL)
and cooled to -20.degree. C. Rh on alumina catalyst (0.06 g) was
added, the reaction vessel was pressurized to 1500 psi with
hydrogen gas, and the mixture was shaken for 5 h. After removal of
the catalyst by filtration and concentration, the resultant
colorless oil was dissolved in methylene chloride (5 mL) and TFA (3
mL) and stirred for 15 min. All volatiles were removed by rotary
evaporation and the resultant colorless oil placed under high
vacuum to give Compound (N) as a 6:1 cis to trans mixture.
[0159] Compound (ZZ) 49
[0160] To a solution of acid (N) (300 mg, 1.4 mmol) in DMF (10 mL)
was added EDC (268 mg, 1.40 mmol), HOAt (190 mg, 1.40 mmol) and
methanesulfonic acid (3,4-diamino-phenyl)-amide (II) (281 mg, 1.40
mmol). The reaction mixture was stirred at room temperature for 16
h followed by quenching with aqueous NaHCO.sub.3 and EtOAc. The
layers were separated and the organic was washed twice with water,
dried over Na.sub.2SO.sub.4, filtered and concentrated.
[0161] The resulting crude product was dissolved in acetic acid (10
mL) and heated to 130.degree. C. for 15 min. The reaction mixture
was cooled, concentrated and partitioned between aqueous
NaHCO.sub.3 and EtOAc. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude oil was used
without purification. The crude ester was dissolved in HBr/H.sub.2O
(48%, 10 mL) and was then heated to 100.degree. C. for 30 min. The
resulting reaction mixture was cooled, concentrated and purified by
preparative reverse-phase HPLC, to give Compound (ZZ) as the pure
cis isomer: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.75 (d, 1
H), 7.69 (d, 1 H), 7.39 (dd, 1 H), 3.09 (d, 2 H), 2.99 (s, 3 H),
2.60 (m, l H), 2.08 (m, 3 H), 1.62 (m, 4 H);1.40 (m, 2 H) ppm; mass
spectrum m/z 352 [(M+H).sup.+; calcd for
C.sub.16H.sub.22N.sub.3O.sub.4S: 352].
EXAMPLE 14
[0162] 50
[0163] Example 14 was prepared by the following procedure: To a
solution of (ZZ) (10 mg, 0.03 mmol), EDC (10 mg, 0.06 mmol) and
HOAt (8 mg, 0.06 mmol) in anhydrous DMF (0.3 mL) was added
2-fluorobenzylarnine (2 mg, 0.06 mmol) and the reaction mixture was
stirred for 2 h. The reaction mixture was partitioned between
saturated aqueous NaHCO.sub.3 and EtOAc. The organic layer was
washed 2.times. with water. The EtOAc was dried with MgSO.sub.4 and
concentrated. The resulting crude material was purified by reverse
phase HPLC to give Example 14: mass spectrum m/z 459 [(M+H).sup.+;
calcd for C.sub.23H.sub.28FN.sub.4O.sub.3S: 459].
EXAMPLE 15
[0164] 51
[0165] Example 15 was prepared by following the above procedure for
Example 14 except 2,6-diflouorobenzylamine was used instead of
2-fluorobenzylamine: mass spectrum m/z 477 [(M+H).sup.+; calcd for
C.sub.23H.sub.27F.sub.2N.sub.4O.sub.3S: 477].
[0166] COMPOUND (ZZ1) 52
[0167] Compound (ZZ1) was prepared by following the above procedure
for Compound (ZZ) except 4-methoxy-1,2-phenylenediamine was used
instead of methanesulfonic acid (3,4-diamino-phenyl)-amide: mass
spectrum m/z 275 [(M+H).sup.+; calcd for
C.sub.15H.sub.19N.sub.2O.sub.3: 275].
EXAMPLE 16
[0168] 53
[0169] Example 16 was prepared by following the above procedure for
Example 14 except Compound (ZZ1) was used instead of Compound (ZZ):
mass spectrum m/z 382 [(M+H).sup.+; calcd for
C.sub.22H.sub.24FN.sub.3O.sub.2: 382].
EXAMPLE 17
[0170] 54
[0171] Example 17 was prepared by following the above procedure for
Example 15 except Compound (ZZ1) was used instead of Compound (ZZ):
mass spectrum m/z 400 [(M+H).sup.+; calcd for
C.sub.22H.sub.24F.sub.2N.sub.3O.- sub.2: 400].
[0172] Compound (ZZ2) 55
[0173] Compound (ZZ2 was prepared by following the above procedure
for Compound (ZZ) except ethanesulfonic acid
(3,4-diamino-phenyl)-amide was used instead of methanesulfonic acid
(3,4-diamino-phenyl)-aniide: mass spectrum m/z 366 [(M+H).sup.+;
calcd for C.sub.17H.sub.24N.sub.3O.sub.4S: 366].
EXAMPLE 18
[0174] 56
[0175] Example 18 was prepared by following the above procedure for
Example 14 except Compound (ZZ2) was used instead of Compound (ZZ):
mass spectrum m/z 473 [(M+H).sup.+; calcd for
C.sub.24H.sub.30FN.sub.4O.sub.3S- : 473].
EXAMPLE 19
[0176] 57
[0177] Example 19 was prepared by following the above procedure for
Example 15 except Compound (ZZ2) was used instead of Compound (ZZ):
mass spectrum m/z 491 [(M+H).sup.+; calcd for
C.sub.24H.sub.29F.sub.2N.sub.4O.- sub.3S: 491]. 58
[0178] methanesulfonic acid (3,4-diamino-phenyl)-amide: mass
spectrum m/z 275 [(M+H).sup.+; calcd for
C.sub.15H.sub.19N.sub.2O.sub.3: 275].
EXAMPLE 20
[0179] 59
[0180] Example 20 was prepared by following the above procedure for
Example 14 except Compound (ZZ3) was used instead of Compound (ZZ):
mass spectrum m/z 382 [(M+H).sup.+; calcd for
C.sub.22H.sub.25FN.sub.3O.sub.2: xx].
EXAMPLE 21
[0181] 60
[0182] Example 20 was prepared by following the above procedure for
Example 14 except Compound (ZZ3) was used instead of Compound (ZZ),
and benzylamine was used instead of 2-fluorobenzylamine: mass
spectrum m/z 364 [(M+H).sup.+; calcd for
C.sub.22H.sub.26N.sub.3O.sub.2: 364]. 61
[0183] (PPh3).sub.2PdCl.sub.2 (0.91 g, 1.3 mmol) and triethylamine
(5.4 mL, 39 mmol). The reaction mixture was pressurized with CO
(100 psi) and heated to 100.degree. C. for 60 h. After cooling, the
mixture was filtered, concentrated and purified by reverse phase
HPLC to give ester (P): .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.03 (d, 2 H), 7.61 (d, 2 H), 5.25 (s, 1 H), 3.90 (s, 3 H) ppm.
[0184] Compound (P) (0.35 g, 1.7 mmol) was dissolved in MeOH (10
mL) and Rh on alumina catalyst (0.05 g) was added. The reaction
vessel was pressurized to 50 psi with hydrogen gas, and the mixture
was shaken for 24 h. After filtration and concentration, the
product (Q) was used without purification as a 3:1 cis:trans
mixture of isomers: mass spectrum m/z 217 [(M+H).sup.+; calcd for
C.sub.10H.sub.17O.sub.5: 217]. 62
[0185] To a solution of acid (Q) (100 mg, 0.46 mmol) in DMF (6 mL)
was added EDC (97 mg, 0.51 mmol), HOAt (70 mg, 0.51 mmol) and
methanesulfonic acid (3,4-diamino-phenyl)-amide (II) (100 mg, 0.46
mmol). The reaction mixture was stirred at room temperature for 1 h
followed by quenching with aqueous NaHCO.sub.3 and EtOAc. The
layers were separated and the organic was washed twice with water,
dried over Na.sub.2SO.sub.4, filtered and concentrated.
[0186] The resulting crude product was dissolved in acetic acid (5
mL) and heated to 130.degree. C. for 15 min. The reaction mixture
was cooled, concentrated and partitioned between aqueous
NaHCO.sub.3 and EtOAc. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The resulting crude
oil was without purification.
[0187] The crude ester was dissolved in HBr/H.sub.2O (48%, 3 mL)
and then was heated to 100.degree. C. for 10 min. The reaction
mixture was cooled, concentrated and purified by preparative
reverse-phase HPLC, to give (R) as the pure cis isomer: mass
spectrum m/z 368 [(M+H).sup.+; calcd for
C.sub.16H.sub.22N.sub.3O.sub.5S: 368].
EXAMPLE 22
[0188] 63
[0189] Example 22 was prepared by the following procedure: To a
solution of (R) (35 mg, 0.1 mmol), EDC (36 mg, 0.2 mmol) and HOAt
(26 mg, 0.2 mmol) in anhydrous DMP (2 mL) was added
2-fluorobenzylamine (24 mg, 0.2 mmol) and the resulting reaction
mixture was stirred for 3 h. The reaction mixture was then
partitioned between saturated aqueous NaHCO.sub.3 and EtOAc, and
the organic layer washed 2.times. with water. The EtOAc was dried
with MgSO.sub.4 and concentrated. The resulting crude material was
purified by reverse phase HPLC to give Example 22: .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 7.74 (m, 2 H), 7.41 (d, 1 H), 7.25 (m, 2
H); 7.09 (m, 2 H), 5.06 (d, 1 H), 4.40 (s, 2 H), 3.00 (s, 3 H),
2.47 (m, 1 H), 2.10 (m, 3 H), 1.6 (m, 6 H) ppm; mass spectrum m/z
475 [(M+H).sup.+; calcd for C.sub.23H.sub.28FN.sub.4O.sub.4S:
475].
EXAMPLE 23
[0190] 64
[0191] Example 23 was prepared by following the above procedure for
Example 22 except 2,6-diflouorobenzylamine was used instead of
2-fluorobenzylamine: mass spectrum m/z 493 [(M+H).sup.+; calcd for
C.sub.23H.sub.27F.sub.2N.sub.4O.sub.4S: 493].
[0192] Compound (S): 65
[0193] Compound (S) was prepared by following the above procedure
for (R) except ethanesulfonic acid (3,4-diamino-phenyl)-amide was
used instead of methanesulfonic acid (3,4-diamino-phenyl)-amide:
mass spectrum m/z 382 [(M+H).sup.+; calcd for
C.sub.17H.sub.24N.sub.3O.sub.5S: 382].
EXAMIPLE 24
[0194] 66
[0195] Example 24 wa prepared by following the above procedure for
Example 22 except acid (S) was used instead of (R): mass spectrum
m/z 489 [(M+H).sup.+; calcd for C.sub.24H.sub.30FN.sub.4O.sub.4S:
489].
EXAMPLE 25
[0196] 67
[0197] Example 25 was prepared by following the above procedure for
Example 23 except acid Compound (S) was used instead of Compound
(R): mass spectrum m/z 507 [(M+H).sup.+; calcd for
C.sub.24H.sub.29F.sub.2N.su- b.4O.sub.4S: 507].
[0198] Compound (T): 68
[0199] Acid (T) was prepared by following the above procedure for
Compound (R) except phenylene diamine was used instead of
methanesulfonic acid (3,4-diamino-phenyl)-amide: mass spectrum m/z
275 [(M+H).sup.+; calcd for C.sub.15H.sub.19N.sub.2O.sub.3:
275].
EXAMPLE 26
[0200] 69
[0201] Example 26 was prepared by following the above procedure for
Example 22 except acid (T) was used instead of Compound (R): mass
spectrum m/z 382 [(M+H).sup.+; calcd for
C.sub.22H.sub.25FN.sub.3O.sub.2: 382].
EXAMPLES 26a and 26b:
[0202] Racemate Example 26 was separated into its enantiomers by
chiral HPLC on a Chiralpack AD column (250.times.4.6cm) eluting
with 75% hexane +0.1% diethylamine and 25% 2-propanol. The faster
eluting compound was Example 26a. The slower eluting compound was
Example 26b.
EXAMPLE 27
[0203] 70
[0204] Example 27 was prepared by the following procedure: To a
solution of amide (This does not seem to be an Example above)
L-478,227 (200 mg, 0.52 mmol) in THF (1 mL) was added BH3-THF (1M,
5.0 mL). The reaction mixture was heated to 50.degree. C. for 12 h,
cooled and carefully quenched with HCl (1 M). The resulting mixture
was partitioned between EtOAc/aqueous NaHCO.sub.3. The organic
layer was dried over Na.sub.2SO.sub.4, filtered, concentrated and
purifed by reverse phase HPLC to give Example 27: .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 7.71 (m, 2 H), 7.57 (m, 3 H), 7.18 (t, 2
H); 4.35 (s, 2 H), 3.14 (t, 4 H), 2.21 (m, 1 H), 2.00 (m, 1 H),
1.75-1.40 (m, 8 H) ppm; mass spectrum m/z 370 [(M+H).sup.+; calcd
for C.sub.22H.sub.26F.sub.2N.sub.3: 370].
EXAMPLE 28
[0205] 71
[0206] Example 28 was prepared by following the above procedure for
Example 27 except acid Example 19 was used instead of L-478,227:
mass spectrum m/z 477 [(M+H).sup.+; calcd for
C.sub.24H.sub.31F.sub.2N.sub.4O.- sub.2S: 477]. 72
[0207] Compound (V) was prepared by the following procedure: To a
solution of acid (N) (900 mg, 4.2 mmol) in DMF (10 mL) was added
EDC (886 mg, 4.6 mmol), HOAt (629 mg, 4.6 mmol) and
4-nitro-1,2-phenylenediamne (643 mg, 4.2 mmol). The resulting
reaction mixture was stirred at room temperature for 16 h followed
by quenching with aqueous NaHCO.sub.3 and EtOAc. The layers were
separated and the organic layer was washed twice with water, dried
over Na.sub.2SO.sub.4, filtered and concentrated.
[0208] The resulting crude product was dissolved in acetic acid (5
mL) and heated to 130.degree. C. for 1.5 h. The reaction mixture
was cooled, concentrated and partitioned between aqueous
NaHCO.sub.3 and EtOAc, and the organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The resulting crude
oil was used without purification: mass spectrum m/z 332
[(M+H).sup.+; calcd for C.sub.17H.sub.22N.sub.3O.sub.4: 332].
EXAMPLE 29
[0209] 73
[0210] Example 29 was prepared by the following procedure: Ester
Compound (V) (450 mg, 1.36 mmol) was dissolved in HBr/H.sub.2O
(48%, 5 mL) and heated to 100.degree. C. for 10 min. The reaction
mixture was cooled, concentrated and the corresponding resulting
acid was used without further purification: mass spectrum m/z 304
[(M+H).sup.+; calcd for C.sub.15H.sub.18N.sub.3O.sub.4: 304].
[0211] To a solution of the above resulting acid (400 mg, 1.32
mmol), EDC (379 mg, 1.98 mmol) and HOAt (269 mg, 1.98 mmol) in
anhydrous DMF (5 mL) was added 2-fluorobenzylamine (247 mg, 1.98
mmol) and the resulting reaction mixture was stirred for 2 h. The
reaction mixture was partitioned between saturated aqueous
NaHCO.sub.3 and EtOAc and the organic layer was washed 2.times.
with water. The EtOAc was dried with MgSO.sub.4 and concentrate.
The crude material was purified by reverse phase HPLC to give
Example 29: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.61 (d, 1
H), 8.42 (dd, 1 H), 7.88 (d, 1 H); 7.24 (m, 2 H), 7.10 (m, 2 H),
4.40 (s, 2 H), 3.10 (d, 2 H), 2.43 (m, 1 H), 2.17 (m, 1 H), 1.90
(m, 3 H), 1.61 (m, 5 H) ppm; mass spectrum m/z 411 [(M+H).sup.+;
calcd for C.sub.22H.sub.24FN.sub.4O.sub.3: 411].
EXAMPLE 30
[0212] 74
[0213] Example 30 was prepared by the following procedure: To a
solution of Example 29 (0.3 g, 0.73 mmol) in EtOH (4wL) was added
10% Pd/C (0.05 g). The resulting reaction mixture was stirred under
a balloon of hydrogen. After 2 h, the reaction mixture was filtered
through celite, concentrated and the crude product purified by
reverse phase HPLC to give Example 30: mass spectrum m/z 381
[(M+H).sup.+; calcd for C.sub.22H.sub.25FN.sub.4O: 381].
EXAMPLE 31
[0214] 75
[0215] Example 31 was prepared by the following procedure: To a
solution of Example 30 (15 mg, 0.04 mmol) in dichloromethane (1 mL)
was added triethylamine (11 .mu.L, 0.08 mmol) and sulfonyl chloride
Compound (U) (12 mg, 0.04 mmol). The resulting mixture was stirred
at room temperature for 30 min, concentrated and purified by
reverse phase HPLC to give Example 31: mass spectrum m/z 660
[(M+H).sup.+; calcd for C.sub.35H.sub.39FN.sub.5O.sub.5S: 660].
EXAMPLE 32
[0216] 76
[0217] Example 32 was prepared by the following procedure: To a
room temperature solution of Example 31 (10 mg, 0.015 mmol) in EtOH
(0.5 mL) was added hydrazine (4w, 0.15 mmol) and the reaction
mixture was stirred for 2 h. The reaction mixture was concentrated
and purified by reverse phase HPLC to give Example 32: mass
spectrum m/z 530 [(M+H).sup.+; calcd for
C.sub.27H.sub.37FN.sub.5O.sub.3S: 530].
EXAMPLE 33
[0218] 77
[0219] Example 33 was prepared by the following procedure: To a
room temperature solution of Example 32 (8 mg, 0.015 mmol) in
dichloromethane (1 mL) and MeOH (0.2 mL) was added
fluoroscein-5-isothiocyanate (5 mg, 0.02 mmol) and triethylamine
(10 .mu.L). The resulting mixture was stirred for 30 min,
concentrated, and purified by reverse phase HPLC to give Example
33: mass spectrum m/z 919 [(M+H).sup.+; calcd for
C.sub.48H.sub.48FN.sub.6O.sub.8S.sub.2: 919].
EXAMPLES 34-106
[0220] Examples 34-106 were prepared by procedures similar to those
descirbed above.
[0221] In Table 1 below, the substituents are shown wherein X.sub.1
corresponds to the NH group of the amide:
1TABLE 1 78 Example SUBSTITUENT MS NAME 34 79 348
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid
benzylamide 35 80 362 cis-4-(1H-Benzoimidazol-2-ylmethyl)- -
cyclohexanecarboxyilic acid 2- methyl-benzylamide 36 81 362
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid 3-
methyl-benzylamide 37 82 362 cis-4-(1H-Benzoimidazol-2-yl- methyl)-
cyclohexanecarboxyilic acid 4- methyl-benzylamide 38 83 366
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid 2-
fluoro-benzylamide 39 84 366 cis-4-(1H-Benzoimidazol-2-ylmethyl)-
cyclohexanecarboxyilic acid 3- fluoro-benzylamide 40 85 366
cis-4-(1H-Benzoimidazol-2-yl- methyl)- cyclohexanecarboxyilic acid
4- fluoro-benzylamide 41 86 416
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid 2-
trifluoromethyl-benzylamide 42 87 416
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid 3-
trifluoromethyl-benzylamide 43 88 416
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid 4-
trifluoromethyl-benzylamide 44 89 432
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid 2-
trifluoromethoxy-benzylamide 45 90 382
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid 2-
chloro-benzylamide 46 91 424 cis-4-(1H-Benzoimidazol-2-yl- methyl)-
cyclohexanecarboxyilic acid 2- phenyl-benzylamide 47 92 378
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid 2-
methoxy-benzylamide 48 93 392 cis-4-(1H-Benzoimidazol-2-ylmethyl)-
cyclohexanecarboxyilic acid 2- ethoxy-benzylamide 49 94 400
cis-4-(1H-Benzoimidazol-2-yl- methyl)- cyclohexanecarboxyilic acid
2- fluoro-4chloro-benzylamide 50 95 408
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid
2,6- dimethoxy-benzylamide 51 96 417
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid
2,4- dichloro-benzylamide 52 97 362
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxylic acid (1-
phenyl-ethyl)-amide 53 98 426 cis-4-(1H-Benzoimidazol-2-y-
lmethyl)- cyclohexanecarboxyilic acid 4-
methanesulfonyl-benzylamide 54 99 417
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid
2,6- dichloro-benzylamide 55 100 384
cis-4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic acid
2,6- difluoro-benzylamide
[0222] In Table 2 below, the substituents are shown wherein X.sub.1
corresponds to the NH group of the amide:
2TABLE 2 101 Example SUBSTITUENT MASS NAME 56 102 362
trans-4-(1H-Benzoimidazol-2- ylmethyl)-cyclohexanecarboxyilic acid
2-methyl-benzylamide 57 103 362 trans-4-(1H-Benzoimidazol- -2-
ylmethyl)-cyclohexanecarboxyilic acid 3-methyl-benzylamide 58 104
362 trans-4-(1H-Benzoimidazol-2- ylmethyl)-cyclohexanecarboxyi- lic
acid 4-methyl-benzylamide 59 105 366 trans-4-(1H-Benzoimidazol-2-
ylmethyl)-cyclohexanecarboxyilic acid 2-fluoro-benzylamide 60 106
366 trans-4-(1H-Benzoimidazol- -2- ylmethyl)-cyclohexanecarboxyilic
acid 3-fluoro-benzylamide 61 107 348 trans-4-(1H-Benzoimidazol-2-
ylmethyl)-cyclohexanecarboxyi- lic acid benzylamide 62 108 366
trans-4-(1H-Benzoimidazol-- 2- ylmethyl)-cyclohexanecarboxyilic
acid 4-fluoro-benzylamide 63 109 416 trans-4-(1H-Benzoimidazol-2-
ylmethyl)-cyclohexanecarboxyil- ic acid
2-trifluoromethyl-benzylamide 64 110 416
trans-4-(1H-Benzoimidazol-2- ylmethyl)-cyclohexanecarboxyilic acid
3-trifluoromethyl-benzylamide 65 111 416
trans-4-(1H-Benzoimidazol-2- ylmethyl)-cyclohexanecarboxyilic acid
4-trifluoromethyl-benzylamide
[0223] In Table 3 below, the substituents are shown wherein X.sub.1
corresponds to th NH group of the amide:
3TABLE 3 112 Example SUBSTITUENT MS NAME 66 113 349
trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyilic acid
benzylamide 67 114 335 trans-4-(1H-Benzoimidazol-2-
ylamino)-cyclohexanecarboxyilic acid phenylamide 68 115 379
trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyilic acid
2-methoxy-benzylamide 69 116 399 trans-4-(1H-Benzoimidazo- l-2-
ylamino)-cyclohexanecarboxylic acid (naphthalen-1-ylmethyl)-amide
70 117 433 trans-4-(1H-Benzoimidazol-2-
ylamino)-cyclohexanecarboxylic acid 4-(1,2,3)thiadiazol-4-yl-
benzylamide 71 118 375 trans-4-(1H-Benzoimidazol-2-
ylamino)-cyclohexanecarboxylic acid indan-2-ylamide 72 119 363
trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyilic acid
2-methyl-benzylamide 73 120 363 trans-4-(1H-Benzoimidazol- -2-
ylamino)-cyclohexanecarboxyilic acid 3-methyl-benzylamide 74 121
363 trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyili- c
acid 4-methyl-benzylamide 75 122 383 trans-4-(1H-Benzoimidazol-2-
ylamino)-cyclohexanecarboxyilic acid 2-chloro-benzylamide 76 123
383 trans-4-(1H-Benzoimidazol- -2- ylamino)-cyclohexanecarboxyilic
acid 3-chloro-benzylamide 77 124 383 trans-4-(1H-Benzoimidazol-2-
ylamino)-cyclohexanecarboxyili- c acid 4-chloro-benzylamide 78 125
367 trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyilic
acid 2-fluoro-benzylamide 79 126 367 trans-4-(1H-Benzoimidazol- -2-
ylamino)-cyclohexanecarboxyilic acid 3-fluoro-benzylamide 80 127
367 trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyili- c
acid 4-fluoro-benzylamide 81 128 379 trans-4-(1H-Benzoimidazol-2-
ylamino)-cyclohexanecarboxyilic acid 3-methoxy-benzylamide 82 129
379 trans-4-(1H-Benzoimidazo- l-2- ylamino)-cyclohexanecarboxyilic
acid 4-methoxy-benzylamide 83 130 417 trans-4-(1H-Benzoimidazol-2-
ylamino)-cyclohexanecarboxyi- lic acid
2-trifluoromethyl-benzylamide 84 131 417
trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyilic acid
3-trifluoromethyl-benzylamide 85 132 417
trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyilic acid
4-trifluoromethyl-benzylamide 86 133 433
trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyilic acid
2-trifluoromethoxy- benzylamide 87 134 433
trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyilic acid
3-trifluoromethoxy- benzylamide 88 135 433
trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyilic acid
4-trifluoromethoxy- benzylamide 89 136 377
trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyilic acid
3,5-dimethyl-benzylamide 90 137 379 trans-4-(1H-Benzoimidazol-2-
ylamino)-cyclohexanecarboxyilic acid
(benzo(1,3)dioxol-5-ylmethyl)-amide 91 138 379
trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyilic acid
2-methoxy-benzylamide 92 139 363 trans-4-(1H-Benzoimidazo- l-2-
ylamino)-cyclohexanecarboxylic acid (1-phenyl-ethyl)-amide 93 140
363 trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarboxyl- ic
acid phenethyl-amide 94 141 385 trans-4-(1H-Benzoimidaz- ol-2-
ylamino)-cyclohexanecarboxyilic acid 3,4-difluoro-benzylamide 95
142 425 trans-4-(1H-Benzoimidazol-2- ylamino)-cyclohexanecarb-
oxyilic acid 3-phenyl-benzylamide
[0224]
4TABLE 4 143 96 144 349 cis-4-(1H-Benzoimidazol-2-ylamino)-
cyclohexanecarboxyilic acid benzylamide 97 145 335
cis-4-(1H-Benzoimidazol-2-yla- mino)- cyclohexanecarboxyilic acid
phenylamide 98 146 379 cis-4-(1H-Benzoimidazol-2-ylamino)-
cyclohexanecarboxyilic acid 2- methoxy-benzylamide 99 147 399
cis-4-(1H-Benzoimidazol-2-- ylamino)- cyclohexanecarboxylic acid
(naphthalen-1-ylmethyl)-amide 100 148 425
cis-4-(1H-Benzoimidazol-2-ylamino)- cyclohexanecarboxyilic acid 3-
phenyl-benzylamide Examples 102-106: Example Structure MASS NAME
101 149 348 4-(1H-Benzoimidazol-2-ylmethyl)- cyclohexanecarboxyilic
acid benzylamide 102 150 362 4-(1H-Benzoimidazol-2-ylamino)-
cyclohexanecarboxylic acid benzyl- methyl-amide 103 151 364
cis-4-(3-Hydroxy-1H-benzoimidazol-2-
ylmethyl)-cyclohexanecarboxyilic acid benzylamide 104 152 382
cis-4-(3-Hydroxy-1H-benzoimi- dazol-2-
ylmethyl)-cyclohexanecarboxyilic acid 2-fluoro-benzylamide 105 153
364 trans-4-(3-Hydroxy-1H- benzoimidazol-2-ylmethyl)-
cyclohexanecarboxyilic acid benzylamide 106 154 382
trans-4-(3-Hydroxy-1H- benzoimidazol-2-ylmethyl)-
cyclohexanecarboxyilic acid 2- fluoro-benzylamide
[0225] Quinazoline compounds analogous to the above Imidazolyl can
be similarly prepared.
[0226] Compound (BBA)
[0227]
4-(4-Oxo-3,4-dihydro-quinazolin-2-ylmethyl)-cyclohexanecarboxylic
acid ethyl ester. 155
[0228] To a solution of 4-carboxymethyl-cyclohexanecarboxylic acid
ethyl ester (1 g, 4.9 mmol) in 100 nmL of dichloromethane was added
lmL of oxalyl chloride and 1 drop of DMF. After the evolution of
gas subsided, the resulting reaction mixture was stirred for 1 h,
then concentrated to dryness under reduced pressure. The resulting
crude acid chloride was dissolved in 50InL of dichloromethane and
treated with 1 g of anthranilamide and then lmL of triethylamine.
The resulting bright yellow solution was allowed to stir overnight,
then partitioned between saturated aqueous NaHCO.sub.3 and EtOAc,
and the organic portion washed 3.times. with water. The organic
layer was dried with MgSO.sub.4 and concentrated to yield a yellow
oil. The reaction mixture was then concentrated and purified by
column chromatography on silica using EtOAc. Data for cis/trans
mixture: mass spectrum m/z 315 [(M+H).sup.+; calcd for
C.sub.18H.sub.22N.sub.2O.sub.3: 314].
[0229] Compound (BBB)
[0230]
4-(4-Oxo-3,4-dihydro-quinazolin-2-ylmethyl)-cyclohexanecarboxylic
acid. 156
[0231] The cis/trans mixture of
4-(4-oxo-3,4-dihydro-quinazolin-2-ylmethyl- )-cyclohexanecarboxylic
acid ethyl ester (Compound BBA) (1 g) was dissolved in a minimal
amount of THF (10 mL) and mixed with concentrated aqueous LiOH (5
mL). The resulting reaction mixture was stirred vigorously and
heated at 65.degree. C. for 3 h. After cooling and concentration,
the reaction mixture was acidified to pH 4 with dilute HCl and
concentrated to dryness: mass spectrum m/z 287 [(M+H).sup.+; calcd
for C.sub.16H.sub.18N.sub.3O.sub.3: 286].
EXAMPLE 107
[0232]
Cis-4-(4-Oxo3,4-dihydro-quinazolin-2-ylmethyl)-cyclohexanecarboxyli-
c acid 2-fluoro-benzylaniide. 157
[0233] To a solution of
4-(4-oxo-3,4-dihydro-quinazolin-2-ylmethyl)-cycloh- exanecarboxylic
acid (275 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg,
1.05 mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine
(131 mg, 1.05 mmol), and the resulting reaction mixture was stirred
for 1 h. The reaction mixture was partitioned between saturated
aqueous NaHCO.sub.3 and EtOAc, and the organic layer washed
2.times. with water. The EtOAc was dried with MgSO.sub.4 and
concentrated to give a yellow solid. Preparative chromatography
eluting with chloroform:methanol gave the cis
4-(4-oxo-3,4-dihydro-quinazolin-2-ylmethyl)-cyclohexanecarboxylic
acid 2-fluoro-benzylamide as a white solid: mass spectrum m/z 394
[(M+H).sup.+; calcd for C.sub.23H.sub.24FN.sub.3O.sub.2: 393].
* * * * *