U.S. patent application number 09/973826 was filed with the patent office on 2002-09-26 for benzoic acid derivatives and related compounds as antiarrhythmic agents.
Invention is credited to Ahmad, Saleem, Atwal, Karnail S., Caulfield, Thomas J., Lloyd, John, Poss, Michael A., Rovnyak, George C., Stein, Philip D..
Application Number | 20020137968 09/973826 |
Document ID | / |
Family ID | 21902036 |
Filed Date | 2002-09-26 |
United States Patent
Application |
20020137968 |
Kind Code |
A1 |
Lloyd, John ; et
al. |
September 26, 2002 |
Benzoic acid derivatives and related compounds as antiarrhythmic
agents
Abstract
Benzoic acid derivatives of the formula I 1 where X is oxygen,
sulfur, --NH, --NR.sup.1, --N--CN, --N--OR.sup.1 or --N--NO.sub.2;
Y is a single bond, --C.dbd.C--, or --NH; R.sup.1 is alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocyclo, or
(heterocyclo)alkyl; and R.sup.2 is aryl or heterocyclo. The
compounds of formula I are useful in the treatment of
arrhythmia.
Inventors: |
Lloyd, John; (Yardley,
PA) ; Rovnyak, George C.; (Hopewell, NJ) ;
Stein, Philip D.; (Pennington, NJ) ; Ahmad,
Saleem; (Wall, NJ) ; Atwal, Karnail S.;
(Newtown, PA) ; Caulfield, Thomas J.;
(Lawrenceville, NJ) ; Poss, Michael A.;
(Lawrenceville, NJ) |
Correspondence
Address: |
MARLA J MATHIAS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
21902036 |
Appl. No.: |
09/973826 |
Filed: |
October 10, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09973826 |
Oct 10, 2001 |
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09468648 |
Dec 21, 1999 |
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09468648 |
Dec 21, 1999 |
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09008825 |
Jan 20, 1998 |
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60038811 |
Feb 21, 1997 |
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Current U.S.
Class: |
564/26 ; 564/104;
564/112; 564/161; 564/237; 564/47; 564/74 |
Current CPC
Class: |
C07D 209/08 20130101;
C07D 231/16 20130101; C07C 235/32 20130101; C07D 213/30 20130101;
C07D 333/24 20130101; C07C 2601/08 20170501; C07C 233/65 20130101;
C07D 207/12 20130101; C07D 239/52 20130101; C07D 215/12 20130101;
C07D 213/82 20130101; C07D 257/04 20130101; C07C 235/46 20130101;
C07D 231/12 20130101; C07D 271/06 20130101; C07D 261/08 20130101;
C07C 2601/14 20170501; C07D 233/56 20130101; C07D 473/00 20130101;
C07C 2601/02 20170501; C07D 235/06 20130101; C07D 213/56 20130101;
C07D 271/10 20130101; C07D 211/22 20130101; C07C 235/84 20130101;
C07D 211/46 20130101; C07C 235/48 20130101; C07C 237/30 20130101;
C07D 213/80 20130101; C07D 409/04 20130101; C07D 249/08
20130101 |
Class at
Publication: |
564/26 ; 564/47;
564/74; 564/112; 564/104; 564/161; 564/237 |
International
Class: |
C07C 335/16; C07C
277/00; C07C 275/28 |
Claims
What is claimed is:
1. A method of treating cardiac arrhythmia which comprises
administering to a mammal in need thereof an effective amount of a
compound of the formula I 301where X is oxygen, sulfur, --NH,
--NR.sup.1, --N--CN, --N--OR.sup.1 or --N--NO.sub.2; Y is a single
bond, --C.dbd.C--, or --NH; R.sup.1 is alkyl, alkenyl, alkynyl,
aryl, cycloalkyl, heterocyclo, or (heterocyclo)alkyl; and R.sup.2
is aryl or heterocyclo.
2. A compound of the formula I 302where X is oxygen, sulfur, --NH,
--NR.sup.1, --N--CN, --N--OR.sup.1 or --N--NO.sub.2; Y is a single
bond, --C.dbd.C--, or --NH; R.sup.1 is alkyl, alkenyl, alkynyl,
aryl, cycloalkyl, heterocyclo, or (heterocyclo)alkyl; and R.sup.2
is aryl or heterocyclo.
3. A compound as recited in claim 2 wherein X is oxygen or N--CN; Y
is a single bond or NH; and R.sup.1 is alkyl, cycloalkyl,
(aryl)alkyl, (cycloalkyl)alkyl, or (substituted-amino)alkyl.
4. A compound as recited in claim 2 wherein X is oxygen; Y is a
single bond or NH; and R.sup.1 is alkyl, cycloalkyl, (aryl)alkyl,
(cycloalkyl)alkyl, or (substituted-amino)alkyl.
5. A compound as recited in claim 2 wherein X is N--CN; Y is a
single bond or NH; and R.sup.1 is alkyl, cycloalkyl, (aryl)alkyl,
(cycloalkyl)alkyl, or (substituted-amino)alkyl.
6. A compound as recited in claim 2 wherein X is oxygen or N--CN; Y
is NH; and R.sup.1 is alkyl, cycloalkyl, (aryl)alkyl,
(cycloalkyl)alkyl, or (substituted-amino)alkyl.
7. A compound as recited in claim 2 wherein X is oxygen; Y is a
single bond; and R.sup.1 is alkyl, cycloalkyl, (aryl)alkyl,
(cycloalkyl)alkyl, or (substituted-amino)alkyl.
8. A compound as recited in claim 2 wherein X is N--CN Y is a
single bond; and R.sup.1 is alkyl, cycloalkyl, (aryl)alkyl,
(cycloalkyl)alkyl, or (substituted-amino)alkyl.
9. A compound as recited in claim 2 wherein X is oxygen or N--CN; Y
is single bond or NH; and R.sup.1 is alkyl.
10. A compound as recited in claim 2 wherein X is oxygen or N--CN;
Y is single bond or NH and R.sup.1 is cycloalkyl.
11. A compound as recited in claim 2 wherein X is N--CN; Y is
single bond or NH; and R.sup.1 is (aryl)alkyl.
12. A compound as recited in claim 2 wherein X is N--CN; Y is
single bond or NH; and R.sup.1 is (cycloalkyl)alkyl.
13. A compound as recited in claim 2 wherein X is N--CN; Y is
single bond or NH and R.sup.1 is (substituted-amino)alkyl.
14. A compound as recited in claim 2 which is:
(+)-N-[(2,2-dimethylcyclope- ntyl)methyl]-4-hexyloxybenzamide and
(-)-N-[(2,2-dimethylcyclopentyl)-meth- yl]-4-hexyloxybenzamide;
N-(3,3-dimethylbutyl)-4-(1H-indol-1-yl)benzamide;
4-(3-butyl-1,2,4-oxadiazol-5-yl)-N-(3,3-dimethylbutyl)-benzamide;
N-(3,3-dimethylbutyl)-2-(hexyloxy)-5-pyridine carboxamide;
N-(3,3-dimethylbutyl)-1-hexyl-1,2-dihydro-2-oxo-5-pyridinecarboxamide;
N-cyano-N'-(3,3-dimethylbutyl)-6-(hexyloxy)benzene-carboximidamide;
N-(3,3-dimethylbutyl)-N'-[4-(hexyloxy)phenyl]urea; N-(3,
3-dimethylbutyl)-N'-[4-(hexyloxy)phenyl]urea; or a compound of
claim 2 having the structure; 303
Description
BRIEF DESCRIPTION OF THE INVENTION
[0001] This invention is concerned with compounds of the formula I
2
[0002] where
[0003] X is oxygen, sulfur, --NH, --NR.sup.1, --N--CN,
--N--OR.sup.1 or --N--NO.sub.2;
[0004] Y is a single bond, --C.dbd.C--, or --NH;
[0005] R.sup.1 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocyclo, or (heterocyclo)alkyl; and
[0006] R.sup.2 is aryl or heterocyclo.
[0007] The compounds of formula I are useful in the treatment of
arrhythmia. The invention is also concerned with pharmaceutical
compositions comprising one or more of the novel compounds as an
active antiarrhythmic agent either alone or in combination with
other cardiovascular agents such as a .beta.-blocker or other
antiarrhythmic agent; and a method of treating arrhythmia by
administration of one of the novel compounds or compositions
thereof to a patient in need of such treatment.
DETAILED DESCRIPTION OF THE INVENTION
[0008] Definition of Terms
[0009] Listed below are definitions of various terms used to
describe the compounds of the instant invention. These definitions
apply to the terms as they are used throughout the specification
(unless they are otherwise limited in specific instances) either
individually or as part of a larger group.
[0010] The term "alkyl" refers to both straight and branched chain
groups having 1 to 8 carbon atoms, preferably 1 to 5 carbons, such
as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, the
various branched chain isomers thereof, such as isopropyl, t-butyl,
isobutyl, isohexyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl and
the like; as well as such groups substituted by, one or more
substituents such as halo, alkoxy, amino, substituted amino, aryl,
cycloalkyl, hydroxy, alkanoylamino, arylcarbonylamino, nitro,
cyano, thiol, alkylthio and the like.
[0011] The term "alkoxy" refers to alkyl--O--.
[0012] The term "alkylthio" refers alkyl--S--.
[0013] The term "alkenyl" refers to any of the above alkyl groups
further containing at least one carbon to carbon double bond.
[0014] The term "alkynyl" refers to any of the above alkyl groups
further containing at least one carbon to carbon triple bond.
[0015] The term "alkanoyl" refers to alkyl--C(O)--
[0016] The term "cycloalkyl" refers to saturated cyclic hydrocarbon
groups containing 3 to 8 ring carbons optionally substitued with
one or more substituents such as alkyl or hydroxy.
[0017] The term "halogen" or "halo" refers to chlorine, bromine,
iodine and fluorine.
[0018] The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon groups having 6 to 12 carbon atoms in the ring portion,
such as phenyl, 1-naphthyl, 2-naphthyl, phenanthrene or
dihydrophenanthrene; or such groups substituted with one or more
substituents such as alkyl, alkenyl, alkynyl, alkylthio, alkoxy,
halo, nitro, cyano, hydroxy, amino, substituted amino, phenyl,
--C(O)--phenyl, substituted phenyl, --C(O)--substituted amino,
heterocycle, carboxylic acid or carboxylic ester.
[0019] The term "aryl" also includes those groups listed above
fused to a five- or six-membered ring which optionally contains an
oxygen, sulfur or nitrogen atom. The five- or six-membered ring may
further optionally be substituted with for example, alkyl or
-phenyl-CF.sub.3.
[0020] The term "heterocyclo" or "hetero" refers to fully saturated
or unsaturated rings of five or six atoms containing one or two
oxygen and/or sulfur atoms and/or one to four nitrogen atoms
provided that the total number of hetero atoms in the ring is four
or less. Exemplary monocyclic heterocyclo groups include 2- and
3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl and imidazolyl.
[0021] The term heterocyclo or hetero also includes bicyclic rings
wherein the five- or six-membered ring containing oxygen and/or
sulfur and/or nitrogen atoms as defined above is fused to a benzene
ring and the bicyclic ring is attached by way of an available
atom.
[0022] Exemplary bicyclic hetero groups include 4-, 5-, 6- or
7-indolyl, 4-, 5-, 6- or 7-isoindolyl, 5-, 6-, 7- or 8-quinolinyl,
5-, 6-, 7- or 8-isoquinolinyl, 4-, 5-, 6- or 7-benzothiazolyl, 4-,
5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-,
6- or 7-benzoxadiazolyl and 4-, 5-, 6- or 7-benzofuranyl.
[0023] The term heterocyclo or hetero also includes such monocyclic
and bicyclic rings wherein an available atom is substituted by one
or more substituents such as alkyl, aryl, alkylthio, alkoxy, halo,
nitro, keto, cyano, hydroxy, azo, oxo, thiazo, amino, substituted
amino, carboxylic acid, carboxylic ester, or alkoxy further
substituted with a carboxylic acid or a five- to eight-membered
ring optionally containing 1 to 4 heteroatoms selected from oxygen,
nitrogen and sulfur, optionally substituted by groups such as alkyl
or halogen.
[0024] The term "substituted amino" refers to a group of the
formula -NZ.sup.2Z.sup.3 wherein Z.sup.2 is hydrogen, alkyl,
cycloalkyl, aryl, morpholinylalkyl, heterocyclo or
(heterocyclo)alkyl and Z.sup.3 is hydrogen, alkyl, cycloalkyl or
aryl further substituted with a carboxylic acid or carboxylic
ester, provided that when Z.sup.2 is hydrogen, then Z.sup.3 is
other than hydrogen; or Z.sup.2 and Z.sup.3 taken together with the
nitrogen atom to which they are attached are 1-pyrrolidinyl,
1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl,
1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl,
4-diarylalkyl-1-piperazinyl; or 1-pyrrolidinyl, 1-piperidinyl, or
1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio,
halo, aryl or hydroxy.
[0025] Throughout the specification, groups and substituents
thereof are chosen to provide stable moieties and compounds.
[0026] The compounds of formula I may form salts which are also
within the scope of this invention. Pharmaceutically acceptable
(i.e., non-toxic, physiologically acceptable) salts are preferred,
although other salts are also useful, e.g., in isolating or
purifying the compounds of this invention.
[0027] The compounds of formula I may form salts with alkali metals
such as sodium, potassium and lithium, with alkaline earth metals
such as calcium and magnesium, with organic bases such as
dicyclohexylamine, tributylamine, pyridine and amino acids such as
arginine, lysine and the like. Such salts may be obtained, for
example, by exchanging the carboxylic acid protons, if they contain
a carboxylic acid, in compound I with the desired ion in a medium
in which the salt precipitates or in an aqueous medium followed by
evaporation. Other salts can be formed as known to those having
ordinary skill in the art.
[0028] The compounds of formula I may form salts with a variety of
organic and inorganic acids. Such salts include those formed with
hydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuric
acid, acetic acid, trifluoroacetic acid, maleic acid,
benzenesulfonic acid, toluenesulfonic acid and various others
(e.g., nitrates, phosphates, borates, tartrates, citrates,
succinates, benzoates, ascorbates, salicylates and the like). Such
salts may be formed by reacting compound I in an equivalent amount
of the acid in a medium in which the salt precipitates or in an
aqueous medium followed by evaporation.
[0029] In addition, zwitterions ("inner salts") may be formed.
[0030] A compound of the formula I may also have prodrug forms. Any
compound that will be converted in vivo to provide the bioactive
agent (i.e., the compound of formula 1) is a prodrug within the
scope and spirit of the invention.
[0031] Various forms of prodrugs are well known in the art. For
examples of such prodrug derivatives, see:
[0032] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier,
1985);
[0033] b) Methods in Enzymology, Vol. 42, 309-396, edited by K.
Widder et al. (Academic Press, 1985);
[0034] c) A Textbook of Drug Design and Development, edited by
Krogsgaard-Larsen and H. Bundgaard, Chapter 5, "Design and
Application of Prodrugs," by H. Bundgaard, 113-191 (1991);
[0035] d) Advanced Drug Delivery Reviews, H. Bundgaard, 8, 1-38
(1992);
[0036] e) Journal of Pharmaceutical Sciences, H. Bundgaard et al.,
77, 285 (1988); and
[0037] f) Chem Pharm Bull, N. Kakeya et al., 32, 692 (1984).
[0038] It should further be understood that solvates (e.g.,
hydrates) of the compounds of formula I are also within the scope
of the present invention. Methods of salvation are generally known
in the art.
[0039] All stereoisomers of the compounds of the instant invention
are contemplated, either in admixture or in pure or substantially
pure form. The compounds of the present invention can have
asymmetric centers at any of the carbon atoms including any one of
the R substituents. Consequently, compounds of formula I can exist
in diastereomeric forms or in mixtures thereof. The below described
processes can utilize racemates, enantiomers or diastereomers as
starting materials. When diastereomeric products are prepared, they
can be separated by conventional methods for example,
chromatographyc or fractional crystallization.
[0040] Use and Utility
[0041] The compounds of formula I are useful in the treatment of
arrhythmia. More specifically, the compounds of the present
invention have the pharmacological properties required for the
antiarrhythmic agents of Class III.
[0042] Class III agents increase myocardial refractoriness via a
prolongation of cardiac action potential duration. Theoretically,
prolongation of the cardiac action potential can be achieved by
enhancing inward currents (i.e. Na.sup.+ or Ca.sup.2+ currents;
hereinafter I.sub.Na and I.sub.Ca respectively) or by reducing
outward repolarizing potassium (K.sup.+) currents. The delayed
rectifier (I.sub.K)K.sup.+ current is the main outward current
involved in the overall repolarization process during the action
potential plateau, whereas the transient outward (I.sub.to) and
inward rectifier (I.sub.K1)K.sup.+ current are responsible for the
rapid initial and terminal phases of repolarization, respectively.
Cellular electrophysiologic studies have demonstrated that I.sub.K
consists of two pharmacologically and kinetically distinct K.sup.+
current subtypes, I.sub.Kr (rapidly activating and deactivating)
and I.sub.KS (slowly activating and deactivating).
[0043] Most Class III agents that are known to be in development
predominantly block I.sub.Kr. These agents have a potential
liability in that they have an enhanced risk of proarrhythmia at
slow heart rates. The compounds of the present invention prolong
the mycocardial action potential in vitro without a significant
depression of the Vmax and with the prolongation of Qtc-interval in
anesthetized dogs. In addition the compounds of the present
invention selectively block I.sub.Ks. The preferred compounds of
the present invention are those which have selectivity of
I.sub.Ks:I.sub.Kr greater than or equal to 5.
[0044] The compounds of the present invention are effective in
treating and preventing all types of arrhythmias including
ventricular and atrial (supraventricular) arrhythmias. The
compounds of the present invention are especially useful to control
reentrant arrhythmias and prevent sudden death due to the
ventricular fibrillation.
[0045] In the novel method of this invention of treating
arrhythmia, a novel compound or pharmaceutically acceptable salt
thereof, is administered in an amount ranging from about 0.0001 to
about 20 mg per kg of body weight per day, preferably from about
0.001 to about 10 mg per kg of body weight per day in a single dose
or in 2 to 4 divided doses.
[0046] The novel compounds of this invention can be administered as
the sole active ingredient or in combination with other
antiarrhythmic agents or other cardiovascular agents.
[0047] The compounds, or pharmaceutically acceptable salts thereof,
of the present invention, in the described dosages, are
administered orally, intraperitoneally, subcutaneously,
intramuscularly, transdermally, sublingually or intravenously. They
are preferably administered orally, for example in the form of
tablets, troches, capsules, elixirs, suspensions, syrups, wafers,
chewing gum, or the like prepared by art recognized procedures. The
amount of active compound in such therapeutically useful
compositions or preparations is such that a suitable dosage will be
obtained.
[0048] Preferred Moieties
[0049] The preferred compounds of the present invention are those
compounds of formula I where:
[0050] X is oxygen or N--CN;
[0051] Y is a single bond or --C.dbd.C--; and
[0052] R.sup.1 is alkyl, cycloalkyl, (aryl)alkyl,
(cycloalkyl)alkyl, or (substituted amino)alkyl.
[0053] Process of Preparation
[0054] The compounds of the instant invention may be obtained by
methods exemplified by the following descriptions.
[0055] The compounds of formula I wherein X is O and Y is a single
bond or --C.dbd.C-- (compounds of formula Ia), can be prepared as
outlined in Scheme 1 below. 3
[0056] The acid chloride (Z.dbd.Cl) of formula 2 is reacted with an
amine of formula 3 in the presence of a base such as triethylamine
and an organic solvent such as dichloromethane, tetrahydrofuran or
dimethylformamide etc. to form the compounds of formula Ia.
[0057] Alternatively, compounds of formula Ia can be prepared from
an acid of formula 2 (Z.dbd.OH) and an amine of formula 3 in an
organic solvent in the presence of a carbodiimide such as
dicyclohexylcabodiimide or
1-(3-dimethylaminopropyl)-2-ethylcarbodiimide hydrochloride
(WSC).
[0058] Compounds of formula I wherein X is S, can be prepared from
compounds of formula I wherein X is O by treatment with a
thionating agent such as phosphorus pentasulfide (P.sub.4S.sub.10)
or the Lawesson's reagent. Compounds of formula 2 and 3 are
commercially available or they can be prepared by methods described
in the literature.
[0059] The compounds of formula I wherein X is NCN and Y is a
single bond or --C.dbd.C-- (i.e., compounds of formula Ib), can be
prepared as outlined in Scheme 2. 4
[0060] The nitrile of formula 4 is converted to the imino ether of
formula 5 by treatment with hydrochloric acid in ethanol. The imino
ether 6 is then reacted with cyanamide to provide a compound of
formula 6 which on reaction with an amine of formula 3 provides the
compounds of formula Ib. Compounds of formula 4 are commercially
available or they can be prepared by methods described in the
literature.
[0061] The compounds of formula I wherein X is NCN and Y is NH
(i.e., compounds of formula Ic), can be prepared as outlined in
Scheme 3. 5
[0062] The amine of formula 7 is converted to the phenyl ester of
formula 8 by treatment with diphenylcyanocarbonimidate in the
presence of a base (e.g., sodium hydride, diisopropylethyl amine).
The compound of formula 8 is converted to the compounds of formula
Ic by treatment with an amine of formula 3 in an organic solvent.
Compounds of formula 7 are commercially available or they can be
prepared by methods described in the literature.
[0063] Alternatively, compounds of formula I wherein X is NCN and Y
is NH, can be prepared by methods similar to those described in the
literature such as that by Atwal et. al. Tetrahedron Letters, Vol.
30, pp 7313-7316 (1989) and references therein.
[0064] The compounds of formula I wherein X is O or S and Y is NH
(i.e., compounds of formula Id), can be prepared as outlined in
Scheme 4. 6
[0065] The amine of formula 7 is reacted with an isocyanate or
isothiocyanate of formula 9 in an organic solvent to provide the
compounds of formula Id.
[0066] Alternatively, the compounds of formula I wherein X is O or
S and Y is NH, can be prepared by sequential treatment of an amine
of formula 7 with an arylchloroformate (e.g., phenylchloroformate)
and an amine of formula 3.
[0067] Compounds of formula I wherein X is S, can be prepared from
compounds of formula I wherein X is O by treatment with a standard
thionating agent such as phosphorus pentasulfide (P.sub.4S.sub.10)
or the Lawesson's reagent. Compounds of formula 9 are commercially
available or they can be prepared by conventional methods described
in the literature.
[0068] The compounds of formula I wherein R.sup.2 contains an aryl
or a heterocyclo substituent (formula le) may be prepared according
to Scheme 5. 7
[0069] Compounds of formula Ie can be prepared from compounds of
formula 8 wherein W is a suitable leaving group such as halogen or
triflate by treatment with a heterocyclo group or an aryl ring
containing a suitable reacting group such as an amino group,
boronic acid and trialkyltin in the presence of a suitable catalyst
(base, palladium etc.). Compounds of formula 8 are prepared by
methods described in Schemes 1 to 4.
[0070] The compounds of formula I wherein R.sup.2 contains a
heterocyclic substituent (oxazole, imidazole, oxadiazole,
thiadiazole etc.), can also be prepared from compounds of formula
1* wherein R.sup.2 contains a suitable heterocyclo forming group
such as an acid or a derivative thereof as described in Scheme 6.
8
[0071] Compounds of formula If are prepared by treatment with a
suitable heterocyclo forming reagent (amidine, hydroxyamidine
etc.). This transformation can also be accomplished in a stepwise
fashion by modification of methods described in the literature.
[0072] All other compounds of formula I may be prepared by
modification of the procedures discussed herein as known by those
having ordinary skill in the art. The intermediates used to prepare
compounds of formula I are described herein or may be derived from
known compounds by those having ordinary skill in the art or are
commercially available.
EXAMPLES
[0073] The following examples and preparations describe the manner
and process of making and using the invention and are illustrative
rather than limiting. It should be understood that there may be
other embodiments which fall within the spirit and scope of the
invention as defined by the claims appended hereto.
Example 1
(+)--N--[(2,2-Dimethylcyclopentyl)methyl]-4-hexyloxybenzamide and
(-)--N--[(2,2-Dimethylcyclopentyl)methyl]4-hexyloxybenzamide
[0074] 9
[0075] A. 2,2-Dimethylcyclopentanecarbonitrile
[0076] Tosylmethyl isocyanide (3.76 g, 19.3 mmol) was dissolved in
dimethylsulfoxide (15 mL) and cooled to 0.degree. C. Solid
potassium t-butoxide (6.3 g, 59.2 mmol) was added and a thick brown
precipitate formed. The reaction mixture was warmed to room
temperature and 2,2-dimethylcyclopentanone (2.0 mL, 16.0 mmol) was
added in anhydrous methanol (680 .mu.L) and the reaction mixture
was stirred for 30 hours. It was diluted with ethyl acetate,
acidified with hydrochloric acid and extracted with hexanes. The
extracts were dried over magnesium sulfate, filtered and the
solvent was removed to provide a brown oil which was purified by
chromatography on silica gel eluted with 0-50% dichloromethane in
hexanes to yield a yellow oil (612 mg, 31%).
[0077] B. 2,2-Dimethylcyclopentanemethanamine
[0078] Compound 2 (600 mg, 4.87 mmol) was dissolved in
tetrahydrofuran (10 mL) and cooled to 0.degree. C. Lithium aluminum
hydride (185 mg, 4.87 mmol) was added and the mixture was stirred
for 17 hours. The reaction mixture was then quenched by addition of
sodium sulfate decahydrate, filtered through celite and the celite
washed with ether. To the solution was added hydrogen chloride (3
mL, 3.9 M in dioxane) and the solvent was removed. The residue was
dissolved in water and lyophilized to yield a white solid (613 mg,
77%).
[0079] C.
(+)--N--[(2,2-Dimethylcyclopentyl)methyl]4-hexyloxybenzamide and
(-)--N--[(2,2-Dimethyl-cyclopentyl)methyl]-4-hexyloxybenzamide:
[0080] To compound 3 (300 mg, 1.83 mmol) in dichloromethane (8 mL)
was added triethylamine (766 .mu.L, 5.50 mmol) and
4-hexyloxybenzoyl chloride (4) (430 .mu.L, 1.92 mmol) and the
reaction mixture was stirred for 24 hours at room temperature. The
reaction mixture was diluted with ethyl acetate and washed with
hydrochloric acid, saturated sodium bicarbonate and brine. The
organic layer was dried over magnesium sulfate, filtered and the
solvent was removed to yield a white solid (600 mg). Purification
by preparative HPLC (Chiracel OD, 50.times.500 mm; 10% isopropanol,
hexane; 90 mL/min) provided 99 mg of a faster moving isomer, 342 mg
of mixed fraction and 65 mg of a slower moving isomer. Further
purification of the faster moving isomer by flash chromatography on
silica gel eluted with 10% acetone in hexanes provided
(+)--N--[(2,2-dimethylcyclopentyl)me- thyl]-4-hexyloxybenzamide as
a white solid (90 mg): mp 68-69.degree. C.; [.alpha.].sub.D (MeOH,
c 0.55) +20.7.degree..
[0081] Analysis calculated for C.sub.21H.sub.33NO.sub.2: C, 76.09;
H, 10.03; N, 4.24. Found: C, 75.99; H, 10.11; N, 4.11.
[0082] Further purification of the slower moving isomer by flash
chromatography on silica gel eluting with 10% acetone in hexane
provided
(-)--N--[(2,2-dimethylcyclopentyl)-methyl]-4-hexyloxybenzamide as a
white solid (57 mg): mp 69-70.degree. C.; [.alpha.].sub.D (MeOH, c
0.55)-18.5.degree.;
[0083] Analysis calculated for C.sub.21H.sub.33NO.sub.2: C, 76.09;
H, 10.03; N, 4.24. Found: C, 75.95; H, 10.12; N, 4.13.
Example 1a
N--(3,3-Dimethylcyclopentyl)-4-hexyloxybenzamide
[0084] 10
[0085] A. N--(3,3-Dimethylcyclopentyl)benzenemethanamine
[0086] 4,4-Dimethyl-2-cyclopenten-1-one (804 mg, 7.30 mmol) and
benzylamine (877 .mu.L, 8.03 mmol) were dissolved in 15 mL of
ethanol. Charcoal (400 mg) and platinum oxide (Adams' catalyst, 331
mg, 1.46 mmol) were added and the mixture was stirred under
hydrogen (balloon) for 24 hours. The reaction was purged with argon
and diluted with ethyl acetate. The mixture was loaded onto silica
gel and purified by flash chromatography on silica gel eluted with
5% triethylamine and hexane to provide 1.24 g (84%) of a clear
colorless oil.
[0087] B. 3,3-Dimethylcyclopentanamine hydrochloride
[0088] The amine (2, 130 mg, 0.64 mmol) was dissolved in 2 mL of
ethanol. Palladium (5% on charcoal, 13 mg) was added and the
reaction was stirred under hydrogen (balloon) at 50.degree. C. for
10 hours then at room temperature for 10 hours. The mixture was
diluted with ether then filtered through Celite. Hydrogen chloride
(3.86 M, 300 .mu.L) was added and the solvent removed to yield 87
mg (91%) of a white solid.
[0089] C. N-(3,3-Dimethylcyclopentyl)-4-hexyloxybenzamide
[0090] The amine hydrochloride (3, 87 mg, 0.58 mmol) was dissolve
in 2 mL dichloromethane. Triethylamine (244 .mu.L, 1.75 mmol) and
4-hexyloxybenzoyl chloride (155 .mu.L, 0.70 mmol) were added and
the mixture was stirred for 4 hours at room temperature. The
reaction was diluted with ethyl acetate and washed with
hydrochloric acid (1.0 M, aq.), sodium bicarbonate (sat'd., aq.)
and sodium chloride (sat'd., aq.). The organic layer was dried over
magnesium sulfate, filtered and the solvent removed. Purification
by flash chromatography on silica gel eluted with 10% acetone,
hexane provided 138 mg (75%) of a white solid. mp 82-83.degree. C.;
Anal calc'd for C.sub.20H.sub.31 NO.sub.2: C, 75.67; H, 9.84; N,
4.41. Found: C, 75.86; H, 10.10; N, 4.37.
Example 1c
N--(3,3-Dimethylcyclopentyl)-4-benzoylbenzamide
[0091] 11
[0092] 4-Benzoylbenzoic acid (0.20 mmol) and the title B compound
of example 1b (0.22 mmol) were dissolved in 1 mL of THF and
triethylamine (0.22 mmol) and 4-dimethylamino-pyridine (0.02 mmol)
were added. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (1.6 ML, 0.15 M in dichloromethane, 0.24 mmol) was
added and the mixture was allowed to stand for 48 hours.
Purification by preparative HPLC (YMC ODS-A S% 30.times.250 mm
column, 50-90% methanol water with 0.10% TFA gradient over 20
minutes, 25 mL/minute flow) provided 40 mg (61%) of a white solid.
C.sub.21H.sub.23NO.sub.2: m/z=322 (M+H).
Example 1d
N--[(3,3-Dimethylcyclopentyl)methyl]4-(hexyloxy)benzamide
[0093] 12
[0094] A. 3,3-Dimethylcyclopentanone
[0095] 4,4-Dimethyl-2-cyclopenten-1-one (1, 1.0 g, 9.08 mmol) was
dissolved in 5 mL of ethyl acetate and palladium (10% on carbon, 50
mg) was added. The mixture was stirred under a hydrogen atmosphere
(balloon) for 23 hours. The reaction was then filtered through
Celite and the Celite washed with ether. The solvent was removed by
distillation at atmospheric pressure to provide 1.11 g (>100%)
of a clear colorless oil that was used without further
purification.
[0096] B. 3,3-Dimethylcyclopentanecarbonitrile
[0097] Solid potassium t-butoxide (3.57 g, 31.8 mmol) was dissolved
in 10 mL of anhydrous dimethylsulfoxide. Tosylmethyl isocyanide
(2.13 g, 10.9 mmol) was dissolved in 8 mL of dimethyisulfoxide and
added to the potassium-t-butoxide. A thick brown precipitate
formed. The ketone (2, assumed 9.08 mmol) was added in 386 .mu.L of
anhydrous methanol. The mixture was heated to 45.degree. C. and
stirred for 24 hours. The reaction was diluted with water (100 mL),
acidified to pH 3, and extracted with pentane. The extracts were
dried over magnesium sulfate, filtered and the solvent removed to
provide a yellow oil (>100%) that was used without
purification.
[0098] C. 3,3-Dimethylcyclopentanemethanamine Hydrochloride
[0099] The nitrile (3, assumed 9.08 mmol) was dissolved in 10 mL of
anhydrous tetrahydrofuran and cooled to 0.degree. C. Lithium
aluminum hydride (335 mg, 9.08 mmol) was added and the mixture was
stirred for 20 hours. The reaction was then quenched by addition of
sodium sulfate decahydrate, filtered through celite and the celite
washed with ether. Hydrogen chloride (2.5 mL, 4 M in dioxane) was
added and the solvent removed to provide a brown oil. This oil was
dissolved in water, filtered and lyophilized to yield 296 mg (20%)
of a brown solid.
[0100] D.
N-[(3,3-Dimethylcyclopentyl)Methyl]-4-(Hexyloxy)Benzamide
[0101] The amine hydrochloride (4, 100 mg, 0.61 mmol) was dissolved
in 2 mL of dichloromethane. Triethylamine (255 .mu.L, 1.83 mmol)
and 4-hexyloxybenzoyl chloride (5, 136 .mu.L, 0.61 mmol) were added
and the mixture was stirred for 6 hours at room temperature. The
reaction was diluted with ethyl acetate and washed with
hydrochloric acid (1.0 M, aq.), sodium bicarbonate (sat'd., aq.)
and sodium chloride (sat'd., aq.). The organic layer was dried over
magnesium sulfate, filtered and the solvent removed to provide 210
mg of a brown solid. Purification by flash chromatography on silica
gel eluting with 5% acetone, hexane provided 111 mg (55%) of a
white powder. mp 85-86.degree. C.; Anal. calc'd for
C.sub.21H.sub.33NO.sub.2: C, 76.09; H, 10.03; N, 4.23. Found: C,
76.02; H, 10.23; N, 4.20.
Example 1e
N--[(3,3-Dimethylcyclohexyl)Methyl]-4-(Hexyloxy)Benzamide
[0102] 13
[0103] A. 3,3-Dimethylcyclohexanecarbonitrile
[0104] Tosylmethyl isocyanide (3.0 g, 15.4 mmol) was dissolved in
15 mL of anhydrous dimethylsulfoxide and the solution was cooled to
5-10.degree. C. in an ice water bath. Potassium tert-butoxide
(5.03g, 44.8 mmol) was then added and the solution turned dark
brown in color. The reaction was allowed to warm to room
temperature and stirred for 1 hour. A solution of the cyclohexanone
(1) (1.62 g, 12.8 mmol) in anhydrous methanol (685 .mu.L) was added
to the reaction via syringe and the reaction was stirred at room
temperature under argon for 40 hours. The reaction was then diluted
with 25 mL of water and placed in an ice water bath and the
reaction was made acidic by the dropwise addition of aqueous HCl
(6.0 M, aq.). The aqueous phase was extracted 2 times with hexane,
and the organic phases were combined and dried over MgSO.sub.4,
filtered and concentrated to provide 2.24 g of a yellow mixture of
oil and solid. The crude mixture was purified by chromatography on
silica gel (eluted with 0-50% dichloromethane in hexanes) and the
fractions were concentrated and monitored by IR to find 870 mg
(50%) of the nitrile product (2) as a transparent oil.
[0105] B. 3,3-Dimethylcyclohexanemethanamine Hydrochloride
[0106] The nitrile (2) (410 mg, 2.99 mmol) was dissolved in 6 mL of
anhydrous tetrahydrofuran and the resulting solution was cooled to
0.degree. C. on an ice water bath. Solid lithium aluminum hydride
(114 mg, 3.0 mmol) was then slowly added to the reaction in small
portions. Upon full addition, the bath was removed and the reaction
was stirred at room temperature under argon for 16 hours. The
reaction was then cooled on an ice water bath and solid
Na.sub.2SO.sub.4.multidot.10 H.sub.2O was slowly added until gas
evolution ceased. The reaction was diluted in 10 mL of Et.sub.2O
and several drops of water were added to produce a filterable
solid. The reaction was then filtered through a pad of Celite and
1.5 mL of 4.0 M HCl in dioxane was added to the filtrate. The
cloudy reaction solution was stirred for 15 minutes and then
concentrated in vacuo to provide 477 mg (90%) of a white solid.
[0107] C.
N--[(3,3-Dimethylcyclohexyl)Methyl]-4-(Hexyloxy)-benzamide
[0108] The amine (3) was dissolved in 5 mL of anhydrous
dichloromethane and triethylamine (171 .mu.L, 1.23 mmol) was added
at room temperature under argon. The solution was cooled in an ice
water bath and hexyloxybenzoyl chloride (134 .mu.L, 0.61 mmol) was
added via syringe and the reaction was allowed to warm to room
temperature and stirred for 64 hours. The reaction was partitioned
between HCl (1.0 M , aq) and dichloromethane and the organic phase
was washed with NaHCO.sub.3 (sat'd, aq.), dried over MgSO.sub.4,
filtered and concentrated to provide 224 mg of a white solid. The
solid was purified by flash chromatography on silica gel eluted
with 15% acetone, hexane to provide 142 mg (67%) of the desired
amide. Analysis calculated for C.sub.22H.sub.35NO.sub.2: C, 76.48;
H, 10.21; N, 4.05. Found: C, 76.42; H, 10.27; N, 3.98.
Example 1f
4-(Hexyloxy)-N-[(2-methylcyclohexyl)Methyl]Benzamide
[0109] 14
[0110] A. 6-methyl-1-cyclohexenenitrile and
2-methyl-1-cyclohexenenitrile
[0111] Trimethylsilyl cyanide (8.0 mL, 60.0 mmol) was added
dropwise over a 5 minute period to a suspension of
2-methylcyclopentanone (1) (6.1 mL, 50.0 mmol) and zinc iodide (399
mg, 1.25 mmol) in methylene chloride (25 mL). After stirring for 3
hours, a mixture of phosphorous oxychloride (11.2 mL, 120 mmol) and
pyridine (60 mL) was added to the reaction. The reaction was heated
at 110.degree. C. for 23 hours and then cooled to room temperature.
The reaction was carefully poured onto 250 g of crushed ice,
acidified with 6 N HCl (30 mL), and extracted with ether
(3.times.150 mL). The combined organic layers were washed with
water (50 mL), saturated NaHCO.sub.3 (50 mL), dried (MgSO.sub.4)
and concentrated by distillation. Vacuum distillation (10 mm Hg)
provided 5.56 g of a mixture of 6-methyl-1-cyclohexenenitrile and
2-methyl-1-cyclohexenenitril- e (bp 86-91.degree. C.).
[0112] B. ((2-Methylcylohexyl)Methyl)Amine Hydrochloride
[0113] The mixture of title A compounds (2.00 g, 16.5 mmol),
PtO.sub.2 (120 mg), and saturated ethanolic HCl (4.5 mL) in ethanol
(75 mL) was shaken under a hydrogen atmosphere (55 psi) on a Parr
shaker for 3.5 hours. After purging with nitrogen, the reaction was
filtered through Celite AFA. The pad was rinsed with ethanol
(3.times.15 mL) and the combined filtrates were concentrated in
vacuo. Trituration of the solid residue with ether (1.times.50 mL,
2.times.20 mL) provided 2.29 g (85%) of
((2-methylcylohexyl)methyl)amine hydrochloride as a mixture of
isomers.
[0114] C. 4-(Hexyloxy)-N-[(2-methylcyclohexyl)Methyl]Benzamide
[0115] To a suspension of title B compound (213 mg, 1.30 mmol) in
THF (6 mL) was added triethylamine 0.42 mL, 3.0 mmol). After
stirring for 5 minutes, 4-hexyloxybenzoyl chloride (0.223 mL, 1.00
mmol) was added. After stirring for 4 hours, the reaction was
filtered through a Celite pad. The pad was rinsed with ether
(4.times.5 mL) and the combined filtrates were concentrated in
vacuo. Purification by RP-HPLC (YMC SH-365-10 120A S-110
30.times.500 mm column, 40 mL/minute, 90:10 methanol/water
(containing 0.1% TFA)) afforded the title compound as a 1:1 mixture
of cis- and trans- isomers (43 mg). MS: (ESI) (m/z) 332.
[0116] Using the procedure described for the synthesis of the title
B compound of Example 1f, ((2-ethylcyclohexyl)-methyl)amine
hydrochloride (from 2-ethylcyclohexanone, 71% yield, isomer
mixture), ((2-phenylcyclohexyl)methyl)amine hydrochloride (from
2-phenylcyclohexanone, 44% yield, isomer mixture),
((2-methylcyclopentyl)methyl)amine hydrochloride (from
2-methylcyclopentanone, 49% yield, isomer mixture), and
((2-ethylcyclopentyl)methyl)amine hydrochloride (from
2-ethylcyclopentanone, 42% yield, isomer mixture) were
prepared.
[0117] Using methodology analogous to that described for the title
compounds of Example 1, the compounds of Examples 2 to 20 were
prepared.
1 Example # Structure Characterization 2 15
C.sub.21H.sub.36N.sub.2O.sub.2.HCl: mp 131-134.degree. C. Analysis
calculated: C, 65.5; H, 9.69: N, 7.27; Cl. 9.21. Found: C, 65.6; H,
9.79; N, 7.17; Cl, 8.97. 3 16 C.sub.19H.sub.31NO.sub.2: mp
74-76.degree. C. Analysis calculated: C, 74.71; H, 10.23; N, 4.59.
Found: C, 75.01; H, 10.40, N, 4.52. 4 17
C.sub.22H.sub.23F.sub.6NO.sub.2: mp 105-106.degree. C. Analysis
calculated: C, 59.06; H, 5.18; N, 3.13; F, 25.48. Found: C, 58.88;
H, 5.15; N, 2.98; F, 25.36. 5 18 C.sub.20H.sub.31NO.sub.2: mp
82-83.degree. C. Analysis calculated: C, 75.67; H, 9.84; N, 4.41.
Found: C, 75.86; H, 10.10; N, 4.37. 6 19 C.sub.18H.sub.29NO.sub.2:
m/e =291. 7 20 C.sub.23H.sub.37NO.sub.3: m/e =375. 7a 21
C.sub.22H.sub.35NO.sub.2ESI (m/z) 346 Rf (silica, 25% EtOAc/hex)
0.34. 7b 22 C.sub.26H.sub.35NO.sub.2ESI (m/z) 394 Rf (silica, 25%
EtOAc/hex) 0.27. 7c 23 C.sub.26H.sub.35NO.sub.2ESI (m/z) 394 Rf
(silica, 25% EtOAc/hex) 0.28. 7d 24 C.sub.21H.sub.35NO.sub.2ESI
(m/z) 334 Rf (silica, 25% EtOAc/hex) 0.39. 7e 25
C.sub.21H.sub.35NO.sub.2ESI (m/z) 334 Rf (silica, 25% EtOAc/hex)
0.41. 7f 26 C.sub.23H.sub.35NO.sub.2: ESI (m/z) 358 mp
68.0-69.0.degree. C. Analysis calculated: C, 77.27; H, 9.87; N,
3.92. Found: C, 77.02; H, 10.12; N, 3.74. 7g 27
C.sub.20H.sub.31NO.sub.2: mp 98.0-100.0.degree. C. Analysis
calculated: C, 75.67; H, 9.84; N, 4.41. Found: C, 75.57; H, 10.02;
N, 4.26. 7h 28 C.sub.21H.sub.33NO.sub.2.0.14 H.sub.2O: mp
93.0-95.5.degree. C. Analysis calculated: C, 75.50; H, 10.04; N,
4.19. Found: C, 75.50; H, 10.20; N, 3.94. 7i 29
C.sub.19H.sub.29NO.sub.2.0.17 H.sub.2O: mp 107.0-109.5.degree. C.
Analysis calculated: C, 74.45; H, 9.65; N, 4.57. Found: C, 74.45;
H, 9.89; N, 4.71. 7j 30 C.sub.25H.sub.33NO.sub.2: mp
87.0-88.0.degree. C. Analysis calculated: C, 79.12; H, 8.76; N,
3.69. Found: C, 79.09; H, 8.67; N, 3.58. 7k 31 mp 77.0-78.0.degree.
C. ESI (m/z) 380. 8 32 C.sub.19H.sub.23NO: mp 126-127.degree. C.
Analysis calculated: C, 81.00; H, 8.24; N, 4.98. Found: C, 81.17;
H, 8.19; N, 4.93. 9 33 C.sub.17H.sub.24N.sub.2O: m/e =272. 10 34
C.sub.20H.sub.23NO.sub.2: m/e =309. 10a 35 ESI (m/z) 398 Rf
(silica, 25% EtOAc/hex) 0.21. 10b 36 ESI (m/z) 338 Rf (silica, 25%
EtOAc/hex) 0.24. 10c 37 mp 56.0-57.0.degree. C. ESI (m/z) 358 10d
38 mp 62.5-64.0.degree. C. ESI (m/z) 332 10e 39 mp
50.5-51.5.degree. C. ESI (m/z) 332 10f 40 mp 109.5-113.0.degree. C.
ESI (m/z) 336 10g 41 mp 133.0-133.5.degree. C. ESI (m/z) 350 10h 42
C.sub.22H.sub.29NO.sub.2: mp 161.0-163.0.degree. C. Analysis
calculated: C, 81.69; H, 9.04; N, 4.33. Found: C, 81.65; H, 8.91;
N, 4.13. 10i 43 C.sub.20H.sub.21NO.sub.2.0.27 H.sub.2O: mp
96.9-97.0.degree. C. Analysis calculated: C, 76.94; H, 6.95; N,
4.49. Found: C, 76.94; H, 6.90; N, 4.59. 10j 44 ESI (m/z) 362 Rf
(silica, 25% EtOAc/hex) 0.20. 10k 45 C.sub.20H.sub.21NO.sub.2.0.16
H.sub.2O: mp 96.0-97.0.degree. C. Analysis calculated: C, 77.40; H,
6.93; N, 4.51. Found: C, 77.40; H, 6.66, N, 4.47. 10l 46
C.sub.22H.sub.25NO.sub.2: mp 106.0-107.5.degree. C. Analysis
calculated: C, 78.77; H, 7.51; N, 4.18. Found: C, 78.53; H, 7.51;
N, 3.89. 10l' 47 C.sub.21H.sub.23NO.sub.2: mp 103.5-106.0.degree.
C. Analysis calculated: C, 78.47; H, 7.21; N, 4.36. Found: C,
78.32; H, 7.20; N, 4.29. 10m 48 mp 58.0-59.0.degree. C. ESI (m/z)
356. 10m' 49 C.sub.19H.sub.27NO.sub.2.0.42 H.sub.2O: mp
104.0-107.5.degree. C. Analysis calculated: C, 73.86; H, 9.08; N,
4.53. Found: C, 73.86; H, 9.26; N, 4.36. 10n 50
C.sub.20H.sub.29NO.sub.2.0.13 H.sub.2O: mp 107.0-110.0.degree. C.
Analysis calculated: C, 75.59; H, 9.28; N, 4.41. Found: C, 75.59;
H, 9.51; N, 4.79. 10o 51 C.sub.21H.sub.31NO.sub.2: mp
90.0-92.5.degree. C. Analysis calculated: C, 76.55; H, 9.48; N,
4.25. Found: C, 76.80; H, 9.73; N, 4.04. 10p 52
C.sub.20H.sub.29NO.sub.2.0.18 H.sub.2O: mp 115.5-118.5.degree. C.
Analysis calculated: C, 75.38; H, 9.29; N, 4.40. Found: C, 75.38;
H, 9.40; N, 4.65. 10q 53 C.sub.19H.sub.28NO.sub.2: mp
88.5-90.0.degree. C. Analysis calculated: C, 75.46; H, 9.33; N,
4.63. Found: C, 75.72; H, 9.19; N, 4.44. 10r 54 mp
85.5-87.0.degree. C. ESI (m/z) 322 10s 55 mp 122.0-125.0.degree. C.
ESI (m/z) 322 10t 56 mp 151.0-153.0.degree. C. ESI (m/z) 316 10u 57
C.sub.26H.sub.25NO.sub.2.0.15 H.sub.2O: ESI (m/z) 384. Analysis
calculated: C, 80.85; H, 6.60; N, 3.63. Found: C, 80.85; H, 6.33;
N, 3.52. 10v 58 C.sub.25H.sub.31NO.sub.2.0.19 H.sub.2O: ESI (m/z)
378. Analysis calculated: C, 78.83; H, 8.30; N, 3.68. Found: C,
78.83; H, 8.50; N, 3.57. 10w 59 C.sub.21H.sub.33NO.sub.2: mp
97.0-99.0.degree. C. Analysis calculated: C, 76.09; H, 10.03; N,
4.23. Found: C, 75.81; H, 10.23; N, 4.13. 11 60 C.sub.21H.sub.25NO:
m/e =307. 12 61 C.sub.16H.sub.20F.sub.3N.sub.3OS: m/e =359. 13 62
C.sub.16H.sub.23NO: m/e =245. 14 63 C.sub.19H.sub.29NO.sub.2: mp
82-84.degree. C. Analysis calculated: C, 75.21; H, 9.63; N, 4.62.
Found: C, 75.34; H, 9.44; N, 4.43. 14a 64 C.sub.20H.sub.29NO.sub.2:
m/z =316 (M + H) 14b 65 C.sub.22H.sub.21F.sub.6NO.sub.2: m/z 446 (M
+ H) 14c 66 MW m/z = 304 (M + H) 14d 67
C.sub.21H.sub.31F.sub.6NO.sub.2: m/z 330 (M + H) 15 68
C.sub.19H.sub.30N.sub.2O.sub.2.0.25 H.sub.2O: mp 221.degree. C.
Analysis calculated: C, 70.67; H, 9.52; N, 8.67. Found: C, 70.67;
H, 9.58; N, 8.57. 16 69 C.sub.18H.sub.13F.sub.6NO.sub.3: mp
149-150.degree. C. Analysis calculated: C, 54.05; H, 3.35; H, 3.50.
Found: C, 53.60; H, 3.07; N, 3.48. 17 70 C.sub.17H.sub.23NO.sub.3:
mp 80-81.degree. C. Analysis calculated: C, 70.56; H, 8.01; N,
4.84. Found: C, 70.27; H, 8.06; N, 4.74. 17a 71 C.sub.22H.sub.25NO:
m/z =320 (M + H) 17b 72 C.sub.18H.sub.24N.sub.2O: m/z =285 (M + H)
18 73 C.sub.17H.sub.21NO: m/e =255.18 18a 74
C.sub.19H.sub.12F.sub.9N.sub.3OS: m/z =501 (M + H) 18b 75
C.sub.23H.sub.15F6NO.sub.2: m/z =452 (M + H) 18c 76
C.sub.22H.sub.25NO.sub.2: m/z =336 (M + H) 18d 77
C.sub.23H.sub.27NO: m/z =334 (M + H) 18e 78 C.sub.21H.sub.25NO: m/z
=308 (M + H) 19 79 C.sub.22H.sub.23F.sub.3N.sub.2O: mp
135-137.degree. C. Analysis calculated: C, 68.02; H, 5.97; N, 7.21;
F, 14.67. Found: C, 67.78; H, 5.71; N, 7.02; F, 14.67. 19a 80
C.sub.17H.sub.9F.sub.9N.s- ub.2O.sub.3C: m/z 460 19b 81
C.sub.19H.sub.16F.sub.6N.sub.- 2O.sub.2: m/z 418 19c 82
C.sub.24H.sub.19F.sub.6NO.sub.3: m/z 483 20 83
C.sub.21H.sub.32N.sub.2O.0.32 H.sub.2O: mp 86-87.degree. C.
Analysis calculated: C, 75.46; H, 9.84; N, 8.38. Found: C, 75.44;
H, 9.67; N, 8.27. 20a 84 C.sub.20H.sub.23Cl.sub.2NO.sub.2: mp
84-94.degree. C. Analysis calculated: C, 63.16; H, 6.10; N, 3.68;
Cl, 18.64. Found: C, 63.19; H, 5.99; N, 3.55; Cl, 18.58. 20b 85
C.sub.22H.sub.29NO.sub.4- : mp 80-83.degree. C. Analysis
calculated: C, 71.13; H, 7.87; N, 3.77. Found: C, 71.12; H, 7.86;
N, 3.67. 20c 86 C.sub.22H.sub.29NO.sub.2: mp 116-118.degree. C.
Analysis calculated: C, 77.84; H, 8.61; N, 4.13. Found: C, 78.05,
H, 8.58, N, 4.10. 20d 87 C.sub.22H.sub.29NO.sub.2: mp
109-111.degree. C. Analysis calculated: C, 77.50; H, 8.36; N, 4.30.
Found: C, 77.69; H, 8.47; N, 4.31. 20e 88
C.sub.22H.sub.26F.sub.3NO.sub.2: mp 86-87.degree. C. Analysis
calculated: C, 67.16; H, 6.66; N, 3.56; F, 14.49. Found: C, 67.11;
H, 6.62; N, 3.54; F, 14.71. 20f 89 C.sub.23H.sub.25F.sub.6NO.sub.2:
mp 86-87.degree. C. Analysis calculated for 0.1 mole hexane: C,
60.30; H, 5.66; N, 2.98; F, 24.25. Found: C, 59.91; H, 5.33; N,
3.00; F, 23.88. 20g 90 C.sub.17H.sub.10F.sub.6N.sub.2O: m/z 372 20h
91 C.sub.16H.sub.10ClF.sub.6NO: m/z 381 20i 92
C.sub.17H.sub.10F.sub.9NO: m/z 415 20j 93
C.sub.18H.sub.16F.sub.6N.sub.2O: m/z 390 20k 94
C.sub.16H.sub.10F.sub.6N.sub.2O.sub.3: m/z 392 20l 95
C.sub.17H.sub.10F.sub.9NO.sub.2: m/z 431 20m 96
C.sub.17H.sub.10F.sub.9NO.sub.2: m/z 431 20n 97
C.sub.22H.sub.23F.sub.6NO.sub.2: m/z 447 20o 98
C.sub.22H.sub.23F.sub.6NO.sub.2: m/z 447 20p 99
C.sub.18H.sub.13F.sub.6NO.sub.2: m/z 389 20q 100
C.sub.18H.sub.14F.sub.6N.sub.2O.sub.2: m/z 404 20r 101
C.sub.19H.sub.17F.sub.6NO.sub.2: m/z 405 20s 102
C.sub.21H.sub.20F.sub.6N.sub.2O.sub.2: m/z 446 20t 103
C.sub.23H.sub.15F.sub.6NO.sub.2: m/z 451 20u 104
C.sub.22H.sub.18BrF.sub.6N.sub.3O: m/z 534 20v 105
C.sub.18H.sub.15F.sub.6N.sub.3O.sub.2: m/z 419 20w 106
C.sub.17H.sub.12F.sub.6N.sub.2O.sub.3: m/z 406 20x 107
C.sub.17H.sub.12F.sub.6N.sub.2O.sub.4: m/z 422 20y 108
C.sub.16H.sub.9ClF.sub.6N.sub.2O.sub.3: m/z 426 20z 109
C.sub.20H.sub.18F.sub.6N.sub.2O.sub.4: m/z 464
Example 21
N-(3,3-Dimethylbutyl)-4-(1H-indol-1-yl)Benzamide
[0118] 110
[0119] A. N-(3,3-Dimethylbutyl)-4-fluorobenzamide
[0120] This compound was prepared from 4-fluorobenzoyl chloride (1)
and 3,3-dimethylbutyl amine by the same procedure as described for
the title compound of Example 1, part C.
[0121] B. N-(3,3-Dimethylbutyl)-4-(1 H-indol-1-yl)Benzamide
[0122] Compound 2 (186 mg, 0.83 mmol) and indole (127 mg, 1.08
mmol) were dissolved in dimethylsulfoxide (8 mL). 18-Crown-6 (66
mg, 0.25 mmol) and 37% by weight KF on basic alumina were added and
the reaction mixture was heated at 120.degree. C. for 4 days. The
reaction was cooled to room temperature, diluted with ethyl acetate
and washed with brine. The organic layer was dried over magnesium
sulfate and the solvent was removed to yield an orange oil.
Purification by flash chromatography on silica gel eluting with 10%
ethyl acetate in hexane provided a tan solid (180 mg, 67%): mp
51-54.degree. C. Analysis calculated for C.sub.21H.sub.24N.sub.2O:
C, 78.72; H, 7.55; N, 8.74. Found: C, 78.59; H, 7.41; N, 8.69.
[0123] Using methodology analogous to that described for the title
compound of Example 21, the compounds of Examples 22 and 23 were
prepared.
2 Example # Structure Characterization 22 111
C.sub.20H.sub.23N.sub.3O.0.8H.sub.2O: mp 134-135.degree. C.
Analysis calculated: C, 71.53; H, 7.38; N, 12.51. Found: C71.42; H,
6.98; N, 12.43. 23 112 C.sub.22H.sub.25N.sub.3O.0.55 H.sub.2O: mp
170-171.degree. C. Analysis calculated: C, 73.94; H, 7.36; N,
11.76. Found: C, 73.94; H, 6.97; N, 11.74.
Example 23a
N-(3,3-Dimethylcyclopentyl)-4-(1 H-indol-1-yl)Benzamide
[0124] 113
[0125] A. 4-(1H-Indol-1-yl)Benzoic Acid Methyl Ester
[0126] Ethyl-4-fluorobenzoate (4 mL, 27.3 mmol) and indole (3.51 g,
30 mmol) were dissolved in 50 mL of dimethylsulfoxide (DMSO).
Potassium fluoride (37% on basic alumina, 12.8 g) and 18-crown-6
(720 mg, 2.73 mmol) were added and the mixture was heated to
120.degree. C. for 24 hours. The reaction was diluted with ethyl
acetate and washed with hydrochloric acid (1.0 M, aq.), sodium
bicarbonate (sat'd., aq.) and sodium chloride (sat'd., aq.). The
organic layer was dried over magnesium sulfate, filtered and the
solvent removed. Purification by flash chromatography on silica gel
eluted with 5% ethyl acetate, hexane provided 1.45 g (20%) of a
white solid.
[0127] B. 4-(1H-Indol-1-yl)Benzoic Acid
[0128] The ester (2, 1.4 g, 5.23 mmol) was dissolved in 45 mL of
dioxane. Lithium hydroxide (15.8 mL, 15.8 mmol) was added and the
mixture was stirred for 4 hours. The reaction was diluted with
water and washed with ethyl acetate. The aqueous phase was
acidified with HCl and extracted with ethyl acetate. The organic
layer was dried over magnesium sulfate, filtered and the solvent
removed to provide 1.04 g (83%) of a pale yellow solid. mp
222-224.degree. C.
[0129] C.
N-(3,3-Dimethylcyclopentyl)-4-(1H-indol-1-yl)Benzamide
[0130] The acid (3, 0.20 mmol) and the amine compound 3 from
Example 1 (0.22 mmol) were dissolved in 1 mL of THF and
triethylamine (0.22 mmol) and 4-dimethylaminopyridine (0.02 mmol)
were added. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (1.6 mL, 0.15 M in dichloromethane, 0.24 mmol) was
added and the mixture was allowed to stand for 48 hours.
Purification by preparative HPLC (YMC ODS-A 5S 30.times.250 mm
column, 50-90% methanol water with 0.10% TFA gradient over 20
minutes, 25 mL/minute flow) provided 50 mg (72%) of a white solid.
C.sub.23H.sub.26N.sub.2O: m/z=347 (M+H).
[0131] The following compounds can be prepared using methodology
analogous to that described for the title compound of Example 23a
above.
3 Example # Structure Characterization 23b 114
C.sub.22H.sub.24N.sub.2O: m/z =333 (M + H) 23c 115
C.sub.22H.sub.31N.sub.3O.0.67 H.sub.2O: Analysis calculated: C,
72.29; H, 8.92; N, 11.5. Found: C, 72.29; H, 9.11; N, 11.34.
Example 24
4-(3-Butyl-1,2,4-oxadiazol-5-yl)-N-(3,3-dimethylbutyl)Benzamide
[0132] 116
[0133] A. N-(3,3-Dimethylbutyl)-4-fluorobenzamide
[0134] A solution of mono-methylterephthalate (1) (260 mg, 1.44
mmol) in DMF (3 mL) under argon at room temperature was treated
with 3,3-dimethylbutylamine (145 mg, 1.43 mmol),
ethyl-3-(3-dimethylamino)prop- yl carbodiimide hydrochloride (420
mg, 1.41 mmol) and hydroxybenzotriazole monohydrate (192 mg, 1.42
mmol) and stirred overnight. The reaction mixture was diluted with
ethyl acetate and washed with 10% citric acid, water, sodium
bicarbonate, water and brine. The dried (anhydrous magnesium
sulfate) organic fraction was concentrated and the residue was
purified by flash chromatography on silica gel, eluting with ethyl
acetate/hexanes (1:4) to give compound 2 (327 mg, mp 88-90.degree.
C.).
[0135] B.
4-(3-Butyl-1,2,4-oxadiazol-5-yl)-N-(3,3-dimethylbutyl)-benzamide
[0136] A solution of compound 2 (137 mg, 0.52 mmol) and
N-hydroxypentamidine (75 mg, 0.65 mmol) in dimethylformamide (1.5
mL) under argon at 0-5.degree. C. was treated with sodium hydride
(45 mg, 60%/m.o., 1.14 mmol) and allowed to stir at room
temperature for 4 hours. The mixture, diluted with ethyl acetate,
was washed with water and brine. The organic fraction was dried
(anhydrous magnesium sulfate) and concentrated in vacuo to give a
solid. Flash chromatography on silica gel, eluting with ethyl
acetate/hexanes (1:4) gave the title compound (140 mg, 81%): mp
95-97.degree. C. Analysis calculated for
C.sub.19H.sub.27N.sub.3O.sub.2: C, 69.27; H, 8.26; N, 12.75. Found:
C, 69.01; H, 8.29; N, 12.50.
[0137] Using methodology analogous to that described for the title
compound of Example 24, the compounds of Examples 25 to 29 were
prepared.
4 Example # Structure Characterization 25 117
C.sub.21H.sub.23N.sub.3O.sub.2: mp 169-170.degree. C. Analysis
calculated: C, 72.18; H, 6.63; N, 12.03. Found: C, 71.92; H, 6.63;
N, 11.63. 26 118 C.sub.24H.sub.15F.sub.6N.sub.3O.su- b.2: mp
209-210.degree. C. Analysis calculated: C, 58.66; H, 3.08; N, 8.55;
F, 23.20. Found: C, 58.52; H, 3.08; N, 8.51; F, 22.85. 27 119
C.sub.22H.sub.19F.sub.6N.sub.3O.sub.2: mp, 156-157.degree. C.
Analysis calculated: C, 56.56; H, 4.15; N, 8.99; F, 23.45. Found:
C, 56.23; H, 3.88; N, 8.89; F, 23.28. 27a 120
C.sub.18H.sub.23N.sub.3O.sub.2: mp 155-156.degree. C.
[.alpha.].sub.D = +22.8.degree.(c = 1.02, CHCl.sub.3). Analysis
calculated for 0.56 mole water: C, 66.83; H, 7.52; N, 12.99. Found:
C, 66.82; H, 7.01; N, 12.57. 27b 121
C.sub.18H.sub.23N.sub.3O.sub.2: mp 155-156.degree. C.
[.alpha.].sub.D = -22.8.degree. (c = 1.00, CHCl.sub.3). Analysis
calculated: C, 68.98; H, 7.40; N, 13.41. Found: C, 68.78; H, 6.85;
N, 13.10. 27c 122 C.sub.20H.sub.27N.sub.3O.sub.2: mp 88-90.degree.
C. [.alpha.].sub.D = +21.4.degree.(c = 0.49, CHCl.sub.3). Analysis
calculated: C, 70.35; H, 7.97; N, 12.31. Found: C, 70.09; H, 7.91;
N, 12.17. 27d 123 C.sub.20H.sub.27N.sub.3O.sub.2: mp 88-90.degree.
C. [.alpha.].sub.D = -21.6.degree.(c = 0.50, CHCl.sub.3). Analysis
calculated: C, 70.35; H, 7.97; N, 12.31. Found: C, 70.14; H, 7.84;
N, 12.09. 27e 124 C.sub.20H.sub.27N.sub.3- O.sub.2: mp
94-95.degree. C. [.alpha.].sub.D = +18.8.degree.(c = 0.32,
CHCl.sub.3). Analysis calculated: C, 71.51; H, 8.46; N, 11.37.
Found: C, 71.33; H, 8.49; N, 11.29. 27f 125
C.sub.20H.sub.27N.sub.3- O.sub.2: mp 94-95.degree. C.
[.alpha.].sub.D = +19.5.degree.(c = 0.41, CHCl.sub.3). Analysis
calculated: C, 71.51; H, 8.46; N, 11.37. Found: C, 71.60; H, 8.47;
N, 11.20. 27g 126 C.sub.21H.sub.27N.sub.3- O.sub.2: mp
116-117.degree. C. [.alpha.].sub.D = +16.6.degree.(c = 0.35,
CHCl.sub.3). Analysis calculated: C, 71.36; H, 7.70; N, 11.89.
Found: C, 71.57; H, 7.81; N, 11.76. 27h 127
C.sub.20H.sub.27N.sub.3- O.sub.2: mp 94-95.degree. C.
[.alpha.].sub.D = -17.6.degree.(c = 0.33, CHCl.sub.3). Analysis
calculated: C, 71.51; H, 8.46; N, 11.37. Found: C, 71.29; H, 7.68;
N, 11.78. 27i 128 C.sub.22H.sub.31N.sub.3- O.sub.2: mp
92-93.degree. C. [.alpha.].sub.D = +18.4.degree.(c = 0.25,
CHCl.sub.3). Analysis calculated: C, 71.51; H, 8.46; N, 11.37.
Found: C, 71.37; H, 8.33; N, 11.14. 27j 129
C.sub.22H.sub.31N.sub.3- O.sub.2: mp 94-95.degree. C.
[.alpha.].sub.D = -17.0.degree.(c = 0.20, CHCl.sub.3). Analysis
calculated: C, 71.51; H, 8.46; N, 11.37. Found: C, 71.51; H, 8.58;
N, 11.30. 27k 130 C.sub.21H.sub.29N.sub.3- O.sub.2: mp
114-115.degree. C. [.alpha.].sub.D = +18.1.degree.(c = 0.43,
CHCl.sub.3). Analysis calculated: C, 70.96; H, 8.22; N, 11.82.
Found: C, 70.83; H, 8.30; N, 11.63. 27l 131
C.sub.21H.sub.29N.sub.3- O.sub.2: mp 116-117.degree. C.
[.alpha.].sub.D = -18.0.degree.(c = 0.20, CHCl.sub.3). Analysis
calculated: C, 70.96; H, 8.22; N, 11.82. Found: C, 70.80; H, 8.22;
N, 11.70. 27m 132 C.sub.24H.sub.27N.sub.3- O.sub.2.0.16H.sub.2O.
0.03EtOAc: mp 138-139.degree. C. [.alpha.].sub.D =+15.1.degree. (c
= 0.37, CHCl.sub.3). Analysis calculated: C, 73.25; H, 7.02; N,
10.62. Found: C, 73.04; H, 6.96; N, 10.45. 27n 133
C.sub.24H.sub.27N.sub.3O.sub.2: mp 139-140.degree. C.
[.alpha.].sub.D = -15.6.degree.(c = 0.23, CHCl.sub.3). Analysis
calculated: C, 74.01; H, 6.99; N, 10.79. Found: C, 73.73; H, 6.77;
N, 10.54. 27o 134 C.sub.20H.sub.24F.sub.3N.sub.3O.sub.2
[.alpha.].sub.D =+11.8.degree. (c = 0.49, CHCl.sub.3). m/s MW
=395.18 27p 135 C.sub.20H.sub.24F.sub.3N.sub.3O.sub.2
[.alpha.].sub.D =-13.7.degree. (c = 0.90, CHCl.sub.3). m/s MW
=395.18 27q 136 C.sub.21H.sub.26F.sub.3N.sub.3O.sub.2: mp
83-84.degree. C. [.alpha.].sub.D =+15.6.degree. (c = 0.23
CHCl.sub.3). Analysis calculated: C, 61.60; H, 6.40; N, 10.26; F,
13.92. Found: C,; H,; N,; F,. 27r 137
C.sub.21H.sub.26F.sub.3N.sub.3O.sub.2: mp 83-84.degree. C.
[.alpha.].sub.D =-15.0.degree. (c = 0.36, CHCl.sub.3). Analysis
calculated: C, 61.60; H, 6.40; N, 10.26; F, 13.92. Found: C, 61.58;
H, 6.49; N, 10.19; F, 13.66. 27s 138
C.sub.20H.sub.24F.sub.3N.sub.3O.sub.3: mp .degree. C.
[.alpha.].sub.D = +13.8 (c = 0.24, CHCl.sub.3). Analysis
calculated: C, 58.39; H, 5.88; N, 10.21; F, 13.85. Found: C,; H,;
N,; F. 27t 139 C.sub.20H.sub.24F.sub.3N.sub.3O.sub.3: mp
83-84.5.degree. C. [.alpha.].sub.D =-17.5.degree. (c = 0.24
CHCl.sub.3). Analysis calculated: C, 58.39; H, 5.88; N, 10.21; F,
13.85. Found: C, 58.52; H, 5.95; N, 10.16; F. 13.34. 28 140
C.sub.21H.sub.29N.sub.3O- .sub.2.0.3 hexanes: mp 74-76.degree.
C.,[.alpha.].sub.D = +17.3.degree.(c = 0.11, CHCl.sub.3). Analysis
calculated: C, 71.81; H, 8.78; N, 11.02. Found: C, 71.85; H, 8.69;
N, 11.09. 29 141 C.sub.21H.sub.29N.sub.3O.sub.2.0.3 hexanes: mp
74-76.degree. C., [.alpha.].sub.D = -20.degree. (c =0.12,
CHCl.sub.3). Analysis calculated: C, 71.81; H, 8.78; N, 11.02.
Found: C, 71.85; H, 8.69; N, 11.09.
Example 29a
4-(5-Butyl-1,2,4-oxadiazol-3-yl)-N-(3,3-dimethylbutyl)Benzamide
[0138] 142
[0139] A. 4-Cyano-N-(3,3-dimethylbutyl)Benzamide
[0140] A solution of methyl 4-cyanobenzoic acid (1, 735 mg, 5.0
mmol) in 12 mL of DMF under argon at room temperature was treated
3,3-dimethylbutylamine (2, 505 mg, 5.0 mmol),
ethyl-3-(3-dimethylamino)-p- ropyl carbodiimide hydrochloride (1.5
g, 5.0 mmol) and hydroxybenzotriazole monohydrate (685 mg, 5.0
mmol) and stirred overnight. The reaction mixture was diluted with
ethyl acetate and washed with 10 percent citric acid, water, dilute
sodium bicarbonate, water and brine. The dried (anhydrous magnesium
sulfate) organic fraction was concentrated to give 1.5 g. Flash
chromatography on 150 mL of EM-60 silica gel, eluting with ethyl
acetate/hexanes (1:4) gave the title compound (1.06 g, 92%), mp
154-157.degree. C. Analysis calculated for
C.sub.14H.sub.18N.sub.2O: C, 73.01; H, 7.88; N, 12.16. Found: C,
73.00; H, 7.92; N, 12.17.
[0141] B.
4-[Amino(Hydroxyimino)Methyl]-N-(3,3-dimethylbutyl)Benzamide
[0142] A slurry of hydroxylamine hydrochloride (100 mg, 1.4 mmole)
in water (0.1 mL) at room temperature was treated with sodium
ethoxide in ethanol (prepared from 33 mg sodium in 2 mL ethanol)
and the title A compound and stirred for 48 hours. The mixture was
diluted with a small amount of ethanol and filtered to remove
solids. The filtrate was concentrated, redissolved in ethanol,
cooled in ice and filtered. The filtrate was concentrated and dried
under high vacuum over P.sub.2O.sub.5 to give 348 mg hydroxyamidine
product 4. m/z MH.sup.+ @ 264, MW=263.
[0143] C.
4-(5-Butyl-1,2,4-oxadiazol-3-yl)-N-(3,3-dimethylbutyl)-benzamide
[0144] A solution of the title B compound (200 mg, 0.76 mmol) and
methyl valerate (90 mg, 0.78 mmol) in 2 mL of dimethylformamide
under argon at 0-5.degree. C. was treated with sodium hydride (33
mg, 60%/m.o., 0.82 mmol) and allowed to stir at room temperature
overnight. The mixture, diluted with ethyl acetate, was washed with
water and brine. The organic fraction was dried (anhydrous
magnesium sulfate) and concentrated. Flash chromatography on 150 mL
of EM-60 silica gel, eluting with ethyl acetate/hexanes (1:4) gave
the desired compound (145 mg, 58%), mp 78-80.degree. C. Analysis
calculated for C.sub.19H.sub.27N.sub.3O.sub.2: C, 69.27; H, 8.26;
N, 12.75. Found: C, 69.14; H, 8.37; N, 12.71.
[0145] Using the above methodology, the following compounds were
prepared.
5 Example # Structure Characterization 29b 143
C.sub.16H.sub.20N.sub.2O: mp 156-158.5.degree. C. Analysis
calculated: C, 74.97; H, 7.86; N, 10.93;. Found: C, 74.87; H, 7.99;
N, 10.79. 29c 144 C.sub.20H.sub.24F.sub.3N.sub.3O.s- ub.2: mp
116-118.degree. C. [a].sub.D =+16.8.degree. (c = 0.88 CHCl.sub.3).
Analysis calculated: C, 60.75; H, 6.12; N, 10.63; F, 14.41. Found:
C, 60.57; H, 6.22; N, 10.48; F. 14.02. 29d 145
C.sub.20H.sub.24F.sub.3N.sub.3O.sub.2: mp 116-118.degree. C.
[.alpha.].sub.D =-16.9.degree. (c = 0.96 CHCl.sub.3). Analysis
calculated: C, 60.75; H, 6.12; N, 10.63; F, 14.41. Found: C, 60.87;
H, 6.21; N, 10.45; F. 14.10. 29e 146 C.sub.21H.sub.29N.sub.3-
O.sub.2 .multidot. 0.1H.sub.2O mp 86-88.degree. C. [.alpha.].sub.D
=+20.1.degree. (c = 0.63 CHCl.sub.3). Analysis calculated: C,
70.60: H, 8.24; N, 11.76. Found: C, 70.57: H, 8.49: N, 11.26. 29f
147 C.sub.21H.sub.29N.sub.3O.sub.2: mp 86-88.degree. C.
[.alpha.].sub.D =+18.1.degree. (c = 0.63 CHCl.sub.3). Analysis
calculated: C, 70.96; H, 8.22; N, 11.82. Found: C, 70.76; H, 8.49;
N, 11.57. 29g 148 C.sub.20H.sub.24F.sub.3N.sub.3O.sub.3: mp
73-75.degree. C. [.alpha.].sub.D =+17.6.degree. (c = 0.75
CHCl.sub.3). Analysis calculated: C, 58.39; H, 5.88; N, 10.21; F,
13.85. Found: C, 58.51; H, 5.87; N, 10.02; F, 13.49. 29h 149
C.sub.20H.sub.24F.sub.3- N.sub.3O.sub.3: mp 73-75.degree. C.
[.alpha.].sub.D =-17.2.degree. (c = 0.89 CHCl.sub.3). Analysis
calculated: C, 58.39; H, 5.88; N, 10.21; F, 13.85. Found: C, 57.98;
H, 5.90; N, 9.87; F, 13.45.
Example 29i
4-(2-Butyl-1
H-imidazol-4-yl)-N-[(2,2-dimethylcyclopentyl)-methyl]Benzamid-
e
[0146] 150
[0147] A. 4-Acetyl-N-[(2,2-dimethylcyclopentyl)Methyl]Benzamide
[0148] 4-Acetylbenzoic acid (200 mg, 1.20 mmol) and amine 2 (from
Example 1, 199 mg, 1.22 mmol) were dissolved in 5 mL of
dichloromethane and triethylamine (187 .mu.L, 1.34 mmol) and
4-dimethylaminopyridine (15 mg, 0.12 mmol) were added.
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (398
mg, 1.34 mmol) was added and the mixture was stirred for 18 hours.
The reaction was diluted with ethyl acetate and washed with
hydrochloric acid (1.0 M, aq.), sodium bicarbonate (sat'd., aq.)
and sodium chloride (sat'd., aq.). The organic layer was dried over
magnesium sulfate, filtered and the solvent removed to yield 216 mg
(65%) of a white solid.
[0149] B.
4-(Bromoacetyl)-N-[(2,2-dimethylcyclopentyl)-methyl]Benzamide
[0150] The amide 3 (160 mg, 0.585 mmol) was dissolved in 3 mL of
tetrahydrofuran (THF) and cooled to 0.degree. C.
Phenyltrimethyl-ammonium tribromide (220 mg, 0.585 mmol) was
dissolved in 1 mL of THF and added dropwise. The reaction was
allowed to warm to room temperature and stir for 22 hours. The
mixture was quenched with water and extracted with ethyl acetate.
The organic layer was dried over magnesium sulfate, filtered and
the solvent removed to yield 230 mg of a tan solid. Purification by
flash chromatography on silica gel eluted with 30% ethyl acetate,
hexane provided 157 mg (76%) of a white solid.
[0151] C. 4-(2-Butyl-1
H-imidazol-4-yl)-N-[(2,2-dimethylcyclopentyl)-methy-
l]Benzamide
[0152] A solution of n-pentamidine hydrochloride (180 mg, 1.32
mmol) was dissolved in 1 mL of ethanol and sodium ethoxide (2 M in
ethanol, 0.66 mL, 1.32 mmol) was added and the mixture was heated
to 75.degree. C. The title B compound (155 mg, 0.440 mmol) was
dissolved in 1.5 mL of ethanol and added in small portions over 30
minutes. The reaction was stirred for 4 hours, quenched with sodium
bicarbonate and the aqueous layer was extracted with ethyl acetate.
The organic extracts were dried over magnesium sulfate, filtered
and the solvent removed to provide 173 mg of a brown solid.
Purification by flash chromatography on silica gel eluted with 70%
ethyl acetate, hexane provided 49 mg (31%) of a white solid, mp
98-105.degree. C.; Analysis calculated for
C.sub.22H.sub.31N.sub.3O.multi- dot.0.59 H.sub.2O: C, 72.57; H,
8.91; N, 11.54. Found: C, 72.56; H, 9.00; N, 11.39.
Example 29j
N-(3,3-Dimethylbutyl)-1-[4-(Trifluoromethyl)Phenyl]-1H-indole-5-carboxamid-
e
[0153] 151
[0154] A. N-(3,3-Dimethylbutyl)-1H-indole-5-carboxamide
[0155] Indole-5-carboxylic acid (322 mg, 2.00 mmol),
3,3-dimethylbutylamine (296 .mu.L, 2.20 mmol) and
4-dimethyl-aminopyridin- e (24 mg, 0.20. mmol) were suspended in 10
mL of dichloromethane and 5 mL of N,N-dimethylformamide.
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI,
653 mg, 2.2 mmol) was added and the mixture stirred for 16 hours.
The reaction was diluted with ethyl acetate and washed with
hydrochloric acid (1.0 M, aq.), sodium bicarbonate and brine. The
organic layer was dried over magnesium sulfate, filtered and the
solvent removed to yield a white solid (448 mg). Recrystallization
from hexane provided pale yellow needles which were dissolved in
ether, filtered and the solvent removed to provide 300 mg (61%) of
an off white solid, mp 132-133.degree. C.; Analysis calculated for
C.sub.15H.sub.20N.sub.2O.mult- idot.0.10 H.sub.2O: C, 73.20; H,
8.27; N, 11.38. Found: C, 73.17; H, 8.25; N, 11.20.
[0156] B.
N-(3,3-Dimethylbutyl)-1-[4-(Trifluoromethyl)Phenyl]-1H-indole-5--
carboxamide
[0157] The title A compound (40 mg, 0.16 mmol) and
4-fluorobenzotrifluorid- e (42 .mu.L, 0.33 mmol) were dissolved in
2 mL of dimethylsulfoxide. 18-Crown-6 (9 mg, 0.03 mmol) and 37% by
weight KF on basic alumina (51 mg, 0.33 mmol) were added and the
mixture was heated to 120.degree. C. for 4 days. The reaction was
cooled to room temperature, diluted with ethyl acetate and washed
with sodium chloride (sat'd., aq.). The organic layer was dried
over magnesium sulfate, filtered and the solvent removed to yield
57 mg of a yellow solid. Purification by flash chromatography on
silica gel eluted with 15% acetone, hexane provided 49 mg (77%) of
a white solid. mp 135-137.degree. C.; Analysis calculated for
C.sub.22H.sub.23F.sub.3N.sub.2O: C, 68.02; H, 5.97; N, 7.21; F,
14.67. Found: C, 67.78; H, 5.71; N, 7.02; F, 14.67.
Example 29k
N-(3,3-Dimethylbutyl)-1-(1-oxohexyl)-1H-indole-5-carboxamide
[0158] 152
[0159] The title A compound of example 29j (44 mg, 0.18 mmol) and
tetrabutylammonium hydrogen sulfate (6 mg, 0.02 mmol) were
dissolved in 1 mL of dichloromethane. Powdered sodium hydroxide (18
mg, 0.45 mmol) and hexanoyl chloride (38 .mu.L, 0.27 mmol) were
added and the mixture was stirred for 2 hours. The reaction was
diluted with ethyl acetate and washed with 1N hydrochloric acid,
sodium bicarbonate and brine. The organic layer was dried over
magnesium sulfate, filtered and the solvent removed to yield 58 mg
of a white solid. Purification by flash chromatography on silica
gel eluting with 20% acetone, hexane provided 52 mg (84%) of a
white solid. mp 136-138.degree. C.; Analysis calculated for
C.sub.21H.sub.30N.sub.2O.sub.2: C, 73.65; H, 8.83; N, 8.18. Found:
C, 73.53; H, 8.94; N, 8.13.
Example 29k'
[0160] 4-(3-Butyl-1,2,4-oxadiazol-5-yl)-N-
[(2-methylcyclohexyl)Methyl]-be- nzamide 153
[0161] A. 4-(3-Butyl-1,2,4-oxadiazol-5-yl)Benzoic Acid Methyl
Ester
[0162] Diisopropylethylamine (1.1 ml, 6.0 mmol) was added to a
solution of terephthalic acid, monomethyl ester chloride (1.0 g,
5.0 mmol) and N-hydroxypentamidine (0.70 g, 6.0 mmol) in THF (8
mL). After stirring at ambient temperature for 1 hour, cesium
carbonate (3.6 g, 11 mmol) was added and the reaction was stirred
at 50.degree. C. After stirring at 50.degree. C. for 3.5 hours, the
reaction was transferred to a separatory funnel with
CH.sub.2Cl.sub.2/H.sub.2O. The aqueous layer was acidified with 1N
HCl to pH 1 and extracted with CH.sub.2Cl.sub.2 (3.times.40 mL).
The combined organic layers were dried (MgSO.sub.4) and
concentrated in vacuo. Flash chromatography (silica, 50 mm dia, 10%
EtOAc/hexane) afforded 1.2 g (93%) of methyl
(3-butyl-1,2,4-oxadiazol-5-yl)benzoate.
[0163] B. 4-(3-Butyl-1,2,4-oxadiazol-5-yl)Benzoic Acid
[0164] Lithium hydroxide (1.0 N, 9.8 ml, 9.8 mmol) was added to a
stirring solution of the title A compound (1.2 g, 4.6 mmol) in THF
(45 mL). After stirring at ambient temperature for 17 hours, the
reaction was evaporated in vacuo. Water was added and the solution
acidified with 1N HCl. The resulting solid was collected, washed
with H.sub.2O, and dried under high vacuum over P.sub.2O.sub.5 to
afford 1.1 g (99%) of (3-butyl-1,2,4-oxadiazol-5-yl)benzoic
acid.
[0165] C. 4-(3-Butyl-1,2,4-oxadiazol-5-yl)-N-
[(2-methylcyclohexyl)-methyl- ]Benzamide
[0166] A solution of ((2-methylcyclohexyl)methyl)amine
hydrochloride, prepared according to Example 1f, part B (104 mg,
0.633 mmol), title B compound (130 mg, 0.528 mmol), HOBT hydrate
(86 mg), triethylamine (0.15 mL, 1.1 mmol), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC,
121 mg, 0.633 mmol) in DMF (5 mL) was stirred for 17 hours. The
reaction was diluted with ether (25 mL); washed with 0.3 N HCl
(3.times.7 mL), and saturated NaHCO.sub.3 (10 mL); dried
(MgSO.sub.4) and concentrated in vacuo. Purification by HPLC
provided the title compound as a 1:1 mixture of isomers: MS: (ESI)
m/z 356.
[0167] Using the procedure described for example 29k, the following
compounds were prepared.
6 Example # Structure Characterization 29l 154 ESI (m/z) 370 Rf
(silica, 25% EtOAc/hex) 0.25. 29m 155 mp 141.5-142.0.degree. C. ESI
(m/z) 418 29n 156 mp 162.0-162.5.degree. C. ESI (m/z) 418 29o 157
mp 79.0-79.5.degree. C. ESI (m/z) 358 29p 158 mp 50.0-52.0.degree.
C. ESI (m/z) 358 29q 159 C.sub.19H.sub.25N.sub.3O.sub.2: mp
98.0-99.5.degree. C. Analysis calculated: C, 69.70; H, 7.70; N,
12.83. Found: C, 69.70; H, 7.88; N, 12.68. 29r 160
C.sub.23H.sub.31N.sub.3O.sub.2 .multidot. 0.09 H.sub.2O: mp
59-60.0.degree. C. Analysis calculated: C, 72.10; H, 8.20; N,
10.97. Found: C, 72.10; H, 8.49: N, 10.84. 29s 161
C.sub.19H.sub.25N.sub.3O.sub.2: mp 127.0-128.5.degree. C. Analysis
calculated: C, 69.70; H, 7.70; N, 12.83. Found: C, 69.53; H, 7.93;
N, 12.64. 29t 162 C.sub.20H.sub.27N.sub.3O.sub.2: mp
111.0-113.0.degree. C. Analysis calculated: C, 70.35; H, 7.97; N,
12.31. Found: C, 70.24; H, 8.20; N, 12.27. 29u 163
C.sub.21H.sub.29N.sub.3O.sub.2: mp 121.0-124.5.degree. C. Analysis
calculated: C, 70.95; H, 8.22; N, 11.82. Found: C, 71.00; H, 8.40;
N, 11.99. 29v 164 mp 105.0-107.0.degree. C. ESI (m/z) 342 29w 165
mp 132.0-133.5.degree. C. ESI (m/z) 342 29x 166
C.sub.25H.sub.29N.sub.3O.sub.2: mp 112.0-115.0.degree. C. Analysis
calculated: C, 74.41; H, 7.24; N, 10.41. Found: C, 74.38; H, 7.29;
N, 10.36. 29y 167 mp 92.0-93.0.degree. C. ESI (m/z) 404
Example 30
N-(3,3-Dimethylbutyl)-6-(Hexyloxy)-3-pyridine Carboxamide
[0168] 168
[0169] A. 6-(Hexyloxy)-3-pyridinecarboxylic Acid Hexyl Ester and
1-Heptyl-1,6-dihydro-6-oxo-3-pyridinecarboxylic Acid Hexyl
Ester
[0170] A stirred mixture of 6-hydroxynicotinic acid (10.0 g, 0.072
mole) in dimethylformamide (100 mL) under argon at room temperature
was treated with 1-bromohexane (30 mL, 35.6 g, 0.216 mole) and
powdered potassium carbonate (49.7 g, 0.36 mole) and heated at
110.degree. C. for 3 days. The reaction mixture, diluted with ethyl
acetate, was washed with water and brine, dried (anhydrous
magnesium sulfate) and concentrated. Flash chromatography on silica
gel and elution with ethyl acetate/hexanes (1:8) gave 2 (4.77 g,
21.5%) and 3 (14.86 g, 67.5%).
[0171] B. 6-(Hexyloxy)-3-pyridinecarboxylic Acid
[0172] A solution of compound 2 (1.0 g, 3.25 mmole) in
tetrahydrofuran (15 mL) was treated with 1 N lithium hydroxide (6.5
mL) and heated at reflux for 24 hours. Solvent was removed in vacuo
and the residue was partitioned between ethyl acetate and water.
The aqueous fraction was acidified with 6 N hydrochloric acid and
extracted with ethyl acetate (2.times.). The combined organic
extracts were washed with water and brine, dried (anhydrous
magnesium sulfate) and concentrated to give 4 (480 mg, 66%), mp
90-93.degree. C.
[0173] C. N-(3,3-Dimethylbutyl)-6-(Hexyloxy)-3-pyridine
Carboxamide
[0174] A solution of compound 4 (223 mg, 1.0 mmol) in
dimethylformamide (2.5 mL) under argon at room temperature was
treated with 3,3-dimethylbutyl amine (111 mg, 1.1 mmol),
ethyl-3-(3-dimethylamino)-pro- pylcarbodiimide hydrochloride (327
mg, 1.1 mmol) and hydroxybenzotriazole monohydrate (148 mg, 1.1
mmol) and stirred overnight. The reaction mixture was diluted with
ethyl acetate and washed with 10% citric acid, water, dilute sodium
bicarbonate, water and brine, dried (anhydrous mnagnesium sulfate)
and concentrated to give an oil. Flash chromatography on silica gel
and elution with ethyl acetate/hexanes (1:4) gave an oil (274 mg)
that slowly solidified, mp 75-76.5.degree. C.
[0175] Analysis calculated for C.sub.18H.sub.30N.sub.2O.sub.2: C,
70.55; N, 9.87; N, 9.14. Found: C, 70.46; H, 10.06; N, 9.02.
Example 31
N-(3,3-Dimethylbutyl)-1-hexyl-1,6-dihydro-6-oxo-3-pyridinecarboxamide
[0176] 169
[0177] A. 1-Hexyl-1,6-dihydro-6-oxo-3-pyridinecarboxylic Acid
[0178] This compound was prepared from compound
1-Hexyl-1,6-dihydro-6-oxo-- 3-pyridinecarboxylic acid hexyl ester
by the same procedure (lithium hydroxide, THF) as described for the
preparation of compound 4 from 2 (Example 30, part B).
[0179] B.
N-(3,3-Dimethylbutyl)-1-hexyl-1,6-dihydro-6-oxo-3-pyridinecarbox-
amide
[0180] The title compound was prepared from compound 2 by the same
procedure as described for the preparation of the title compound of
Example 30, part C: mp 80-83.degree. C.
[0181] Analysis calculated for C.sub.18H.sub.30N.sub.2O.sub.2: C,
70.55; N, 9.87; N, 9.14. Found: C, 70.41; H, 9.91; N, 9.37.
[0182] Using methodology analogous to that described for the title
compounds of Examples 30 and 31, the compounds of Examples 32 and
33 were prepared.
7 Example # Structure Characterization 32 170
C.sub.21H.sub.22F.sub.6N.sub.2O.sub.2: m/e = 448. Analysis
calculated: C, 56.25; H, 4.95; N, 6.25; F, 25.42. Found: C, 56.21;
H, 4.80; N, 6.16; F, 25.72. 33 171
C.sub.21H.sub.22F.sub.6N.sub.2O.sub.2.multidot.0.25 hexane: mp
92-95.degree. C. Analysis calculated: C, 57.46; H, 5.47; N, 5.96;
F, 24.24. Found: C, 57.46; H, 5.21; N, 6.01; F, 24.04.
Example 34
N-Cyano-N'-(3,3-dimethylbutyl)-4-(Hexyloxy)Benzene-carboximidamide
[0183] 172
[0184] A. 4-(Hexyloxy)Benzonitrile
[0185] A solution of 4-cyanophenol (20 g, 168 mmol) in
dimethylformamaide was treated with potassium carbonate (2 eq., 338
mmol, 47 g) and 1-bromohexane (1.1 eq., 185 mmol, 35 mL) and
stirred at room temperature for 18 hours. The solid was filtered
off and the solution was partitioned between ethyl acetate and 1 N
HCl. The organic phase was washed with brine, dried over
MgSO.sub.4, filtered and the solvent was removed to give compound 2
(45 g, >100%).
[0186] B. 4-(Hexyloxy)Benzenecarboximidic Acid Ethyl Ester
[0187] A solution of compound 2 (5.00 9, 24.6 mmol) in diethyl
ether was cooled to 0.degree. C. and treated slowly with excess
freshly prepared cold saturated ethereal-hydrochloric acid (g). The
reaction mixture was treated with ethanol (30 mL) and allowed to
warm to room temperature and stirred for 18 hours. The solvent was
removed to give compound 3 as an oil (4.09 g, 85%).
[0188] C. N-Cyano-4-(Hexyloxy)Benzenecarboximidic Acid Ethyl
Ester
[0189] A solution of compound 3 (1.0 g, 4.0 mmol) in water/THF (10
mL, 1:1) was treated with sodium dihydrogenphosphate (1.13 g, 8
mmol, in 10 mL water) followed by an aqueous solution of cyanamide
(202 mg, 4.8 mmol in 2 mL water). The biphasic solution was stirred
vigoriously for 24 hours. The solution was partitioned between
ethyl acetate and saturated sodium bicarbonate solution. The
organic phase was washed with brine, dried over magnesium sulfate
and the solvent was removed to give compound 4 as a white solid
(1.01 g, 87%).
[0190] D.
N-Cyano-N'-(3,3-dimethylbutyl)-6-(Hexyloxy)-benzenecarboximidami-
de
[0191] A solution of compound 4 (200 mg, 0.73 mmol) in acetonitrile
was treated with 3,3-dimethylbutyl amine (118 .mu.l, 0.875 mmol)
and heated to 50.degree. C. in a sand bath for 18 hours. The
solution was partitioned between ethyl acetate and 10% citric acid
solution. The organic phase was washed with brine, dried over
magnesium sulfate and evaporated. The residue was purified by flash
column chromatography on silica gel using 20% ethyl acetate in
hexane to give the title product (90 mg, 38%), mp 89-90.degree. C.
Analysis calculated for C.sub.20H.sub.31N.sub.3O: C, 72.91, H,
9.48, N, 12.75. Found: C, 72.77, H, 9.47, N, 12.66.
[0192] Using methodology analogous to that described for the title
compound of Example 34, the compounds of Examples 35 and 36 were
prepared.
8 Example # Structure Characterization 35 173
C.sub.23H.sub.23F.sub.6N.sub.3O: mp 118-129.degree. C. Analysis
calculated: C, 58.60; H, 4.92; N, 8.91; F, 24.18. Found: C, 58.99;
H, 4.67; N, 8.76; F, 23.93. 36 174 C.sub.22H.sub.33N.sub.3O
.multidot. 0.03EtO Ac. Analysis calculated: C, 73.18; H, 9.67; N,
12.12. Found: C, 73.69: H, 9.67; N, 11.62. 36a 175
C.sub.19H.sub.29N.sub.3O: mp 69-71.degree. C. Analysis calculated:
C, 72.34: H, 9.27; N, 13.31. Found: C, 72.11; H, 9.36; N, 13.21.
36b 176 C.sub.19H.sub.29N.sub.3O: mp 106-107.degree. C. Analysis
calculated: C, 72.34; H, 9.27; N, 13.31. Found: C, 72.08; H, 9.35;
N, 13.19. 36c 177 C.sub.22H.sub.36N.sub.4O .multidot.0.17H.sub.2O:
mp 106-107.degree. C. Analysis calculated: C, 70.93; H, 9.75; N,
14.92. Found: C, 70.35; H, 9.75: N, 14.44. 38 178
C.sub.18H.sub.30N.sub.2O.sub.2 .multidot. 0.17 H.sub.2O: mp
108-109.degree. C. Analysis calculated: C, 69.85; H, 9.88;N, 9.05.
Found: C, 69.84; H, 9.85; N, 8.89.
Example 37
N-(3,3-Dimethylbutyl)-N'-[4-(Hexyloxy)Phenyl]Urea
[0193] 179
[0194] A. [4-(Hexyloxy)Phenyl]Carbamic Acid 4-nitrophenyl Ester
[0195] A solution of 4-hexyloxyaniline (1.00 g, 5.17 mmol) in
dichloromethane (10 mL) was treated with diisopropyl-ethylamine
(1.80 mL, 10.3 mmol) followed by p-nitrophenylchloroformate (1.05
g, 5.71 mmol). The reaction mixture was stirred for 3 hours at room
temperature and diluted with ethyl acetate. The ethyl acetate
solution was washed with hydrochloric acid and brine. After drying
over magnesium sulfate the solvent was removed to yield a brown
oil. Purification by flash chromatography on silica gel eluted with
15% acetone in hexanes provided compound 2 as a tan solid (241 mg,
13%).
[0196] B. N-(3,3-Dimethylbutyl)-N'-[4-(Hexyloxy)Phenyl]Urea
[0197] To a solution of compound 2 (90 mg, 0.25 mmol) in
tetrahydrofuran (1 mL) was added 3,3-dimethylbutylamine (41 .mu.L,
0.30 mmol). The reaction was stirred for 18 hours and then purified
by flash chromatography on silica gel eluted with 5% 2-propanol in
hexanes to provide the title compound as a white solid (75 mg,
94%): mp 103-104.degree. C. Analysis calculated for
C.sub.19H.sub.32N2O.sub.2.mult- idot.0.14 H.sub.2O: C, 70.65; H,
10.07; N, 8.67. Found: C, 70.67; H, 10.12; N, 8.52.
[0198] Using methodology analogous to that described for the title
compound of Example 37, the compound of Example 38 was
prepared.
9 Example # Structure Characterization 38 180
C.sub.18H.sub.30N.sub.2O.sub.2 .multidot. 0.17 H.sub.2O: mp
108-109.degree. C. Analysis calculated: C, 69.85; H, 9.88; N, 9.05.
Found: C, 69.84; H, 9.85; N, 8.89.
Example 39
(BMS-207307)
N-Cyano-N'-(3,3-dimethylbutyl)-N"-[4-(Hexyloxy)Phenyl]-guanidine
[0199] 181
[0200] A. N-Cyano-N'-[4-(Hexyloxy)Phenyl]Carbamimidic Acid Phenyl
Ester
[0201] A solution of 4-hexyloxyaniline (1.0 g, 5.17 mmol) in
tetrahydrofuran (2 mL) was added to a -25.degree. C. solution of
potassium hydride (652 mg of 35% in oil, 5.6 mmol, washed 3 times
with hexane) in dry tetrahydrofuran (2 mL) and was stirred for 30
minutes. The reaction mixture was then treated with
diphenylcyanocarbonimidate (1.48 g, 6.2 mmol) and stirred overnight
while warming to room temperature. The reaction mixture was
quenched with water and then partitioned between ethyl acetate and
10% citric acid solution. The organic phase was washed with brine,
dried over MgSO.sub.4, filtered and the solvent was removed. The
residue was purified first by flash column chromatography on silica
gel using 25% ethyl acetate/hexane as the mobile phase and the
product was recrystallized from isopropyl
ether/hexane/CH.sub.2Cl.sub.2 to give compound 2 as white needles
(424 mg, 24%).
[0202] B.
N-Cyano-N'-(3,3-dimethylbutyl)-N"-[4-(Hexyloxy)Phenyl]-guanidine
[0203] A solution of compound 2 (400 mg, 1.19 mmol) in
acetonitrile/isopropanol (2 mL of 1:1 mixture) was treated with
3,3-dimethylbutylamine (240 p1, 1.79 mmol) and heated to 60.degree.
C. in a sand bath for 24 hours. The solution was cooled to room
temperature, diluted with ethyl ether and washed with 1N HCl. The
organic phase was washed with brine, dried over MgSO.sub.4 and the
solvent was removed. The residue was crystallized from EtOAc to
give the title compound as a colorless solid (168 mg, 41%), mp
183-184.degree. C. Analysis calculated for
C.sub.20H.sub.32N.sub.4O: C, 69.93; H, 9.36; N, 16.26. Found: C,
69.54; H, 9.47; N, 16.05.
[0204] Using methodology analogous to that described for the title
compound of Example 39, the compounds of Examples 40 to 42 were
prepared.
10 Example # Structure Characterization 40 182
C.sub.19H.sub.30N.sub.4O: mp 119-120.degree. C. Analysis
calculated: C, 69.06; H, 9.15: N, 16.95. Found: C, 69.02; H, 9.16;
N, 16.88. 41 183 C.sub.22H.sub.37N.sub.5O: mp 88-89.degree. C.
Analysis calculated: C, 68.18; H, 9.61; N, 18.07. Found: C, 68.29:
H, 9.48; N, 17.82. 42 184 C.sub.19H.sub.30N.sub.4O: m/e = 330. 42a
185 C.sub.23H.sub.24N.sub.4F.sub.6O .multidot. 0: mp
122-123.degree. C. Analysis calculated: C, 56.79; H, 4.97; N,
11.52; F, 23.43. Found: C, 56.79; H, 4.84; N, 11.52; F, 23.10.
Example 43
N-(3,3-Dimethylbutyl)-4-(Hexyloxy)Benzenecarboximidamide,
Monohydrochloride
[0205] 186
[0206] A solution of the title B compound of Example 34 (500 mg,
1.75 mmol) in acetonitrile was treated triethylamine (2.4 eq., 596
.mu.l), followed by 3,3-dimethylbutylamine (1.5 eq., 2.6 mmol, 353
.mu.l) and heated at 50.degree. C. for 18 hours. The reaction
mixture was partitioned between ethyl acetate and saturated sodium
bicarbonate. The organic phase was washed with brine, dried over
anhydrous magnesium sulfate, filtered and concentrated. The residue
was purified by recrystallization from isopropyl ether/hexane to
give the title compound (510 mg, 96%), mp 235-237.degree. C.
Analysis calculated for C.sub.19H.sub.32N.sub.2O.multidot.1.22
HCl.multidot.1.12 H.sub.2O: C, 61.82; H, 9.68; N, 7.59; Cl, 11.72.
Found: C, 61.83; H, 9.60; N, 7.54; Cl, 12.14.
[0207] Using the above methodology, the following compounds were
prepared.
11 Example # Structure Characterization 44 187
C.sub.22H.sub.24F.sub.6N.sub.2O .multidot. 1.0 HCl: mp
168-169.5.degree. C. Analysis calculated: C, 54.72; H, 5.22; N,
5.80; F, 23.61: Cl, 7.34, Found: C, 55.27; H, 5.34; N, 5.65; F,
23.37; Cl, 7.41.
Example 45
N-[4-(Hexyloxy)Phenyl]-4,4-dimethyl-3-oxopentanamide
[0208] 188
[0209] A. N-[4-(Hexyloxy)Phenyl]-4,4-dimethyl-3-oxopentanamide
[0210] 4-Hexyloxyaniline (1, 1.00 g, 5.17 mmol) and
methyl-4,4-dimethyl-3-oxopentanoate (1.65 mL, 10.3 mmol) were
suspended in 5 mL p-xylene and heated to reflux for 17 hours. The
reaction was cooled to room temperature and purified by flash
chromatography on silica gel eluting with 10% acetone, hexane to
yield a brown solid. Recrystallization from hexane provided 1.35 g
(82%) of a white solid. mp 70-72.degree. C.; Analysis calculated
for C.sub.19H.sub.29NO.sub.3: C, 71.44; H, 9.15; N, 4.38. Found: C,
71.72; H, 9.42; N, 4.30.
Example 46
4-(2-Butyl-2H-tetrazol-5-yl)-N-[(2,2-dimethylcyclopentyl)-methyl]Benzamide
and
4-(1-butyl-1H-tetrazol-5-yl)-N-[(2,2-dimethylcyclopentyl)Methyl]Benza-
mide
[0211] 189
[0212] A. 4-(1
H-Tetrazol-5-yl)-N-[(2,2-dimethylcyclopentyl)-methyl]Benzam-
ide
[0213] Azidotributyl stannane (5.2 g, 4.4 mL, 15.8 mmol) was added
to a solution of the title compound of Example 29b (0.60 g, 2.3
mmol) in xylene (5.1 mL) and the mixture was stirred at 120.degree.
C. for 15 hours. After cooling, the reaction was diluted with
CH.sub.2Cl.sub.2 (40 mL) and 1N HCl (10 mL) and stirred vigorously
for 30 minutes. The solid was filtered and rinsed with alternating
portions of CH.sub.2Cl.sub.2 (3.times.20 mL) and 1N HCl (3.times.20
mL) and dried under high vacuum overnight to afford the title
compound as a white solid.
[0214] B.
4-(2-Butyl-2H-tetrazol-5-yl)-N-[(2,2-dimethylcyclopentyl)-methyl-
]Benzamide and 4-(1-butyl-1
H-tetrazol-5-yl)-N-[(2,2-dimethylcyclopentyl)M- ethyl]Benzamide
[0215] A mixture of the title A compound (0.60 g, 2.0 mmol),
iodobutane (0.38 g, 0.24 mL, 2.1 mmol), K.sub.2CO.sub.3 (0.40 g,
3.0 mmol), and DMF (5.0 mL) in acetonitrile (20 mL) was stirred at
55.degree. C. After 19 hours, the reaction was transferred to a
separatory funnel with EtOAc/1N HCl. The mixture was extracted with
EtOAc (2.times.40 mL), washed with brine, dried (MgSO.sub.4) and
concentrated in vacuo. Flash chromatography (silica, 50 mm, 25%
EtOAc/hexane) afforded the 4-(2-butyl-2H-tetrazol-5-y-
l)-N-[(2,2-dimethylcyclopentyl)methy] benzamide (0.57 g, 81%): mp
121-123.degree. C. Analysis calculated for
C.sub.20H.sub.29N.sub.5O-C, 67.58; H, 8.22; N, 19.7; Found: C,
67.48; H, 8.46; N, 19.68.
[0216] Further elution afforded
4-(1-butyl-1H-tetrazol-5-yl)-N-[(2,2-dimet-
hylcyclopentyl)methy]benzamide (46 mg, 6%): mp 106-109.degree. C.
Analysis calculated for C.sub.20H.sub.29N.sub.5O.multidot.H.sub.2O:
C, 65.27; H, 8.32; N, 19.03. Found: C, 65.32; H, 8.31; N,
18.63.
Example 47
(R)-N-[(2,2-Dimethylcyclopentyl)Methyl]-4-(5-butyl-1,2,4-4H-triazol-3-yl)B-
enzamide
[0217] 190
[0218] A. 4-[[(1-Ethoxypentylidene)Amino]Carbonyl]Benzoic Acid
Methyl Ester
[0219] To a solution of ethyl pentanimidate hydrochloride (9 g, 54
mmol) and triethyl amine (17 mL, 120 mmol) in toluene (110 mL) at
0.degree. C. was added, over 20 minutes, a solution of terephthalic
acid, monomethyl ester chloride (10.8 g, 54 mmol) in toluene (21
mL). After stirring at ambient temperature for 19 hours, the
reaction was filtered and the solids were rinsed with toluene (200
mL). The combined filtrates were concentrated in vacuo. Flash
chromatography (silica gel, CH.sub.2Cl.sub.2) of a portion of this
material afforded the title compound (1.9 g, 47%).
[0220] B. 4-(5-Butyl-I H-1,2,4-triazol-3-yl)Benzoic Acid Methyl
Ester
[0221] Hydrazine (0.23 g, 0.22 mL, 7.0 mmol) was added to a
solution of the title A compound (1.9 g, 6.4 mmol) in CCl.sub.4 (32
mL). After standing at ambient temperature for 19 hours, the
reaction was transferred to a separatory funnel containing
CH.sub.2Cl.sub.2/H.sub.2O. The mixture was extracted with
CH.sub.2Cl.sub.2 (2.times.50 mL) and 10% MeOH/CH.sub.2Cl.sub.2
(3.times.30 mL). The combined organic layers were dried
(MgSO.sub.4) and concentrated in vacuo. Flash chromatography
(silica gel, 50% EtOAc/hexane) gave the title compound (1.06 g,
64%).
[0222] C. 4-(5-Butyl-1,2,4-1 H-triazol-3-yl)Benzoic Acid
[0223] Lithium hydroxide (1 N, 8.2 mL, 8.2 mmol) was added to a
solution of the title B compound (1.06 g, 4.1 mmol) in THF (45 mL).
After stirring at ambient temperature for 28 hours, the reaction
was evaporated in vacuo. The aqueous residue was acidified with 1 N
HCl to pH 3 to 4. The resulting solid was filtered, washed with
H.sub.2O, and dried under high vacuum to afford the title compound
(0.90 g, 91%).
[0224] D.
(R)-N-[(2,2-Dimethylcyclopenyl)Methyl]-4-(5-butyl-1,2,4-1H-triaz-
ol-3-yl)Benzamide
[0225] 1-Hydroxybenzotriazole hydrate (70 mg, 0.51 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC,
156 mg, 0.51 mmol) were added to a solution of the title C compound
(123 mg, 0.50 mmol) in CH.sub.2Cl.sub.2 (2.2 mL) and DMF (0.57 mL)
stirring at ambient temperature. After stirring for 30 minutes,
(R)-((2,2-dimethylcyclopentyl- )methyl)amine, hydrochloride (82 mg,
0.50 mmol) in CH.sub.2 Cl.sub.2 (0.64 mL) was added followed by
triethylamine (0.070 mL, 0.50 mmol). After stirring for 20 hours,
the reaction was transferred to a separatory funnel with
ether/H.sub.2O and the aqueous layer acidified with 1N HCl. The
mixture was extracted with ether (2.times.80 mL), washed with
saturated NaHCO.sub.3, brine, dried (MgSO.sub.4) and concentrated
in vacuo. Flash chromatography (silica gel, 50%
EtOAc/CH.sub.2Cl.sub.2) afforded the title compound (0.12 g, 69%):
mp 182.0-184.5.degree. C. Analysis calculated for
C.sub.21H.sub.30N.sub.4O.multidot.0.27 H.sub.2O: C, 70.20; H, 8.57;
N, 15.59. Found: C, 70.20; H, 8.80; N, 15.43.
[0226] Using the procedure described in Example 47, the following
compounds were prepared.
12TABLE 47 Example # Structure Characterization 48 191
C.sub.21H.sub.30N.sub.4O .multidot. 0.18 H.sub.2O: ESI (m/z) 355.
Analysis calculated: C, 70.50; H, 8.55; N, 15.66. Found: C, 70.50:
H, 8.72; N, 15.44.
Example 49
4-(3-Butyl-5-isoxazolyl)-N-[(2,2-dimethylcyclopentyl)-methyl]Benzamide
[0227] 192
[0228] A. 4-(3-Butyl-5-isoxazolyl)Benzoic Acid Ethyl Ester
[0229] A solution of ethyl 4-acetylbenzoate (2.93 g, 15.3 mmol) in
25 mL ether was added to a solution of lithium diisopropylamide
(0.805 M in THF-hexane, 20.85 mL, 16.79 mmol) in 200 mL of ether at
-70.degree. C. The mixture was stirred at -78.degree. C. for 30
minutes, magnesium bromide etherate (3.94 g, 15.26 mmol) was added
and the reaction mixture was stirred for 30 minutes followed by the
addition of valeryl chloride (1.47 g, 12.2 mmol) in 3 mL ether.
Stirring was continued at -78.degree. C. for an additional 30
minutes. The mixture was allowed to come to room temperature,
quenched by adding saturated ammonium chloride and acidified
(pH=3.0) by adding 20% sulfuric acid. The mixture was extracted
with ethyl acetate, the organic layer was dried over magnesium
sulfate, concentrated, and the residue subjected to flash
chromatography (silica gel/hexane-ethyl acetate 95:5) to afford the
title compound (1.35 g).
[0230] B. 4-(3-Butyl-5-isoxazolyl)Benzoic Acid Ethyl Ester
[0231] A solution of the title A compound (150 mg, 0.54 mmol) in
1.5 mL ethanol was treated with a solution of hydroxylamine
hydrochloride (41.4 mg, 0.6 mmol) in 0.15 mL of water. The mixture
was heated at 80.degree. C. in a sealed tube for 2 hours,
concentrated, and the residue partitioned between water and
methylene chloride. The methylene chloride layer was dried over
magnesium sulfate and concentrated to afford the desired product
(145 mg).
[0232] C. 4-(3-Butyl-5-isoxazolyl)Benzoic Acid
[0233] A solution of the the title B compound (145 mg) in 6 mL
dioxane was treated with 10% aqueous potassium hydroxide (6 mL) and
the mixture was stirred at room temperature for 14 hours. The
mixture was diluted with water, washed with ether, the aqueous
layer was acidified with 10% sodium hydrogen sulfate and extracted
with ethyl acetate. The ethyl acetate layer was dried over
magnesium sulfate, concentrated to give the desired compound (88
mg) as a white solid.
[0234] D.
4-(3-Butyl-5-isoxazolyl)-N-[(2,2-dimethylcyclopentyl)-methyl]Ben-
zamide
[0235] The title C compound was sequentially treated with
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP) (174.4 mg, 0.395 mmol),
2,2-dimethylcyclopentylmethyl amine (59 mg, 0.359 mmol; the title B
compound of Example 1) and N-methylmorpholine in 3 mL DMF. The
mixture was stirred at room temperature for 14 hours, diluted with
water, stirred for 5 minutes and the resulting precipitate was
isolated by filtration. The crude product was recrystallized from
hexane to give the title compound (90 mg) as a white solid.
Example 50
4-(3-Butyl-1H-pyrazol-5-yl)-N-[(2,2-dimethylcyclopentyl)-methyl]Benzamide
[0236] 193
[0237] A. 4-(3-Butyl-1H-pyrazol-5-yl)Benzoic Acid Ethyl Ester
[0238] This title compound was prepared from compound 1 (title A
compound of Example 49) and hydrazine by a similar procedure as
described for the title B compound of Example 49.
[0239] B.
4-(3-Butyl-1H-pyrazol-5-yl)-N-[(2,2-dimethylcyclopentyl)-methyl]-
Benzamide
[0240] The title A compound was converted to the desired product by
a sequence of reactions as described for the preparation of the
title compound of Example 49 from the title B compound of Example
49. The product was obtained as a white solid, MS:m/e=353.
Example 51
4-(5-Butyl-1,3,4-oxadiazol-2-yl)-N-[(2,2-dimethylcyclopentyl)-methyl]Benza-
mide, Enantiomer A and Enantiomer B
[0241] 194
[0242] A.
4-[[[(2,2-Dimethylcyclopentyl)Methyl]Amino]-carbonyl]Benzoic Acid
Methyl Ester
[0243] The title compound was prepared from monomethylterephthalate
and 2,2-dimethylcyclopentylmethyl amine (title B compound of
Example 1) in a manner as described for the title A compound of
Example 24.
B. 4-[[[(2,2-Dimethylcyclopentyl)Methyl]Amino]-carbonyl]Benzoic
Acid Hydrazide
[0244] The title A compound (275 mg) was treated with hydrazine
monohydrate and heated at 120.degree. C. for 2 hours. The reaction
mixture was diluted with water, saturated with potassium carbonate
and extracted with ethyl acetate. The organic layer was dried over
magnesium sulfate and concentrated to give the title compound (270
mg) as a white solid which was used in the next reaction without
isolation.
[0245] C.
4-(5-Butyl-1,3,4-oxadiazol-2-yl)-N-[(2,2-dimethyl-cyclopentyl)Me-
thyl]Benzamide, Enantiomer A and Enantiomer B
[0246] The title B compound was heated in trimethyl orthovalerate
(3 mL), at 120.degree. C. for 2 hours. The excess trimethyl
orthovaerate was removed by purging with a stream of nitrogen at
140.degree. C. The residue was heated at 140.degree. C. for 1.5
hours, diluted with methylene chloride, washed with 10% potassium
carbonate and the organic layer was dried (magnesium sulfate) and
concentrated. The crude product was subjected sequentially to flash
chromatography (silica gel/hexane-EtOAc 1:1) and chiral preparative
HPLC (Chirapak AD column/hexane-isopropanol-triethylamine
80:20:0.2) to give the two enantiomers: (+)-enantiomer A (104 mg,
[.alpha.].sub.D=+22.degree. C.=0.36, methylene chloride, m/e 355)
and the (-)-enantiomer B (100 mg, [.alpha.].sub.D=-19.5.degree.
C.=0.36, methylene chloride, m/e 355) as white solids.
Example 52
3-[4-(3-Butyl-1,2,4-oxadiazol-5-yl)Phenyl]-N-[(2,2-dimethyl-cyclopentyl)Me-
thyl]-2-propenamide
[0247] 195
[0248] A.
N-[(2,2-Dimethylcyclopentyl)Methyl]-3-(4-formylphenyl)-2-propena-
mide
[0249] To a cold (0.degree. C.) solution of 4-formylcinnamic acid
(345 mg, 1.96 mmol) and 2,2-dimethylcyclopentylmethylamine,
hydrochloride (321 mg, 1.96 mmol; title B compound of Example 1) in
DMF (5 mL) was added
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP) (954 mg, 2.16 mmol) and
N-methylmorpholine (0.47 mL, 4.31 mmol). The cooling bath was
removed and the reaction mixture was stirred at room temperature
for 18 hours. The reaction mixture was diluted with dichloromethane
and washed with 1N HCl and saturated NaHCO.sub.3 solution. The
organic layer was dried (MgSO.sub.4) and concentrated in vacuo to
yield a light amber gum. MS: (ESI), (M+H).sup.+286.
[0250] B.
4-[3-[[(2,2-Dimethylcyclopentyl)methyl]amino]-3-oxo-1-propenyl]B-
enzoic Acid
[0251] To stirred solution of the title A compound in THF/H.sub.2O
(15 mL of a 1:1 mixture) at 0.degree. C. was added sodium chlorite
(329 mg, 3.64 mmol) and sulfamic acid (353 mg, 3.64 mmol). The
cooling bath was removed and the reaction was allowed to warm up to
room temperature. Once the reaction was complete, the mixture was
diluted with dichloromethane and washed with saturated potassium
bisulfate solution. The organic layers were separated and the
aqueous layer was backwashed with fresh dichloromethane (twice).
The combined organic extracts were washed with freshly prepared 2%
sodium bisulfite solution, dried (MgSO.sub.4) and concentrated in
vacuo to afford a light yellow solid (583 mg, 98%), mp
138-140.degree. C.
[0252] C.
4-[3-[[(2,2-Dimethylcyclopentyl)Methyl]amino]-3-oxo-1-propenyl]B-
enzoic Acid Methyl Ester
[0253] The freshly prepared excess diazomethane was slowly added to
a cold (0.degree. C.) solution of the title B compound (583 mg,
1.93 mmol) in diethyl ether (50 mL) until a yellow color persisted.
The reaction was quenched with a few drops of glacial acetic acid
until the yellow color disappeared. The reaction was then
concentrated in vacuo to afford a yellow gum which was purified by
flash chromatography on silica gel (10% EtAc in hexane) gave the
desired product as a creamy light yellow solid. MS: (ESI)
(M+H).sup.+316.
[0254] D.
3-[4-(3-Butyl-1,2,4-oxadiazol-5-yl)Phenyl]-N-[(2,2-dimethylcyclo-
pentyl)Methyl]-2-propenamide
[0255] To a solution of the title C compound (100 mg, 0.32 mmol)
and n-butylhydroxyamidine (46 mg, 0.40 mmol) in DMF (2 mL) was
added NaH (17 mg, 0.70 mmol). After stirring for 18 hours at room
temperature, the reaction mixture was diluted with dichloromethane
and washed with water. The combined organic extracts were dried
(MgSO.sub.4), and concentrated in vacuo to yield a yellow solid (90
mg, 74%), mp 144-145.degree. C. MS (ESI): (M+H).sup.+382.
[0256] Using the procedures described above the following compounds
were prepared.
13 Example # Structure Characterization 53 196
C.sub.18H.sub.23N.sub.3O.sub.2: mp 185-186.degree. C. 54 197
C.sub.20H.sub.27N.sub.3O.sub.2: mp 162-164.degree. C. 55 198
C.sub.21H.sub.29N.sub.3O.sub.2: mp 164-166.degree. C. 56 199
C.sub.20H.sub.25N.sub.3O.sub- .2: mp 160-161.degree. C. 57 200
C.sub.22H.sub.29N.sub.3O.- sub.2: mp 147-149.degree. C. 58 201
C.sub.23H.sub.31N.sub.3O.sub.2: mp 146-148.degree. C. 59 202
C.sub.19H.sub.25N.sub.3O.sub.2: mp 162-163.degree. C. 60 203
C.sub.21H.sub.27N.sub.3O.sub.2: mp 145-1464.degree. C. 61 204
C.sub.24H.sub.21F.sub.6N.sub.3O.sub.2: mp 178-179.degree. C. 62 205
C.sub.23H.sub.19F.sub.6N.sub.3O.sub.2: mp 178-179.degree. C. 63 206
C.sub.22H.sub.17F.sub.6N.sub.3O- .sub.2: MS: M + H = 468 64 207
C.sub.24H.sub.33N.sub.3O.su- b.2: mp 131-132.degree. C. 65 208
C.sub.24H.sub.33N.sub.3O- .sub.2: mp 130-131.degree. C. 66 209
C.sub.24H.sub.33N.sub.3O.sub.2: mp 144-145.degree. C. 67 210
C.sub.24H.sub.33N.sub.3O.sub.2: mp 140-141.degree. C.
[0257] 211
A. Resin
[0258] To a stirred suspension of NaH (5.25 g, 131 mmol) in 100 mL
of dry DMF at 4.degree. C. was added a solution of
4-hydroxy-2-methoxybenzaldehy- de (20.0 g, 131 mmol) in 100 mL of
dry DMF drop-wise via addition funnel over a period of 30 minutes.
The addition funnel was washed with 30 mL of dry DMF which was
added to the reaction flask. After stirring at 4.degree. C. for one
hour, the ice-water bath was removed and the reaction was allowed
to warm to room temperature over the period of 1/2 hour. At the end
of this period, tetra-n-butylammonium iodide (6.5 g, 17.6 mmol) was
added followed by Merrifield resin (52.8 g, loading=1.24 mmol/g,
65.5 mmol). The reaction flask was immersed in an oil bath which
was heated to 70.degree. C. After 20 hours, the heating bath was
removed and the reaction was allowed to cool to room temperature.
The reaction was filtered with suction and the residual resin
rinsed with water:DMF (3.times.200 mL), DMF (3.times.200 mL), THF
(3.times.200 mL), methanol (2.times.200 mL). The resin was dried
under (20 mm Hg) for 18 hours to yield 62.86 g of resin 1.
Elemental analysis indicated less than 0.1% residual Cl.
B. Resin 2
[0259] Resin 1 (10 g, loading=1.08 mmol/g, 10.8 mmol) was weighed
into a glass solid phase organic synthesis (SPOS) reaction vessel.
The resin was swelled with dry DMF (50 mL) which was drained after
10 minutes. Dry DMF (60 mL) was then added followed by
3,3-dimethylbutylamine (3.0 g, 29.6 mmol). The reaction vessel was
agitated on a wrist-action shaker for 10 minutes and trimethyl
orthoformate (30 mL) was added. After agitating for 14 hours, the
reaction was drained and 50 mL of dry DMF was added. The reaction
was agitated for approximately 1 minute and drained. Dry DMF (10
mL) was added followed by sodium triacetoxyborohydride (6.35 g, 30
mmol) and acetic acid (0.60 mL, 1 mmol). After 6 hours of
agitation, the reaction was drained and rinsed with DMF (3.times.50
mL), DMF-water (3.times.50 mL), DMF (3.times.50 mL),
dichloromethane (3.times.50 mL), methanol (3.times.50 mL) and THF
(3.times.50 mL). The resin was used in the next step without
characterization.
[0260] C. Compound 4
[0261] To a stirred solution of pentafluorophenol (7.6 g, 41.3
mmol) in dry dichloromethane at 4.degree. C. was added
N,N-diispropylethylamine (19.6 mL, 112.5 mmol) drop-wise via
syringe over a period of 5 minutes. After 20 minutes, 4-iodobenzoyl
chloride (10.0 g, 37.5 mmol) was added as a solid. The reaction was
stirred at 4.degree. C. for 2 hours and the ice-water bath was
removed. The reaction was allowed to warm to room temperature over
a half hour period. TLC analysis indicated complete consumption of
starting material. The reaction was poured into 500 mL of
dichloromethane which was washed with 1N aq. HCl (3.times.200 mL),
water (2.times.200 mL), sat. aq. sodium bicarbonate (3.times.200
mL) and brine (200 mL), dried over magnesium sulfate, filtered and
stripped. The product was dried under vacuum to yield 15.35 g (37.0
mmol) of a white waxy solid. This material was dissolved in 100 mL
of dry toluene and bis(tributyltin) (28 mL, 55.4 mmol) was added.
The reaction mixture was degassed by bubbling with dry nitrogen for
a period of 15 minutes. At the end of this period,
tetrakistriphenylphosphine palladium (0) (427 mg, 0.37 mmol) was
added. The reaction flask was fitted with a reflux condenser and
immersed in an oil bath which was heated to 120.degree. C. After
stirring for 14 hours, the reaction was allowed to cool and
filtered through a pad of silica. The solvent was removed in vacuo.
The residual oil was purified by flash reverse-phase chromatography
(YMC-gel, dichloromethane-acetonitrile). The tubes containing the
product were pooled and concentrated to yield 16.31 g (28.3 mmol,
75.5% from 4-iodobenzoyl chloride) of 4.
[0262] D. Resin 5
[0263] Resin 3 (4.3 g, loading=0.99 mmol/g, 4.3 mmol) was
transferred into a glass SPOS reaction vessel. The resin was
swelled with 20 mL of dry THF. After 10 minutes the solvent was
drained away and 5 mL of dry THF was added. A solution of compound
4 (4.9 g, 8.5 mmol) in 15 mL of dry THF was added via syringe. The
reaction was agitated on a wrist-action shaker for 16 hours. The
solvent was drained from the resin which was then washed with THF
(3.times.40 mL), dichloromethane (3.times.40 mL), methanol
(3.times.40 mL) and THF (3.times.40 mL). The resin was dried in
vacuo at 20 mm Hg for 18 hr. The resin was used in the next step
without further characterization.
E. Resin 7
[0264] Resin 5 (300 mg, 0.213 mmol) was transferred into a
polypropylene reaction tube. Dry NMP (2 mL) was added followed by
3- iodoanisole (169 mg, 0.72 mmol), triphenylarsine (45 mg, 0.15
mmol) and tris(dibenzylideneacetone)dipalladium-(0)-chloroform
adduct (35 mg, 0.034 mmol). The reaction was sealed and agitated at
275 rpm on an orbital shaker. The reaction was heated to 55.degree.
C. over a one hour period. After 14 hours, the reaction mixture was
allowed to cool to room temperature. The solvent was drained and
the resin was washed with DMF (3.times.5 mL), DMF-water (3.times.5
mL), dichloromethane (3.times.5 mL), THF (3.times.5 mL), methanol
(3.times.5 mL), and dichloromethane (3.times.5 mL). The resin was
suspended in dichloromethane (0.5 mL) and trifluoroacetic acid (3
mL). After 1 hour, the product was collected into a tared
test-tube. The solvent was removed in vacuo. The crude product was
purified by preparative HPLC using a YMC S3 ODS 20.times.100 mm
column with a 30-100% B gradient over 10 minutes at a flow rate of
25 mL/minute (Solvent A: 90% water/10% methanol with 0.1% TFA;
Solvent B 10% water/90% methanol with 0.1% TFA) to provide the
title compound (3.7 mg).
[0265] Using the procedure described in Example 68, the following
compounds were prepared.
14 Example # Structure Characterization 69 212
C.sub.20H.sub.25NO.sub.2m/z 312 (M + H) 70 213 C.sub.19H.sub.22FNO
m/z 300 (M + H) 71 214 C.sub.20H.sub.25NO.sub.2m/z 312 (M + H) 72
215 C.sub.18H.sub.22N.sub.2O m/z 283 (M + H) 73 216
C.sub.23H.sub.25NO m/z 332 (M + H) 74 217 C.sub.21H.sub.21F.sub.6NO
m/z 418 (M + H) 75 218 C.sub.21H.sub.27NO m/z 310 (M + H) 76 219
C.sub.20H.sub.25NO.sub.2m/z 312 (M + H) .sup. 76a 220
C.sub.19H.sub.22FNO m/z 300 (M + H) 68 221
C.sub.20H.sub.25NO.sub.2m/z 312 (M + H) 77 222
C.sub.20H.sub.25NO.sub.2m/z 312 (M + H) 78 223
C.sub.19H.sub.25N.sub.3O.sub.3m/z 344 (M + H) 79 224
C.sub.18H.sub.21N.sub.5O m/z 324 (M + H) 80 225
C.sub.18H.sub.22N.sub.2O m/z 283 (M + H) 81 226 C.sub.23H.sub.25NO
m/z 332 (M + H) 82 227 C.sub.21H.sub.21F.sub.6NO m/z 418 (M + H) 83
228 C.sub.21H.sub.27NO m/z 310 (M + H) 84 229
C.sub.23H.sub.17F.sub.6NO.sub.2m/z 452 (M - H) 85 230
C.sub.22H.sub.14F.sub.7NO m/z 442 (M + H) 86 231
C.sub.23H.sub.17F.sub.6NO.sub.2m/z 454 (M + H) 87 232
C.sub.21H.sub.14F.sub.6N.sub.2O m/z 425 (M + H) 88 233
C.sub.26H.sub.17F.sub.6NO m/z 474 (M + H) 89 234
C.sub.24H.sub.19F.sub.6NO m/z 452 (M + H) 90 235
C.sub.23H.sub.17F.sub.6NO.sub.2m/z 454 (M + H) 91 236
C.sub.22F.sub.7NO m/z 442 (M + H) 92 237
C.sub.23H.sub.17F.sub.6NO.sub.2m/z 454 (M + H) 93 238
C.sub.23H.sub.17F.sub.6NO.sub.2m/z 454 (M + H) 94 239
C.sub.22H.sub.17F.sub.6N.sub.3O.sub.3m/z 486 (M + H) 95 240
C.sub.21H.sub.14F.sub.6N.sub.2O m/z 425 (M + H) 96 241
C.sub.26H.sub.17F.sub.6NO m/z 472 (M - H) 97 242
C.sub.24H.sub.13F.sub.12NO m/z 558 (M - H) 98 243
C.sub.24H.sub.19F.sub.6NO m/z 452 (M + H)
[0266] 244
A. Resin 1
[0267] The title resin was prepared according to Example 68, part
A.
[0268] B. Resin 3
[0269] 5.0 g of resin 1 (loading=1.08 mmol/g, 5.4 mmol) was weighed
into a glass SPOS reaction vessel. The resin was swelled with dry
DMF (25 ml) which was drained after 10 min. Dry DMF (20 ml) was
then added followed by amine 2 (2,2-dimethylmethylaminocyclopentane
hydrochloride salt 1.33 g, 8.12 mmol) and N,N-diisopropylethylamine
(4.7 ml, 27 mmol). The reaction vessel was agitated on a
wrist-action shaker for 10 min. and trimethyl orthoformate (7 ml)
was added. After agitating for 14 h, the reaction was drained and
20 ml of dry DMF was added. The reaction was agitated for
approximately 1 min. and drained. 25 ml of dry DMF was added
followed by sodium triacetoxyborohydride (3.40 g, 16.0 mmol) and
acetic acid (1.0 ml, 1.6 mmol). After 6 h of agitation, the
reaction was drained and rinsed with DMF (3.times.30 ml), DMF-water
(3.times.30 ml), DMF (3.times.30 ml), dichloromethane (3.times.30
ml), methanol (3.times.30 ml) and THF (3.times.30 ml). The resin
was used in the next step without characterization.
[0270] C. Boronate Ester 4
[0271] To a stirred mixture of 3-carboxyboronic acid (1.65 g, 10.0
mmol) in toluene (60 mL) was added pinacol (1.24 g, 10.5 mmol). The
reaction flask was fitted with a Dean-Stark trap and a reflux
condenser and immersed in an oil bath. The bath was heated to
160.degree. C. After 20 hours, TLC indicated consumption of
starting material. The reaction was allowed to cool. The solvent
was removed in vacuo and the residue purified by flash column
chromatography (silica, methanol-dichloromethane- , 1:19). The
appropriate fractions were collected to give the title compound
(2.3 g, 93%).
[0272] D. Resin 5
[0273] Resin 3 (5.6 g, loading=0.97 mmol/g, 5.4 mmol) was
transferred into a glass SPOS reaction vessel. The resin was
swelled with 20 mL of dry dichloromethane. After 10 minutes the
solvent was drained away and 5 mL of dry dichlormethane was added.
The title 4 compound (1.75 g, 7.06 mmol) was added followed by
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.44
g, 7.01 mmol), triethylamine (3.75 ml, 26.9 mmol) and
N,N-dimethylaminopyridine (50 mg, cat.). The reaction was agitated
on a wrist-action shaker for 16 hour. The solvent was drained from
the resin which was then washed with dichloromethane (3.times.40
mL), THF (3.times.40 mL), methanol (3.times.40 mL) and THF
(3.times.40 mL).
[0274] E. Title compound of Example 99
[0275] Resin 5 (200 mg, 0.158 mmol) was transferred into a glass
reaction tube. DMF-water (9:1, 3 mL) was added followed by
3-bromoanisole (0.50 mL, 0.40 mmol), potassium carbonate (100 mg,
0.72 mmol) and tetrakis(triphenyl-phosphine)palladium-(0) (20 mg,
0.017 mmol). The reaction was sealed and agitated at 250 rpm on an
orbital shaker. The reaction was heated to 81.degree. C. over a one
hour period. After 20 hours, the reaction was allowed to cool to
room temperature. The solvent was drained and the resin was washed
with DMF (3.times.5 mL), DMF-water (3.times.5 mL), DMF (3.times.5
mL), dichloromethane (3.times.5 mL), THF (3.times.5 mL), methanol
(3.times.5 mL), and dichloromethane (3.times.5 mL). Dichloromethane
(0.5 mL) was added followed by TFA (3 mL). After 1 hour, the
product was collected into a tared test-tube. The solvent was
removed from the cleavage product in vacuo. The product was
reconstituted with 3 mL of dichloromethane and the solvent removed
in vacuo to provide the title compound (24.1 mg).
[0276] Using the method described in Example 99, the following
compounds were prepared.
15 Example # Structure Characterization 100 245
C.sub.22H.sub.27NO.sub.2m/z 338 (M + H) 101 246 C.sub.27H.sub.29NO
m/z 384 (M + H) 102 247 C.sub.23H.sub.27NO.sub.2m/z 350 (M + H) 103
248 C.sub.23H.sub.30N.sub.2O m/z 351 (M + H) 104 249
C.sub.19H.sub.23NOS m/z 314 (M + H) 105 250
C.sub.20H.sub.24N.sub.2O m/z 309 (M + H) 106 251
C.sub.20H.sub.24N.sub.2O m/z 309 (M + H) 107 252
C.sub.24H.sub.26N.sub.2O m/z 359 (M + H) 108 253
C.sub.24H.sub.26N.sub.2O m/z 359 (M + H) 109 254
C.sub.23H.sub.29NO.sub.3m/z 368 (M + H) 110 255 C.sub.24H.sub.31NO
m/z 350 (M + H) 111 256 C.sub.24H.sub.29NO.sub.3m/z 380 (M + H) 112
257 C.sub.24H.sub.29NO.sub.3m/z 380 (M + H) 113 258
C.sub.27H.sub.38N.sub.2O.sub.2m/z 423 (M + H) 114 259
C.sub.21H.sub.26N.sub.2O.sub.2m/z 339 (M + H) 115 260
C.sub.21H.sub.23F.sub.3N.sub.2O m/z 377 (M + H) 116 261
C.sub.31H.sub.39N.sub.3O m/z 470 (M + H) 117 262
C.sub.22H.sub.16N.sub.2O.sub.3m/z 367 (M + H) 118 263
C.sub.21H.sub.25N.sub.3O.sub.2m/z 352 (M + H)
Example 120
[0277] 264
A. Compound 2
[0278] A solution of 3-methoxybenzene boronic acid (4.0 g, 26.3
mmol) and benzyl-4-bromobenzoate (7.66 g, 26.3 mmol) in toluene (50
mL) was degassed by bubbling nitrogen through for 15 minutes. A
solution of potassium carbonate in water (2 M, 13.1 mL, 26.2 mmol)
was added followed by the addition of
tetrakis(triphenylphosphine)palladium (0) (0.66 g, 0.57 mmol). The
reaction flak was fitted with a reflux condenser and immersed in an
oil bath which was heated to 150.degree. C. After stirring under
reflux for 14 hours, the reaction was allowed to cool and poured
into an EtOAc (500 mL) -water (200 mL) mixture. The layers were
separated and the organic layer washed with brine, stirred over
magnesium sulfate/charcoal for 15 minutes, filtered through Celite
and concentrated in vacuo to give 7.5 g of a white solid which was
dissolved in ethanol and added to a pressure flask.
Palladium-hydroxide on carbon (10%, 750 mg) was added. The flask
was placed on a Parr shaker and agitated under a hydrogen
atmosphere (63 psi) for 4 hours. At the end of this time, nitrogen
was bubbled through the reaction mixture for 15 minutes. The
reaction mixture was filtered through a pad of Celite and
concentrated in vacuum to afford 5.32 g of a white solid. Dry
dichloromethane (100 mL) was added to the flask containing the
above material. The flask was cooled to -78.degree. C. in a dry
ice-acetone bath and a solution of boron tribromide in
dichloromethane (1 M, 57 mL, 57 mmol) was added via syringe over a
period of 20 minutes. The reaction was stirred at -78.degree. C.
for 2 hours. At this time the dry ice-acetone bath was replaced
with an ice-water bath and the reaction was allowed to warm to
4.degree. C. over the period of 1 hour. At this time, the reaction
was placed in the dry ice-acetone bath. After 10 minutes, methanol
(10 mL) was added via syringe over a 2 minute period. The reaction
was poured into a dichloromethane (500 mL)-water (100 mL) mixture.
The layers were separated and the aqueous layer was extracted with
dichloromethane (5.times.200 mL). The dichloromethane extracts were
combined, dried over magnesium sulfate and concentrated in vacuo.
The resulting material was purified by flash column chromatography
(silica, 9:1-dichloromethane:meth- anol). The appropriate fractions
were pooled and concentrated in vacuo to afford 2.99 g of a white
solid. The above material was suspended in acetic anhydride and 3
drops of an acetic acid:sulfuric acid (1:1) mixture were added. The
reaction flask was immersed in an oil bath which was heated to
160.degree. C. for 1.5 hours. At the end of this time, the reaction
was poured over an ice (50 g)/water (50 mL) mixture. The flask
containing this mixture was heated at 55.degree. C. with stirring
for 1 hour. Over this period a white precipitate appeared in the
flask. The flask was cooled in an ice-water bath for 1/2 hour and
the precipitate was collected by vacuum filtration. This procedure
yielded 3.3 g of 2.
[0279] B. Resin 3
[0280] Resin 1 (the title A resin of example 99, 5.6 g,
loading=0.97 mmol/g, 5.4 mmol) was transferred into a glass SPOS
reaction vessel. The resin was swelled with 20 mL of dry
dichloromethane. After 10 minutes the solvent was drained away and
25 mL of dry dichloromethane was added. Acid 2 (2.07 g, 10.5 mmol)
was added followed by 1-(3-dimethylaminopropyl)-3-e-
thylcarbodiimide hydrochloride (2.82 g, 10.5 mmol), triethylamine
(1.8 mL, 12.9 mmol) and N,N-dimethylaminopyridine (20 mg, cat.).
The reaction was agitated on a wrist-action shaker for 16 hours.
The solvent was drained from the resin which was then washed with
dichloromethane (3.times.40 mL), THF (3.times.40 mL), methanol
(3.times.40 mL) and THF (3.times.40 mL).
[0281] C. Resin 4
[0282] 6.0 g of resin 3 (loading=0.78 mmol/g, 4.7 mmol) was
transferred into a glass SPOS reaction vessel. The resin was
swelled with 50 mL of THF and 20 mL of a solution of sodium
methoxide in methanol (0.5 M, 10 mmol) was added. The reaction was
agitated for 20 hours and drained. The resin was washed with THF
(40 mL) which was drained. A solution of acetic acid in THF (1:9)
was then added. After agitating for 1/2 hour, the reaction was
drained and the resin was then washed with dichloromethane
(3.times.40 mL), THF (3.times.40 mL), methanol (3.times.40 mL) and
THF (3.times.40 mL).
[0283] D. The title compound of Example 120
[0284] Resin 4 (200 mg, 0.164 mmol) was transferred into a
polypropylene reaction tube which was fitted into a solid-phase
reactor. The resin was swelled by the addition of 2.0 mL of
dichloromethane. To the resin was added 4-(dimethylamino)-phenethyl
alcohol (136 mg, 0.82 mmol), 1 mL of a solution of
triphenylphosphine in THF (0.82 M, 0.82 mmol) and 1 mL of a
solution of diisopropyl azodicarboxylate in THF (0.82 M, 0.82
mmol). The reaction block was agitated at 275 rpm for 20 hours. At
the end of this period the solvent was drained and the resin was
washed with DMF (3.times.5 mL), DMF-water (3.times.5 mL), DMF
(3.times.5 mL), dichloromethane (3.times.5 mL), THF (3.times.5 mL),
methanol (3.times.5 mL), and dichloromethane (3.times.5 mL).
Dichloromethane (0.5 mL) was added followed by trifluoroacetic acid
(3 mL). After 1 hour, the product was collected into a tared
test-tube. The solvent was removed from the cleavage product in
vacuo. The product was reconstituted with 3 mL of dichloromethane
and the solvent removed in vacuo to provide the title compound
(30.3 mg).
[0285] Using the procedure described in example 120, the following
compounds were prepared.
16 Example # Structure Characterization 121 265
C.sub.23H.sub.29NO.sub.2m/z 352 (M + H) 122 266
C.sub.24H.sub.31NO.sub.2m/z 366 (M + H) 123 267
C.sub.25H.sub.33NO.sub.2m/z 380 (M + H) 124 268
C.sub.27H.sub.37NO.sub.2m/z 408 (M + H) 125 269
C.sub.21H.sub.25NO.sub.2m/z 324 (M + H) 126 270
C.sub.27H.sub.38N.sub.2O.sub.3m/z 439 (M + H) 127 271
C.sub.29H.sub.33NO.sub.2m/z 428 (M + H) 120 272
C.sub.31H.sub.38N.sub.2O.sub.2m/z 471 (M + H) 128 273
C.sub.28H.sub.38N.sub.2O.sub.3m/z 451 (M + H) 129 274
C.sub.28H.sub.38N.sub.2O.sub.2m/z 435 (M + H) 130 275
C.sub.28H.sub.41N.sub.3O.sub.2m/z 452 (M + H) 131 276
C.sub.28H.sub.40N.sub.2O.sub.2m/z 437 (M + H) 132 277
C.sub.33H.sub.40N.sub.2O.sub.2m/z 497 (M + H) 133 278
C.sub.28H.sub.32N.sub.2O.sub.2m/z 429 (M + H) 134 279
C.sub.25H.sub.33NO.sub.3m/z 396 (M + H) 135 280
C.sub.27H.sub.36N.sub.2O.sub.2m/z 421 (M + H) 136 281
C.sub.29H.sub.40N.sub.2O.sub.2m/z 449 (M + H) 137 282
C.sub.27H.sub.38N.sub.2O.sub.2m/z 423 (M + H) 138 283
C.sub.26H.sub.35NO.sub.2m/z 394 (M + H) 139 284
C.sub.28H.sub.38N.sub.2O.sub.2m/z 435 (M + H) 140 285
C.sub.27H.sub.30N.sub.2O.sub.2m/z 415 (M + H) 141 286
C.sub.27H.sub.36N.sub.2O.sub.2m/z 421 (M + H) 142 287
C.sub.21H.sub.27NO.sub.2m/z 326 (M + H) 143 288
C.sub.22H.sub.29NO.sub.2m/z 340 (M + H) 144 289
C.sub.23H.sub.31NO.sub.2m/z 354 (M + H) 145 290
C.sub.25H.sub.35NO.sub.2m/z 382 (M + H) 146 291
C.sub.21H.sub.23NO.sub.2m/z 298 (M + H) 147 292
C.sub.27H.sub.31NO.sub.2m/z 402 (M + H) 148 293
C.sub.29H.sub.36N.sub.2O.sub.2m/z 445 (M + H) 149 294
C.sub.26H.sub.36N.sub.2O.sub.3m/z 425 (M + H) 150 295
C.sub.26H.sub.36N.sub.2O.sub.2m/z 409 (M + H) 151 296
C.sub.26H.sub.38N.sub.2O.sub.2m/z 411 (M + H) 152 297
C.sub.31H.sub.38N.sub.2O.sub.2m/z 471 (M + H) 153 298
C.sub.26H.sub.30N.sub.2O.sub.2m/z 403 (M + H) 154 299
C.sub.23H.sub.31NO.sub.3m/z 370 (M + H) 155 300
C.sub.27H.sub.38N.sub.2O.sub.2m/z 423 (M + H)
* * * * *