U.S. patent application number 09/935903 was filed with the patent office on 2002-04-25 for heteroaryl amines as novel acetylcholinesterase inhibitors.
Invention is credited to Chen, Yuhpyng L., Nagel, Arthur A..
Application Number | 20020049210 09/935903 |
Document ID | / |
Family ID | 25091318 |
Filed Date | 2002-04-25 |
United States Patent
Application |
20020049210 |
Kind Code |
A1 |
Chen, Yuhpyng L. ; et
al. |
April 25, 2002 |
Heteroaryl amines as novel acetylcholinesterase inhibitors
Abstract
Compounds of the formula 1 wherein ring A, ring B, ring D,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,R.sup.11, R.sup.12,
R.sup.13, E, G, X and P are as defined below. The compounds of
formula I are cholinesterase inhibitors and are useful in enhancing
memory in patients suffering from dementia and Alzheimer's
disease.
Inventors: |
Chen, Yuhpyng L.; (New York,
NY) ; Nagel, Arthur A.; (New York, NY) |
Correspondence
Address: |
Paul H. Ginsburg
Pfizer Inc
235 East 42nd Street, 20th Floor
New York
NY
10017-5755
US
|
Family ID: |
25091318 |
Appl. No.: |
09/935903 |
Filed: |
August 23, 2001 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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09935903 |
Aug 23, 2001 |
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09438712 |
Nov 11, 1999 |
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6303633 |
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09438712 |
Nov 11, 1999 |
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08957639 |
Oct 24, 1997 |
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6124321 |
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08957639 |
Oct 24, 1997 |
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08689745 |
Aug 13, 1996 |
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5965574 |
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08689745 |
Aug 13, 1996 |
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08211044 |
Mar 9, 1994 |
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5574046 |
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08211044 |
Mar 9, 1994 |
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PCT/US92/07230 |
Aug 31, 1992 |
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Current U.S.
Class: |
514/249 ;
514/258.1; 514/260.1; 514/263.1; 514/303; 514/321; 514/322; 540/1;
544/277; 544/350; 546/118; 546/119; 546/198 |
Current CPC
Class: |
C07D 417/14 20130101;
A61P 21/00 20180101; C07D 401/06 20130101; C07D 405/06 20130101;
A61P 25/02 20180101; C07D 417/06 20130101; C07D 409/06 20130101;
A61P 25/28 20180101 |
Class at
Publication: |
514/249 ;
514/258; 514/266; 514/303; 514/321; 514/322; 540/1; 544/277;
544/350; 546/118; 546/198; 546/119 |
International
Class: |
A61K 031/52; A61K
031/519; C07F 001/00; C07D 473/00; C07D 471/02 |
Claims
1. A compound of the formula 15wherein one of R.sup.2, R.sup.3 and
the side chain containing 16may optionally be attached to the
carbon atom designated by an asterisk in ring B rather than to a
member of ring A; ring A is benzo, thieno, pyrido, pyrazino,
pyrimido, furano, seleno, pyrrolo, thiazolo, or imidazolo; R.sup.1
is phenyl, phenyl-(C.sub.1-C.sub.6)alkyl, cinnamyl or
heteroarylmethyl, wherein the heteroaryl moiety of said
heteroarylmethyl is selected from imidazolo, thiazolo, thieno,
pyrido and isoxazolo, and wherein said phenyl and said heteroaryl
moiety may optionally be substituted with one or two substituents
independently selected from (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy and halo; R.sup.2 and R.sup.3 are
independently selected from hydrogen, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl optionally substituted with from one to
three fluorine atoms, benzyloxy, hydroxy, phenyl, benzyl, halo,
nitro, cyano, COOR.sup.4, CONHR.sup.4, NR.sup.4R.sup.5,
NR.sup.4COR.sup.5, or SO.sub.pCH.sub.2-phenyl wherein p is 0, 1 or
2; or R.sup.2 and R.sup.3 are attached to adjacent carbon atoms and
form, together with the carbons to which they are attached, a five
or six membered ring wherein each atom of the ring is carbon,
nitrogen or oxygen (e.g., a methylenedioxy, ethylenedioxy or lactam
ring); R.sup.4 and R.sup.5 are independently selected from hydrogen
and (C.sub.1-C.sub.6)alkyl, or R.sup.4 and R.sup.5, when part of
said NR.sup.4R.sup.5, optionally form, together with the nitrogen
to which they are attached, a ring containing four to eight members
wherein one atom of the ring is nitrogen and the others are carbon,
oxygen or nitrogen, or R.sup.4 and R.sup.5, when part of said
NR.sup.4COR.sup.5, optionally form, together with the nitrogen and
carbon to which they are attached, a four to eight membered lactam
ring; X is nitrogen or CH; Y is oxygen, sulfur or NR.sup.6; R.sup.6
is hydrogen, (C.sub.1-C.sub.6)alkyl, CO(C.sub.1-C.sub.6)alkyl or
SO.sub.2--, phenyl, wherein the phenyl moiety of said
SO.sub.2-phenyl may optionally be substituted with from one to five
substituents independently selected from (C.sub.1-C.sub.4) alkyl; n
is an integer from 1 to 4; each q is independently 1 or 2; and Z is
oxygen or sulfur; with the proviso that any CH.sub.q group wherein
q is 1 must be attached to one and only one other CH.sub.q group
wherein q is 1; or a pharmaceutically acceptable salt of such
compound.
2. A compound according to claim 1, having the formula 17wherein X
is CH, CCH.sub.3 or N; Y is NH, NCH.sub.3, NCH.sub.2CH.sub.3, S, O
or NSO.sub.2C.sub.6H.sub.5; R.sup.2 and R.sup.3 are independently
selected from the group consisting of (C.sub.1-C.sub.4)alkyl,
chloro, fluoro, methoxy, amino and 18or R.sup.2 and R.sup.3,
together with the carbons to which they are attached, form a
.gamma.-lactam ring; and R.sup.1 is benzyl, methoxybenzyl,
fluorobenzyl or a group of the formula 19wherein W is hydrogen,
(C.sub.1-C.sub.6)alkyl, phenyl or benzyl.
3. A compound according to claim 2, wherein X is CH, CCH.sub.3 or
N; Y is NH, NCH.sub.3, sulfur or oxygen; R.sup.2 and R.sup.3 are
independently selected from the group consisting of
(C.sub.1-C.sub.4)alkyl, chloro, fluoro, methoxy, amino and 20and
R.sup.1 is benzyl.
4. A compound according to claim 3, wherein R.sup.2 and R.sup.3 are
independently selected from the group consisting of
(C.sub.1-C.sub.4)alkyl, chloro, amino and 21
5. A compound according to claim 1, selected from the group
consisting of:
1-(2-methyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-pr-
opanone hydrochloride;
1-(2-phenyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethy-
l)-4-piperidinyl]-1-propanone hydrochloride;
1-(1-ethyl-2-methyl-1H-benzim-
idazol-5-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone
hydrochloride;
1-(2-methyl-6-benzothiazolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propan-
one hydrochloride;
1-(2-methyl-6-benzothiazolyl)-3-[1-((2-methyl-4-thiazol-
yl)methyl)-4-piperidinyl]-1-propanone;
1-(5-methyl-benzo[b]thien-2-yl)-3-[-
1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(6-methyl-benzo[b]thien-2-y-
l)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(3,5-dimethyl-benzo[b-
]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(benzofuran-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(1-phenylsulfonyl-6-methyl-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidiny-
l]-1-propanone;
1-(6-methyl-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-
-1-propanone;
1-(1-phenylsulfonyl-5-amino-indol-2-yl)-3-[1-(phenylmethyl)--
4-piperidinyl]-1-propanone;
1-(5-amino-indol-2-yl)-3-[1-(phenylmethyl)-4-p-
iperidinyl]-1-propanone; and
1-(5-acetylamino-indol-2-yl)-3-[1-(phenylmeth-
yl)-4-piperidinyl]-1-propanone.
6. A pharmaceutical composition for enhancing memory or treating or
preventing Alzheimer's disease comprising a compound according to
claim 1 and a pharmaceutically acceptable carrier.
7. A pharmaceutical composition for inhibiting cholinesterase in a
mammal, comprising a compound according to claim 1 and a
pharmaceutically acceptable carrier.
8. A method of inhibiting cholinesterase in a mammal, comprising
administering to a mammal a cholinesterase inhibiting amount of a
compound according to claim 1.
9. A method of enhancing memory or treating or preventing
Alzheimer's disease, comprising administering to a patient a memory
enhancing effective amount of a compound according to claim 1.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to heteroaryl amines of the
formula I below, and pharmaceutically acceptable salts of such
compounds. The compounds of formula I are acetylcholinesterase
inhibitors and are useful in enhancing memory in patients suffering
from dementia and Alzheimer's disease.
[0002] Alzheimer's disease is associated with degeneration of
cholinergic neurons in the basal forebrain that play a fundamental
role in cognitive functions, including memory. Becker et al., Drug
Development Research, 12, 163-195 (1988). As a result of such
degeneration, patients suffering from the disease exhibit a marked
reduction in acetylcholine synthesis, choline acetyltransferase
activity, acetylcholinesterase activity and choline uptake.
[0003] It is known that acetylcholinesterase inhibitors are
effective in enhancing cholinergic activity and useful in improving
the memory of Alzheimer's patients. By inhibiting
acetylcholinesterase enzyme, these compounds increase the level of
the neurotransmitter acetylcholine, in the brain and thus enhance
memory. Becker et al., supra, report that behavioral changes
following cholinesterase inhibition appear to coincide with
predicted peak levels of acetylcholine in the brain. They also
discuss the efficacy of the three known acetylcholinesterase
inhibitors physostigmine, metrifonate, and
tetrahydroaminoacridine.
[0004] U.S. patent application Ser. No. 07/639,614, filed Jan. 10,
1991, and U.S. patent application Ser. No. 07/676,918, filed Mar.
28, 1991, both of which are assigned in common with the present
application, also refer to heteroaryl amine acetylcholinesterase
inhibitors.
SUMMARY OF THE INVENTION
[0005] The present invention relates to compounds of the formula
2
[0006] wherein one of R.sup.2, R.sup.3 and the side chain
containing 3
[0007] may optionally be attached to the carbon atom designated by
an asterisk in ring B rather than to a member of ring A;
[0008] ring A is benzo, thieno, pyrido, pyrazino, pyrimido, furano,
seleno, pyrrolo, thiazolo, or imidazolo;
[0009] R.sup.1 is phenyl, phenyl-(C.sub.1-C.sub.6)alkyl, cinnamyl
or heteroarylmethyl, wherein the heteroaryl moiety of said
heteroarylmethyl is selected from imidazolo, thiazolo, thieno,
pyrido and isoxazolo, and wherein said phenyl and said heteroaryl
moiety may optionally be substituted with one or two substituents
independently selected from (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy and halo;
[0010] R.sup.2 and R.sup.3 are independently selected from
hydrogen, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl
optionally substituted with from one to three fluorine atoms,
benzyloxy, hydroxy, phenyl, benzyl, halo, nitro, cyano, COOR.sup.4,
CONHR.sup.4, NR.sup.4R.sup.5, NR.sup.4COR.sup.5, or
SO.sub.pCH.sub.2-phenyl wherein p is 0, 1 or 2;
[0011] or R.sup.2 and R.sup.3 are attached to adjacent carbon atoms
and form, together with the carbons to which they are attached, a
five or six membered ring wherein each atom of the ring is carbon,
nitrogen or oxygen (e.g., a methylenedioxy, ethylenedioxy or lactam
ring);
[0012] R.sup.4 and R.sup.5 are independently selected from hydrogen
and (C.sub.1-C.sub.6)alkyl, or R.sup.4 and R.sup.5, when part of
said NR.sup.4R.sup.5, optionally form, together with the nitrogen
to which they are attached, a ring containing four to eight members
wherein one atom of the ring is nitrogen and the others are carbon,
oxygen or nitrogen, or R.sup.4 and R.sup.5, when part of said
NR.sup.4COR.sup.5, optionally form, together with the nitrogen and
carbon to which they are attached, a four to eight membered lactam
ring;
[0013] X is nitrogen or CH;
[0014] Y is oxygen, sulfur or NR.sup.6;
[0015] R.sup.6 is hydrogen, (C.sub.1-C.sub.6)alkyl,
CO(C.sub.1-C.sub.6)alkyl or SO.sub.2--, phenyl, wherein the phenyl
moiety of said SO.sub.2-phenyl may optionally be substituted with
from one to five substituents independently selected from
(C.sub.1-C.sub.4) alkyl;
[0016] n is an integer from 1 to 4;
[0017] each q is independently 1 or 2; and
[0018] Z is oxygen or sulfur;
[0019] with the proviso that any CH.sub.q group wherein q is 1 must
be attached to one and only one other q group wherein q is 1.
[0020] The present invention also relates to the pharmaceutically
acceptable acid addition salts of compounds of the formula I.
Examples of such pharmaceutically acceptable acid addition salts
are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaric
acid, maleic acid, citric acid, succinic acid, salicylic acid,
oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic
acid, tartaric acid, di-p-toluoyl tartaric acid, and mandelic
acid.
[0021] This invention further relates to a pharmaceutically
composition for inhibiting acetylcholinesterase comprising a
compound of the formula I or a pharmaceutically acceptable acid
addition salt thereof, and a pharmaceutically acceptable
carrier.
[0022] The invention further relates to a method for inhibiting
acetylcholinesterase in a mammal comprising administering to a
mammal an amount of a compound of the formula I or a
pharmaceutically acceptable acid addition salt thereof effective in
inhibiting acetylcholinesterase.
[0023] The invention further relates to a method for enhancing
memory or treating or preventing Alzheimer's disease in a mammal
comprising administering to a mammal an amount of a compound of the
formula I or a pharmaceutically acceptable acid addition or salt
thereof effective in enhancing memory or treating or preventing
Alzheimer's disease.
[0024] The term "mammal", as used herein, includes humans.
[0025] The term "halo", as used herein, includes chloro, bromo or
fluoro.
[0026] Preferred compounds of this invention are compounds of the
formula 4
[0027] wherein X is CH, CCH.sub.3, CCH.sub.2CH.sub.3 or N; Y is NH,
NCH.sub.3, NCH.sub.2CH.sub.3, S, O or NSO.sub.2C.sub.6H.sub.5;
R.sup.2 and R.sup.3 are independently selected from the group
consisting of (C.sub.1-C.sub.4) alkyl, chloro, fluoro, methoxy,
amino and 5
[0028] or R.sup.2 and R.sup.3, together with the carbons to which
they are attached, form a .gamma.-lactam ring; and R.sup.1 is
benzyl, methoxybenzyl, fluorobenzyl or a group of the formula 6
[0029] wherein W is hydrogen, (C.sub.1-C.sub.6)alkyl, phenyl or
benzyl.
[0030] Specific preferred compounds of the invention are:
[0031]
1-(2-methyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethyl)-4-piperidinyl-
]-1-propanone;
[0032]
1-(2-phenyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethyl)-4-piperidinyl-
]-1-propanone;
[0033]
1-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethyl)-4-pip-
eridinyl]-1-propanone;
[0034]
1-(2-methyl-6-benzothiazolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1--
propanone;
[0035]
1-(2-methyl-6-benzothiazolyl)-3-[1-[(2-methyl-4-thiazolyl)methyl]-4-
-piperidinyl]-1-propanone;
[0036]
1-(5-methyl-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]--
1-propanone;
[0037]
1-(6-methyl-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]--
1-propanone;
[0038]
1-(3,5-dimethyl-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidin-
yl]-1-propanone;
[0039]
1-(benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propano-
ne;
[0040]
1-(benzofuran-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
[0041]
1-(1-phenylsulfonyl-6-methyl-indol-2-yl)-3-[1-(phenylmethyl)-4-pipe-
ridinyl]-1-propanone;
[0042]
1-(6-methyl-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propan-
one;
[0043]
1-(1-phenylsulfonyl-5-amino-indol-2-yl)-3-[1-(phenylmethyl)-4-piper-
idinyl]-1-propanone;
[0044]
1-(5-amino-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propano-
ne; and
[0045]
1-(5-acetylamino-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-p-
ropanone.
[0046] Examples of other compounds of the invention are:
[0047]
1-(6-quinolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
[0048]
1-(5-indolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
[0049]
1-(5-benzthienyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
[0050]
1-(6-quinazolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
[0051]
1-(6-benzoxazolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
[0052]
1-(5-benzofuranyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
[0053]
1-(5-methyl-benzimidazol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-
-propanone;
[0054]
1-(6-methyl-benzimidazol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-
-propanone;
[0055]
1-(5-chloro-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]--
1-propanone;
[0056]
1-(5-azaindol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
[0057]
1-(6-azabenzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-pr-
opanone;
[0058]
1-(1H-2-oxo-pyrrolo[2',3',5,6]benzo[b]thieno-2-yl)-3-[1-(phenylmeth-
yl)-4-piperidinyl]-1-propanone;
[0059]
1-(6-methyl-benzothiazol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-
-propanone;
[0060]
1-(6-methoxy-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propa-
none;
[0061]
1-(6-methoxy-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-
-1-propanone;
[0062]
1-(6-acetylamino-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidi-
nyl]-1-propanone; and
[0063]
1-(5-acetylamino-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidi-
nyl]-1-propanone.
[0064] Formula I above includes compounds identical to those
depicted but for the fact that one or more hydrogen, nitrogen or
carbon atoms are replaced by isotopes thereof (e.g., tritium,
carbon-14 or nitrogen-15 isotopes). Such compounds are useful as
research and diagnostic tools in metabolism pharmacokinetic studies
and in binding assays.
[0065] The compounds of formula I may have optical centers and may
therefore occur in different isomeric forms. The invention includes
all isomers of such compounds having formula I, including mixtures
thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0066] The preparation of compounds having the formula I is
illustrated in the following reaction schemes. Except where
otherwise stated, in the reaction schemes and discussion that
follow, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, n, q,
p, X, Y and Z and structural formula I are defined as above.
[0067] The symbol * (i.e., the asterisk) that appears in several of
the structures in the reaction schemes represents, for each
structure in which it appears, that the side chain containing the
7
[0068] group may optionally be attached to the carbon atom
designated by the asterisk rather than to a member of ring A.
[0069] All articles, books, patents and patent applications cited
in the following discussion are incorporated herein by reference. 8
9 10 11 12
[0070] Scheme I illustrates a method of preparing compounds of the
formula I wherein Z is oxygen and the side chain containing 13
[0071] is attached to the carbon atom designated by an asterisk in
ring B (hereinafter referred to as compounds of the formula
I-A).
[0072] The starting materials having the formulae II and III are
either commercially available or obtainable by synthetic procedures
reported in the literature. (See J. Med. Chem., 33, 2777 (1990);
Tetrahedron Letters, 30, 6117 (1989); Eur. J. Med. Chem., 25, 191
(1990); Heterocycles, 29, 849 (1989); J. Org. Chem., 47, 757
(1982); J. Org. Chem., 54, 4350 (1989); Tetrahedron, 44, 3195
(1988); Zur, J. Med. Chem. & Chim. Ther., 21, 223 (1986); Chem.
Ber., 88, 34 (1954); Tetrahedron, 28, 2553 (1972); J. Chem. Soc.
(C), 1733 (1968); U.S. Pat. No. 4,902,694; J. Heterocyclic Chem.,
25, 1271 (1988); Bull. Chem. Soc. Jpn., 58, 785 (1986); J.Ind.
Chem. Soc., 12, 561 (1975); and Synthetic Communication, 14, 947
(1984).
[0073] Referring to scheme 1, a compound of the formula I: is
reacted with the appropriate compound of formula III in the
presence of a base to form the corresponding compound of the
formula IV. This reaction is usually performed in an appropriate
reaction inert solvent at a temperature from about -78.degree. C.
to about room temperature, preferably from about -78.degree. C. to
about 0.degree. C. Suitable solvents include tetrahydrofuran (THF),
ether, toluene, methylene chloride, benzene and dioxane. Suitable
bases include lithium bis(trimethylsilyl)amide, lithium
diisopropylamide, sodium diisopropylamide, sodium
bis(trimethylsilyl)amid- e, n-butyllithium (n-BuLi), s-butyllithium
(s-BuLi) and t-butyllithium (t-BuLi).
[0074] The compound of formula IV formed in the foregoing step is
then converted into the corresponding compound of formula I-A by
reacting it with an oxidizing agent. Examples of oxidizing agents
that may be used are manganese dioxide, chromium trioxide and
selenium dioxide. Manganese dioxide is preferred. Generally, the
oxidation is conducted in a reaction inert solvent at a temperature
from about room temperature to about 80.degree. C., preferably from
about 50.degree. C. to about 80.degree. C. Examples of suitable
solvents are methylene chloride, chloroform, ethyl acetate, benzene
and toluene. Preferably, the solvent is methylene chloride or
benzene.
[0075] Scheme 2 illustrates a method of preparing compounds of the
formula I wherein Z is oxygen and n is 2, 3 or 4 (hereinafter
referred to as compounds of the formula I-A') and compounds of the
formula I wherein n is 2, 3 or 4 and the (CH.sub.q).sub.a group
contains at least one carbon-carbon double bond (hereinafter
referred to as compounds of the formula I-B). Referring to scheme
2, the starting materials having the formulas V and VI can be
obtained commercially or prepared as described in the literature.
(See J. Org. Chem., 54, 4350 (1989); Tetrahedron, 44, 3195 (1988);
Chem. Pharm. Bull., 39, 181 (1991); Chem. Ber., 119, 2069 (1986);
and J. Ind. Chem. Soc., 12, 561 (1975).
[0076] As shown in scheme 2, a compound of the formula V is reacted
with an aldehyde of the formula VI in the presence of a base to
form the corresponding compound of formula VII. Suitable bases for
this reaction include sodium hydride, lithium
bis(trimethylsilyl)amide, piperidine, pyrrolidine, lithium
diisopropylamide, sodium diisopropylamide, n-butyllithium and
s-butyllithium. The reaction is usually carried out in a reaction
inert solvent such as THF, dimethylformamide (DMF), dioxane,
toluene, methylene chloride or ether, with THF, ether or toluene
being preferred. The reaction temperature may range from about
-78.degree. C. to about 40.degree. C. and is preferably about
-78.degree. C. to about 0.degree. C.
[0077] If the reaction between compounds of the formulae V and VI
is conducted in the presence of a sodium or potassium
(C.sub.1-C.sub.5)alkoxide, it is preferable to use toluene, DMF,
THF or methylene chloride as the solvent, with or without a
(C.sub.1-C.sub.4) alcohol, and to conduct the reaction at a
temperature from about -40.degree. C. and 80.degree. C., more
preferably from about 0.degree. C. to about room temperature.
[0078] Subjecting the compound of formula VII so formed to an
elimination reaction yields the corresponding compound of formula
I-B. The elimination is typically carried out by reacting the
compound of formula VII, in the presence of a base, with a reagent
capable of forming a leaving group upon reaction with the hydroxy
group of formula VII. Appropriate reagents include acetic
anhydride, R.sup.7SO.sub.2Cl, R.sup.7COCl, R.sup.7OCOCl and
R.sup.7NCO, wherein R.sup.7 is selected from (C.sub.1-C.sub.4)
alkyl or phenyl optionally substituted with (C.sub.1-C.sub.6)
alkyl, (C.sub.1-C.sub.4) alkoxy or nitro. Examples of suitable
bases are triethylamine, diisopropylethylamine,
diazabicycloundecane (DBU) and diazabicyclononanone. The solvent
can be any reaction inert solvent (e.g., methylene chloride,
chloroform, THF or toluene). The reaction temperature can range
from about 0.degree. C. to about 60.degree. C., and is preferably
about 0.degree. C. to about room temperature.
[0079] Alternatively, compounds of the formula I-B may be prepared
by reacting the appropriate compound of formula VII with the
Burgess Inner salt. The Burgess Inner salt may be prepared from
chlorosulfonyl isocyanate, methanol and triethylamine, as described
in J. Amer. Chem. Soc., 90, 4744 (1968). Generally, this reaction
is carried out in an inert solvent such as THF, ether, benzene,
toluene or dioxane, preferably THF at a temperature from about room
temperature to about the reflux temperature of the solvent,
preferably from about 50.degree. C. to about 80.degree. C.
[0080] The corresponding compound of the formula I-A' is then
prepared by hydrogenation of the compound of formula I-B formed in
the above step. Generally, the hydrogenation is accomplished using
platinum dioxide or palladium on carbon at a pressure of about 30
psi to about 50 psi. Suitable reaction inert solvents include THF,
methanol, ethanol, ethyl acetate and mixtures thereof. Preferably,
the solvent is a mixture of ethanol and THF or a mixture of ethanol
and ethyl acetate. The reaction temperature may range from about
0.degree. C. to about 60.degree. C. The preferred temperature is
about room temperature.
[0081] The preparation of compounds having the formulae I-C and I-D
are illustrated in scheme 3. Compounds of the formula I-C are those
compounds of the formula I wherein ring A is benzo, Y is NR.sup.6,
R.sup.6 is hydrogen, X is nitrogen, R.sup.3 is hydrogen and R.sup.2
is attached to the carbon atom designated with an asterisk (*) in
ring B. Compounds of the formula I-D are those compounds of the
formula I wherein ring A is benzo, Y is NR.sup.6, R.sup.6 is other
than hydrogen, X is nitrogen, R.sup.3 is hydrogen and R.sup.2 is
attached to the carbon atom designated with an asterisk (*) in ring
B.
[0082] Referring to scheme 3, the reaction of a compound of the
formula IX with an aldehyde of the formula X to produce a compound
of the formula XI is carried out using the procedure depicted in
scheme 2 and described above for reaction steps
V.fwdarw.VII.fwdarw.I-B.fwdarw.I-A'.
[0083] The resulting compound of formula XII is then cyclized in
the presence of an acid to afford the corresponding compound of the
formula I-C. Examples of acids that may be used are acetic acid, a
mixture of acetic acid and a (C.sub.1-C.sub.4)-alcohol,
hydrochloric acid and ether saturated with hydrogen chloride. This
reaction is generally conducted at a temperature from about room
temperature to about 120.degree. C. Temperatures from about
60.degree. C. to about 90.degree. C. are preferred.
[0084] An R.sup.6 group may be added to the compound of formula I-C
to obtain the corresponding compound having the formula I-D by
reacting the appropriate compound of formula I-C with a compound of
the formula R.sup.6L, wherein L is a leaving group. This reaction
is typically carried out in an inert solvent in the presence of a
base at a temperature from about -78.degree. C. to about the reflux
temperature of the solvent. Suitable bases include sodium hydride,
lithium diisopropylamide, t-butyllithium and potassium t-butoxide.
Suitable solvents include THF, methylene chloride, benzene, ether,
toluene or dioxane. The reaction is preferably conducted in THF in
the presence of sodium hydride at a temperature from about
0.degree. C. to about 30.degree. C.
[0085] Scheme 4 illustrates the preparation of compounds of the
formula I wherein Z is sulfur (hereinafter referred to as compounds
of the formula I-F) from compounds of the formula I-E. This
transformation is accomplished by reacting the compound of formula
I-E with Lawesson's Reagent
(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulf-
ide) or phosphorus pentasulfide (P.sub.2S.sub.5). Typically, this
reaction is conducted in a reaction inert solvent such as THF,
acetonitrile, chloroform or toluene at a temperature from about
room temperature to about 110.degree. C. It is preferably conducted
in THF or toluene at a temperature from about 60.degree. C. to
about 80.degree. C.
[0086] Compounds of the formula I wherein R.sup.1 is other than
benzyl may be prepared from the corresponding compounds of the
formula I wherein R.sup.1 is benzyl (hereinafter referred to as
compounds of the formula I-G) as described below and illustrated in
scheme 5.
[0087] First, a compound of the formula I-G is reacted with a
chloroformate of the formula 14
[0088] wherein R.sup.9 is --ClCHCH.sub.3, --CH.sub.2CH.sub.3 or
--CH.sub.2C.sub.6H.sub.5. The preferred reactant is 1-chloroethyl
chloroformate. This reaction, which affords the corresponding
compound of the formula XIV, is generally carried out in a reaction
inert solvent such as methylene chloride, chloroform,
dichloroethane, THF or toluene, preferably toluene, at a
temperature from about 60.degree. C. to about 100.degree. C.,
preferably from about 80.degree. C. to about 85.degree. C.
[0089] Heating the compound of formula XIV so formed in a
(C.sub.1-C.sub.4) alcohol, preferably methanol or ethanol, yields
the corresponding compound of the formula XV. The reaction
temperature may range from about 80.degree. C. to about the reflux
temperature of the solvent and is preferably about the reflux
temperature of the solvent.
[0090] The compound of the formula XV formed in the foregoing step
is then alkylated and thus converted into the corresponding
compound of formula I by reacting it with a compound of the formula
R.sup.1L, wherein L is a leaving group, in the presence of a base.
Examples of suitable leaving groups are chloro, bromo, iodo,
mesylate, tosylate and triflate (OTf). Suitable bases include
pyridine, triethylamine, dimethylaminopyridine and potassium
carbonate. Triethylamine is preferred. Generally, the alkylation is
carried out in a reaction inert solvent such as methylene chloride
or DMF, at a temperature from about 0.degree. C. to about
100.degree. C., preferably from about room temperature to about
60.degree. C.
[0091] In each of the above reactions, pressure is not critical.
Pressures in the range of about 0.5 atm to 3 atm are suitable, and
ambient pressure (generally, about one atmosphere) is preferred as
a matter of convenience. Also, for those reactions where the
preferred temperature varies with the particular compounds reacted,
no preferred temperature is stated. For such reactions, preferred
temperatures for particular reactants may be determined by
monitoring the reaction using thin layer chromatography.
[0092] The compounds of the invention may be administered to a
patient by various methods, for example, orally as capsules or
tablets, parentally as a sterile solution or suspension, and in
some cases, intravenously in the form of a solution. The free base
compounds of the invention may be formulated and administered in
the form of their pharmaceutically acceptable acid addition
salts.
[0093] The daily dose of the compounds of the invention is
generally in the range of from about 1 to 300 mg/day for the
average adult human, and may be administered in single or divided
doses.
[0094] When incorporated for parenteral administration into a
solution or suspension, the compounds of the invention are present
in a concentration of at least 1 weight percent, and preferably
between about 4-70 weight percent (based on the total weight of the
unit). The parenteral dosage unit typically contains between about
5 to 100 mg of active compound(s).
[0095] Compounds of thy present invention may be administered
orally with an inert diluent or an edible carrier, or they may be
enclosed in gelatin capsules or compressed into tablets. Such
preparations should contain at least 0.5% of active compound(s),
but the concentration may vary depending upon the particular form
and may be from 4 to 70 weight percent (based on the total weight
of the unit). The oral dosage unit typically contains between 1.0
mg to 300 mg of active compound.
[0096] The activity of the compounds of the present invention as
acetylcholinesterase inhibitors may be determined by a number of
standard biological or pharmacological tests. One such procedure
for determining cholinesterase inhibition is described by Ellman et
al. in "A New and Rapid Colorimetric Determination of
Acetylcholinesterase Activity", Biochem. Pharm. 1, 88, (1961).
[0097] The present invention is illustrated by the following
examples. It will be understood, however, that the invention is not
limited to the specific details of these examples. Melting points
are uncorrected. Proton nuclear magnetic resonance spectra (.sup.1H
NMR) and C.sup.13 nuclear magnetic resonance spectra (C.sup.13 NMR)
were measured for solutions in deuterochloroform (CDCl.sub.3) and
peak positions are expressed in parts per million (ppm) downfield
from tetramethylsilane (TMS). The peak shapes are denoted as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; b, broad.
Example 1
1-[2-(5-Methyl-benzothienyl)]-3-[1-(phenylmethyl)-4-piperidinyl]-2-propen--
1-ol
[0098] A solution of 5-methyl-benzothiophene (356 mg, 2.4 mmol) in
10 ml of dry tetrahydrofuran (THF) was treated with n-butyllithium
(n-BuLi) at -10.degree. C. and the mixture was stirred at room
temperature for 30 minutes. A solution of
3-[4-(N-benzylpiperidinyl)]propenal (550 mg, 2.4 mmol) in 5 ml of
dry tetrahydrofuran (THF) was added to the reaction mixture at room
temperature. After stirring for 30 minutes, the mixture was
quenched with water and extracted with chloroform. The organic
layer was dried and concentrated to give 750 mg (90%) of desired
product.
[0099] .sup.1H NMR (CDCl.sub.3) .delta. 1.3-2.1 (m, 7H), 2.3-2.5
(m, 3H), 2.7-3.0 (m, 2H), 3.47 (s, 2H), 5.37 (d, 1H), 5.6-5.8 (m,
2H), 7.0-7.7 (m, 9H) ppm.
[0100] The title compounds of Examples 2-4 were prepared by a
method analogous to that described in Example 1.
Example 2
1-[2-(6-Methyl-benzothienyl)]-3-[1-(phenylmethyl)-4-piperidinyl]-2-propen--
1-ol
[0101] .sup.1H NMR (CDCl.sub.3) .delta. 1.3-2.0 (m, 7H), 2.4 (s,
3H), 2.8-2.95 (m, 2H), 3.45 (s, 2H), 5.35 (d, 1H), 5.6-5.8 (m, 2H),
7.0-7.6 (m, 9H) ppm.
Example 3
1-[2-(2,5-Dimethyl-benzothienyl]-3-[1-(phenylmethyl)-4-piperidinyl]-2-prop-
en-1-ol
[0102] .sup.1H NMR (CDCl.sub.3) .delta. 1.35-2.0 (m, 7H), 2.3 (s,
3H), 2.5 (s, 3H), 2.8-2.9 (m, 2H), 3.5 (s, 2H), 3.7-3.8 (m, 1H),
5.5-5.9 (m, 3H), 7.0-7.8 (m, 8H) ppm.
Example 4
1-(2-Benzothienyl)-3-[1-(phenylmethyl)-4-piperidinyl]-2-propen-1-ol
[0103] .sup.1H NMR (CDCl.sub.3) .delta. 1.3-2.0 (m, 7H), 2.7-2.9
(m, 2H), 3.45 (s, 2H), 5.4 (d, 1H), 5.6-5.8 (m, 2H), 7.1 (s, 1H)
7.2-7.3 (m, 7H), 7.65 (dd, 1H), 7.72 (dd, 1H) ppm.
Example 5
5-Methyl-benzothien-2-yl-2-[1-(phenylmethyl)-4-piperidinyl]vinyl
Ketone
[0104] A solution of crude
1-[2-(5-methyl-benzothienyl)]-3-[1-(phenylmethy-
l)-4-piparidinyl]-2-propen-1-ol (750 mg, 2.16 mmol) from Example 1
in 30 ml of benzene was treated with manganese dioxide (1.8 g, 20.7
mmol), and the resulting suspension was heated to reflux for 2
hours. The mixture was cooled to room temperature and filtered
through Celite.RTM.. The filtrate was concentrated to dryness to
give 602 mg of a crude brown semi-solid.
[0105] .sup.1H NMR (CDCl.sub.3) .delta. 1.4-1.9 (m, 4H), 2.0 (dt,
2H), 2.15-2.3 (m, 1H), 2.4 (s, 3H), 2.8-3.0 (m, 2H), 3.5 (s, 2H),
6.8 (s, 0.4H), 6.85 (s, 0.6H), 7.0-7.18 (m, 1H), 7.2-7.9 (m, 9H)
ppm.
[0106] The title compounds of Examples 6 and 7 were prepared by a
method analogous to that described in Example 5.
Example 6
2,5-Dimethyl-benzothien-2-yl-2-[1-(phenylmethyl)-4-piperidinyl]vinyl
Ketone
[0107] .sup.1H NMR (CDCl.sub.3) .delta. 1.5-2.0 (m, 4H), 2.1 (dt,
2H), 2.2-2.4 (m, 1H), 2.56 (s, 3H), 2.8 (s, 3H), 2.9-3.05 (m, 2H),
3.56 (s, 2H), 6.72 (s, 0.4H), 6.8 (s, 0.6H), 7.06 (d, 0.6H), 7.1
(d, 0.4H), 7.3-7.8 (m, 8H) ppm.
Example 7
Benzothien-2-yl-2-[1-(phenylmethyl)-4-piperidinyl]vinyl Ketone
[0108] .sup.1H NMR (CDCl.sub.3) .delta. 1.4-1.9 (m, 4H), 1.95-2.1
(dt, 2H), 2.2-2.35 (m, 1H), 2.8-3.0 (m, 2H), 3.54 (s, 2H), 6.86 (s,
0.4H), 6.9 (s, 0.6H), 7.1 (d, 0.6H), 7.15 (d, 0.4H), 7.2-8.0 (m,
10H) ppm.
Example 8
1-(5-Methyl-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propa-
none
[0109] A solution of crude 5-methyl-benzothien-2-yl
2-[1-(phenylmethyl)-4-piperidinyl)]vinyl ketone from Example 5 (600
mg, 1.6 mmol) in a mixture of ethanol (20 ml) and ethyl acetate (40
ml) was treated with platinum oxide (PtO.sub.2) (60 mg) and
hydrogenated at 50 psi for 2 hours. (Thin layer chromatography
indicated that the reaction was not complete). An additional 45 mg
of PtO.sub.2 was added and the mixture was hydrogenated for an
additional 1 hour. The mixture was filtered through Celite.RTM. and
the filtrate was concentrated to dryness and purified through
chromatography using chloroform to 2% methanol in chloroform as
eluent to give 232 mg of the title compound.
[0110] .sup.1H NMR (CDCl.sub.3) .delta. 1.2-2.1 (m, 9H), 2.52 (s,
3H), 2.9-3.0 (m, 2H), 3.05 (t, 2H), 3.52 (s, 2H), 7.2-7.4 (m, 6H),
7.7 (s, 1H), 7.75 (d, 1), 7.9 (s, 1H) ppm.
[0111] The title compounds of Examples 9-11 were prepared by a
method analogous to that described in Example 8.
Example 9
1-(6-Methyl-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propa-
none
[0112] .sup.1H NMR (CDCl.sub.3) .delta. 1.2-2.05 (m, 9H), 2.5 (s,
3H), 2.7-2.8 (m, 2H), 3.0 (t, 2H), 3.5 (s, 2H), 7.2-7.4 (m, 6H),
7.65 (s, 1H), 7.8 (d, 1H), 7.9 (s, 1H) ppm.
Example 10
1-(3,5-Diethyl-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-pr-
opanone
[0113] .sup.1H NMR (CDCl.sub.3) .delta. 1.2-2.0 (m, 9H), 2.5 (s,
3H), 2.75 (s, 3H), 2.8-3.0 (m, 4H), 3.5 (s, 2H), 7.2-7.8 (m, 8H)
ppm.
Example 11
1-(Benzothien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone
[0114] .sup.1H NMR (CDCl.sub.3) .delta. 1.1-2.0 (m, 9H), 2.8-2.95
(m, 2H), 3.05 (t, 2H), 3.5 (s, 2H), 7.2-7.5 (7H), 7.8-7.9 (m, 2H),
7.95 (s, 1H) ppm.
Example 12
Benzofuran-2-yl-2-[1-(phenylmethyl)-4-piperidinyl]vinyl Ketone
[0115] To a solution of diisopropylamine (0.5 ml, 3.6 mmol) in 15
ml of dry THF was added 2.5 M n-butyllithium (1.3 ml, 3.3 mmol) at
-78.degree. C. After stirring at -78.degree. C. for 20 minutes, a
solution of benzofuran-2-yl methyl ketone (0.48 g, 3 mmol) in 3 ml
of dry THF was added at -78.degree. C. and stirred at that
temperature for 1.5 hours. The mixture was quenched with water and
brine and extracted with ethyl acetate. The organic layer was dried
and concentrated to give 1.117 g of product as an oil. The oil was
dissolved in 15 ml of methylene chloride and treated with mesyl
chloride (0.24 ml, 3 mmol) and triethylamine (0.42 ml, 3 mmol) at
room temperature. The mixture was stirred at room temperature
overnight, then quenched with water and extracted with methylene
chloride. The organic layer was dried and concentrated to give
0.827 g of crude material which was purified through silica gel
column chromatography using chloroform to 5% methanol in chloroform
as eluent to give 430 mg of off-white crystals.
[0116] M.p. 186-188.degree. C.
[0117] .sup.1H NMR (CDCl.sub.3) .delta. 1.8-3.0 (m, 7H), 3.1-3.4
(m, 2H), 4.0 (br s, 2H), 6.9 (s, 0.4H), 6.96 (s, 0.6H), 7.1 (d,
0.6H), 7.15 (d, 0.4H), 7.2-7.7 (m, 10H) ppm.
Example 13
Benzofuran-2-yl-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone
[0118] A solution of benzofuran-2-yl
2-[1-(phenylmethyl)-4-piperidinyl]vin- yl ketone (410 mg) in a
mixture of ethanol (70 ml) and ethyl acetate (40 ml) was treated
with platinum oxide (80 mg) and hydrogenated at 45 psi for 1 hour.
The mixture was filtered through Celite.RTM. and the filtrate was
concentrated to dryness to give an off-white solid which was
recrystallized from ethyl acetate to give 162 mg of white
crystals.
[0119] M.p. 199-200.degree. C.
[0120] .sup.1H NMR (CDCl.sub.3) .delta. 1.4-2.2 (m, 7H), 2.4-2.6
(m, 2H), 2.97 (t, 2H), 3.3-3.5 (m, 2H), 4.1 (AB.sub.q, 2H), 7.1-7.7
(m, 10H) ppm.
Example 14
1-[2-(N-Phenylsulfonyl-6-methyl-indolyl]-3-[1-(phenylmethyl)-4-piperidinyl-
]-2-propen-1-ol
[0121] A solution of N-phenylsulfonyl-6-methyl indole (1.18 g, 4.34
mmol) in 30 ml of dry THF was cooled to -78.degree. C. and treated
with 3.5 ml (5.2 mmol) of 1.5 M lithium diisopropylamide in
cyclohexane at -78.degree. C. After stirring at -78.degree. C. for
1 hour, a solution of 3-[1-(phenylmethyl)-4-piperidinyl]-2-propenal
(1.0 g, 4.36 mmol) in 5 ml of dry THF was added at -78.degree. C.
and stirred at that temperature for 40 minutes. The mixture was
quenched with water and extracted with chloroform. The organic
layer was dried and concentrated to give 2.23 g of an orange oil.
The oil was purified through silica gel column chromatography using
2% methanol in chloroform as eluent to give 1.0 g of the title
compound as a yellow oil.
[0122] .sup.1H NMR (CDCl.sub.3) .delta. 1.4-1.8 (m, 4H), 1.9-2.1
(m, 3H), 2.45 (s, 3H), 2.85-2.95 (m, 2H), 3.3 (br s, 1H), 3.5 (s,
2H), 5.6-5.9 (m, 3H), 6.55 (s, 1H), 7.02 (dd, 1H), 7.2-7.9 (m, 12H)
ppm.
Example 15
N-Phenylsulfonyl-6-methyl-indol-2-yl-2-[1-(phenylmethyl)-4-piperidinyl]vin-
yl Ketone
[0123] A solution of
1-[2-(N-phenylsulfonyl-6-methyl-indolyl)-3-[1-(phenyl-
methyl)-4-piperidinyl]-2-propen-1-ol (1.2 g, 2.4 mmol) in 30 ml of
dry methylene chloride was treated with manganese dioxide
(MnO.sub.2) (1.0 g, 11.5 mmol). The mixture was stirred for 4 hours
under reflux, cooled to room temperature and filtered through
Celite.RTM.. The filtrate was concentrated to give a yellow oil
which was purified through silica gel column chromatography using
chloroform to 2.5% methanol in chloroform as eluent to give 740 mg
(62% yield) of the title compound as a yellow oil.
[0124] .sup.1H NMR (CDCl.sub.3) .delta. 1.4-1.8 (m, 4H), 1.9-2.1
(m, 2H), 2.15-2.3 (m, 1H), 2.5 (s, 3H), 2.85-3.0 (m, 2H), 3.5 (s,
2H), 6.55 (s, 0.45H), 6.65 (s, 0.55H), 6.9 (d, 0.55H), 6.98 (d,
0.45H), 7.0 (s, 1H), 7.1 (d, 1H), 7.25-7.55 (m, 9H), 7.9-8.1 (m,
3H) ppm.
Example 16
1-(1-Phenylsulfonyl-6-methyl-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl-
]-1-propanone
[0125] A solution of
N-phenylsulfonyl-6-methyl-indol-2-yl-2-[1-(phenylmeth-
yl)-4-piperidinyl]vinyl ketone (360 mg, 7.2 mmol) in a mixture of
THF/ethanol (25 ml/25 ml) was treated with platinum oxide
(PtO.sub.2) (40 mg) and hydrogenated at 45 psi for 75 minutes. The
mixture was filtered through Celite.RTM.. The filtrate was
concentrated to dryness to give a dark oil which was purified
though silica gel column chromatography using chloroform as eluent
to give 200 mg of the title compound as a yellow oil.
[0126] .sup.1H NMR (CDCl.sub.3) .delta. 1.2-1.75 (m, 7H), 1.8-2.0
(m, 2H), 2.5 (s, 3H), 2.8-3.0 (m, 4H), 3.5 (s, 2H), 7.0 (s, 1H),
7.1 (d, 1H), 7.2-8.0 (m, 12H) ppm.
Example 17
1-(6-Methyl-indol-2-yl)-3-[1-(phenylmethyl
)-4-piperidinyl]-1-propanone
[0127] A suspension of
N-phenylsulfonyl-6-methyl-indol-2-yl-2-[1-(phenylme-
thyl)-4-piperidinyl]ethyl ketone (150 mg) in 20 ml of methanol was
treated with 1.5 ml of 2N sodium hydroxide (NaOH), heated at reflux
and stirred at that temperature for 70 minutes. The mixture was
quenched with water and extracted with chloroform. The organic
layer was dried and concentrated to give 100 mg of the title
compound as a brown solid.
[0128] .sup.1H NMR (CDCl.sub.3) .delta. 1.2-1.8 (m, 7H), 1.8-2.0
(m, 2H), 2.42 (s, 3H), 2.8-3.0 (m, 4H), 3.5 (s, 2H), 6.95 (d, 1H),
7.1 (s, 1H), 7.2-7.35 (m, 6H), 7.55 (d, 1H) ppm.
Example 18
1-(2-Benzothiazolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-2-propen-1-ol
[0129] A solution of benzothiazole (0.243 g, 1.8 mmol) in 5 ml of
dry THF was treated with 1.5M lithium diisopropylamide in
cyclohexane (1.45 ml) at -78.degree. C. and stirred at that
temperature for 15 minutes. A solution of
3-[1-(phenylmethyl)-4-piperidinyl]propenal (452 mg, 1.97 mol) in 3
ml of dry THF was added at -78.degree. C. and stirred at that
temperature for 30 minutes. The mixture was quenched with water and
extracted with chloroform. The organic layer was dried and
concentrated to give a thick yellow oil in a quantitative
yield.
[0130] .sup.1H NMR (CDCl.sub.3) .delta. 1.6-2.15 (m, 7H), 2.85-3.0
(m, 2H), 3.5 (s, 2H), 5.5 (d, 1H), 5.7-6.1 (m, 2H), 7.2-7.6 (m,
7H), 7.9 (d, 1H), 8.0 (d, 1H) ppm.
Example 19
2-Benzothiazolyl-2-[1-(phenylmethyl)-4-piperidinyl]vinyl Ketone
[0131] A solution of
1-(2-benzothiazolyl)-3-[1-(phenylmethyl)-4-piperidiny-
l]-2-propen-1-ol (654 mg, 1.8 mmol) in 25 ml of methylene chloride
was treated with MnO.sub.2 (0.782 g, 9 mmol) and heated to reflux.
After 3 hours, the mixture was filtered through Celite.RTM. and the
filtrate was concentrated to give 0.655 mg of a dark oil. The oil
was purified through silica gel column chromatography using 2%
methanol in chloroform as eluent to give 0.487 g of an amber oil
which was solidified upon standing overnight.
[0132] .sup.1H NMR (CDCl.sub.3) .delta. 1.5-1.9 (m, 4H), 2.0-2.15
(m, 2H), 2.3-2.5 (m, 1H), 3.5 (s, 2H), 7.2-7.6 (m, 9H); 8.0 (dd,
1H), 8.2 (dd, 1H) ppm.
Example 20
1-(Benzothiazol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone
[0133] A solution of 2-benzothiazolyl
2-[1-(phenylmethyl)-4-piperadinyl]vi- nyl ketone (146 mg, 0.4 mmol)
in a mixture of ethyl acetate/ethanol (10 ml/10 ml) was treated
with PtO.sub.2 (20 mg) and hydrogenated at 50 psi for 3 hours. The
mixture was filtered through Celite.RTM. and the filtrate was
concentrated to dryness to give 0.154 g of a dark oil. The oil was
purified through silica gel column chromatography using chloroform
as eluent to give 37 mg of the title compound as a brown oil.
[0134] .sup.1H NMR (CDCl.sub.3) .delta. 1.2-1.4 (m, 3H), 1.7-1.85
(m, 4H), 1.85-2.1 (m, 2H), 2.8-3.0 (m, 2H), 3.3 (dd, 2H), 3.5 (s,
2H), 7.2-7.4 (m, 5H), 7.45-7.65 (m, 2H), 7.95 (dd, 1H), 8.2 (dd,
1H) ppm.
Example 21
N-Phenylsulfonyl-5-nitroindole
[0135] A solution of 5-nitroindole (1.62 g, 10 mmol) in 30 ml of
dimethylformamide (DMF) was treated with 60% sodium hydride (0.44
g, 11 mmol) at room temperature. After 3 minutes, benzenesulfonyl
chloride (1.766 g, 10 mmol) was added. The mixture was stirred at
room temperature overnight and treated with 250 ml of water. A
precipitate formed and was filtered to give a yellow solid which
was pumped in vacuo to give 2.7 g (89%) of the title compound.
[0136] .sup.1H NMR (CDCl.sub.3) .delta. 6.82 (d, 1H), 7.45-7.55 (m,
2H), 7.6 (d, 1H), 7.72 (d, 1H), 7.9 (m, 2H), 8.1 (d, 1H), 8.2 (dd,
1H), 8.5 (d, 1H) ppm.
Example 22
N-Phenylsulfonyl-5-nitroindol-2-yl-2-[1-(phenylmethyl)-4-piperidinyl]vinyl
Ketone
[0137] A solution of N-phenylsulfonyl-5-nitroindole (646 mg, 2.14
mmol) in 10 ml of dry THF was treated with lithium diisopropylamide
(1.5M in cyclohexane) (1.7 ml, 2.6 mmol) at -78.degree. C. After 1
hour at -78.degree. C., a solution of
3-[4-(N-phenylmethylpiperidinyl)]propenal (490 mg, 2.14 mmol) in 2
ml of dry THF was added at -78.degree. C. After 40 minutes at
-78.degree. C., the mixture was quenched with water and extracted
with methylene chloride. The organic layer was dried and
concentrated to give 1.149 g of a yellow oil. The oil was dissolved
in 30 ml of benzene, treated with MnO.sub.2 (1.86 g, 21.4 mmol) and
heated at reflux for 4 hours. An additional 900 mg of MnO.sub.2 was
added and the mixture was heated at reflux overnight. The mixture
was filtered through Celite.RTM. and the filtrate was concentrated
to give a brown oil which was purified through silica gel column
chromatography using chloroform as eluent to give the title
compound as a brown oil.
[0138] .sup.1H NMR (CDCl.sub.3) .delta. 1.45-1.95 (m, 4H), 1.95-2.1
(m, 2H), 2.15-2.4 (m, 1H), 2.9-3.05 (m, 2H), 3.55 (s, 2H), 6.55 (s,
0.5H), 6.62 (s, 0.5H), 6.98 (d, 0.5H), 7.05 (d, 1H), 7.1 (s, 1H),
7.2-7.4 (m, 4H), 7.5-7.7 (m, 4H), 8.05-8.15 (m, 2H), 8.2-8.4 (m,
2H), 8.5 (d, 1H) ppm.
Example 23
N-Phenylsulfonyl-5-nitroindol-2-yl-2-[1-(phenylmethyl)-4-piperidinyl]ethyl
Ketone
[0139] A solution of N-phenylsulfonyl-5-nitroindol-2-yl
2-[1-(phenylmethyl)-4-piperidinyl]vinyl ketone (187 mg, 0.35 mmol)
in a mixture of ethyl acetate/ethanol (20 ml/8 ml) was treated with
PtO.sub.2 (50 mg) and hydrogenated at 40 psi for 1.5 hours. The
mixture was filtered through Celite.RTM. and the filtrate was
concentrated to give 177 mg (100%) of a brown oil.
[0140] .sup.1H NMR (CDCl.sub.3) .delta. 1.1-2.0 (m, 9H), 2.75-2.9
(m, 2H), 2.92 (t, 2H), 3.42 (s, 2H), 6.68 (d, 1H), 6.72 (dd, 1H),
6.8 (s, 1H), 7.1-7.5 (m, 8H), 7.7-7.9 (m, 3H) ppm.
Example 24
[0141] 5-Nitroindol-2-yl 2-[1-(phenylmethyl)-4-piperidinyl]ethyl
Ketone
[0142] A solution of N-phenylsulfonyl-5-nitroindol-2-yl
2-[1-(phenylmethyl)-4-piperidinyl]ethyl ketone (160 mg, 0.32 mmol)
in 3 ml of methanol and 2 ml of 2N NaOH was heated at reflux for 2
hours. The mixture was concentrated to dryness and the residue was
diluted with brine and extracted with chloroform. The organic layer
was dried and concentrated to dryness to give 144 mg of a brown
solid which was purified through silica gel column chromatography
to give 31 mg of the title compound as a brown solid.
[0143] .sup.1H NMR (CDCl.sub.3) .delta. 1.1-2.0 (m, 9H), 2.8-3.0
(m, 4H), 3.5 (s, 2H), 6.76 (dd, 1H), 6.9 (s, 1H), 6.96 (s, 1H),
7.1-7.3 (m, 6H) ppm.
Example 25
1-(1-Ethyl-2-methyl-1H-benzimidazol-5-yl)-3-[(1-phenylmethyl)-4-piperidiny-
l]-2-propen-1-one
[0144] A mixture of 0.1 g (0.5 mM) of
1-ethyl-2-methylbenzimidazole-5-yl methyl ketone and 0.1 g (0.5 mM)
4-formyl-N-benzylpiperidine in 10 mL of tetrahydrofuran (THF) was
cooled to -78.degree. C. under a nitrogen atmosphere. To this
mixture were added dropwise 0.5 mL (0.5 mM) of a 1M solution of
lithium bis(trimethylsilyl)amide in THF. The reaction was stirred
at -78.degree. C. for 1 hour, then warmed to room temperature. To
the reaction was added 10 mL of water and the pH was adjusted to
2.0 with 1N hydrochloric acid (HCl). The mixture was extracted with
15 mL of ethyl acetate. The pH of the water layer was then
sequentially adjusted to 3.0, 4.0, 5.0, 6.5, and 8.5 with 1N NaOH,
each time extracting with 15 mL of ethyl acetate. The ethyl acetate
extracts at pH=5.0 and 6.5 were combined, dried with sodium sulfate
(Na.sub.2SO.sub.4) and evaporated to yield 50 mg (26%) of the title
compound as an oil.
[0145] Thin layer chromatography (TLC) (10:1
CHCl.sub.3:CH.sub.3OH), R.sub.f=0.58.
[0146] .sup.1H NMR (CDCl.sub.3) .delta. 8.22 (s, 1H), 7.88 (d, 1H),
7.30 (m, 5H), 6.90 (m, 3H), 4.14 (q, 2H), 3.50 (s, 2H), 3.05 (m,
2H), 2.85 (m, 2H), 2.61 (s, 3H), 1.4-2.1 (m, 5H), 1.40 (t, 3H).
Example 26
1-(1-Ethyl-2-methyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethyl)-4-piperidiny-
l]-1-propanone Hydrochloride
[0147] To a solution of the title compound from Example 25 0.14 g
(0.36 mM) in 20 mL of ethanol were added 10 mg of PtO.sub.2 and the
mixture was hydrogenated at 50 psi for 1 hour. The reaction was
filtered and the ethanol solvent evaporated. The residue was
suspended in 50 mL of a 1:1 mixture of ethyl acetate: H.sub.2O, and
the pH adjusted to 8.5 with 1N sodium hydroxide (NaOH). The ethyl
acetate layer was dried (Na.sub.2SO.sub.4) and evaporated to yield
0.1 g (72%) of the free base of the title compound as an oil.
[0148] TLC (10:1 CHCl.sub.3:CH.sub.3OH), R.sub.f=0.64.
[0149] .sup.1H NMR (CDCl.sub.3) .delta. 8.26 (s, 1H), 7.92 (d, 1H),
7.28 (m, 6H), 4.18 (q, 2H), 3.48 (s, 2H), 3.05 (m, 2H), 2.85 (m,
2H), 2.54 (s, 3H), 1.4-2.0 (m, 9H), 1.30 (t, 3H).
[0150] The oil was dissolved in ethyl acetate and to this solution
was added dropwise a solution of HCl dissolved in ether. The
resulting precipitate was filtered and triturated with hexanes to
yield 0.105 g of the title compound as a hygroscopic white
solid.
[0151] M.p.=165-167.degree. C.
[0152] Mass spectrum: 389.2 (p), 298.0 (p-91), 172.0 (p-217), 90.9
(p-298, base peak).
Example 27
1-(2-Methyl-6-benzothiazolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-2-propen--
1-one
[0153] A mixture of 0.191 g (0.001 M) of 2-methyl-6-benzothiazolyl
methyl ketone (prepared as described by S. S. Sawhney, J. Singh,
and O. P. Bansal, J. Ind. Chem. Soc., 12, 561 (1975)) and 0.203 g
(0.001 M) of 4-formyl-N-benzyl piperidine in 5 mL of THF was cooled
to -78.degree. C. under a nitrogen atmosphere. To this solution
were added dropwise 0.73 mL (0.0011 M) of lithium diisopropylamide
(1.5 M solution in THF). The reaction was stirred at -78.degree. C.
for 1 hour and then warmed to 0.degree. C. The reaction was
quenched with 5 mL of water and extracted with ethyl acetate. The
ethyl acetate extracts were dried (Na.sub.2SO.sub.4) and evaporated
to yield 0.4 g of a brown gum. This residue was chromatographed on
30 g of silica gel using a 98:2 mixture of
CH.sub.2Cl.sub.2:CH.sub.3OH as the eluant. Appropriate fractions
were combined to yield 0.122 g (32%) of the title compound as an
amorphous solid. TLC (10:1 CH.sub.2Cl.sub.2:CH.sub.3OH)
R.sub.f=0.63.
[0154] .sup.1H NMR (CDCl.sub.3) .delta. 8.42 (s, 1H), 7.9 (m, 2H),
7.35-7.5 (m, 5H), 6.8-7.1 (m, 2H), 3.52 (s, 2H), 2.95 (m, 2H), 2.8
(s, 3H), 1.4-2.5 (m, 7H).
[0155] Mass spectrum: 376.1600. Calc'd for
C.sub.23H.sub.24N.sub.2OS: .+-.2.6 ppm.
Example 28
1-(2-Methyl-6-benzothiazolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propano-
ne Hydrochloride
[0156] A solution of 0.120 g (0.319 mM) of the free base of the
title compound from Example 27 was dissolved in 50 mL of ethanol.
To this was added 50 mg of Pt.sub.2O and the mixture hydrogenated
at 50 psi for 1 hour. The reaction was filtered and the ethanol was
evaporated to yield 0.112 g (100%) of the title compound (free
base) as an amorphous solid.
[0157] TLC (10:1 CH.sub.2Cl.sub.2:CH.sub.3OH) R.sub.f=0.5.
[0158] .sup.1H NMR (CDCl.sub.3) .delta. 8.45 (s, 1H), 8.02 (dd,
2H), 7.25 (m, 5H), 3.5 (s, 2H), 3.02 (m, 2H), 2.85 (m, 2H), 2.83
(s, 3H), 1.4-2.0 (m, 9H).
[0159] Mass spectrum: 378 (p), 287 (p-91), 172 (p-206), 91 (p-287,
base peak).
[0160] This residue was dissolved in 15 mL of ethyl acetate to
which was added HCl dissolved in ethyl acetate (EtOAc). The
resulting precipitate was filtered and dried under vacuum to yield
92 mg (70%) of the title compound.
[0161] M.p.=110.degree.-112.degree. C.
Example 29
N-Acetyl-4-aminoacetophenone
[0162] A mixture of 5.0 g (0.37 M) of 4-aminoacetophenone, 3.8 mL
(0.04 M) of acetic anhydride, and 5.5 mL (0.04 M) of triethylamine
were dissolved in 50 mL of methylene chloride (CH.sub.2Cl.sub.2)
and stirred at room temperature for 18 hours. A white solid
precipitated from the solution and was collected by filtration. The
solid was washed with water and air dried to yield 3.32 g (49%) of
N-acetyl-4-aminoacetophenone.
[0163] TLC (1:1 CHCl.sub.3:EtOAc) R.sub.f=0.61.
[0164] .sup.1H NMR (CDCl.sub.3) .delta. 8.58 (br s, 1H), 7.90 (d,
2H), 7.64 (d, 2H), 2.56 (s, 3H), 2.19 (s, 3H).
Example 30
N-Benzoyl-4-aminoacetophenone
[0165] A mixture of 5.0 g (0.37 M) of 4-aminoacetophenone, 4.7 mL
(0.04 M) of benzoyl chloride, and 5.5 mL (0.04 M) of triethylamine
were dissolved in 50 mL of methylene chloride (CHCl.sub.2) and
stirred at room temperature for 18 hours. The resulting precipitate
was filtered and washed with water. The residue was dissolved in
chloroform (CHCl.sub.3) and dried with Na.sub.2SO.sub.4.
Evaporation of the CHCl.sub.3 yielded 4.2 g (47%) of
N-benzoyl-4-aminoacetophenone.
[0166] M.p.=206.degree.-208.degree. C.
[0167] .sup.1H NMR (CDCl.sub.3+DMSO) .delta. 9.58 (br s, 1H), 7.80
(m, 6H), 7.34 (m, 3H), 2.44 (s, 3H).
Example 31
N-Acetyl-3-nitro-4-aminoacetophenone
[0168] To 10 mL of fuming nitric acid cooled to 0.degree. C. was
added portionwise 1.0 g (5.6 mM) of N-acetyl-4-aminoacetophenone.
The temperature was maintained below 5.degree. C. to prevent excess
nitration of the benzene ring. The solution was stirred for 15
minutes at 0.degree. C. and then carefully poured onto ice. A
yellow solid precipitated and was collected by filtration to yield
0.42 g (34%) of the title compound.
[0169] TLC (2:1 CHCl.sub.3:EtOAc) R.sub.f=0.78.
[0170] .sup.1H NMR (CDCl.sub.3) .delta. 8.9 (d, 1H), 8.77 (s, 1H),
8.16 (s, 1H), 2.64 (s, 3H), 2.34 (s, 3H).
Example 32
N-Benzoyl-3-nitro-4-aminoacetophenone
[0171] To 10 mL of fuming nitric acid cooled to -5.degree. C. were
added portionwise 2.5 g (0.01 M) of N-benzoyl-4-aminoacetophenone.
The temperature was maintained below 0.degree. C. The reaction was
stirred for 10 minutes and the resulting solution poured onto ice.
A yellow solid precipitate was formed which was collected by
filtration. The solid was dissolved in CHCl.sub.3 and
chromatographed on silica gel using CHCl.sub.3 as the elutant.
Appropriate fractions were combined and evaporated to yield 1.0 g
(35%) of the title compound as a yellow solid.
[0172] .sup.1H NMR (CDCl.sub.3) .delta. 9.12 (d, 1H), 8.84 (s, 1H),
8.25 (d, 1H), 7.96 (d, 2H), 7.6 (m, 3H), 2.66 (s, 3H).
Example 33
3-[1-(1-Phenylmethyl)-4-piperidinyl]-1-(3-nitro-4-acetamido-phenyl)2-prope-
n-1-one
[0173] A solution of 2.6 g (11.7 mM) of
N-acetyl-3-nitro-4-aminoacetopheno- ne in 25 mL of THF was cooled
to -60.degree. C. under a nitrogen atmosphere. To the solution were
added 4.7 mL (11.7 mM) of N-butyllithium (2.5 M in hexanes),
maintaining the temperature below -60.degree. C. The reaction was
stirred for 15 minutes. A solution of 4-formyl-N-benzylpiperidine
dissolved in 5 mL of THF was added dropwise, maintaining the
reaction temperature below -55.degree. C. The reaction was stirred
for 1 hour and then warmed to room temperature. At room
temperature, the reaction was quenched with 10 mL of water and
extracted with ethyl acetate. The ethyl acetate extracts were
combined, dried (Na.sub.2SO.sub.4) and evaporated to yield a dark
oil. This oil was chromatographed on silica gel using 5:1
CHCl.sub.3:EtOAc as the elutant. Appropriate fractions were
combined to yield 1.2 g (25%) of the title compound as an oil which
slowly crystallized.
[0174] TLC (10:1 CHCl.sub.3:CH.sub.3OH), R.sub.f=0.45.
[0175] .sup.1H NMR (CDCl.sub.3) .delta. 8.90 (d, 1H), 8.76 (s, 1H),
8.14 (d, 1H), 8.30 (m, 5H), 3.53 (s, 2H), 2.94 (m, 2H), 2.32 (s,
3H), 1.5-2.15 (m, 5H).
Example 34
3-[1-(Phenylmethyl)-4-piperidinyl]-1-(3-nitro-4-benzoyl-amidophenyl)2-prop-
en-1-one
[0176] A solution of 0.80 g (2.90 mM) of the title compound from
Example 32 in 30 mL of anhydrous THF was cooled to -70.degree. C.
under a nitrogen atmosphere. To the solution were added 1.2 mL (2.9
mM) of N-butyllithium (2.5 M solution in hexanes) dropwise, forming
a dark solution. The solution was stirred at -70.degree. for 10
minutes. To this mixture was added dropwise a solution of 0.6 g
(2.9 mM) of 4-formyl-N-benzylpiperidine in 10 mL of THF. The
reaction was slowly warmed to room temperature and stirred for 18
hours. The reaction mixture was quenched with 25 mL of water and
extracted with ethyl acetate. The ethyl acetate extracts were dried
(Na.sub.2SO.sub.4) and evaporated. The residue was chromatographed
on silica gel using 1:1 CHCl.sub.3:EtOAc as the eluent. Appropriate
fractions were combined to yield 0.45 g (34%) of the title compound
as an amorphous solid.
[0177] TLC (10:1 CHCl.sub.3:CH.sub.3OH), R.sub.f=0.67.
[0178] .sup.1H NMR (CDCl.sub.3) .delta. 9.14 (d, 1H), 8.82 (s, 1H),
8.22 (d, 1H), 7.98 (d, 2H), 7.55 (m, 3H), 7.32 (m, 5H), 7.10 (m,
1H), 6.85 (m, 1H), 3.54 (s, 1H), 2.95 (m, 2H), 1.4-2.3 (m, 7H).
Example 35
1-(3-Amino-4-acetamidophenyl)-3-[(1-phenylmethyl)-4-piperidinyl]-1-propano-
ne
[0179] To a solution of 0.9 g (2.2 mM) of the title compound from
Example 33 in 50 mL of ethanol were added 20 mg of PtO.sub.2, and
the mixture was hydrogenated at 50 psi for one hour. The mixture
was filtered and the ethanol evaporated to yield 0.9 g (100%) of
the title compound as an oil.
[0180] .sup.1H NMR (CDCl.sub.3) .delta. 7.6 (s, 1H), 7.2-7.5 (m,
7H), 3.5 (s, 2H), 2.85 (m, 4H), 2.21 (s, 3H), 1.2-2.0 (m, 9H).
[0181] Mass spectrum: 379.2 (p), 202.3 (p-176.9), 172.3 (p-206.9),
91.0 (p-288.3, base peak).
Example 36
1-(2-Methyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-pro-
panol Hydrochloride
[0182] A solution of 0.6 g (1.6 mM) of the free base of the title
compound from Example 35 in 10 mL of acetic acid was heated on a
steam bath (80.degree.-90.degree. C.) for 1 hour. The acetic acid
was evaporated and the residue dissolved in 25 mL of ethyl acetate.
To this was added 25 mL of water and the pH was adjusted to 3.0.
The ethyl acetate layer was separated from the water layer and the
water layer was sequentially adjusted to pH=5.0, 6.0, and 9.0, each
time extracting with ethyl acetate. The pH=9.0 ethyl acetate
extract was dried (Na.sub.2SO.sub.4) and evaporated to afford 0.4 g
(69%) of the free base of the title compound (free base).
[0183] .sup.1H NMR (CDCl.sub.3) .delta. 8.08 (s, 1H), 7.80 (s, 1H),
7.47 (m, 1H), 7.25 (m, 6H), 3.47 (s, 2H), 2.8-3.0 (m, 4H), 2.59 (s,
3H), 1.90 (t, 2H), 1.64 (m, 4H), 1.25 (m, 3H).
[0184] TLC (10:1:0.1 CHCl.sub.3:CH.sub.3OH:NH.sub.4OH), R.sub.f
(free base)=0.50.
[0185] The amorphous solid was dissolved in ethyl acetate and to
this was added an ether solution of hydrogen chloride (HCl). The
resulting precipitate was filtered and dried to yield 0.26 g (62%)
of the title compound as a tan solid.
[0186] Mass spectrum: 361.3 (p), 270.2 (p-91.1), 172.3 (p-189),
91.1 (0-270.2, base peak).
Example 37
1-(3-Amino-4-benzoylamidophenyl)-3-[(1-phenylmethyl)-4-piperidinyl]-1-prop-
anone
[0187] To a solution of 0.45 g (1.0 mM) of the title compound from
Example 34 in 50 mL of ethanol were added 25 mg of PtO.sub.2 and
the mixture was hydrogenated at 50 psi for 1 hour. After filtration
to remove the catalyst, the ethanol was evaporated to yield the
title compound as an amorphous solid.
[0188] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (s, 1H), 7.90 (d, 2H),
7.2-7.7 (m, 10H), 3.88 (br s, 2H), 3.50 (s, 2H), 2.90 (m, 4H),
1.2-2.0 (m, 9H).
[0189] This material was used in the procedure of Example 38
without further purification.
Example 38
1-(2-Phenyl-1H-benzimidazol-5-yl)-3-[(1-phenylmethyl)-4-piperidinyl]-1-pro-
panone Hydrochloride
[0190] The title compound of Example 37 was dissolved in a
50:50,mixture of ethanol and acetic acid and heated to 75.degree.
C. for 3 hours. The reaction was cooled to room temperature and
diluted with water. The pH of the mixture was adjusted to 9.5 and
the mixture was extracted with ethyl acetate. The ethyl acetate
extracts were dried (Na.sub.2SO.sub.4) and evaporated to yield 0.19
g (45%) of the free base of the title compound.
[0191] TLC (10:1:0.1 CHCl.sub.3:CH.sub.3OH:NH.sub.4OH),
R.sub.f=0.40.
[0192] .sup.1H NMR (CDCl.sub.3) .delta. 8.14 (d, 2H), 7.86 (d, 1H),
7.2-7.6 (m, 11H), 3.58 (s, 2H), 2.92 (m, 4H), 1.2-2.1 (m, 9H).
[0193] The residue was dissolved in ethyl acetate, and to this
solution was added dropwise an ether solution of HCl. The resulting
precipitate was collected via filtration and dried to yield the
title compound as a tan solid.
[0194] M.p. >300.degree. C.
[0195] Mass spectrum: 424.2 (p+1).
Example 39
1-(2-Methyl-6-benzthiazolyl)-3-(4-piperidinyl)-1-propanone
[0196] A mixture of 0.90 g (2.38 mM) of
1-(2-methyl-6-benzthiazolyl)-3-[1--
(phenylmethyl)-4-piperidinyl]-1-propanone (Example 27) and 0.33 mL
(3.1 mM) of 1-chloroethyl chloroformate was refluxed in 10 mL of
1,2-dichloroethane for 2 hours. The resulting brown solution was
cooled to room temperature and diluted with 15 mL of water. This
mixture was extracted twice with 20 mL of ethyl acetate. The ethyl
acetate extracts were combined, dried (Na.sub.2SO.sub.4), and
evaporated to yield 1.0 g (100%)
1-(2-methyl-6-benzothiazolyl)-3-[(1-chloroethylformyl)-4-piperidin-
yl]-1-propanone as an oil.
[0197] TLC (10:1 CH.sub.2Cl.sub.2:CH.sub.3OH) R.sub.f=0.86.
[0198] .sup.1H NMR (CDCl.sub.3) .delta. 8.4 (s, 1H), 7.9 (m, 2H),
6.55 (q, 1H), 2.65-3.2 (m, 4H), 2.77 (s, 3H), 1.83 (d, 3H),
1.4-1.95 (m, 9H). .sup.13C NMR (CDCl.sub.3, ppm) 198.1, 171.3,
155.8, 137.4, 135.8, 133.4, 125.9, 122.1, 122.0, 83.3, 44.2 (2),
35.7, 35.3, 32.0, 30.4 (2), 25.4, 20.3.
[0199] A methanol solution (5 mL) of 0.9 g (2.28 mM) of the above
oil was refluxed for 1 hour. Upon cooling, a yellow precipitate
formed. This precipitate was dissolved in 4N HCl and the solution
extracted with ether. The HCl solution was adjusted to pH 9 with
sodium carbonate (Na.sub.2CO.sub.3) and extracted with ethyl
acetate. The ethyl acetate extracts were dried (Na.sub.2SO.sub.4),
and evaporated to yield 0.250 g (38%) of the title compound as an
amorphous yellow solid.
[0200] TLC (10:1 CH.sub.2Cl.sub.2:CH.sub.3OH) R.sub.f=0.01.
[0201] .sup.1H NMR (CDCl.sub.3) .delta. 8.5 (s, 1H), 7.95 (m, 2H),
32 (m, 2H), 2.85 (s, 1H), 2.6 (m, 2H), 1.1-1.8 (m, 9H). .sup.13C
NMR (CDCl.sub.3, ppm) 198.1, 156.3, 136.0 (2), 132.0, 125.9, 122.3,
122.1, 46.4 (2), 35.8, 35.7, 33.0, 31.4 (2), 20.5.
Example 40
1-(2-Methyl-6-benzothiazolyl)-3-[1-(2-methyl-4-thiazolyl)methyl]-4-piperid-
inyl]-1-propanone Hydrochloride
[0202] A mixture of 250 mg (0.87 mM) of the title compound of
Example 39, 0.160 mg (0.87 mM) of 2-methyl-4-chloromethyl thiazole
and 0.36 mL (2.60 mM) of triethylamine was refluxed in 5 mL
methylene chloride for 12 hours. The reaction was cooled to room
temperature and diluted with 10 mL of water. The mixture was
extracted with ethyl acetate, and the ethyl acetate extracts
combined, dried (Na.sub.2SO.sub.4), and evaporated to yield 0.27 g
of a yellow gum. This material was chromatographed on 10 g of
silica gel using 98:2 CHCl.sub.3:CH.sub.3OH as an elutant.
Appropriate fractions were combined and evaporated to yield 100 mg
(29%) of the title compound as a yellow amorphous solid.
[0203] TLC (10:1 CH.sub.2Cl.sub.2:CH.sub.3OH), R.sub.f=0.21.
[0204] .sup.1H NMR (CDCl.sub.3) .delta. 8.50 (s, 1H), 7.9 (m, 2H),
6.87 (s, 1H), 3.62 (s, 2H), 3.0 (m, 4H), 2.87 (s, 3H), 2.69 (s,
3H), 2.0 (t, 2H), 1.7 (m, 4H), 1.35 (m, 3H).
[0205] Mass Spectrum: 399.2 (p), 287.2 (p-112, base peak), 223.1
(p-176.1), 193.1 (p-206.1), 176.0 (p-223), 112.0 (p-287), 71.0
(p-328).
[0206] This material was dissolved in ethyl acetate and to it was
added an ether solution of HCl gas. The resulting precipitate was
filtered and recrystallized from CH.sub.2Cl.sub.2/ether to yield 92
mg of the title compound.
[0207] M.p.=184.degree.-186.degree. C.
Example 41
1-(5-Amino-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone
[0208] A solution of
1-(1-Phenylsulfonyl-5-amino-indol-2-yl)-3-(N-phenylme-
thylpiperidin-4-yl)-1-propanone (160 mg, 0.32 mmol) in 3 ml of
methanol and 2 ml of 2N NaOH was heated at reflux for 2 hours. The
mixture was concentrated to dryness and the residue was diluted
with brine and extracted with chloroform. The organic layer was
dried and concentrated to dryness to give 144 mg of brown solid
which was purified through silica gel column chromatography to give
31 mg of the title compound as a brown solid.
[0209] .sup.1H NMR (CDCl.sub.3) .delta. 1.1-2.0 (m, 9H), 2.8-3.0
(m, 4H), 3.5 (s, 2H), 6.76 (dd, 1H), 6.9 (s, 1H), 6.96 (s, 1H),
7.1-7.3 (m, 6H)ppm.
Example 42
1-(5-N-acetylamino-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propan-
one
[0210] A solution of
1-(5-amino-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidi-
nyl]-1-propanone (18 mg, 0.05 mmol) in 0.5 ml of methylene chloride
was treated with a solution of triethylamine (6 mg, 0.06 mmol) in
0.5 ml of methylene chloride and a solution of acetyl chloride (4.7
mg, 0.06 mmol) in 0.5 ml of methylene chloride at room temperature
and the mixture was stirred at room temperature for 4 hours. The
mixture was quenched with water and extracted with methylene
chloride. The organic layer was dried and concentrated to give 11
mg of the title compound.
[0211] .sup.1H NMR (CDCl.sub.3) .delta. 1.2-2.1 (m, 9H), 2.2 (s,
3H), 2.8-3.0 (m, 4H), 3.5 (s, 2H), 7.0-7.65 (m, 9H), 8.0 (s, 1H),
9.35 (s, 1H) ppm.
* * * * *