U.S. patent application number 12/787906 was filed with the patent office on 2010-11-04 for spirocyclic heterocyclic derivatives and methods of their use.
This patent application is currently assigned to Adolor Corporation. Invention is credited to Roland E. Dolle, Bertrand Le Bourdonnec.
Application Number | 20100280058 12/787906 |
Document ID | / |
Family ID | 34421676 |
Filed Date | 2010-11-04 |
United States Patent
Application |
20100280058 |
Kind Code |
A1 |
Dolle; Roland E. ; et
al. |
November 4, 2010 |
SPIROCYCLIC HETEROCYCLIC DERIVATIVES AND METHODS OF THEIR USE
Abstract
Spirocyclic heterocyclic derivatives, pharmaceutical
compositions containing these compounds, and methods for their
pharmaceutical use are disclosed. In certain embodiments, the
spirocyclic heterocyclic derivatives are ligands of the .delta.
opioid receptor and may be useful, inter alia, for treating and/or
preventing pain, anxiety, gastrointestinal disorders, and other
.delta. opioid receptor-mediated conditions.
Inventors: |
Dolle; Roland E.; (King of
Prussia, PA) ; Le Bourdonnec; Bertrand; (East
Fallowfield, PA) |
Correspondence
Address: |
FELDMAN GALE, P.A.
1700 Market Street, Suite 3130
Philadelphia
PA
19103
US
|
Assignee: |
Adolor Corporation
Exton
PA
|
Family ID: |
34421676 |
Appl. No.: |
12/787906 |
Filed: |
May 26, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12718439 |
Mar 5, 2010 |
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12787906 |
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11960845 |
Dec 20, 2007 |
7638527 |
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12718439 |
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10957554 |
Oct 1, 2004 |
7338962 |
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11960845 |
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60507864 |
Oct 1, 2003 |
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Current U.S.
Class: |
514/278 |
Current CPC
Class: |
A61P 37/06 20180101;
A61P 15/00 20180101; A61P 25/32 20180101; A61P 29/00 20180101; A61P
43/00 20180101; A61P 11/00 20180101; A61P 23/00 20180101; A61P
25/30 20180101; A61P 37/08 20180101; A61P 25/14 20180101; A61P
13/00 20180101; A61P 25/22 20180101; A61P 1/04 20180101; A61P 9/06
20180101; A61P 15/10 20180101; A61P 25/08 20180101; A61P 25/18
20180101; A61P 17/06 20180101; A61P 25/20 20180101; A61P 25/16
20180101; A61P 13/02 20180101; A61P 31/12 20180101; A61P 25/34
20180101; A61P 27/06 20180101; A61P 15/12 20180101; A61P 37/02
20180101; A61P 25/04 20180101; C07D 401/04 20130101; A61P 25/00
20180101; A61P 11/14 20180101; A61P 9/10 20180101; A61P 9/00
20180101; C07D 311/96 20130101; C07D 491/107 20130101; A61P 25/28
20180101; A61P 41/00 20180101; C07D 493/10 20130101; A61P 31/04
20180101; A61P 19/02 20180101; C07D 221/20 20130101; C07D 495/10
20130101; A61P 9/12 20180101; A61P 25/24 20180101; A61P 25/36
20180101; A61P 1/00 20180101; A61P 11/06 20180101 |
Class at
Publication: |
514/278 |
International
Class: |
A61K 31/444 20060101
A61K031/444; A61P 29/00 20060101 A61P029/00 |
Claims
1-148. (canceled)
149. A method of preventing or treating pain comprising
administering to a patient in need thereof an effective amount of a
compound of the following formula: ##STR00489## or a
pharmaceutically acceptable salt or N-oxide thereof.
150. A method according to claim 149 wherein the pain is selected
from the group consisting of acute pain and chronic pain.
151. A method according to claim 150 wherein the pain is acute
pain.
152. A method according to claim 150 wherein the pain is chronic
pain.
153. A method according to claim 149 wherein the pain is selected
from the group consisting of nociceptive pain, inflammatory pain,
visceral pain, somatic pain, neuralgia, neuropathic pain, AIDS
pain, cancer pain, phantom pain, psychogenic pain, pain resulting
from hyperalgesia, pain caused by rheumatoid arthritis, migraine
and allodynia.
154. A method according to claim 153 wherein the pain is
neuropathic pain.
155. A method according to claim 149 wherein said compound is in
the form of a pharmaceutically acceptable salt.
156. A method according to claim 155 wherein said salt is a
hydrochloride salt.
157. A method of preventing or treating pain comprising
administering to a patient in need thereof an effective amount of a
pharmaceutical composition comprising, in combination with a
pharmaceutically acceptable carrier, a compound of the following
formula: ##STR00490## or a pharmaceutically acceptable salt or
N-oxide thereof.
158. A method according to claim 157 wherein the pain is selected
from the group consisting of acute pain and chronic pain.
159. A method according to claim 158 wherein the pain is acute
pain.
160. A method according to claim 158 wherein the pain is chronic
pain.
161. A method according to claim 157 wherein the pain is selected
from the group consisting of nociceptive pain, inflammatory pain,
visceral pain, somatic pain, neuralgia, neuropathic pain, AIDS
pain, cancer pain, phantom pain, psychogenic pain, pain resulting
from hyperalgesia, pain caused by rheumatoid arthritis, migraine
and allodynia.
162. A method according to claim 161 wherein the pain is
neuropathic pain.
163. A method according to claim 157 wherein said compound is in
the form of a pharmaceutically acceptable salt.
164. A method according to claim 163 wherein said salt is a
hydrochloride salt.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional
Application Ser. No. 60/507,864, filed Oct. 1, 2003, the entire
disclosure of which is incorporated herein by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The invention relates to spirocyclic heterocyclic
derivatives (including derivatives of
spiro(2H-1-benzopyran-2,4'-piperidines), pharmaceutical
compositions containing these compounds, and methods for their
pharmaceutical use. In certain embodiments, the spirocyclic
heterocyclic derivatives are ligands of the .delta. opioid receptor
and are useful, inter alia, for treating and/or preventing pain,
anxiety, gastrointestinal disorders, and other .delta. opioid
receptor-mediated conditions.
BACKGROUND OF THE INVENTION
[0003] There are at least three different opioid receptors (.mu.,
.delta. and .kappa.) that are present in both central and
peripheral nervous systems of many species, including humans. Lord,
J. A. H., et al., Nature, 1977, 267, 495. Activation of the .delta.
opioid receptors induces analgesia in various animal models.
Moulin, et al., Pain, 1985, 23, 213. Some work suggests that the
analgesics working at .delta. opioid receptors do not have the
attendant side effects associated with .mu. and .kappa. opioid
receptor activation. Galligan, et al., J. Pharm. Exp. Ther., 1985,
229, 641. The .delta. opioid receptor has also been identified as
having a role in circulatory systems. Ligands for the 6 receptor
have also been shown to possess immunomodulatory activities.
Dondio, et al., Exp. Opin. Ther. Patents, 1997, 10, 1075. Further,
selective .delta. opioid receptor agonists have been shown to
promote organ and cell survival. Su, T-P, Journal of Biomedical
Science, 2000, 9(3), 195-199. Ligands for the .delta. opioid
receptor may therefore find potential use as analgesics, as
antihypertensive agents, as immunomodulatory agents, and/or
agents.
[0004] Numerous selective .delta. opioid ligands are peptidic in
nature and thus are unsuitable for administration by systemic
routes. Several non-peptidic .delta. opioid receptor ligands have
been developed. See, for example, E. J. Bilsky, et al., Journal of
Pharmacology and Experimental Therapeutics, 1995, 273(1), 359-366;
WO 93/15062, WO 95/04734, WO 95/31464, WO 96/22276, WO 97/10216, WO
01/46192, WO 02/094794, WO 02/094810, WO 02/094811, WO 02/094812,
WO 02/48122, WO 03/029215, WO 03/033486, JP-4275288,
EP-A-0,864,559, U.S. Pat. No. 5,354,863, U.S. Pat. No. 6,200,978,
U.S. Pat. No. 6,436,959 and US 2003/0069241.
[0005] While there are a large number of non-peptidic .delta.
opioid receptor modulators, there is still an unfulfilled need for
compounds with selective .delta. opioid receptor activity that may
be used in methods to provide beneficial pharmaceutical
characteristics while minimizing undesirable side effects. The
present invention is directed to these, as well as other important
ends.
SUMMARY OF THE INVENTION
[0006] In one aspect, the invention is directed to compounds of
formula I:
##STR00001##
wherein: [0007] R.sup.1 and R.sup.3 are each independently H,
alkyl, alkenyl, alkynyl, or aryl, or R.sup.1 and R.sup.3 when taken
together with the atoms through which they are connected, form a 4-
to 8-membered heterocycloalkyl ring; [0008] R.sup.2 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.1 and R.sup.2 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.2 and R.sup.3 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0009] provided that R.sup.2 is
not
[0009] ##STR00002## [0010] each R.sup.a is independently H or
alkyl; [0011] each R.sup.b is independently H, alkyl, or aryl;
[0012] n is the integer 0, 1, 2 or 3; [0013] A and B are each
independently H, fluoro, or alkyl, or together form a double bond
between the carbon atoms to which they are attached; [0014] R.sup.4
is --Y--W; [0015] Y is a single bond, C(R.sup.a)(R.sup.b),
C(R.sup.a)(R.sup.b)C(R.sup.a)(R.sup.b), or
C(R.sup.a)(R.sup.b)C(R.sup.a)(R.sup.b)C(R.sup.a)(R.sup.b); [0016] W
is aryl or heteroaryl; [0017] X is --CH.sub.2--, --O--, --S--,
--SO, --SO.sub.2, or --N(R.sup.5)--; [0018] R.sup.5 is H, alkyl,
cycloalkyl, --(CH.sub.2)-alkenyl, --(CH.sub.2)-alkynyl, aryl,
--COR.sup.b, or --SO.sub.2R.sup.b; and [0019] J forms a 6-membered
aryl or a 5- or 6-membered heteroaryl ring when taken together with
the carbon atoms to which it is attached; [0020] provided that
when: [0021] (a) J taken together with the carbon atoms to which it
is attached forms a phenyl ring substituted with 0-3 groups
selected from the group consisting of: [0022] halogen, [0023]
hydroxy, [0024] --S--C.sub.1-4 alkyl, [0025] C.sub.1-4 alkyl, and
[0026] C.sub.1-4 alkoxy, the latter two optionally substituted with
one or more halogens or with C.sub.1-4 alkoxy; [0027] W is
unsubstituted naphthyl, or phenyl substituted with 0-3 groups
selected from the group consisting of: [0028] halogen, [0029]
C.sub.1-6 alkyl, [0030] C.sub.1-6 alkoxy, [0031] phenyl, [0032]
phenoxy, [0033] 1,3-benzodioxazolyl or
2,2-difluoro-1,3-benzodioxazolyl, [0034] --NH.sub.2, [0035]
--N(C.sub.1-4 alkyl).sub.2, and [0036] pyrrolyl; [0037] n is 1,
[0038] R.sup.1 and R.sup.3 are each H, [0039] A and B together form
a double bond between the carbon atoms to which they are attached,
[0040] Y is a single bond; and [0041] X is --O--; [0042] then
R.sup.2 is other than H or methyl; and [0043] provided that when:
[0044] (b) J taken together with the carbon atoms to which it is
attached forms a phenyl ring, [0045] W is phenyl substituted with
0-3 groups selected from the group consisting of: [0046] fluoro,
[0047] hydroxy, [0048] C.sub.1-6 alkoxy optionally substituted with
one or more fluoro, [0049] C.sub.2-6 alkenyloxy, and [0050]
--S--C.sub.1-4 alkyl, [0051] n is 1, [0052] R.sup.1 and R.sup.3 are
each H, [0053] A and B together form a double bond between the
carbon atoms to which they are attached, [0054] Y is a single bond;
and [0055] X is --O--; [0056] then R.sup.2 is other than H or
benzyl; and [0057] provided that when: [0058] (c) J forms a
6-membered aryl ring, it is not substituted with:
[0058] ##STR00003## [0059] or a stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, or N-oxide thereof.
[0060] In other aspects, the invention is related to compounds of
formula IV:
##STR00004##
[0061] wherein: [0062] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0063] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0064] each R.sup.d is
independently H, alkyl, or aryl; [0065] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0066] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0067] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0068] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0069] each k is independently 1,
2, or 3; [0070] p is 0, 1, 2 or 3; [0071] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0072] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0073] G is H or alkyl; [0074]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0075] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0076] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0077]
provided that when: [0078] (a) J.sup.2 taken together with the
carbon atoms to which it is attached forms a 6- to 10-membered aryl
ring substituted with 0-3 groups selected from the group consisting
of: [0079] halogen, [0080] hydroxy, [0081] --SH, [0082]
--C(.dbd.O)--H [0083] --S--C.sub.1-4 alkyl, [0084]
--NHS(.dbd.O).sub.2--C.sub.1-4 alkyl, [0085]
--NHS(.dbd.O).sub.2--H, [0086] --N(C.sub.1-4
alkyl)S(.dbd.O).sub.2--H, [0087] C.sub.1-4 alkyl, and [0088]
C.sub.1-4 alkoxy, the latter two optionally substituted with one or
more halogens or with C.sub.1-4 alkoxy; [0089] W.sup.2 is phenyl
substituted with 0-3 groups selected from the group consisting of:
[0090] halogen, [0091] cyano, [0092] hydroxy, [0093] C.sub.1-6
alkyl optionally substituted with one or more halogens, [0094]
C.sub.1-6 alkoxy optionally substituted with one or more halogens
or with C.sub.3-6 cycloalkyl, [0095] C.sub.2-6 alkenyloxy, [0096]
C.sub.2-6 alkynyloxy, [0097] C.sub.3-6 cycloalkyloxy, [0098]
C.sub.6-12 aryloxy, [0099] aralkoxy, [0100] heteroaryloxy, [0101]
heteroaralkoxy, [0102] heterocycloalkyl substituted with alkoxy,
[0103] --SH, [0104] --S--C.sub.1-4 alkyl, [0105] --NH.sub.2, [0106]
--N.dbd.C(aryl).sub.2, [0107] --N(H)C.sub.1-4 alkyl, [0108]
--N(C.sub.1-4 alkyl).sub.2, [0109] --OS(.dbd.O).sub.2--C.sub.1-4
alkyl optionally substituted with one or more halogens, [0110]
--OS(.dbd.O).sub.2--C.sub.6-12 aryl optionally substituted with
C.sub.1-4 alkyl, [0111] --NHS(.dbd.O).sub.2--C.sub.1-4 alkyl,
[0112] --N(C.sub.1-4 alkyl)S(.dbd.O).sub.2--C.sub.1-4 alkyl, [0113]
--NHS(.dbd.O).sub.2--H, and [0114] --N(C.sub.1-4
alkyl)S(.dbd.O).sub.2--H; [0115] p and s are each 1, [0116]
R.sup.e, R.sup.f, R.sup.23, R.sup.24, and G are each H, [0117]
A.sup.2 and B.sup.2 together form a double bond, [0118] Y.sup.2 is
a single bond; and [0119] X.sup.2 is --O--; [0120] then Z is other
than:
##STR00005##
[0120] wherein t is an integer from 1 to 20; and [0121] provided
that when: [0122] (b) J.sup.2 taken together with the carbon atoms
to which it is attached forms a phenyl ring substituted with 0-3
groups selected from the group consisting of: [0123] halogen,
[0124] hydroxy, [0125] --S--C.sub.1-4 alkyl, [0126] C.sub.1-4
alkyl, and [0127] C.sub.1-4 alkoxy, the latter two optionally
substituted with one or more halogens or with C.sub.1-4 alkoxy;
[0128] W.sup.2 is unsubstituted naphthyl, or phenyl substituted
with 0-3 groups selected from the group consisting of: [0129]
halogen, [0130] C.sub.1-6 alkyl, [0131] C.sub.1-6 alkoxy, [0132]
phenyl, [0133] phenoxy, [0134] 1,3-benzodioxazolyl, or
2,2-difluoro-1,3-benzodioxazolyl fluoro, [0135] --NH.sub.2, [0136]
--N(C.sub.1-4 alkyl).sub.2, and [0137] pyrrolyl; [0138] p and s are
each 1, [0139] R.sup.e, R.sup.f, R.sup.23, R.sup.24, and G are each
H, [0140] A.sup.2 and B.sup.2 together form a double bond, [0141]
Y.sup.2 is a single bond; and [0142] X.sup.2 is --O--; [0143] then
Z is other than:
##STR00006##
[0143] and [0144] provided that when: [0145] (C) J.sup.2 taken
together with the carbon atoms to which it is attached forms
unsubstituted phenyl, [0146] W.sup.2 is phenyl substituted with 0-3
groups selected from the group consisting of: [0147] fluoro, [0148]
hydroxy, [0149] C.sub.1-6 alkoxy optionally substituted with one or
more fluoro, [0150] C.sub.2-6 alkenyloxy, and [0151] --S--C.sub.1-4
alkyl, [0152] p and s are each 1, [0153] R.sup.e, R.sup.f,
R.sup.23, R.sup.24, and G are each H, [0154] A.sup.2 and B.sup.2
together form a double bond, [0155] Y.sup.2 is a single bond; and
[0156] X.sup.2 is --O--; [0157] then Z is other than:
##STR00007##
[0157] and [0158] provided that when: [0159] (d) J.sup.2 taken
together with the carbon atoms to which it is attached forms a
6-membered aryl ring substituted with:
##STR00008##
[0159] then Z is other than --N(R.sup.25)-- or --CH(NH.sub.2)--;
[0160] or a stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.
[0161] In another aspect, the invention is directed to
pharmaceutical compositions comprising a pharmaceutically
acceptable carrier and an effective amount of a compound of the
invention including, for example, a compound of formulas I, II,
III, IV, V, VI, VII, VIII, IX, X, XI, XII and/or XIII. In certain
embodiments, the pharmaceutical composition further comprises an
effective amount of at least one opioid.
[0162] In yet another aspect, the invention is directed to methods
of binding opioid receptors, preferably .delta. opioid receptors,
in a patient in need thereof, comprising the step of administering
to said patient an effective amount of a compound of the invention
including, for example, a compound of formulas I, II, III, IV, V,
VI, VII, VIII, IX, X, XI, XII and/or XIII. In preferred
embodiments, the binding modulates the activity of the receptor. In
certain other preferred embodiments, the binding agonizes the
activity of said opioid receptors.
[0163] In other aspects, the invention is directed to methods of
preventing or treating pain, comprising the step of administering
to a patient in need thereof an effective amount of a compound of
the invention including, for example, a compound of formulas I, II,
III, IV, V, VI, VII, VIII, IX, X, XI, XII and/or XIII.
[0164] In another aspect, the invention is directed to methods for
preventing or treating gastrointestinal dysfunction, comprising the
step of administering to a patient in need of such treatment an
effective amount of a compound of the invention including, for
example, a compound of formulas I, II, III, IV, V, VI, VII, VIII,
IX, X, XI, XII and/or XIII.
[0165] In another aspect, the invention is directed to methods for
preventing or treating ileus, comprising the step of administering
to a patient in need of such treatment an effective amount of a
compound of the invention including, for example, a compound of
formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and/or
XIII.
[0166] In another aspect, the invention is directed to methods for
preventing or treating a urogenital tract disorder, comprising the
step of administering to a patient in need of such treatment an
effective amount of a compound of the invention including, for
example, a compound of formulas I, II, III, IV, V, VI, VII, VIII,
IX, X, XI, XII and/or XIII.
[0167] In another aspect, the invention is directed to methods of
preventing or treating an immunomodulatory disorder, comprising the
step of administering to a patient in need thereof an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII.
[0168] In another aspect, the invention is directed to methods of
preventing or treating an inflammatory disorder, comprising the
step of administering to a patient in need thereof an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII.
[0169] In another aspect, the invention is directed to methods of
preventing or treating a respiratory function disorder, comprising
the step of administering to a patient in need thereof an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII.
[0170] In another aspect, the invention is directed to methods for
preventing or treating anxiety, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII.
[0171] In another aspect, the invention is directed to methods for
preventing or treating a mood disorder, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII.
[0172] In another aspect, the invention is directed to methods for
preventing or treating a stress-related disorder, comprising the
step of administering to a patient in need of such treatment an
effective amount of a compound of the invention including, for
example, a compound of formulas I, II, III, IV, V, VI, VII, VIII,
IX, X, XI, XII and/or XIII.
[0173] In another aspect, the invention is directed to methods for
preventing or treating attention deficit hyperactivity disorder,
comprising the step of administering to a patient in need of such
treatment an effective amount of a compound of the invention
including, for example, a compound of formulas I, II, III, IV, V,
VI, VII, VIII, IX, X, XI, XII and/or XIII.
[0174] In another aspect, the invention is directed to methods for
preventing or treating sympathetic nervous system disorder,
comprising the step of administering to a patient in need of such
treatment an effective amount of a compound of the invention
including, for example, a compound of formulas I, II, III, IV, V,
VI, VII, VIII, IX, X, XI, XII and/or XIII.
[0175] In another aspect, the invention is directed to methods for
preventing or treating tussis, comprising the step of administering
to a patient in need of such treatment an effective amount of a
compound of the invention including, for example, a compound of
formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and/or
XIII.
[0176] In another aspect, the invention is directed to methods for
preventing or treating a motor disorder, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII.
[0177] In another aspect, the invention is directed to methods for
treating a traumatic injury to the central nervous system,
comprising the step of administering to a patient in need of such
treatment an effective amount of a compound of the invention
including, for example, a compound of formulas I, II, III, IV, V,
VI, VII, VIII, IX, X, XI, XII and/or XIII.
[0178] In another aspect, the invention is directed to methods for
preventing or treating stroke, comprising the step of administering
to a patient in need of such treatment an effective amount of a
compound of the invention including, for example, a compound of
formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and/or
XIII.
[0179] In another aspect, the invention is directed to methods for
preventing or treating cardiac arrhythmia, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII.
[0180] In another aspect, the invention is directed to methods for
preventing or treating glaucoma, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII.
[0181] In another aspect, the invention is directed to methods for
preventing or treating sexual dysfunction, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII.
[0182] In another aspect, the invention is directed to methods for
treating a condition selected from the group consisting of shock,
brain edema, cerebral ischemia, cerebral deficits subsequent to
cardiac bypass surgery and grafting, systemic lupus erythematosus,
Hodgkin's disease, Sjogren's disease, epilepsy, and rejection in
organ transplants and skin grafts, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII.
[0183] In another aspect, the invention is directed to methods for
treating substance addiction, comprising the step of administering
to a patient in need of such treatment an effective amount of a
compound of the invention including, for example, a compound of
formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and/or
XIII.
[0184] In another aspect, the invention is directed to methods for
improving organ and cell survival, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII.
[0185] In another aspect, the invention is directed to methods for
providing cardioprotection following myocardial infarction,
comprising the step of administering to a patient in need of such
treatment an effective amount of a compound of the invention
including, for example, a compound of formulas I, II, III, IV, V,
VI, VII, VIII, IX, X, XI, XII and/or XIII.
[0186] In another aspect, the invention is directed to methods for
reducing the need for anesthesia, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII.
[0187] In another aspect, the invention is directed to methods of
producing or maintaining an anaesthetic state, comprising the step
of administering to a patient in need of such treatment an
effective amount of a compound of the invention including, for
example, a compound of formulas I, II, III, IV, V, VI, VII, VIII,
IX, X, XI, XII and/or XIII. Preferably, the compound of the
invention including, for example, a compound of formula I, II, III,
IV, V, VI, VII, VIII, IX, X, XI, XII, and/or XIII is
co-administered with an anaesthetic agent selected from the group
consisting of an inhaled anaesthetic, a hypnotic, an anxiolytic, a
neuromuscular blocker and an opioid.
[0188] In certain aspects, the invention is directed to the
radiolabeled derivatives and the isotopically labeled derivatives
of compounds of the invention including, for example, radiolabeled
and isotopically labeled derivatives of compounds of formulas I,
II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and/or XIII.
[0189] These and other aspects of the invention will become more
apparent from the following detailed description.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0190] The invention relates to spirocyclic heterocyclic
derivatives, pharmaceutical compositions containing these
compounds, and methods for their pharmaceutical use. In certain
embodiments, the spirocyclic heterocyclic derivatives are ligands
of the .delta. opioid receptor and may be useful, inter alia, in
methods for treating and/or preventing diseases and conditions that
may be mediated or modulated by the .delta. opioid receptor
including, for example, pain, gastrointestinal disorders,
urogenital tract disorders including incontinence and overactive
bladder, immunomodulatory disorders, inflammatory disorders,
respiratory function disorders, anxiety, mood disorders,
stress-related disorders, attention deficit hyperactivity
disorders, sympathetic nervous system disorders, depression,
tussis, motor disorders, traumatic injuries, especially to the
central nervous system, stroke, cardiac arrhythmias, glaucoma,
sexual dysfunctions, shock, brain edema, cerebral ischemia,
cerebral deficits subsequent to cardiac bypass surgery and
grafting, systemic lupus erythematosus, Hodgkin's disease,
Sjogren's disease, epilepsy, rejections in organ transplants and
skin grafts, and substance addiction. In certain other embodiments,
the spirocyclic heterocyclic derivatives are ligands of the .delta.
opioid receptor and may be useful in, inter alia, methods for
improving organ and cell survival, methods for providing
cardioprotection following myocardial infarction, methods for
reducing the need for anesthesia, methods for producing and/or
maintaining an anaesthetic state, and methods of detecting, imaging
or monitoring degeneration or dysfunction of opioid receptors in a
patient.
[0191] As employed above and throughout the disclosure, the
following terms, unless otherwise indicated, shall be understood to
have the following meanings.
[0192] "Alkyl" refers to an optionally substituted, saturated
straight, branched, or cyclic hydrocarbon having from about 1 to
about 20 carbon atoms (and all combinations and subcombinations of
ranges and specific numbers of carbon atoms therein), with from
about 1 to about 8 carbon atoms, herein referred to as "lower
alkyl," being preferred. Alkyl groups include, but are not limited
to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,
n-pentyl, cyclopentyl, isopentyl, neopentyl, n-hexyl, isohexyl,
3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
[0193] "Cycloalkyl" refers to an optionally substituted alkyl group
having one or more rings in their structures and having from about
3 to about 20 carbon atoms (and all combinations and
subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 3 to about 10 carbon atoms being
preferred. Multi-ring structures may be bridged or fused ring
structures. Cycloalkyl groups include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl,
2-[4-isopropyl-1-methyl-7-oxa-bicyclo[2.2.1]heptanyl],
2-[1,2,3,4-tetrahydro-naphthalenyl], and adamantyl.
[0194] "Alkylcycloalkyl" refers to an optionally substituted ring
system comprising a cycloalkyl group having one or more alkyl
substituents, wherein cycloalkyl and alkyl are each as previously
defined. Exemplary alkylcycloalkyl groups include, for example,
2-methylcyclohexyl, 3,3-dimethylcyclopentyl,
trans-2,3-dimethylcyclooctyl, and
4-methyldecahydronaphthalenyl.
[0195] "Heterocycloalkyl" refers to an optionally substituted ring
system composed of a cycloalkyl radical wherein in at least one of
the rings, one or more of the carbon atom ring members is
independently replaced by a heteroatom group selected from the
group consisting of O, S, N, and NH, wherein cycloalkyl is as
previously defined. Heterocycloalkyl ring systems having a total of
from about 5 to about 14 carbon atom ring members and heteroatom
ring members (and all combinations and subcombinations of ranges
and specific numbers of carbon and heteroatom ring members) are
preferred. In other preferred embodiments, the heterocyclic groups
may be fused to one or more aromatic rings. Exemplary
heterocycloalkyl groups include, but are not limited to,
tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl,
isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,
thiazolidinyl, piperazinyl, morpholinyl, piperadinyl,
decahydroquinolyl, octahydrochromenyl,
octahydrocyclopenta[c]pyranyl, 1,2,3,4,-tetrahydroquinolyl,
octahydro-[2]pyrindinyl, decahydrocycloocta[c]furanyl,
tetrahydroquinolyl, and imidazolidinyl.
[0196] "Alkylheterocycloalkyl" refers to an optionally substituted
ring system comprising a heterocycloalkyl group having one or more
alkyl substituents, wherein heterocycloalkyl and alkyl are each as
previously defined. Exemplary alkylheterocycloalkyl groups include,
for example, 2-methylpiperidinyl, 3,3-dimethylpyrrolidinyl,
trans-2,3-dimethylmorpholinyl, and 4-methyldecahydroquinolinyl.
[0197] "Alkenyl" refers to an optionally substituted alkyl group
having from about 2 to about 10 carbon atoms and one or more double
bonds (and all combinations and subcombinations of ranges and
specific numbers of carbon atoms therein), wherein alkyl is as
previously defined.
[0198] "Alkynyl" refers to an optionally substituted alkyl group
having from about 2 to about 10 carbon atoms and one or more triple
bonds (and all combinations and subcombinations of ranges and
specific numbers of carbon atoms therein), wherein alkyl is as
previously defined.
[0199] "Aryl" refers to an optionally substituted, mono-, di-,
tri-, or other multicyclic aromatic ring system having from about 5
to about 50 carbon atoms (and all combinations and subcombinations
of ranges and specific numbers of carbon atoms therein), with from
about 6 to about 10 carbons being preferred. Non-limiting examples
include, for example, phenyl, naphthyl, anthracenyl, and
phenanthrenyl.
[0200] "Aralkyl" refers to an optionally substituted moiety
composed of an alkyl radical bearing an aryl substituent and having
from about 6 to about 50 carbon atoms (and all combinations and
subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 6 to about 10 carbon atoms being
preferred. Non-limiting examples include, for example, benzyl,
diphenylmethyl, triphenylmethyl, phenylethyl, and
diphenylethyl.
[0201] "Halo" refers to a fluoro, chloro, bromo, or iodo
moiety.
[0202] "Heteroaryl" refers to an optionally substituted aryl ring
system wherein in at least one of the rings, one or more of the
carbon atom ring members is independently replaced by a heteroatom
group selected from the group consisting of S, O, N, and NH,
wherein aryl is as previously defined. Heteroaryl groups having a
total of from about 5 to about 14 carbon atom ring members and
heteroatom ring members (and all combinations and subcombinations
of ranges and specific numbers of carbon and heteroatom ring
members) are preferred. Exemplary heteroaryl groups include, but
are not limited to, pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl,
pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl,
pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl,
benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl,
carbazolyl, benzimidazolyl, and isoxazolyl. Heteroaryl may be
attached via a carbon or a heteroatom to the rest of the
molecule.
[0203] "Heteroarylalkyl" and "heteroaralkyl" each refers to an
optionally substituted, heteroaryl substituted alkyl radical where
heteroaryl and alkyl are as previously defined Non-limiting
examples include, for example, 2-(1H-pyrrol-3-yl)ethyl,
3-pyridylmethyl, 5-(2H-tetrazolyl)methyl, and
3-(pyrimidin-2-yl)-2-methylcyclopentanyl.
[0204] "Perhaloalkyl" refers to an alkyl group, wherein two or more
hydrogen atoms are replaced by halo (F, Cl, Br, I) atoms, and alkyl
is as previously defined. Exemplary perhaloalkyl groups include,
for example, perhalomethyl, such as perfluoromethyl and
difluoromethyl.
[0205] "Alkoxy" and "alkoxyl" refer to an optionally substituted
alkyl-O-- group wherein alkyl is as previously defined. Exemplary
alkoxy and alkoxyl groups include, for example, methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy, and heptoxy.
[0206] "Alkenyloxy" refers to an optionally substituted alkenyl-O--
group wherein alkenyl is as previously defined. Exemplary
alkenyloxy and alkenyloxyl groups include, for example, allyloxy,
butenyloxy, heptenyloxy, 2-methyl-3-buten-1-yloxy, and
2,2-dimethylallyloxy.
[0207] "Alkynyloxy" refers to an optionally substituted alkynyl-O--
group wherein alkynyl is as previously defined. Exemplary
alkynyloxy and alkynyloxyl groups include, for example,
propargyloxy, butynyloxy, heptynyloxy, 2-methyl-3-butyn-1-yloxy,
and 2,2-dimethylpropargyloxy.
[0208] "Aryloxy" and "aryloxyl" refer to an optionally substituted
aryl-O-- group wherein aryl is as previously defined. Exemplary
aryloxy and aryloxyl groups include, for example, phenoxy and
naphthoxy.
[0209] "Aralkoxy" and "aralkoxyl" refer to an optionally
substituted aralkyl-O-- group wherein aralkyl is as previously
defined. Exemplary aralkoxy and aralkoxyl groups include, for
example, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, and
3-naphthylheptoxy.
[0210] "Cycloalkoxy" refers to an optionally substituted
cycloalkyl-O-- group wherein cycloalkyl is as previously defined.
Exemplary cycloalkoxy groups include, for example, cyclopropanoxy,
cyclobutanoxy, cyclopentanoxy, cyclohexanoxy, and
cycloheptanoxy.
[0211] "Heteroaryloxy" refers to an optionally substituted
heteroaryl-O-- group wherein heteroaryl is as previously defined.
Exemplary heteroaryloxy groups include, but are not limited to,
pyrryloxy, furyloxyl, pyridyloxy, 1,2,4-thiadiazolyloxy,
pyrimidyloxy, thienyloxy, isothiazolyloxy, imidazolyloxy,
tetrazolyloxy, pyrazinyloxy, pyrimidyloxy, quinolyloxy,
isoquinolyloxy, thiophenyloxy, benzothienyloxy, isobenzofuryloxy,
pyrazolyloxy, indolyloxy, purinyloxy, carbazolyloxy,
benzimidazolyloxy, and isoxazolyloxy.
[0212] "Heteroaralkoxy" refers to an optionally substituted
heteroarylalkyl-O-- group wherein heteroarylalkyl is as previously
defined. Exemplary heteroaralkoxy groups include, but are not
limited to, pyrrylethyloxy, furylethyloxy, pyridylmethyloxy,
1,2,4-thiadiazolylpropyloxy, pyrimidylmethyloxy, thienylethyloxy,
isothiazolylbutyloxy, and imidazolyl-2-methylpropyloxy.
[0213] "Heterocycloalkylaryl" refers to an optionally substituted
ring system composed of an aryl radical bearing a heterocycloalkyl
substituent wherein heterocycloalkyl and aryl are as previously
defined. Exemplary heterocycloalkylaryl groups include, but are not
limited to, morpholinylphenyl, piperidinylnaphthyl,
piperidinylphenyl, tetrahydrofuranylphenyl, and
pyrrolidinylphenyl.
[0214] "Alkylheteroaryl" refers to an optionally substituted ring
system composed of a heteroaryl radical bearing an alkyl
substituent wherein heteroaryl and alkyl are as previously defined.
Exemplary alkylheteroaryl groups include, but are not limited to,
methylpyrryl, ethylfuryl, 2,3-dimethylpyridyl,
N-methyl-1,2,4-thiadiazolyl, propylpyrimidyl, 2-butylthienyl,
methylisothiazolyl, 2-ethylimidazolyl, butyltetrazolyl,
5-ethylbenzothienyl, and N-methylindolyl. Alkyheteroaryl groups may
be attached via a carbon or a heteroatom to the rest of the
molecule.
[0215] "Heteroarylaryl" refers to an optionally substituted ring
system composed of an aryl radical bearing a heteroaryl substituent
wherein heteroaryl and aryl are as previously defined. Exemplary
heteroarylaryl groups include, but are not limited to,
pyrrylphenyl, furylnaphthyl, pyridylphenyl,
1,2,4-thiadiazolylnaphthyl, pyrimidylphenyl, thienylphenyl,
isothiazolylnaphthyl, imidazolylphenyl, tetrazolylphenyl,
pyrazinylnaphthyl, pyrimidylphenyl, quinolylphenyl,
isoquinolylnaphthyl, thiophenylphenyl, benzothienylphenyl,
isobenzofurylnaphthyl, pyrazolylphenyl, indolylnaphthyl,
purinylphenyl, carbazolylnaphthyl, benzimidazolylphenyl, and
isoxazolylphenyl. Heteroarylaryl may be attached via a carbon or a
heteroatom to the rest of the molecule.
[0216] "Alkylheteroarylaryl" refers to an optionally substituted
ring system composed of an aryl radical bearing an alkylheteroaryl
substituent and have from about 12 to about 50 carbon atoms (and
all combinations and subcombinations of ranges and specific numbers
of carbon atoms therein), with from about 12 to about 30 carbon
atoms being preferred wherein aryl and alkylheteroaryl are as
previously defined. Exemplary heteroarylaryl groups include, but
are not limited to, methylpyrrylphenyl, ethylfurylnaphthyl,
methylethylpyridylphenyl, dimethylethylpyrimidylphenyl, and
dimethylthienylphenyl.
[0217] Typically, substituted chemical moieties include one or more
substituents that replace hydrogen. Exemplary substituents include,
for example, halo (e.g., F, Cl, Br, I), alkyl, cycloalkyl,
alkylcycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl,
heteroaralkyl, spiroalkyl, heterocycloalkyl, hydroxyl (--OH), oxo
(.dbd.O), alkoxyl, aryloxyl, aralkoxyl, nitro (--NO.sub.2), cyano
(--CN), amino (--NH.sub.2), --N-substituted amino (--NHR''),
--N,N-disubstituted amino (--N(R'')R''), carboxyl (--COOH),
--C(.dbd.O)R'', --OR'', --C(.dbd.O)OR'', --C(.dbd.O)NHSO.sub.2R'',
--NHC(.dbd.O)R'', aminocarbonyl (--C(.dbd.O)NH.sub.2),
--N-substituted aminocarbonyl (--C(.dbd.O)NHR''),
--N,N-disubstituted aminocarbonyl (--C(.dbd.O)N(R'')R''), thiol,
thiolato (SR''), sulfonic acid and its esters (SO.sub.3R''),
phosphonic acid and its mono-esters (P(.dbd.O)OR''OH) and di-esters
(P(.dbd.O)OR''OR''), S(.dbd.O).sub.2R'', S(.dbd.O).sub.2NH.sub.2,
S(.dbd.O).sub.2NHR'', S(.dbd.O).sub.2NR''R'',
SO.sub.2NHC(.dbd.O)R'', NHS(.dbd.O).sub.2R'',
NR''S(.dbd.O).sub.2R'', CF.sub.3, CF.sub.2CF.sub.3,
NHC(.dbd.O)NHR'', NHC(.dbd.O)NR''R'', NR''C(.dbd.O)NHR'',
NR''C(.dbd.O)NR''R'', NR''C(.dbd.O)R'', NR''C(.dbd.N--CN)NR''R'',
and the like. Aryl substituents may also include
(CH.sub.2).sub.pSO.sub.2NR''(CH.sub.2).sub.q and
(CH.sub.2).sub.pCO.sub.2NR''(CH.sub.2).sub.q, where p and q are
independently integers from 0 to 3, where the methylene units are
attached in a 1,2 arrangement yielding substituted aryls of the
type:
##STR00009##
[0218] In relation to the aforementioned substituents, each moiety
R'' can be, independently, any of H, alkyl, cycloalkyl, alkenyl,
aryl, aralkyl, heteroaryl, or heterocycloalkyl, or when (R''(R''))
is attached to a nitrogen atom, R'' and R'' can be taken together
to form a 4- to 8-membered nitrogen heterocycloalkyl ring, wherein
said heterocycloalkyl ring is optionally interrupted by one or more
additional --O--, --S--, --SO, --SO.sub.2--, --NH--, --N(alkyl)-,
or --N(aryl)- groups, for example.
[0219] As used herein, an "*" denotes the presence of a chiral
center in a molecule, wherein one stereoisomeric form (R or S)
predominates, more preferably is substantially enriched, and even
more preferably is enantiomerically pure at a specific center in
the molecule, but the absolute configuration at this center has not
been conclusively established. This can be expressed, for example
in a compound's identification number such as 4*, and indicates
that the stereochemical configuration of at least one chiral center
of the identified compound has not been established. The specific
center is identified within a structure by placing the "*" adjacent
the chiral center in question, such as, for example, in the
structure below.
##STR00010##
[0220] In some compounds, several chiral centers may be present.
The presence of two asterisks "*" in a single structure indicates
that two racemic pairs may be present, but that each pair is
diastereomeric relative to the other pair. As such, the first pair
of enantiomers having two chiral centers may have the
configurations, for example, (R, R) and (S, S). The second pair
then have configurations, for example, (R, S) and (S, R). For
example, compounds 37A and 37B are diastereomeric with respect to
one another, but each is a racemic mixture of its two possible
enantiomers. Their absolute stereochemistry has not been
conclusively established.
[0221] "Ligand" or "modulator" refers to a compound that binds to a
receptor to form a complex, and includes, agonists, partial
agonists, antagonists and inverse agonists.
[0222] "Agonist" refers to a compound that may bind to a receptor
to form a complex that may elicit a full pharmacological response,
which is typically peculiar to the nature of the receptor involved
and which may alter the equilibrium between inactive and active
receptor.
[0223] "Partial agonist" refers to a compound that may bind to a
receptor to form a complex that may elicit only a proportion of the
full pharmacological response, typically peculiar to the nature of
the receptor involved, even if a high proportion of the receptors
are occupied by the compound.
[0224] "Antagonist" refers to a compound that may bind to a
receptor to form a complex that may not elicit any response,
typically in the same manner as an unoccupied receptor, and which
preferably does not alter the equilibrium between inactive and
active receptor.
[0225] "Inverse agonist" refers to a compound that may bind to a
receptor to form a complex that may preferentially stabilize the
inactive conformation of the receptor.
[0226] "Prodrug" refers to compounds specifically designed to
maximize the amount of active species that reaches the desired site
of reaction that are themselves typically inactive or minimally
active for the activity desired, but through biotransformation are
converted into biologically active metabolites.
[0227] "Stereoisomers" refers to compounds that have identical
chemical constitution, but differ as regards the arrangement of the
atoms or groups in space.
[0228] "N-oxide" refers to compounds wherein the basic nitrogen
atom of either a heteroaromatic ring or tertiary amine is oxidized
to give a quaternary nitrogen bearing a positive formal charge and
an attached oxygen atom bearing a negative formal charge.
[0229] "Hydrate" refers to a compound of the present invention
which is associated with water in the molecular form, i.e., in
which the H--OH bond is not split, and may be represented, for
example, by the formula R.H.sub.2O, where R is a compound of the
invention. A given compound may form more than one hydrate
including, for example, monohydrates (R.H.sub.2O), dihydrates
(R.2H.sub.2O), trihydrates (R.3H.sub.2O), and the like.
[0230] "Pharmaceutically acceptable salts" refer to derivatives of
the disclosed compounds wherein the parent compound is modified by
making acid or base salts thereof. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines; alkali or
organic salts of acidic residues such as carboxylic acids; and the
like. The pharmaceutically acceptable salts include the
conventional non-toxic salts or the quaternary ammonium salts of
the parent compound formed, for example, from non-toxic inorganic
or organic acids. For example, such conventional non-toxic salts
include those derived from inorganic acids such as hydrochloric,
hydrobromic, sulfuric, sulfamic, phosphoric, nitric glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and the
like. These physiologically acceptable salts are prepared by
methods known in the art, e.g., by dissolving the free amine bases
with an excess of the acid in aqueous alcohol, or neutralizing a
free carboxylic acid with an alkali metal base such as a hydroxide,
or with an amine.
[0231] Compounds described herein throughout can be used or
prepared in alternate forms. For example, many amino-containing
compounds can be used or prepared as an acid addition salt. Often
such salts improve isolation and handling properties of the
compound. For example, depending on the reagents, reaction
conditions and the like, compounds as described herein can be used
or prepared, for example, as their hydrochloride or tosylate salts.
Isomorphic crystalline forms, all chiral and racemic forms,
N-oxide, hydrates, solvates, and acid salt hydrates, are also
contemplated to be within the scope of the present invention.
[0232] Certain acidic or basic compounds of the present invention
may exist as zwitterions. All forms of the compounds, including
free acid, free base and zwitterions, are contemplated to be within
the scope of the present invention. It is well known in the art
that compounds containing both basic nitrogen atom and acidic
groups often exist in equilibrium with their zwitterionic forms.
Thus, any of the compounds described herein throughout that
contain, for example, both basic nitrogen and acidic groups, also
include reference to their corresponding zwitterions.
[0233] "Effective amount" refers to an amount of a compound as
described herein that may be therapeutically effective to inhibit,
prevent or treat the symptoms of particular disease, disorder,
condition, or side effect. Such diseases, disorders, conditions,
and side effects include, but are not limited to, those
pathological conditions associated with the binding of .delta.
opioid receptor (for example, in connection with the treatment
and/or prevention of pain), wherein the treatment or prevention
comprises, for example, agonizing the activity thereof by
contacting cells, tissues or receptors with compounds of the
present invention. Thus, for example, the term "effective amount,"
when used in connection with compounds of the invention, opioids,
or opioid replacements, for example, for the treatment of pain,
refers to the treatment and/or prevention of the painful condition.
The term "effective amount," when used in connection with compounds
active against gastrointestinal dysfunction, refers to the
treatment and/or prevention of symptoms, diseases, disorders, and
conditions typically associated with gastrointestinal dysfunction.
The term "effective amount," when used in connection with compounds
useful in the treatment and/or prevention of urogenital tract
disorders, refers to the treatment and/or prevention of symptoms,
diseases, disorders, and conditions typically associated with
urogenital tract disorders and other related conditions. The term
"effective amount," when used in connection with compounds useful
in the treatment and/or prevention of immunomodulatory disorders,
refers to the treatment and/or prevention of symptoms, diseases,
disorders, and conditions typically associated with
immunomodulatory disorders and other related conditions. The term
"effective amount," when used in connection with compounds useful
in the treatment and/or prevention of inflammatory disorders,
refers to the treatment and/or prevention of symptoms, diseases,
disorders, and conditions typically associated with inflammatory
disorders and other related conditions. The term "effective
amount," when used in connection with compounds useful in the
treatment and/or prevention of respiratory function disorders,
refers to the treatment and/or prevention of symptoms, diseases,
disorders, and conditions typically associated with respiratory
function disorders and other related conditions. The term
"effective amount," when used in connection with compounds useful
in the treatment and/or prevention of anxiety, mood disorders,
stress-related disorders, and attention deficit hyperactivity
disorder, refers to the treatment and/or prevention of symptoms,
diseases, disorders, and conditions typically associated with
anxiety, mood disorders, stress-related disorders, attention
deficit hyperactivity disorder and other related conditions. The
term "effective amount," when used in connection with compounds
useful in the treatment and/or prevention of sympathetic nervous
system disorders, refers to the treatment and/or prevention of
symptoms, diseases, disorders, and conditions typically associated
with sympathetic nervous system disorders and other related
conditions. The term "effective amount," when used in connection
with compounds useful in the treatment and/or prevention of tussis,
refers to the treatment and/or prevention of symptoms, diseases,
disorders, and conditions typically associated with tussis and
other related conditions. The term "effective amount," when used in
connection with compounds useful in the treatment and/or prevention
of motor disorders, refers to the treatment and/or prevention of
symptoms, diseases, disorders, and conditions typically associated
with motor disorders and other related conditions. The term
"effective amount," when used in connection with compounds useful
in the treatment of traumatic injuries of the central nervous
system, refers to the treatment and/or prevention of symptoms,
diseases, disorders, and conditions typically associated with the
central nervous system and other related conditions. The term
"effective amount," when used in connection with compounds useful
in the treatment and/or prevention of stroke, cardiac arrhythmia or
glaucoma, refers to the treatment and/or prevention of symptoms,
diseases, disorders, and conditions typically associated with
stroke, cardiac arrhythmia, glaucoma and other related conditions.
The term "effective amount," when used in connection with compounds
useful in the treatment and/or prevention of sexual dysfunction,
refers to the treatment and/or prevention of symptoms, diseases,
disorders, and conditions typically associated with sexual
dysfunction and other related conditions. The term "effective
amount," when used in connection with compounds useful in improving
organ and cell survival, refers to refers to the maintenance and/or
improvement of a minimally-acceptable level of organ or cell
survival, including organ preservation. The term "effective
amount," when used in connection with compounds useful in the
treatment and/or prevention of myocardial infarction, refers to the
minimum level of compound necessary to provide cardioprotection
after myocardial infarction. The term "effective amount," when used
in connection with compounds useful in the treatment and/or
prevention of shock, brain edema, cerebral ischemia, cerebral
deficits subsequent to cardiac bypass surgery and grafting,
systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease,
epilepsy, and rejection in organ transplants and skin grafts,
refers to the treatment and/or prevention of symptoms, diseases,
disorders, and conditions typically associated with shock, brain
edema, cerebral ischemia, cerebral deficits subsequent to cardiac
bypass surgery and grafting, systemic lupus erythematosus,
Hodgkin's disease, Sjogren's disease, epilepsy, and rejection in
organ transplants and skin grafts and other related conditions. The
term "effective amount," when used in connection with compounds
useful in the treatment of substance addiction, refers to the
treatment of symptoms, diseases, disorders, and conditions
typically associated with substance addiction and other related
conditions. The term "effective amount," when used in connection
with compounds useful in reducing the need for anesthia or
producing and/or maintaining an anaesthetic state, refers to the
production and/or maintenance of a minimally-acceptable anaesthetic
state.
[0234] "Pharmaceutically acceptable" refers to those compounds,
materials, compositions, and/or dosage forms that are, within the
scope of sound medical judgment, suitable for contact with the
tissues of human beings and animals without excessive toxicity,
irritation, allergic response, or other problems or complications
commensurate with a reasonable benefit/risk ratio. The term
specifically encompasses veterinary uses.
[0235] "In combination with," "combination therapy," and
"combination products" refer, in certain embodiments, to the
concurrent administration to a patient of a compound of the
invention including, for example, a compound of formulas I, II,
III, IV, V, VI, VII, VIII, IX, X, XI, XII, and/or XIII, and one or
more additional agents including, for example, an opioid, an
anaesthetic agent (such as for example, an inhaled anesthetic,
hypnotic, anxiolytic, neuromuscular blocker and opioid), an
antiParkinson's agent (for example, in the case of treating or
preventing a motor disorder, particularly Parkinson's disease), an
antidepressant (for example, in the case of treating or preventing
a mood disorder, particularly depression), an agent for the
treatment of incontinence (for example, in the case of treating or
preventing a urogenital tract disorder), an agent for the treatment
of pain, including neuralgias or neuropathic pain, and/or other
optional ingredients (including, for example, antibiotics,
antivirals, antifangals, anti-inflammatories, anesthetics and
mixtures thereof). When administered in combination, each component
may be administered at the same time or sequentially in any order
at different points in time. Thus, each component may be
administered separately but sufficiently closely in time so as to
provide the desired therapeutic effect.
[0236] "Dosage unit" refers to physically discrete units suited as
unitary dosages for the particular individual to be treated. Each
unit may contain a predetermined quantity of active compound(s)
calculated to produce the desired therapeutic effect(s) in
association with the required pharmaceutical carrier. The
specification for the dosage unit forms of the invention may be
dictated by (a) the unique characteristics of the active
compound(s) and the particular therapeutic effect(s) to be
achieved, and (b) the limitations inherent in the art of
compounding such active compound(s).
[0237] "Pain" refers to the perception or condition of unpleasant
sensory or emotional experience, associated with actual or
potential tissue damage or described in terms of such damage.
"Pain" includes, but is not limited to, two broad categories of
pain: acute and chronic pain (Buschmann, H.; Christoph, T;
Friderichs, E.; Maul, C.; Sundermann, B; eds.; Analgesics,
Wiley-VCH, Verlag GMbH & Co. KgaA, Weinheim; 2002; Jain, K. K.
"A Guide to Drug Evaluation for Chronic Pain"; Emerging Drugs,
5(2), 241-257 (2000)) Non-limiting examples of pain include, for
example, nociceptive pain, inflammatory pain, visceral pain,
somatic pain, neuralgias, neuropathic pain, AIDS pain, cancer pain,
phantom pain, and psychogenic pain, and pain resulting from
hyperalgesia, pain caused by rheumatoid arthritis, migraine,
allodynia and the like.
[0238] "Gastrointestinal dysfunction" refers collectively to
maladies of the stomach, small and large intestine. Non-limiting
examples of gastrointestinal dysfunction include, for example,
diarrhea, nausea, emesis, post-operative emesis, opioid-induced
emesis, irritable bowel syndrome, opioid-bowel dysfunction,
inflammatory bowel disease, colitis, increased gastric motility,
increased gastric emptying, stimulation of small intestinal
propulsion, stimulation of large intestinal propulsion, decreased
amplitude of non-propulsive segmental contractions, disorders
associated with sphincter of Oddi, disorders associated with anal
sphincter tone, impaired reflex relaxation with rectal distention,
disorders associated with gastric, biliary, pancreatic or
intestinal secretions, changes to the absorption of water from
bowel contents, gastro-esophageal reflux, gastroparesis, cramping,
bloating, distension, abdominal or epigastric pain and discomfort,
non-ulcerogenic dyspepsia, gastritis, or changes to the absorption
of orally administered medications or nutritive substances.
[0239] "Urogenital tract disorders" refers collectively to maladies
of the urinary and genital apparati. Non-limiting examples of
urogenital tract disorders include incontinence (i.e., involuntary
loss of urine) such as stress urinary incontinence, urge urinary
incontinence and benign prostatic hyperplasia, overactive bladder
disorder, urinary retention, renal colic, glomerulonephritis, and
interstitial cystitis.
[0240] "Overactive bladder disorder" refers to a condition with
symptoms of urgency with or without incontinence, and is typically
associated with increased urinary frequency and nocturia.
Overactive bladder disorders are typically associated with
urodynamic finding of involuntary bladder contractions, generally
referred to as bladder instability.
[0241] "Immunomodulatory disorders" refers collectively to maladies
characterized by a compromised or over-stimulated immune system.
Non-limiting examples of immunomodulatory disorders include
autoimmune diseases (such as arthritis, autoimmune disorders
associated with skin grafts, autoimmune disorders associated with
organ transplants, and autoimmune disorders associated with
surgery), collagen diseases, allergies, side effects associated
with the administration of an anti-tumor agent, side effects
associated with the administration of an antiviral agent, multiple
sclerosis and Guillain-Barre syndrome.
[0242] "Inflammatory disorders" refers collectively to maladies
characterized by cellular events in injured tissues. Non-limiting
examples of inflammatory diseases include arthritis, psoriasis,
asthma, and inflammatory bowel disease.
[0243] "Respiratory function disorders" refers to conditions in
which breathing and/or airflow into the lung is compromised.
Non-limiting examples of respiratory function disorders include
asthma, apnea, tussis, chronic obstruction pulmonary disease, and
lung edema.
[0244] "Lung edema" refers to the presence of abnormally large
amounts of fluid in the intercellular tissue spaces of the
lungs.
[0245] "Anxiety" refers to the unpleasant emotional state
consisting of psychophysiological responses to anticipation of
real, unreal or imagined danger, ostensibly resulting from
unrecognized intrapsychic conflict.
[0246] "Mood disorders" refers to disorders that have a disturbance
in mood as their predominant feature, including depression, bipolar
manic-depression, borderline personality disorder, and seasonal
affective disorder.
[0247] "Depression" refers to a mental state of depressed mood
characterized by feelings of sadness, despair and discouragement,
including the blues, dysthymia, and major depression.
[0248] "Stress-related disorders" refer collectively to maladies
characterized by a state of hyper- or hypoarousal with hyper- and
hypovigilance. Non-limiting examples of stress-related disorders
include post-traumatic stress disorder, panic disorder, generalized
anxiety disorder, social phobia, and obsessive-compulsive
disorder.
[0249] "Attention deficit hyperactivity disorder" refers to a
condition characterized by an inability to control behavior due to
difficulty in processing neural stimuli.
[0250] "Sympathetic nervous system disorders" refer collectively to
maladies characterized by disturbances of the autonomic nervous
system. Non-limiting examples of sympathetic nervous system
disorders include hypertension, and the like.
[0251] "Tussis" refers to a coughing condition, and "antitussive"
agents refer to those materials that modulate the coughing
response.
[0252] "Motor disorders" refers to involuntary manifestations of
hyper or hypo muscle activity and coordination Non-limiting
examples of motor disorders include tremors, Parkinson's disease,
tourette syndrome, parasomnias (sleep disorders) including restless
leg syndrome, postoperative shivering and dyskinesia.
[0253] "Traumatic injury of the central nervous system" refers to a
physical wound or injury to the spinal cord or brain.
[0254] "Stroke" refers to a condition due to the lack of oxygen to
the brain.
[0255] "Cardiac arrhythmia" refers to a condition characterized by
a disturbance in the electrical activity of the heart that
manifests as an abnormality in heart rate or heart rhythm. Patients
with a cardiac arrhythmia may experience a wide variety of symptoms
ranging from palpitations to fainting.
[0256] "Glaucoma" refers collectively to eye diseases characterized
by an increase in intraocular pressure that causes pathological
changes in the optic disk and typical defects in the field of
vision.
[0257] "Sexual dysfunction" refers collectively to disturbances,
impairments or abnormalities of the functioning of the male or
female sexual organs, including, but not limited to premature
ejaculation and erectile dysfunction.
[0258] "Cardioprotection" refers to conditions or agents that
protect or restore the heart from dysfunction, heart failure and
reperfusion injury.
[0259] "Myocardial infarction" refers to irreversible injury to
heart muscle caused by a local lack of oxygen.
[0260] "Addiction" refers to a pattern of compulsive substance
abuse (alcohol, nicotine, or drug) characterized by a continued
craving for the substance and, in some cases, the need to use the
substance for effects other than its prescribed or legal use.
[0261] "Anaesthetic state" refers to the state of the loss of
feeling or sensation, including not only the loss of tactile
sensibility or of any of the other senses, but also to the loss of
sensation of pain, as it is induced to permit performance of
surgery or other painful procedures, and specifically including
amnesia, analgesia, muscle relaxation and sedation.
[0262] "Improving organ and cell survival" refers to the
maintenance and/or improvement of a minimally-acceptable level of
organ or cell survival.
[0263] "Patient" refers to animals, including mammals, preferably
humans.
[0264] "Side effect" refers to a consequence other than the one(s)
for which an agent or measure is used, as the adverse effects
produced by a drug, especially on a tissue or organ system other
then the one sought to be benefited by its administration. In the
case, for example, of opioids, the term "side effect" may refer to
such conditions as, for example, constipation, nausea, vomiting,
dyspnea and pruritus.
[0265] When any variable occurs more than one time in any
constituent or in any formula, its definition in each occurrence is
independent of its definition at every other occurrence.
Combinations of substituents and/or variables are permissible only
if such combinations result in stable compounds.
[0266] It is believed the chemical formulas and names used herein
correctly and accurately reflect the underlying chemical compounds.
However, the nature and value of the present invention does not
depend upon the theoretical correctness of these formulae, in whole
or in part. Thus it is understood that the formulas used herein, as
well as the chemical names attributed to the correspondingly
indicated compounds, are not intended to limit the invention in any
way, including restricting it to any specific tautomeric form or to
any specific optical or geometric isomer, except where such
stereochemistry is clearly defined.
[0267] In certain preferred embodiments, the compounds,
pharmaceutical compositions and methods of the present invention
may involve a peripheral .delta. opioid modulator compound. The
term "peripheral" designates that the compound acts primarily on
physiological systems and components external to the central
nervous system. In preferred form, the peripheral .delta. opioid
modulator compounds employed in the methods of the present
invention exhibit high levels of activity with respect to
peripheral tissue, such as, gastrointestinal tissue, while
exhibiting reduced, and preferably substantially no, CNS activity.
The phrase "substantially no CNS activity," as used herein, means
that less than about 50% of the pharmacological activity of the
compounds employed in the present methods is exhibited in the CNS,
preferably less than about 25%, more preferably less than about
10%, even more preferably less than about 5% and most preferably 0%
of the pharmacological activity of the compounds employed in the
present methods is exhibited in the CNS.
[0268] Furthermore, it is preferred in certain embodiments of the
invention that the .delta. opioid modulator compound does not
substantially cross the blood-brain barrier. The phrase "does not
substantially cross," as used herein, means that less than about
20% by weight of the compound employed in the present methods
crosses the blood-brain barrier, preferably less than about 15% by
weight, more preferably less than about 10% by weight, even more
preferably less than about 5% by weight and most preferably 0% by
weight of the compound crosses the blood-brain barrier. Selected
compounds can be evaluated for CNS penetration, for example, by
determining plasma and brain levels following i.v.
administration.
[0269] Accordingly, in one embodiment, the invention provides
compounds of formula I:
##STR00011##
[0270] wherein:
[0271] R.sup.1 and R.sup.3 are each independently H, alkyl,
alkenyl, alkynyl, or aryl, or R.sup.1 and R.sup.3 when taken
together with the atoms through which they are connected, form a 4-
to 8-membered heterocycloalkyl ring;
[0272] R.sup.2 is H, alkyl, alkenyl, alkynyl, cycloalkyl,
alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R.sup.1 and
R.sup.2 when taken together with the atoms through which they are
connected, form a 4- to 8-membered heterocycloalkyl ring, or
R.sup.2 and R.sup.3 when taken together with the atoms through
which they are connected, form a 4- to 8-membered heterocycloalkyl
ring; [0273] provided that R.sup.2 is not
[0273] ##STR00012## [0274] each R.sup.a is independently H or
alkyl; [0275] each R.sup.b is independently H, alkyl, or aryl;
[0276] n is the integer 0, 1, 2 or 3; [0277] A and B are each
independently H, fluoro, or alkyl, or together form a double bond
between the carbon atoms to which they are attached; [0278] R.sup.4
is --Y--W; [0279] Y is a single bond, C(R.sup.a)(R.sup.b),
C(R.sup.a)(R.sup.b)C(R.sup.a)(R.sup.b), or
C(R.sup.a)(R.sup.b)C(R.sup.a)(R.sup.b)C(R.sup.a)(R.sup.b); [0280] W
is aryl or heteroaryl; [0281] X is --CH.sub.2--, --O--, --S--,
--SO, --SO.sub.2, or --N(R.sup.5)--; [0282] R.sup.5 is H, alkyl,
cycloalkyl, --(CH.sub.2)-alkenyl, --(CH.sub.2)-alkynyl, aryl,
--COR.sup.b, or --SO.sub.2R.sup.b; and [0283] J forms a 6-membered
aryl or a 5- or 6-membered heteroaryl ring when taken together with
the carbon atoms to which it is attached; [0284] provided that
when: [0285] (a) J taken together with the carbon atoms to which it
is attached forms a phenyl ring substituted with 0-3 groups
selected from the group consisting of: [0286] halogen, [0287]
hydroxy, [0288] --S--C.sub.1-4 alkyl, [0289] C.sub.1-4 alkyl, and
[0290] C.sub.1-4 alkoxy, the latter two optionally substituted with
one or more halogens or with C.sub.1-4 alkoxy; [0291] W is
unsubstituted naphthyl, or phenyl substituted with 0-3 groups
selected from the group consisting of: [0292] halogen, [0293]
C.sub.1-6 alkyl, [0294] C.sub.1-6 alkoxy, [0295] phenyl, [0296]
phenoxy, [0297] 1,3-benzodioxazolyl, or
2,2-difluoro-1,3-benzodioxazolyl, [0298] --NH.sub.2, [0299]
--N(C.sub.1-4 alkyl).sub.2, and [0300] pyrrolyl; [0301] n is 1,
[0302] R.sup.1 and R.sup.3 are each H, [0303] A and B together form
a double bond between the carbon atoms to which they are attached,
[0304] Y is a single bond; and [0305] X is --O--; [0306] then
R.sup.2 is other than H or methyl; and [0307] provided that when:
[0308] (b) J taken together with the carbon atoms to which it is
attached forms a phenyl ring, [0309] W is phenyl substituted with
0-3 groups selected from the group consisting of: [0310] fluoro,
[0311] hydroxy, [0312] C.sub.1-6 alkoxy optionally substituted with
one or more fluoro, [0313] C.sub.2-6 alkenyloxy, and [0314]
--S--C.sub.1-4 alkyl, [0315] n is 1, [0316] R.sup.1 and R.sup.3 are
each H, [0317] A and B together form a double bond between the
carbon atoms to which they are attached, [0318] Y is a single bond;
and [0319] X is --O--; [0320] then R.sup.2 is other than H or
benzyl; and
[0321] provided that when: [0322] (c) J forms a 6-membered aryl
ring, it is not substituted with:
[0322] ##STR00013## [0323] or a stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, or N-oxide thereof.
[0324] In certain preferred embodiments of formula I compounds, J
is --C-D-E- or --C-D-E-F--;
[0325] wherein C, D, E and F are each independently --O--, --S--,
--SO--, --SO.sub.2--, .dbd.N--, .dbd.CH-- or --NH--;
[0326] wherein the latter two moieties are each independently
optionally substituted;
[0327] provided that each --O-- ring atom within J is directly
attached only to carbon or nitrogen atoms;
[0328] provided that each --S-- ring atom within J is directly
attached only to carbon or nitrogen atoms; and
[0329] provided that when J is --C-D-E-F--, at least one of C, D, E
and F is .dbd.CH--.
[0330] In certain preferred embodiments of formula I compounds, X
is --CH.sub.2--, --O--, --S--, --SO, or --SO.sub.2, more preferably
--CH.sub.2-- or --O--, still more preferably --O--.
[0331] In other preferred embodiments of formula I compounds, J,
taken together with the carbon atoms to which it is attached, forms
an optionally substituted 6-membered aryl ring, preferably,
optionally substituted phenyl, or an optionally substituted 5- or
6-membered heteroaryl ring. Preferably, J is optionally
substituted, including fully substituted, phenyl, 3-pyridinyl,
4-pyridinyl, 5-pyridinyl, 6-pyridinyl, thienyl, oxazolyl,
1,2,5-oxadiazolyl, imidazolyl, N-methylimidazolyl or indolyl.
[0332] In certain preferred embodiments of formula I compounds, at
least one of R.sup.1 and R.sup.3 is H. In other preferred
embodiments of formula I, R.sup.1 and R.sup.3 are each
independently H, alkyl, alkenyl, or alkynyl; more preferably
R.sup.1 and R.sup.3 are each independently H, C.sub.1-C.sub.3
alkyl, C.sub.2-C.sub.3 alkenyl, or C.sub.2-C.sub.3 alkynyl; even
more preferably R.sup.1 and R.sup.3 are each independently H,
C.sub.1-C.sub.3 alkyl, or C.sub.2-C.sub.3 alkenyl.
[0333] In certain preferred embodiments of formula I compounds,
R.sup.2 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl,
aralkyl, or heteroarylalkyl, more preferably H or alkyl, more
preferably alkyl, even more preferably lower alkyl.
[0334] In certain preferred embodiments of formula I compounds, n
is the integer 1.
[0335] In certain preferred embodiments of formula I compounds, A
and B are taken together from a double bond between the carbon
atoms to which they are attached. More preferably, A and B are
taken together to form a double bond between the carbon atoms to
which they are attached and n is the integer 1. Even more
preferably, A and B are taken together to form a double bond
between the carbon atoms to which they are attached, n is the
integer 1 and at least one of R.sup.1 and R.sup.3 is H.
[0336] In certain preferred embodiments of formula I compounds, A
and B are each H. More preferably, A and B are each H and n is the
integer 1. Even more preferably, A and B are each H, n is the
integer 1 and at least one of R.sup.1 and R.sup.3 is H.
[0337] In certain preferred embodiments of formula I compounds,
R.sup.4 is aryl substituted with --C(.dbd.O)NR.sup.11R.sup.12,
wherein:
[0338] R.sup.11 is H, alkyl, cycloalkyl, heterocycloalkyl,
alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl,
heteroarylalkyl, or COR.sup.12;
[0339] R.sup.12 is H, alkyl, cycloalkyl, heterocycloalkyl,
alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl,
or heteroarylalkyl, or R.sup.11 and R.sup.12 are taken together
with the nitrogen atom to which they are attached to form a 4- to
8-membered heterocycloalkyl ring, wherein 1 or 2 of the
heterocycloalkyl ring carbon atoms independently may be optionally
replaced by --O--, --S--, --SO--, --SO.sub.2--, --NH--,
--N(alkyl)-, or --N(aryl)- groups.
[0340] In other embodiments, the invention provides compounds of
formula II:
##STR00014##
[0341] wherein: [0342] R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are
each independently H or --(CH.sub.2).sub.mR.sup.10; [0343] m is the
integer 0, 1, 2, 3, or 4; [0344] each R.sup.10 is independently
alkyl, halo, perhaloalkyl, --OR.sup.5, --OCF.sub.2H, --OCF.sub.3,
--CN, --CO.sub.2R.sup.5, --C(.dbd.O)NR.sup.11R.sup.12,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2NR.sup.11R.sup.12,
--NR.sup.11R.sup.12, --NR.sup.14C(.dbd.O)R.sup.15,
--NR.sup.14S(.dbd.O).sub.2R.sup.15, aryl, or heteroaryl; [0345]
each R.sup.11 is independently H, alkyl, cycloalkyl,
heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl,
heteroaryl, aralkyl, heteroarylalkyl, or COR.sup.12; [0346] each
R.sup.12 is independently H, alkyl, cycloalkyl, heterocycloalkyl,
alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl,
or heteroarylalkyl, or R.sup.11 and R.sup.12 taken together with
the nitrogen atom to which they are attached form a 4- to
8-membered heterocycloalkyl ring, wherein 1 or 2 of the
heterocycloalkyl ring carbon atoms independently may be optionally
replaced by --O--, --S--, --SO--, --SO.sub.2--, --NH--,
--N(alkyl)-, or --N(aryl)- groups; [0347] each R.sup.13 is
independently --OH, alkyl, aryl, aralkyl, heteroaryl,
heteroarylalkyl, cycloalkyl, or alkylcycloalkyl; [0348] each
R.sup.14 is independently H, alkyl, cycloalkyl, heterocycloalkyl,
alkylcycloalkyl, aryl, heteroaryl, alkylheterocycloalkyl, aralkyl,
or heteroarylalkyl; and [0349] each R.sup.15 is independently
alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl,
alkylcycloalkyl, heterocycloalkyl, or alkylheterocycloalkyl.
[0350] In certain preferred embodiments of formula II compounds,
R.sup.1 and R.sup.3 are each H. In certain preferred embodiments of
formula II, R.sup.4 is aryl substituted with
--C(.dbd.O)NR.sup.11R.sup.12.
[0351] In yet other embodiments of formula I compounds, the
invention provides compounds of formula III:
##STR00015##
[0352] wherein: [0353] R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are
each independently H or --(CH.sub.2).sub.mR.sup.10; [0354] m is the
integer 0, 1, 2, 3 or 4; [0355] each R.sup.10 is independently
alkyl, halo, perhaloalkyl, --OR.sup.5, --OCF.sub.2H, --OCF.sub.3,
--CN, --CO.sub.2R.sup.5, --C(.dbd.O)NR.sup.11R.sup.12,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2NR.sup.11R.sup.12,
--NR.sup.11R.sup.12, --NR.sup.14C(.dbd.O)R.sup.15,
--NR.sup.14S(.dbd.O).sub.2R.sup.15, aryl, or heteroaryl; [0356]
each R.sup.11 is independently H, alkyl, cycloalkyl,
heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl,
heteroaryl, aralkyl, heteroarylalkyl, or COR.sup.12; [0357] each
R.sup.12 is independently H, alkyl, cycloalkyl, heterocycloalkyl,
alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl,
or heteroarylalkyl, or R.sup.11 and R.sup.12 taken together with
the nitrogen atom to which they are attached form a 4- to
8-membered heterocycloalkyl ring, wherein 1 or 2 of the
heterocycloalkyl ring carbon atoms independently may be optionally
replaced by --O--, --S--, --SO--, --SO.sub.2--, --NH--,
--N(alkyl)-, or --N(aryl)- groups; [0358] each R.sup.13 is
independently --OH, alkyl, aryl, aralkyl, heteroaryl,
heteroarylalkyl, cycloalkyl, or alkylcycloalkyl; [0359] each
R.sup.14 is independently H, alkyl, cycloalkyl, heterocycloalkyl,
alkylcycloalkyl, aryl, heteroaryl, alkylheterocycloalkyl, aralkyl,
or heteroarylalkyl; and [0360] each R.sup.15 is independently
alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl,
alkylcycloalkyl, heterocycloalkyl, or alkylheterocycloalkyl.
[0361] In certain preferred embodiments of formula II compounds,
R.sup.1 and R.sup.3 are each H.
[0362] In certain preferred embodiments of formula II compounds,
R.sup.4 is aryl substituted with --C(.dbd.O)NR.sup.11R.sup.12.
[0363] In certain preferred embodiments of the invention, the
compound is selected from the group consisting of: [0364]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-piperid-
ine]; [0365]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-6-fluoro-spiro[2H,1-benzopyran-2,4-
'-piperidine]hydrochloride; [0366]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-6-hydroxyspiro[2H,1-benzopyran-2,4-
'-piperidine]; [0367]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-3,4-dihydrospiro[2H,1-benzopyran-2-
,4'-piperidine]hydrochloride; [0368]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-N-methyl-spiro[2H,1-benzopyran-2,4-
'-piperidine]; [0369]
4-[(4-N-ethylaminocarbonyl)phenyl]spiro[2H,1-benzopyran-2,4'-piperidine];
[0370]
4-[(4-N-propyl-N-cyclopropylmethylaminocarbonyl)phenyl]-spiro[2H,1-
-benzopyran-2,4'-piperidine]; [0371]
4-[4-(isoindolineaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-piperid-
ine]; [0372]
4-[4-(4-carboxypiperidineaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-
-piperidine]; [0373]
4-[4-(2H-tetrazolyl)phenyl]-spiro[2H,1-benzopyran-2,4'-piperidine];
[0374]
4-[4-(4-carboxypropyl-tetrazol-2-yl)phenyl]-spiro[2H,1-benzopyran--
2,4'-piperidine]; [0375]
4-(3-pyridyl)-spiro[2H,1-benzopyran-2,4'-piperidine]; [0376]
4-[4-(methanesulfonyl)-phenyl]-spiro[2H,1-benzopyran-2,4'-piperidine];
and [0377]
4-[(4-N,N-diethylaminocarbonyl)phenyl]spiro[2H,1-benzopyran-2,4'-nortropi-
ne]; or
[0378] a stereoisomer, prodrug, pharmaceutically acceptable salt,
hydrate, solvate, acid salt hydrate, or N-oxide thereof.
[0379] In other aspects, the invention is related to compounds of
formula IV:
##STR00016##
[0380] wherein: [0381] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0382] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0383] each R.sup.d is
independently H, alkyl, or aryl; [0384] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0385] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0386] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0387] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0388] each k is independently 1,
2, or 3; [0389] p is 0, 1, 2 or 3; [0390] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0391] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0392] G is H or alkyl; [0393]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0394] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0395] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0396]
provided that when: [0397] (a) J.sup.2 taken together with the
carbon atoms to which it is attached forms a 6- to 10-membered aryl
ring substituted with 0-3 groups selected from the group consisting
of: [0398] halogen, [0399] hydroxy, [0400] --SH, [0401]
--C(.dbd.O)--H [0402] --S--C.sub.1-4alkyl, [0403]
--NHS(.dbd.O).sub.2--C.sub.1-4 alkyl, [0404]
--NHS(.dbd.O).sub.2--H, [0405] --N(C.sub.1-4
alkyl)S(.dbd.O).sub.2--H, [0406] C.sub.1-4 alkyl, and [0407]
C.sub.1-4 alkoxy, the latter two optionally substituted with one or
more halogens or with C.sub.1-4 alkoxy; [0408] W.sup.2 is phenyl
substituted with 0-3 groups selected from the group consisting of:
[0409] halogen, [0410] cyano, [0411] hydroxy, [0412] C.sub.1-6
alkyl optionally substituted with one or more halogens, [0413]
C.sub.1-6 alkoxy optionally substituted with one or more halogens
or with C.sub.3-6 cycloalkyl, [0414] C.sub.2-6 alkenyloxy, [0415]
C.sub.2-6 alkynyloxy, [0416] C.sub.3-6 cycloalkyloxy, [0417]
C.sub.6-12 aryloxy, [0418] aralkoxy, [0419] heteroaryloxy, [0420]
heteroaralkoxy, [0421] heterocycloalkyl substituted with alkoxy,
[0422] --SH, [0423] --S--C.sub.1-4 alkyl, [0424] --NH.sub.2, [0425]
--N.dbd.C(aryl).sub.2, [0426] --N(H)C.sub.1-4 alkyl, [0427]
--N(C.sub.1-4 alkyl).sub.2, [0428] --OS(.dbd.O).sub.2--C.sub.1-4
alkyl optionally substituted with one or more halogens, [0429]
--OS(.dbd.O).sub.2--C.sub.6-12 aryl optionally substituted with
C.sub.1-4 alkyl, [0430] --NHS(.dbd.O).sub.2--C.sub.1-4 alkyl,
[0431] --N(C.sub.1-4 alkyl)S(.dbd.O).sub.2--C.sub.1-4 alkyl, [0432]
--NHS(.dbd.O).sub.2--H, and [0433] --N(C.sub.1-4
alkyl)S(.dbd.O).sub.2--H; [0434] p and s are each 1, [0435]
R.sup.e, R.sup.f, R.sup.23, R.sup.24, and G are each H, [0436]
A.sup.2 and B.sup.2 together form a double bond, [0437] Y.sup.2 is
a single bond; and [0438] X.sup.2 is --O--; [0439] then Z is other
than:
##STR00017##
[0439] wherein t is an integer from 1 to 20; and [0440] provided
that when: [0441] (b) J.sup.2 taken together with the carbon atoms
to which it is attached forms a phenyl ring substituted with 0-3
groups selected from the group consisting of: [0442] halogen,
[0443] hydroxy, [0444] --S--C.sub.1-4 alkyl, [0445] C.sub.1-4
alkyl, and [0446] C.sub.1-4 alkoxy, the latter two optionally
substituted with one or more halogens or with C.sub.1-4 alkoxy;
[0447] W.sup.2 is unsubstituted naphthyl, or phenyl substituted
with 0-3 groups selected from the group consisting of: [0448]
halogen, [0449] C.sub.1-6 alkyl, [0450] C.sub.1-6 alkoxy, [0451]
phenyl, [0452] phenoxy, [0453] 1,3-benzodioxazolyl, or
2,2-difluoro-1,3-benzodioxazolyl fluoro, [0454] --NH.sub.2, [0455]
--N(C.sub.1-4 alkyl).sub.2, and [0456] pyrrolyl; [0457] p and s are
each 1, [0458] R.sup.e, R.sup.f, R.sup.23, R.sup.24, and G are each
H, [0459] A.sup.2 and B.sup.2 together form a double bond, [0460]
Y.sup.2 is a single bond; and [0461] --X.sup.2 is --O--; [0462]
then Z is other than:
##STR00018##
[0462] and [0463] provided that when: [0464] (c) J.sup.2 taken
together with the carbon atoms to which it is attached forms
unsubstituted phenyl, [0465] W.sup.2 is phenyl substituted with 0-3
groups selected from the group consisting of: [0466] fluoro, [0467]
hydroxy, [0468] C.sub.1-6 alkoxy optionally substituted with one or
more fluoro, [0469] C.sub.2-6 alkenyloxy, and [0470] --S--C.sub.1-4
alkyl, [0471] p and s are each 1, [0472] R.sup.e, R.sup.f,
R.sup.23, R.sup.24, and G are each H, [0473] A.sup.2 and B.sup.2
together form a double bond, [0474] Y.sup.2 is a single bond; and
[0475] X.sup.2 is --O--; [0476] then Z is other than:
##STR00019##
[0476] and [0477] provided that when: [0478] (d) J.sup.2 taken
together with the carbon atoms to which it is attached forms a
6-membered aryl ring substituted with:
##STR00020##
[0478] then Z is other than --N(R.sup.25)-- or --CH(NH.sub.2)--;
[0479] or a stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.
[0480] In certain preferred embodiments of compounds of formula IV,
Y.sup.2 is a single bond.
[0481] In some preferred embodiments of compounds of formula IV,
R.sup.c, R.sup.e, and R.sup.f are each independently H or lower
alkyl; more preferably H or C.sub.1-C.sub.3 alkyl; more preferably
still H or methyl; yet more preferably, each is H. In some
alternative preferred embodiments, at least one of R.sup.c,
R.sup.e, and R.sup.f is H.
[0482] In other preferred embodiments of compounds of formula IV,
each R.sup.d is independently H, alkyl, or phenyl, the later two
optionally substituted; more preferably H, alkyl, or unsubstituted
phenyl; yet more preferably H or alkyl; still more preferably H or
methyl; most preferably H.
[0483] In certain preferred embodiments of compounds of formula IV,
W.sup.2 is aryl, alkaryl, heteroaryl, alkylheteroaryl,
heteroarylaryl, or alkylheteroarylaryl, each of which is optionally
substituted. More preferably W.sup.2 is aryl, alkaryl, heteroaryl,
or heteroarylaryl, each of which is optionally substituted. Even
more preferably, W.sup.2 is phenyl, pyridyl, tetrazolylphenyl,
benzothienyl, benzofuranyl, thienyl, furanyl, indolyl, thiazolyl,
pyrimidinyl, or diazolyl, each of which is optionally substituted;
with optionally substituted phenyl or optionally substituted
pyridyl being still more preferred.
[0484] As noted above, the ring systems in W.sup.2 are optionally
substituted. In preferred embodiments, the ring systems in W.sup.2
are optionally substituted with at least one of alkyl, aryl,
hydroxyl, carboxyl, N,N-dialkylaminocarbonyl,
--S(.dbd.O).sub.2--N(alkyl).sub.2, --N(H)S(.dbd.O).sub.2-alkyl, and
--N(alkyl)C(.dbd.O)-alkyl. In particularly preferred embodiments,
W.sup.2 is:
##STR00021##
[0485] wherein W.sup.2 is optionally substituted with at least one
of alkyl, aryl, hydroxyl, carboxyl, N,N-dialkylaminocarbonyl,
--S(.dbd.O).sub.2--N(alkyl).sub.2, --N(H)S(.dbd.O).sub.2-alkyl, and
--N(alkyl)C(.dbd.O)-alkyl; and L is H or alkyl.
[0486] In other preferred embodiments of compounds of formula IV,
R.sup.23 and R.sup.24 are each independently H or alkyl, alkenyl,
alkynyl, or aryl, each of the latter four groups being optionally
substituted. More preferably, R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, or alkynyl; with H or alkyl being
yet more preferred and H or methyl being still more preferred. In
particularly preferred embodiments, R.sup.23 and R.sup.24 are H. In
alternate preferred embodiments of compounds of formula IV,
R.sup.23 and R.sup.24 are each independently H, alkyl, alkenyl, or
alkynyl; more preferably R.sup.23 and R.sup.24 are each
independently H, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, or
C.sub.2-C.sub.3 alkynyl; more preferably still R.sup.23 and
R.sup.24 are each independently H, C.sub.1-C.sub.3 alkyl, or
C.sub.2-C.sub.3 alkenyl. In still other preferred embodiments, at
least one of R.sup.23 and R.sup.24 is H.
[0487] In certain preferred embodiments of compounds of formula IV,
Z is --N(R.sup.25)--, --CH(N(R.sup.c)(R.sup.d))--, or --O--; more
preferably --N(R.sup.25)-- or --O--; yet more preferably
--N(R.sup.25)--. In other preferred embodiments of compounds of
formula IV, Z is --N(R.sup.25)--, --CH(OH)--, or
--CH(N(R.sup.c)(R.sup.d)).
[0488] In preferred embodiments of compounds of formula IV,
R.sup.25 is H, alkyl, alkenyl, alkynyl, cycloalkyl,
alkylcycloalkyl, aralkyl, or heteroarylalkyl, each of the latter
seven groups being optionally substituted. More preferably,
R.sup.25 is H, alkyl, or aralkyl, still more preferably H or alkyl,
even more preferably H or lower alkyl, yet more preferably H or
methyl, most preferably H.
[0489] In certain preferred embodiments of compounds of formula IV,
k is 1.
[0490] In certain preferred embodiments of compounds of formula IV,
p is 0, 1 or 2, with 1 or 2 being more preferred, and 1 being even
more preferred.
[0491] In certain preferred embodiments of compounds of formula IV,
s is 0, 1, or 2, with 1 or 2 being more preferred, and 1 being even
more preferred.
[0492] In preferred embodiments of compounds of formula IV, the sum
of p and s is 2 or 3, with 2 being more preferred.
[0493] In some preferred embodiments of compounds of formula IV,
A.sup.2 and B.sup.2 are each independently H, fluoro, or alkyl, or
together form a double bond; more preferably each is independently
H or alkyl, or together they form a double bond; still more
preferably each is independently H or lower alkyl, or together they
form a double bond; yet more preferably H or methyl, or together
they form a double bond; even more preferably together they form a
double bond. In other preferred embodiments of compounds of formula
IV, A.sup.2 and B.sup.2 are each independently H, fluoro, or alkyl.
Alternatively, A.sup.2 and B.sup.2 together form --CH.sub.2--.
[0494] In other preferred embodiments of compounds of formula IV, G
is H or lower alkyl; more preferably H or methyl; still more
preferably G is H.
[0495] In certain preferred embodiments of compounds of formula IV,
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, or --N(R.sup.26)--; more preferably
--C(R.sup.c)(R.sup.d)--, --O--, or --S(.dbd.O).sub.2--; yet more
preferably --C(R.sup.c)(R.sup.d)-- or --O--; still more preferably
--O--.
[0496] In some preferred embodiments of compounds of formula IV,
R.sup.26 is H or alkyl; more preferably H or lower alkyl; more
preferably still H or methyl; yet more preferably H.
[0497] In preferred embodiments of compounds of formula IV, J.sup.2
forms a 6- to 10-membered optionally substituted aryl ring when
taken together with the carbon atoms to which it is attached; more
preferably optionally substituted phenyl or optionally substituted
naphthyl; still more preferably optionally substituted phenyl.
[0498] In certain preferred embodiments, the compounds of formula
IV have the structure according to formula V:
##STR00022##
[0499] In certain preferred embodiments, the compounds of formula
IV have the structure according to formula VI:
##STR00023##
[0500] wherein A.sup.2 and B.sup.2 are each independently H, fluoro
or alkyl.
[0501] In certain preferred embodiments, the compounds of formula
IV have the structure according to formula VII:
##STR00024##
[0502] In certain preferred embodiments, the compounds of formula
IV have the structure according to formula VIII:
##STR00025##
[0503] wherein A.sup.2 and B.sup.2 are each independently H, fluoro
or alkyl
[0504] In certain preferred embodiments, the compounds of formula
IV have the structure according to formula IX:
##STR00026##
[0505] In certain preferred embodiments, the compounds of formula
IV have the structure according to formula X:
##STR00027##
[0506] In certain preferred embodiments, the compounds of formula X
have the structure according to formula XI:
##STR00028##
[0507] In certain preferred embodiments, the compounds of formula X
have the structure according to formula XII:
##STR00029##
[0508] wherein: [0509] Q.sup.1 and Q.sup.2 are each independently
H, halo, alkyl, hydroxyl, alkoxyl, cycloalkyl substituted alkoxyl,
aminocarbonyl, --S(.dbd.O).sub.2-alkyl,
--S(.dbd.O).sub.2--N(H)alkyl,
--S(.dbd.O).sub.2--N(H)cycloalkylalkyl, or
--N(H)S(.dbd.O).sub.2-alkyl.
[0510] In certain other more preferred embodiments, the compounds
of formula XII have the structure according to formula XIII:
##STR00030##
[0511] In certain preferred embodiments of compounds of formula IV,
the compound is selected from the group consisting of: [0512]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-piperid-
ine]; [0513]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[6-fluoro-2H,1-benzopyran-
-2,4'-piperidine]; [0514]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[5-methoxy-2H,1-benzopyra-
n-2,4'-piperidine]; [0515]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[5-hydroxy-2H,1-benzopyran-2,-
4'-piperidine]; [0516]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-azepane-
]; [0517]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-cyclopropylmethyl-
aminosulfonyl-2H,1-benzopyran-2,4'-azepane]; [0518]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[3,4-dihydro-2H,1-benzopyran--
2,4'-piperidine]; [0519]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[1,2-dihydronaphthalene-2,4'--
piperidine]; [0520]
4-[(4-N,N-diethylaminocarbonyl-2-hydroxy)phenyl]-spiro[2H,1-benzopyran-2,-
4'-piperidine]; [0521]
4-[(4-N,N-diethylaminocarbonyl-3-hydroxy)phenyl]-spiro[2H,1-benzopyran-2,-
4'-piperidine]; [0522]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-3-methyl-spiro[2H,1-benzopyran-2,4-
'-piperidine]; [0523]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[2H,1-benzopyran-2,4'-pip-
eridine]; [0524]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-cyclopropylmethoxy-2H,1-be-
nzopyran-2,4'-piperidine]; [0525]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[-6-cyclopropylmethoxy-2H-
,1-benzopyran-2,4'-piperidine]; [0526]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-aminocarbonyl-2H,1-benzopy-
ran-2,4'-piperidine]; [0527]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-propylaminosulfonyl-2H,1-b-
enzopyran-2,4'-azepane]; [0528]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-methanesulfonyl-2H,1-benzo-
pyran-2,4'-azepane]; [0529]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[3,4-dihydro-2H,1-benzopy-
ran-2,4'-piperidine]; [0530]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[6-fluoro-3,4-dihydro-2H,-
1-benzopyran-2,4'-piperidine]; [0531]
4-[(5-N,N-diisopropylaminocarbonyl)pyrid-2-yl]-spiro[2H,1-benzopyran-2,4'-
-piperidine]; [0532]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-ethylsulfonylamino-2H,1-be-
nzopyran-2,4'-piperidine]; [0533]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-methylsulfonylamino-2H,1-b-
enzopyran-2,4'-piperidine]; [0534]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[5-methyl-2H,1-benzopyran-2,4-
'-piperidine]; [0535]
4-[4-(2H-tetrazol-5-yl)phenyl]-spiro[2H,1-benzopyran-2,4'-piperidine];
[0536]
4-[4-(2-methyl-tetrazol-5-yl)phenyl]-spiro[2H,1-benzopyran-2,4'-pi-
peridine]; [0537]
4-[3-(2-(3-carboxyprop-1-yl)-tetrazol-5-yl)phenyl]-spiro[2H,1-benzopyran--
2,4'-piperidine]; [0538]
4-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)phenyl]-spiro[2H,1-benzopyran-2,4'-p-
iperidine]; [0539]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-(1'-met-
hyl-piperidine]; [0540]
4-[(4-N,N-diethylaminosulfonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-piperid-
ine]; and [0541]
4-[(4-(N-methyl-N-(3-methylbutanoyl)-amino)phenyl]-spiro[2H,1-benzopyran--
2,4'-piperidine];
[0542] or a stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, and N-oxide thereof.
[0543] In certain preferred embodiments of compounds of formula IV,
the compound is selected from the group consisting of: [0544]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-piperid-
ine]; [0545]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[6-fluoro-2H,1-benzopyran-
-2,4'-piperidine]; [0546]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[5-methoxy-2H,1-benzopyra-
n-2,4'-piperidine]; [0547]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[5-hydroxy-2H,1-benzopyran-2,-
4'-piperidine]; [0548]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-azepane-
]; [0549]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-cyclopropylmethyl-
aminosulfonyl-2H,1-benzopyran-2,4'-azepane]; [0550]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[3,4-dihydro-2H,1-benzopyran--
2,4'-piperidine]; [0551]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[1,2-dihydronaphthalene-2,4'--
piperidine]; [0552]
4-[(4-N,N-diethylaminocarbonyl-2-hydroxy)phenyl]-spiro[2H,1-benzopyran-2,-
4'-piperidine]; [0553]
4-[(4-N,N-diethylaminocarbonyl-3-hydroxy)phenyl]-spiro[2H,1-benzopyran-2,-
4'-piperidine]; [0554]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-3-methyl-spiro[2H,1-benzopyran-2,4-
'-piperidine]; [0555]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[2H,1-benzopyran-2,4'-pip-
eridine]; [0556]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-cyclopropylmethoxy-2H,1-be-
nzopyran-2,4'-piperidine]; [0557]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[-6-cyclopropylmethoxy-2H-
,1-benzopyran-2,4'-piperidine]; [0558]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-aminocarbonyl-2H,1-benzopy-
ran-2,4'-piperidine]; [0559]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-propylaminosulfonyl-2H,1-b-
enzopyran-2,4'-azepane]; [0560]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-methanesulfonyl-2H,1-benzo-
pyran-2,4'-azepane]; [0561]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[3,4-dihydro-2H,1-benzopy-
ran-2,4'-piperidine]; [0562]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[6-fluoro-3,4-dihydro-2H,-
1-benzopyran-2,4'-piperidine]; and [0563]
4-[(5-N,N-diisopropylaminocarbonyl)pyrid-2-yl]-spiro[2H,1-benzopyran-2,4'-
-piperidine];
[0564] or a stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, and N-oxide thereof.
[0565] In certain preferred embodiments of compounds of formula IV,
the compound is selected from the group consisting of: [0566]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-piperid-
ine]; [0567]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[6-fluoro-2H,1-benzopyran-
-2,4'-piperidine]; [0568]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[5-methoxy-2H,1-benzopyra-
n-2,4'-piperidine]; [0569]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[5-hydroxy-2H,1-benzopyran-2,-
4'-piperidine]; [0570]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-azepane-
]; [0571]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-cyclopropylmethyl-
aminosulfonyl-2H,1-benzopyran-2,4'-azepane]; [0572]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[3,4-dihydro-2H,1-benzopyran--
2,4'-piperidine]; [0573]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[1,2-dihydronaphthalene-2,4'--
piperidine]; [0574]
4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[6-cyclopropylmethoxy-2H,-
1-benzopyran-2,4'-piperidine]; [0575]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-methanesulfonyl-2H,1-benzo-
pyran-2,4'-azepane]; [0576]
4-[(4-N,N-diethylaminocarbonyl-2-hydroxy)phenyl]-spiro[2H,1-benzopyran-2,-
4'-piperidine]; and [0577]
4-[(4-N,N-diethylaminocarbonyl-3-hydroxy)phenyl]-spiro[2H,1-benzopyran-2,-
4'-piperidine]; or
[0578] a stereoisomer, prodrug, pharmaceutically acceptable salt,
hydrate, solvate, acid salt hydrate, and N-oxide thereof.
[0579] In certain preferred embodiments of compounds of formula IV,
the compound is selected from the group consisting of: [0580]
4*-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[3,4-dihydro-2H,1-benzopyran-
-2,4'-piperidine]; and [0581]
4*-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[3,4-dihydro-2H,1-benzop-
yran-2,4'-piperidine];
[0582] or a partial stereoisomer, prodrug, pharmaceutically
acceptable salt, hydrate, solvate, acid salt hydrate, and N-oxide
thereof.
[0583] In certain preferred embodiments of compounds of formula IV,
the compound is selected from the group consisting of: [0584]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro*[2H,1-benzopyran-2,4'-azepan-
e]; [0585]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro*[6-cyclopropylmeth-
ylaminosulfonyl-2H,1-benzopyran-2,4'-azepane]; [0586]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro*[6-propylaminosulfonyl-2H,1--
benzopyran-2,4'-azepane]; and [0587]
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro*[6-methanesulfonyl-2H,1-benz-
opyran-2,4'-azepane];
[0588] or a partial stereoisomer, prodrug, pharmaceutically
acceptable salt, hydrate, solvate, acid salt hydrate, and N-oxide
thereof.
[0589] In an alternate preferred embodiment, the present invention
is directed to compounds selected from the group consisting of:
[0590] 4-[(4-methoxyphenyl]-spiro[2H,1-benzopyran-2,4'-piperidine];
[0591] 4-[(4-methylphenyl]-spiro[2H,1-benzopyran-2,4'-piperidine];
[0592] 4-phenyl-spiro[2H,1-benzopyran-2,4'-piperidine]; [0593]
4-[(3-methoxyphenyl]-spiro[2H,1-benzopyran-2,4'-piperidine]; and
[0594]
4-[(2-methoxyphenyl]-spiro[2H,1-benzopyran-2,4'-piperidine];
[0595] or a stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, and N-oxide thereof.
[0596] In another aspect, the invention is directed to
pharmaceutical compositions, comprising:
[0597] a pharmaceutically acceptable carrier; and an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and/or XIII. In certain embodiments, the pharmaceutical
composition further comprises an effective amount of at least one
opioid.
[0598] In some preferred aspects, the invention is directed to
pharmaceutical compositions comprising a pharmaceutically
acceptable carrier; and a compound of formula IV:
##STR00031##
[0599] wherein: [0600] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0601] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0602] each R.sup.d is
independently H, alkyl, or aryl; [0603] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0604] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0605] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0606] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0607] each k is independently 1,
2, or 3; [0608] p is 0, 1, 2 or 3; [0609] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0610] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0611] G is H or alkyl; [0612]
X.sup.2 is C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0613] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0614] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0615]
provided that when: [0616] (a) J.sup.2 taken together with the
carbon atoms to which it is attached forms a 6- to 10-membered aryl
ring substituted with 0-3 groups selected from the group consisting
of: [0617] halogen, [0618] hydroxy, [0619] --SH, [0620]
--C(.dbd.O)--H [0621] --S--C.sub.1-4 alkyl, [0622]
--NHS(.dbd.O).sub.2--C.sub.1-4 alkyl, [0623]
--NHS(.dbd.O).sub.2--H, [0624] --N(C.sub.1-4
alkyl)S(.dbd.O).sub.2--H, [0625] C.sub.1-4 alkyl, and [0626]
C.sub.1-4 alkoxy, the latter two optionally substituted with one or
more halogens or with C.sub.1-4 alkoxy; [0627] W.sup.2 is phenyl
substituted with 0-3 groups selected from the group consisting of:
[0628] halogen, [0629] cyano, [0630] hydroxy, [0631] C.sub.1-6
alkyl optionally substituted with one or more halogens, CO.sub.1
alkoxy optionally substituted with one or more halogens or with
C.sub.3-6 cycloalkyl, [0632] C.sub.2-6 alkenyloxy, [0633] C.sub.2-6
alkynyloxy, [0634] C.sub.3-6 cycloalkyloxy, [0635] C.sub.6-12
aryloxy, [0636] aralkoxy, [0637] heteroaryloxy, [0638]
heteroaralkoxy, [0639] heterocycloalkyl substituted with alkoxy,
[0640] --SH, [0641] --S--C.sub.1-4 alkyl, [0642] --NH.sub.2, [0643]
--N.dbd.C(aryl).sub.2, [0644] --N(H)C.sub.1-4 alkyl, [0645]
--N(C.sub.1-4 alkyl).sub.2, [0646] --OS(.dbd.O).sub.2--C.sub.1-4
alkyl optionally substituted with one or more halogens, [0647]
--OS(.dbd.O).sub.2--C.sub.6-12 aryl optionally substituted with
C.sub.1-4 alkyl, [0648] --NHS(.dbd.O).sub.2--C.sub.1-4 alkyl,
[0649] --N(C.sub.1-4 alkyl)S(.dbd.O).sub.2--C.sub.1-4 alkyl, [0650]
--NHS(.dbd.O).sub.2--H, and [0651] --N(C.sub.1-4
alkyl)S(.dbd.O).sub.2--H; [0652] p and s are each 1, [0653]
R.sup.e, R.sup.f, R.sup.23, R.sup.24, and G are each H, [0654]
A.sup.2 and B.sup.2 together form a double bond, [0655] Y.sup.2 is
a single bond; and [0656] X.sup.2 is --O--; [0657] then Z is other
than:
##STR00032##
[0657] wherein t is an integer from 1 to 20; and [0658] provided
that when: [0659] (b) J.sup.2 taken together with the carbon atoms
to which it is attached forms a phenyl ring substituted with 0-3
groups selected from the group consisting of: [0660] halogen,
[0661] hydroxy, [0662] --S--C.sub.1-4 alkyl, [0663] C.sub.1-4
alkyl, and [0664] C.sub.1-4 alkoxy, the latter two optionally
substituted with one or more halogens or with C.sub.1-4 alkoxy;
[0665] W.sup.2 is unsubstituted naphthyl, or phenyl substituted
with 0-3 groups selected from the group consisting of: [0666]
halogen, [0667] C.sub.1-6 alkyl, [0668] C.sub.1-6 alkoxy, [0669]
phenyl, [0670] phenoxy, [0671] 1,3-benzodioxazolyl, or
2,2-difluoro-1,3-benzodioxazolyl fluoro, [0672] --NH.sub.2, [0673]
--N(C.sub.1-4 alkyl).sub.2, and [0674] pyrrolyl; [0675] p and s are
each 1, [0676] R.sup.e, R.sup.f, R.sup.23, R.sup.24, and G are each
H, [0677] A.sup.2 and B.sup.2 together form a double bond, [0678]
Y.sup.2 is a single bond; and [0679] X.sup.2 is --O--; [0680] then
Z is other than:
##STR00033##
[0680] and [0681] provided that when: [0682] (c) J.sup.2 taken
together with the carbon atoms to which it is attached forms
unsubstituted phenyl, [0683] W.sup.2 is phenyl substituted with 0-3
groups selected from the group consisting of: [0684] fluoro, [0685]
hydroxy, [0686] C.sub.1-6 alkoxy optionally substituted with one or
more fluoro, [0687] C.sub.2-6 alkenyloxy, and [0688] --S--C.sub.1-4
alkyl, [0689] p and s are each 1, [0690] R.sup.e, R.sup.f,
R.sup.23, R.sup.24, and G are each H, [0691] A.sup.2 and B.sup.2
together form a double bond, [0692] Y.sup.2 is a single bond; and
[0693] X.sup.2 is --O--; [0694] then Z is other than:
##STR00034##
[0694] and [0695] provided that when: [0696] (d) J.sup.2 taken
together with the carbon atoms to which it is attached forms a
6-membered aryl ring substituted with:
##STR00035##
[0696] then Z is other than --N(R.sup.25)-- or
--CH(NH.sub.2)--;
[0697] or a stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.
[0698] Compounds of the invention may be useful as analgesic agents
for use during general anesthesia and monitored anesthesia care.
Combinations of agents with different properties are often used to
achieve a balance of effects needed to maintain the anaesthetic
state (e.g., amnesia, analgesia, muscle relaxation and sedation).
Included in this combination are inhaled anesthetics, hypnotics,
anxiolytics, neuromuscular blockers and opioids.
[0699] In any of the above teachings, a compound of the invention
may be either a compound of one of the formulae herein described,
or a stereoisomer, prodrug, pharmaceutically acceptable salt,
hydrate, solvate, acid salt hydrate, N-oxide or isomorphic
crystalline form thereof.
[0700] The compounds employed in the methods and compositions of
the present invention may exist in prodrug form. As used herein,
"prodrug" is intended to include any covalently bonded carriers
which release the active parent drug, for example, as according to
formula I or other formulas or compounds as described herein, in
vivo when such prodrug is administered to a mammalian subject.
Since prodrugs are known to enhance numerous desirable qualities of
pharmaceuticals (e.g., solubility, bioavailability, manufacturing,
etc.), the compounds described herein may, if desired, be delivered
in prodrug form. Thus, the present invention contemplates
compositions and methods involving prodrugs. Prodrugs of the
compounds employed in the present invention, for example formula I,
may be prepared by modifying functional groups present in the
compound in such a way that the modifications are cleaved, either
in routine manipulation or in vivo, to the parent compound.
[0701] Accordingly, prodrugs include, for example, compounds
described herein in which a hydroxy, amino, or carboxy group is
bonded to any group that, when the prodrug is administered to a
mammalian subject, cleaves to form a free hydroxyl, free amino, or
carboxylic acid, respectively. Examples include, but are not
limited to, acetate, formate and benzoate derivatives of alcohol
and amine functional groups; and alkyl, carbocyclic, aryl, and
alkylaryl esters such as methyl, ethyl, propyl, iso-propyl, butyl,
isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and
phenethyl esters, and the like.
[0702] Compounds described herein may contain one or more
asymmetrically substituted carbon atoms, and may be isolated in
optically active or racemic forms. Thus, all chiral,
diastereomeric, racemic forms and all geometric isomeric forms of a
structure are intended, unless the specific stereochemistry or
isomeric form is specifically indicated. It is well known in the
art how to prepare and isolate such optically active forms. For
example, mixtures of stereoisomers may be separated by standard
techniques including, but not limited to, resolution of racemic
forms, normal, reverse-phase, and chiral chromatography,
preferential salt formation, recrystallization, and the like, or by
chiral synthesis either from chiral starting materials or by
deliberate synthesis of target chiral centers.
[0703] The compounds of the present invention may be prepared in a
number of ways well known to those skilled in the art. The
compounds can be synthesized, for example, by the methods described
below, or variations thereon as appreciated by the skilled artisan.
All processes disclosed in association with the present invention
are contemplated to be practiced on any scale, including milligram,
gram, multigram, kilogram, multikilogram or commercial industrial
scale.
[0704] As will be readily understood, functional groups present may
contain protecting groups during the course of synthesis.
Protecting groups are known per se as chemical functional groups
that can be selectively appended to and removed from
functionalities, such as hydroxyl groups and carboxyl groups. These
groups are present in a chemical compound to render such
functionality inert to chemical reaction conditions to which the
compound is exposed. Any of a variety of protecting groups may be
employed with the present invention. Preferred protecting groups
include the benzyloxycarbonyl group and the tert-butyloxycarbonyl
group. Other preferred protecting groups that may be employed in
accordance with the present invention may be described in Greene,
T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis
2d. Ed., Wiley & Sons, 1991, the disclosures of which are
hereby incorporated herein by reference, in their entirety.
[0705] The .delta. agonist compounds of the present invention may
be administered by any means that results in the contact of the
active agent with the agent's site of action in the body of a
patient. The compounds may be administered by any conventional
means available for use in conjunction with pharmaceuticals, either
as individual therapeutic agents or in a combination of therapeutic
agents. For example, they may be administered as the sole active
agent in a pharmaceutical composition, or they can be used in
combination with other therapeutically active ingredients
including, for example, opioid analgesic agents. In such
combinations, selected compounds of the invention may provide
equivalent or even enhanced therapeutic activity such as, for
example, pain ameliorization, while providing reduced adverse side
effects associated with opioids, such as addiction or pruritus, by
lowering the amount of opioid required to achieve a therapeutic
effect.
[0706] The compounds are preferably combined with a pharmaceutical
carrier selected on the basis of the chosen route of administration
and standard pharmaceutical practice as described, for example, in
Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton,
Pa., 1980), the disclosures of which are hereby incorporated herein
by reference, in their entirety.
[0707] In addition to the pharmaceutical carrier, the compounds of
formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and/or
XIII may be co-administered with at least one opioid, preferably a
.mu. opioid receptor modulator compound. In certain embodiments,
the combination of the compounds of formula I, II, III, IV, V, VI,
VII, VIII, IX, X, XI, XII, and/or XIII with at least one opioid,
preferably a .mu. opioid receptor modulator compound, provides a
synergistic analgesic effect. The utility of the instant
combination product may be determined by those skilled in the art
using established animal models. Suitable opioids include, without
limitation, alfentanil, allylprodine, alphaprodine, anileridine,
benzyl-morphine, bezitramide, buprenorphine, butorphanol,
clonitazene, codeine, cyclazocine, desomorphine, dextromoramide,
dezocine, diampromide, diamorphone, dihydrocodeine,
dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl,
heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
ketobemidone, levallorphan, levorphanol, levophenacylmorphan,
lofentanil, loperamide, meperidine (pethidine), meptazinol,
metazocine, methadone, metopon, morphine, myrophine, nalbuphine,
narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,
normorphine, norpinanone, opium, oxycodone, oxymorphone,
papavereturn, pentazocine, phenadoxone, phenomorphan, phanazocine,
phenoperidine, piminodine, piritramide, propheptazine, promedol,
properidine, propiram, propoxyphene, sulfentanil, tilidine,
tramadol, diastereoisomers thereof, pharmaceutically acceptable
salts thereof, complexes thereof, and mixtures thereof.
[0708] The pain ameliorating and/or opioid combination products of
the present compositions may further include one or more other
active ingredients that may be conventionally employed in analgesic
and/or cough-cold-antitussive combination products. Such
conventional ingredients include, for example, aspirin,
acetaminophen, phenylpropanolamine, phenylephrine,
chlorpheniramine, caffeine, and/or guaifenesin. Typical or
conventional ingredients that may be included in the opioid
component are described, for example, in the Physicians'Desk
Reference, 1999, the disclosure of which is hereby incorporated
herein by reference, in its entirety.
[0709] In addition, the opioid component may further include one or
more compounds that may be designed to enhance the analgesic
potency of the opioid and/or to reduce analgesic tolerance
development. Such compounds include, for example, dextromethorphan
or other NMDA antagonists (Mao, M. J. et al., Pain 1996, 67, 361),
L-364,718 and other CCK antagonists (Dourish, C. T. et al., Eur J
Pharmacol 1988, 147, 469), NOS inhibitors (Bhargava, H. N. et al.,
Neuropeptides 1996, 30, 219), PKC inhibitors (Bilsky, E. J. et al.,
J Pharmacol Exp Ther 1996, 277, 484), and dynorphin antagonists or
antisera (Nichols, M. L. et al., Pain 1997, 69, 317). The
disclosures of each of the foregoing documents are hereby
incorporated herein by reference, in their entireties.
[0710] Other opioids, optional conventional opioid components, and
optional compounds for enhancing the analgesic potency of the
opioid and/or for reducing analgesic tolerance development, that
may be employed in the methods and compositions of the present
invention, in addition to those exemplified above, would be readily
apparent to one of ordinary skill in the art, once armed with the
teachings of the present disclosure.
[0711] Compounds of the present invention can be administered to a
mammalian host in a variety of forms adapted to the chosen route of
administration, e.g., orally or parenterally. Parenteral
administration in this respect includes administration by the
following routes: intravenous, intramuscular, subcutaneous, rectal,
intraocular, intrasynovial, transepithelial including transdermal,
ophthalmic, sublingual and buccal; topically including ophthalmic,
dermal, ocular, rectal, and nasal inhalation via insufflation
aerosol.
[0712] The active compound may be orally administered, for example,
with an inert diluent or with an assimilable edible carrier, or it
may be enclosed in hard or soft shell gelatin capsules, or it may
be compressed into tablets, or it may be incorporated directly with
the food of the diet. For oral therapeutic administration, the
active compound may be incorporated with excipient and used in the
form of ingestible tablets, buccal tablets, troches, capsules,
elixirs, suspensions, syrups, wafers, and the like. Such
compositions and preparations should preferably contain at least
0.1% of active compound. The percentage of the compositions and
preparations may, of course, be varied and may conveniently be, for
example, from about 2 to about 6% of the weight of the unit. The
amount of active compound in such therapeutically useful
compositions is preferably such that a suitable dosage will be
obtained. Preferred compositions or preparations according to the
present invention may be prepared so that an oral dosage unit form
contains from about 0.1 to about 1000 mg of active compound.
[0713] The tablets, troches, pills, capsules and the like may also
contain one or more of the following: a binder, such as gum
tragacanth, acacia, corn starch or gelatin; an excipient, such as
dicalcium phosphate; a disintegrating agent, such as corn starch,
potato starch, alginic acid and the like; a lubricant, such as
magnesium stearate; a sweetening agent such as sucrose, lactose or
saccharin; or a flavoring agent, such as peppermint, oil of
wintergreen or cherry flavoring. When the dosage unit form is a
capsule, it may contain, in addition to materials of the above
type, a liquid carrier. Various other materials may be present as
coatings or to otherwise modify the physical form of the dosage
unit. For instance, tablets, pills, or capsules may be coated with
shellac, sugar or both. A syrup or elixir may contain the active
compound, sucrose as a sweetening agent, methyl and propylparabens
as preservatives, a dye and flavoring, such as cherry or orange
flavor. Of course, any material used in preparing any dosage unit
form is preferably pharmaceutically pure and substantially
non-toxic in the amounts employed. In addition, the active compound
may be incorporated into sustained-release preparations and
formulations.
[0714] The active compound may also be administered parenterally or
intraperitoneally. Solutions of the active compound as a free base
or a pharmacologically acceptable salt can be prepared in water
suitably mixed with a surfactant, such as hydroxypropylcellulose. A
dispersion can also be prepared in glycerol, liquid polyethylene
glycols and mixtures thereof and in oils. Under ordinary conditions
of storage and use, these preparations may contain a preservative
to prevent the growth of microorganisms.
[0715] The pharmaceutical forms suitable for injectable use
include, for example, sterile aqueous solutions or dispersions and
sterile powders for the extemporaneous preparation of sterile
injectable solutions or dispersions. In all cases, the form is
preferably sterile and fluid to provide easy syringability. It is
preferably stable under the conditions of manufacture and storage
and is preferably preserved against the contaminating action of
microorganisms such as bacteria and fungi. The carrier may be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (for example, glycerol, propylene glycol, liquid
polyethylene glycol and the like), suitable mixtures thereof, and
vegetable oils. The proper fluidity can be maintained, for example,
by the use of a coating, such as lecithin, by the maintenance of
the required particle size in the case of a dispersion, and by the
use of surfactants. The prevention of the action of microorganisms
may be achieved by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal
and the like. In many cases, it will be preferable to include
isotonic agents, for example, sugars or sodium chloride. Prolonged
absorption of the injectable compositions may be achieved by the
use of agents delaying absorption, for example, aluminum
monostearate and gelatin.
[0716] Sterile injectable solutions may be prepared by
incorporating the active compound in the required amount, in the
appropriate solvent, with various of the other ingredients
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions may be prepared by incorporating the
sterilized active ingredient into a sterile vehicle that contains
the basic dispersion medium and the required other ingredients from
those enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation may include vacuum drying and the freeze-drying
technique that yield a powder of the active ingredient, plus any
additional desired ingredient from the previously sterile-filtered
solution thereof.
[0717] The therapeutic compounds of this invention may be
administered to a patient alone or in combination with a
pharmaceutically acceptable carrier. As noted above, the relative
proportions of active ingredient and carrier may be determined, for
example, by the solubility and chemical nature of the compound,
chosen route of administration and standard pharmaceutical
practice.
[0718] The dosage of the compounds of the present invention that
will be most suitable for prophylaxis or treatment will vary with
the form of administration, the particular compound chosen and the
physiological characteristics of the particular patient under
treatment. Generally, small dosages may be used initially and, if
necessary, increased by small increments until the desired effect
under the circumstances is reached. The therapeutic human dosage,
based on physiological studies using rats, may generally range from
about 0.01 mg to about 100 mg/kg of body weight per day, and all
combinations and subcombinations of ranges and specific dosages
therein. Alternatively, the therapeutic human dosage may be from
about 0.4 mg to about 10 g or higher, and may be administered in
several different dosage units from once to several times a day.
Generally speaking, oral administration may require higher
dosages.
[0719] It will be further appreciated that the amount of the
compound, or an active salt or derivative thereof, required for use
in treatment will vary not only with the particular salt selected
but also with the route of administration, the nature of the
condition being treated and the age and condition of the patient
and will be ultimately at the discretion of the attendant physician
or clinician.
[0720] The desired dose may conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations; such as multiple
inhalations from an insufflator or by application of a plurality of
drops into the eye.
[0721] The dose may also be provided by controlled release of the
compound, by techniques well known to those in the art.
[0722] The compounds of the invention may also be formulated with
other optional active ingredients, in addition to or instead of the
optional opioids, and in addition to the optional
pharmaceutical-acceptable carriers. Other active ingredients
include, but are not limited to, antibiotics, antivirals,
antifungals, anti-inflammatories, including steroidal and
non-steroidal anti-inflammatories, anesthetics and mixtures
thereof. Such additional ingredients include any of the
following:
[0723] a. Antibacterial Agents
[0724] Aminoglycosides, such as Amikacin Apramycin, Arbekacin,
Bambermycins, Butirosin, Dibekacin, Dihydrostreptomycin,
Fortimicin(s), Fradiomycin, Gentamicin, Ispamicin, Kanamycin,
Micronomicin, Neomycin, Neomycin Undecylenate Netilmicin,
Paromomycin, Ribostamycin, Sisomicin Spectinomycin, Streptomycin,
Streptonicozid and Tobramycin;
[0725] Amphenicols, such as Azidamfenicol, Chloramphenicol,
Chloramphenicol Palmirate, Chloramphenicol Pantothenate,
Florfenicol, Thiamphenicol;
[0726] Ansamycins, such as Rifamide, Rifampin, Rifamycin and
Rifaximin;
[0727] .beta.-Lactams;
[0728] Carbapenems, such as Imipenem;
[0729] Cephalosporins, such as 1-Carba (dethia) Cephalosporin,
Cefactor, Cefadroxil, Cefamandole, Cefatrizine, Cefazedone,
Cefazolin, Cefixime, Cefmenoxime, Cefodizime, Cefonicid,
Cefoperazone, Ceforanide, Cefotaxime, Cefotiam, Cefpimizole,
Cefpirimide, Cefpodoxime Proxetil, Cefroxadine, Cefsulodin,
Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftizoxime,
Ceftriaxone, Cefuroxime, Cefuizonam, Cephacetrile Sodium,
Cephalexin, Cephaloglycin, Cephaloridine, Cephalosporin,
Cephalothin, Cephapirin Sodium, Cephradine and Pivcefalexin;
[0730] Cephamycins such as Cefbuperazone, Cefmetazole, Cefminox,
Cefetan and Cefoxitin;
[0731] Monobactams such as Aztreonam, Carumonam and Tigemonan;
[0732] Oxacephems such as Flomoxef and Moxolactam;
[0733] Penicillins such as Amidinocillin, Amdinocillin, Pivoxil,
Amoxicillin, Ampicillan, Apalcillin, Aspoxicillin, Azidocillan,
Azlocillan, Bacampicillin Benzylpenicillinic Acid Benzylpenicillin,
Carbenicillin, Carfecillin, Carindacillin, Clometocillin,
Cloxacillin, Cyclacillin, Dicloxacillin, Diphenicillin, Epicillin,
Fenbenicillin, Floxicillin, Hetacillin, Lenampicillin,
Metampicillin Methicillin, Mezlocillin, Nafcillin, Oxacillin,
Penamecillin, Penethamate Hydriodide, Penicillin G Benethamine,
Penicillin G Benzathine, Penicillin G Benzhydrylamine, Penicillin G
Calcium, Penicillin G Hydragamine, Penicillin G Potassium,
Penicillin G. Procaine, Penicillin N, Penicillin O, Penicillin V,
Penicillin V Benzathine, Penicillin V Hydrabamine, Penimepicycline,
Phenethicillin, Piperacillin, Pivapicillin Propicillin,
Quinacillin, Sulbenicillin, Talampicillin, Temocillin and
Ticarcillin;
[0734] Lincosumides such as Clindamycin and Lincomycin;
[0735] Macrolides such as Azithromycin, Carbomycin, Clarithromycin,
Erythromycin(s) and Derivatives, Josamycin, Leucomycins,
Midecamycins, Miokamycin, Oleandomycin, Primycin, Rokitamycin,
Rosaramicin, Roxithromycin, Spiramycin and Troleandomycin;
[0736] Polypeptides such as Amphomycin, Bacitracin, Capreomycin,
Colistin, Enduracidin, Enviomycin, Fusafungine, Gramicidin(s),
Gramicidin S, Mikamycin, Polymyxin, Polymyxin
.beta.-Methanesulfonic Acid, Pristinamycin, Ristocetin,
Teicoplanin, Thiostrepton, Tuberactinomycin, Tyrocidine,
Tyrothricin, Vancomycin, Viomycin(s), Virginiamycin and Zinc
Bacitracin;
[0737] Tetracyclines such as Spicycline, Chlortetracycline,
Clomocycline, Demeclocycline, Doxycycline, Guamecycline,
Lymecycline, Meclocycline Methacycline, Minocycline,
Oxytetracycline, Penimepicycline, Pipacycline, Rolitetracycline,
Sancycline Senociclin and Tetracycline; and
[0738] others such as Cycloserine, Mupirocin, Tuberin.
[0739] b. Synthetic Antibacterials
[0740] 2,4-Diaminopyrimidines such as Brodimoprim, Tetroxoprim and
Trimethoprim;
[0741] Nitrofurans such as Furaltadone, Furazolium, Nifuradene,
Nifuratel, Nifurfoline, Nifuirpirinol, Nifurprazine, Nifurtoinol
and Nitrofurantoin;
[0742] Quinolones and analogs thereof, such as Amifloxacin,
Cinoxacin, Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin,
Flumequine, Lomefloxacin, Miloxacin, Nalidixic Acid, Norfloxacin,
Ofloxacin, Oxolinic Acid, Perfloxacin, Pipemidic Acid, Piromidic
Acid, Rosoxacin, Temafloxacin and Tosufloxacin;
[0743] Sulfonamides such as Acetyl Sulfamethoxypyrazine, Acetyl
Sulfisoxazole, Azosulfamide Benzylsulfamide, Chloramine-.beta.,
Chloramine-T, Dichloramine-T, Formosulfathiazole,
N.sup.2-Formyl-sulfisomidine,
N.sup.4-.beta.-D-Glucosylsulfanilamide, Mafenide,
4'-(Methyl-sulfamoyl)sulfanilanilide, p-Nitrosulfathiazole,
Noprylsulfamide, Phthalylsulfacetamide, Phthalylsulfathiazole,
Salazosulfadimidine, Succinylsulfathiazole, Sulfabenzamide,
Sulfacetamide, Sulfachlorpyridazine, Sulfachrysoidine, Sulfacytine,
Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine,
Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic
Acid, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole,
Sulfamethomidine, Sulfamethoxazole, Sulfamethoxypyridazine,
Sulfametrole, sulfamidochrysoidine, Sulfamoxole, Sulfanilamide,
Sulfanilamidomethanesulfonic Acid Triethanolamine Salt,
4-Sulfanilamidosalicyclic Acid, N.sup.4-Sulfanilylsulfanilamide,
Sulfanilylurea, N-Sulfanilyl-3,4-xylamide, Sulfanitran,
Sulfaperine, Sulfaphenazole, Sulfaproxyline, Sulfapyrazine,
Sulfapyridine, Sulfasomizole, Sulfasymazine, Sulfathiazole,
Sulfathiourea, Sulfatolamide, Sulfisomidine and Sulfisoxazole;
[0744] Sulfones, such as Acedapsone, Acediasulfone, Acetosulfone,
Dapsone, Diathymosulfone, Glucosulfone, Solasulfone, Succisulfone,
Sulfanilic Acid, p-Sulfanilylbenzylamine,
p,p'-sulfonyldianiline-N,N'-digalactoside, Sulfoxone and
Thiazolsulfone;
[0745] Others such as Clofoctol, Hexedine, Magainins Methenamine
Methenamine Anhydromethylene-citrate Methenamine Hippurate
Methenamine Mandelate Methenamine Sulfosalicylate, Nitroxoline,
Squalamine and Xibomol.
[0746] c. Antifungal (Antibiotics)
[0747] Polyenes such as Amphotericin-B, Candicidin, Dermostatin,
Filipin Fungichromin, Hachimycin, Hamycin, Lucensomycin,
Mepartricin, Natamycin, Nystatin, Pecilocin, Perimycin; and others,
such as Azaserine, Griseofulvin, Oligomycins, PyrroInitrin,
Siccanin, Tubercidin and Viridin.
[0748] d. Antifungal (Synthetic)
[0749] Allylamines such as Naftifine and terbinafine;
[0750] Imidazoles such as Bifonazole, Butoconazole, Chlordantoin,
Chlormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole,
Finticonazole, Isoconazole, Ketoconazole, Miconazole, Omoconazole,
Oxiconazole Nitrate, Sulconazole and Tioconazole;
[0751] Triazoles such as Fluconazole, Itraconazole,
Terconazole;
[0752] Others such as Acrisorcin, Amorolfine, Biphenamine,
Bromosalicylchloranilide, Buclosamide, Chlophenesin, Ciclopirox,
Cloxyquin, Coparaffinate, Diamthazole, Dihydrochloride, Exalamide,
Flucytosine, Halethazole, Hexetidine, Loflucarban, Nifuratel,
Potassium Iodide Propionic Acid, Pyrithione, Salicylanilide,
Sulbentine, Tenonitrozole, Tolciclate, Tolindate, Tolnaftate,
Tricetin, Ujothion, and Undecylenic Acid.
[0753] e. Antiglaucoma Agents
[0754] Antiglaucoma agents, such as Dapiprazoke, Dichlorphenamide,
Dipivefrin and Pilocarpine.
[0755] f. Anti-Inflammatory Agents
[0756] Corticosteroids, aminoarylcarboxylic Acid Derivatives such
as Etofenamate, Meclofenamic Acid, Mefanamic Acid, Niflumic
Acid;
[0757] Arylacetic Acid Derivatives such as Acemetacin, Amfenac
Cinmetacin, Clopirac, Diclofenac, Fenclofenac, Fenclorac, Fenclozic
Acid, Fentiazac, Glucametacin, Isozepac, Lonazolac, Metiazinic
Acid, Oxametacine Proglumetacin, Sulindac, Tiaramide and
Tolmetin;
[0758] Arylbutyric Acid Derivatives such as Butibufen and
Fenbufen;
[0759] Arylcarboxylic Acids such as Clidanac, Ketorolac and
Tinoridine;
[0760] Arylpropionic Acid Derivatives such as Bucloxic Acid,
Carprofen, Fenoprofen, Flunoxaprofen, Ibuprofen, Ibuproxam,
Oxaprozin, Piketoprofen, Pirprofen, Pranoprofen Protizinic Acid and
Tiaprofenic Add;
[0761] Pyrazoles such as Mepirizole;
[0762] Pyrazolones such as Clofezone, Feprazone, Mofebutazone,
Oxyphenbutazone, Phenylbutazone, Phenyl Pyrazolidininones,
Suxibuzone and Thiazolinobutazone;
[0763] Salicylic Acid Derivatives such as Bromosaligenin, Fendosal,
Glycol Salicylate, Mesalamine, 1-Naphthyl Salicylate, Olsalazine
and Sulfasalazine;
[0764] Thiazinecarboxamides such as Droxicam, Isoxicam and
Piroxicam;
[0765] Others such as e-Acetamidocaproic Acid,
S-Adenosylmethionine, 3-Amino-4-hydroxybutyric Acid, Amixetrine
Bendazac, Bucolome, Carbazones, Difenpiramide, Ditazol,
Guaiazulene, Heterocyclic Aminoalkyl Esters of Mycophenolic Acid
and Derivatives, Nabumetone, Nimesulide Orgotein, Oxaceprol,
Oxazole Derivatives, Paranyline, Pifoxime,
2-substituted-4,6-di-tertiary-butyl-s-hydroxy-1,3-pyrimidines
Proquazone and Tenidap.
[0766] g. Antiseptics
[0767] Guanidines such as Alexidine, Ambazone, Chlorhexidine and
Picloxydine;
[0768] Halogens/Halogen Compounds such as Bomyl Chloride, Calcium
Iodate, Iodine, Iodine Monochloride, Iodine Trichloride, Iodoform,
Povidone-Iodine, Sodium Hypochlorite, Sodium Iodate, Symclosene,
Thymol Iodide, Triclocarban, Triclosan and Troclosene
Potassium;
[0769] Nitrofurans such as Furazolidone,
2-(Methoxymethyl)-5-Nitrofuran, Nidroxyzone, Nifuroxime, Nifurzide
and Nitrofurazone;
[0770] Phenols such as Acetomeroctol, Chloroxylenol,
Hexachlorophene, 1-Naphthyl Salicylate, 2,4,6-Tribromo-m-cresol and
3',4',5-Trichlorosalicylanilide;
[0771] Quinolines such as Aminoquinuride, Chloroxine,
Chlorquinaldol, Cloxyquin, Ethylhydrocupreine, Halquinol,
Hydrastine, 8-Hydroxyquinoline and Sulfate; and
[0772] others, such as Boric Acid, Chloroazodin, m-Cresyl Acetate,
Cupric sulfate and Ichthammol.
[0773] h. Antivirals
[0774] Purines/Pyrimidinones, such as 2-Acetyl-Pyridine
5-((2-pyridylamino)thiocarbonyl) Thiocarbonohydrazone, Acyclovir,
Dideoxyadenosine, Dideoxycytidine, Dideoxyinosine, Edoxudine,
Floxuridine, Ganciclovir, Idoxuridine, MADU, Pyridinone,
Trifluridine, Vidrarbine and Zidovudline;
[0775] others such as Acetylleucine Monoethanolamine, Acridinamine,
Alkylisooxazoles, Amantadine, Amidinomycin, Cuminaldehyde
Thiosemicarbzone, Foscamet Sodium, Kethoxal, Lysozyme Methisazone
Moroxydine, Podophyllotoxin, Ribavirin, Rimantadine, Stallimycin,
Statolon, Thymosins, Tromantadine and Xenazoic Acid.
[0776] i. Agents for Neuralgia/Neuropathic Pain
[0777] Mild OTC (over the counter) analgesics, such as aspirin,
acetaminophen, and ibuprophen.
[0778] Narcotic analgesics, such as codeine.
[0779] Anti seizure medications, such as carbamazepine, gabapentin,
lamotrigine and phenyloin.
[0780] Anti-depressants, such as amitryptiline.
[0781] j. Agents for the Treatment of Depression
[0782] Selective serotonin re-uptake inhibitors (SSRIs), such as
Fluoxetine, Paroxetine, Fluvoxamine, Citaprolam, and
Sertraline.
[0783] Tricyclics, such as Imipramine, Amitriptyline, Desipramine,
Nortriptyline Protriptyline, Trimipramine, Doxepin, Amoxapine, and
Clomipramine.
[0784] Monoamine Oxidase Inhibitors (MAOIs), such as
Tranylcypromine, Phenelzine, and Isocarboxazid.
[0785] Heterocyclics, such as Amoxipine, Maprotiline and
Trazodone.
[0786] others such as Venlafaxine, Nefazodone and Mirtazapine.
[0787] k. Agents for the Treatment of Incontinence
[0788] Anticholinergic agents such as propantheline.
[0789] Antispasmodic medications such as oxybutynin, tolterodine,
and flavoxate.
[0790] Tricyclic antidepressants such as imipramine, and
doxepin.
[0791] Calcium channel blockers such as tolterodine.
[0792] Beta agonists such as terbutaline.
[0793] l. AntiParkinson's Agents
[0794] Deprenyl, Amantadine, Levodopa, and Carbidopa.
[0795] In yet another aspect, the invention is directed to methods
of binding opioid receptors, preferably .delta. opioid receptors,
in a patient in need thereof, comprising the step of administering
to said patient an effective amount of a compound of the invention
including, for example, a compound of formulas I, II, III, IV, V,
VI, VII, VIII, IX, X, XI, XII, and/or XIII. The .delta. opioid
receptors may be located in the central nervous system or located
peripherally to the central nervous system. In certain preferred
embodiments, the binding of the present compounds modulates the
activity, preferably as an agonist, of said opioid receptors. In
certain preferred embodiments, the compound of formula I, II, III,
IV, V, VI, VII, VIII, IX, X, XI, XII, and/or XIII does not
substantially cross the blood-brain barrier. Preferably, the
compounds of the present invention are peripherally selective.
[0796] In certain preferred aspects, the methods comprise the step
of administering to said patient an effective amount of a compound
of formula IV:
##STR00036##
[0797] wherein: [0798] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0799] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0800] each R.sup.d is
independently H, alkyl, or aryl; [0801] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0802] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0803] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0804] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0805] each k is independently 1,
2, or 3; [0806] p is 0, 1, 2 or 3; [0807] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0808] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0809] G is H or alkyl; [0810]
X.sup.2 is C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0811] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0812] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[0813] The spirocyclic heterocyclic derivatives of the present
invention and pharmaceutical compositions containing these
compounds may be utilized in a number of ways. In certain
embodiments, the spirocyclic heterocyclic derivatives are ligands
of the .delta. opioid receptor and are useful, inter alia, in
methods for treating and/or preventing pain, gastrointestinal
disorders, urogenital tract disorders including incontinence, for
example, stress urinary incontinence, urge urinary incontinence and
benigh prostatic hyperplasia, and overactive bladder disorder (see,
e.g., R. B. Moreland et al., Perspectives in Pharmacology, Vol.
308(3), pp. 797-804 (2004) and M. O. Fraser, Annual Reports in
Medicinal Chemistry, Chapter 6, pp. 51-60 (2003), the disclosures
of which are hereby incorporated herein by reference, in their
entireties), immunomodulatory disorders, inflammatory disorders,
respiratory function disorders, depression, anxiety, mood
disorders, stress-related disorders, sympathetic nervous system
disorder, tussis, motor disorder, traumatic injury, stroke, cardiac
arrhythmia, glaucoma, sexual dysfunction, shock, brain edema,
cerebral ischemia, cerebral deficits subsequent to cardiac bypass
surgery and grafting, systemic lupus erythematosus, Hodgkin's
disease, Sjogren's disease, epilepsy, and rejection in organ
transplants and skin grafts, and substance addiction. In certain
other embodiments, the spirocyclic heterocyclic derivatives are
ligands of the .delta. opioid receptor and are useful, inter alia,
in methods for providing cardioprotection following myocardial
infarction, in methods for providing and maintaining an anaesthetic
state, and in methods of detecting, imaging or monitoring
degeneration or dysfunction of opioid receptors in a patient.
[0814] Thus, in accordance with preferred aspects of the invention,
there are provided methods of preventing or treating pain,
comprising the step of administering to said patient an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII and/or XIII. More preferably, there are provided methods of
preventing or treating pain, comprising the step of administering
to said patient an effective amount of a compound of formula
IV:
##STR00037##
[0815] wherein: [0816] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0817] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0818] each R.sup.d is
independently H, alkyl, or aryl; [0819] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0820] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0821] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0822] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0823] each k is independently 1,
2, or 3; [0824] p is 0, 1, 2 or 3; [0825] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0826] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0827] G is H or alkyl; [0828]
X.sup.2 is C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0829] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0830] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0831] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[0832] In certain preferred embodiments, the present methods of
preventing or treating pain may further comprise the administration
to a patient of an effective amount of an agent for the treatment
of neuralgia and/or neuropathic pain.
[0833] In another aspect, the invention is directed to methods for
preventing or treating gastrointestinal dysfunction, comprising the
step of administering to a patient in need of such treatment an
effective amount of a compound of the invention including, for
example, a compound of formulas I, II, III, IV, V, VI, VII, VIII,
IX, X, XI, XII, and/or XIII. In certain preferred aspects, the
methods comprise the step of administering to said patient an
effective amount of a compound of formula IV:
##STR00038##
[0834] wherein: [0835] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0836] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0837] each R.sup.d is
independently H, alkyl, or aryl; [0838] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0839] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0840] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0841] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0842] each k is independently 1,
2, or 3; [0843] p is 0, 1, 2 or 3; [0844] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0845] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0846] G is H or alkyl; [0847]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0848] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0849] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0850] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[0851] In another aspect, the invention is directed to methods for
preventing or treating a urogenital tract disorder, such as
incontinence (including, for example, stress urinary incontinence
and urge urinary incontinence, and overactive bladder), comprising
the step of administering to a patient in need of such treatment an
effective amount of a compound of the invention including, for
example, a compound of formulas I, II, III, IV, V, VI, VII, VIII,
IX, X, XI, XII, and/or XIII. In certain preferred aspects, the
methods comprise the step of administering to said patient an
effective amount of a compound of formula IV:
##STR00039##
[0852] wherein: [0853] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0854] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0855] each R.sup.d is
independently H, alkyl, or aryl; [0856] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0857] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0858] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0859] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0860] each k is independently 1,
2, or 3; [0861] p is 0, 1, 2 or 3; [0862] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0863] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0864] G is H or alkyl; [0865]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --C(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0866] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0867] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0868] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[0869] In certain preferred embodiments, the present methods of
preventing or treating a urogenital tract disorder may further
comprise the administration to a patient of an effective amount of
an agent for the treatment of incontinence.
[0870] In another aspect, the invention is directed to methods of
preventing or treating an immunomodulatory disorder, comprising the
step of administering to a patient in need thereof an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and/or XIII. Immunomodulatory disorders include, but are not
limited to, autoimmune diseases, collagen diseases, allergies, side
effects associated with the administration of an anti-tumor agent,
and side effects associated with the administration of an antiviral
agent. Autoimmune diseases include, but are not limited to,
arthritis, autoimmune disorders associated with skin grafts,
autoimmune disorders associated with organ transplants, and
autoimmune disorders associated with surgery. In certain preferred
aspects, the methods comprise the step of administering to said
patient an effective amount of a compound of formula IV:
##STR00040##
[0871] wherein: [0872] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0873] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0874] each R.sup.d is
independently H, alkyl, or aryl; [0875] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0876] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0877] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0878] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0879] each k is independently 1,
2, or 3; [0880] p is 0, 1, 2 or 3; [0881] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0882] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0883] G is H or alkyl; [0884]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0885] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0886] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0887] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[0888] In another aspect, the invention is directed to methods of
preventing or treating an inflammatory disorder, comprising the
step of administering to a patient in need thereof an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and/or XIII. Inflammatory disorders include, but are not
limited to, arthritis, psoriasis, asthma, or inflammatory bowel
disease. In certain preferred aspects, the methods comprise the
step of administering to said patient an effective amount of a
compound of formula IV:
##STR00041##
[0889] wherein: [0890] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0891] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0892] each R.sup.d is
independently H, alkyl, or aryl; [0893] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0894] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0895] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0896] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0897] each k is independently 1,
2, or 3; [0898] p is 0, 1, 2 or 3; [0899] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0900] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0901] G is H or alkyl; [0902]
X is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0903] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0904] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0905] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[0906] In another aspect, the invention is directed to methods of
preventing or treating a respiratory function disorder, comprising
the step of administering to a patient in need thereof an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and/or XIII. Respiratory function disorders include but are
not limited to asthma or lung edemal. In certain preferred aspects,
the methods comprise the step of administering to said patient an
effective amount of a compound of formula IV:
##STR00042##
[0907] wherein: [0908] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0909] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0910] each R.sup.d is
independently H, alkyl, or aryl; [0911] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0912] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0913] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0914] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0915] each k is independently 1,
2, or 3; [0916] p is 0, 1, 2 or 3; [0917] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0918] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0919] G is H or alkyl; [0920]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0921] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0922] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0923] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[0924] In another aspect, the invention is directed to methods for
preventing or treating anxiety, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and/or XIII. In certain preferred aspects, the methods
comprise the step of administering to said patient an effective
amount of a compound of formula IV:
##STR00043##
[0925] wherein: [0926] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0927] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0928] each R.sup.d is
independently H, alkyl, or aryl; [0929] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0930] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0931] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0932] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0933] each k is independently 1,
2, or 3; [0934] p is 0, 1, 2 or 3; [0935] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0936] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0937] G is H or alkyl; [0938]
X.sup.2 is C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0939] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0940] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0941] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[0942] In another aspect, the invention is directed to methods for
preventing or treating a mood disorder, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and XIII. Mood disorders include but are not limited to
depression, bipolar manic-depression, and seasonal affective
disorder. In certain preferred aspects, the methods comprise the
step of administering to said patient an effective amount of a
compound of formula IV:
##STR00044##
[0943] wherein: [0944] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0945] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0946] each R.sup.d is
independently H, alkyl, or aryl; [0947] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0948] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0949] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0950] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0951] each k is independently 1,
2, or 3; [0952] p is 0, 1, 2 or 3; [0953] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0954] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0955] G is H or alkyl; [0956]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0957] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0958] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0959] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[0960] In certain preferred embodiments, the present methods of
preventing or treating a mood disorder may further comprise the
administration to a patient of an effective amount of an agent for
the treatment of depression.
[0961] In another aspect, the invention is directed to methods for
preventing or treating a stress-related disorder, comprising the
step of administering to a patient in need of such treatment an
effective amount of a compound of the invention including, for
example, a compound of formulas I, II, III, IV, V, VI, VII, VIII,
IX, X, XI, XII, and/or XIII. Stress-related disorders include, but
are not limited to, post-traumatic stress disorder, panic disorder,
generalized anxiety disorder, social phobia, and obsessive
compulsive disorder. In certain preferred aspects, the methods
comprise the step of administering to said patient an effective
amount of a compound of formula IV:
##STR00045##
[0962] wherein: [0963] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0964] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0965] each R.sup.d is
independently H, alkyl, or aryl; [0966] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0967] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0968] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0969] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0970] each k is independently 1,
2, or 3; [0971] p is 0, 1, 2 or 3; [0972] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0973] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0974] G is H or alkyl; [0975]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0976] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0977] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0978] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[0979] In another aspect, the invention is directed to methods for
preventing or treating attention deficit hyperactivity disorder,
comprising the step of administering to a patient in need of such
treatment an effective amount of a compound of the invention
including, for example, a compound of formulas I, II, III, IV, V,
VI, VII, VIII, IX, X, XI, XII, and/or XIII. In certain preferred
aspects, the methods comprise the step of administering to said
patient an effective amount of a compound of formula IV:
##STR00046##
[0980] wherein: [0981] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [0982] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [0983] each R.sup.d is
independently H, alkyl, or aryl; [0984] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [0985] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [0986] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [0987] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [0988] each k is independently 1,
2, or 3; [0989] p is 0, 1, 2 or 3; [0990] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [0991] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [0992] G is H or alkyl; [0993]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[0994] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [0995] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [0996] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[0997] In another aspect, the invention is directed to methods for
preventing or treating sympathetic nervous system disorders,
including hypertension, comprising the step of administering to a
patient in need of such treatment an effective amount of a compound
of the invention including, for example, a compound of formulas I,
II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and/or XIII. In
certain preferred aspects, the methods comprise the step of
administering to said patient an effective amount of a compound of
formula IV:
##STR00047##
[0998] wherein: [0999] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1000] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1001] each R.sup.d is
independently H, alkyl, or aryl; [1002] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1003] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1004] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1005] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1006] each k is independently 1,
2, or 3; [1007] p is 0, 1, 2 or 3; [1008] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1009] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1010] G is H or alkyl; [1011]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1012] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1013] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1014] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1015] In another aspect, the invention is directed to methods for
preventing or treating tussis, comprising the step of administering
to a patient in need of such treatment an effective amount of a
compound of the invention including, for example, a compound of
formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and/or
XIII. In certain preferred aspects, the methods comprise the step
of administering to said patient an effective amount of a compound
of formula IV:
##STR00048##
[1016] wherein: [1017] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1018] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1019] each R.sup.d is
independently H, alkyl, or aryl; [1020] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1021] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1022] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1023] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1024] each k is independently 1,
2, or 3; [1025] p is 0, 1, 2 or 3; [1026] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1027] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1028] G is H or alkyl; [1029]
X is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1030] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1031] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1032] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1033] In another aspect, the invention is directed to methods for
preventing or treating a motor disorder, including tremors,
Parkinson's disease, Tourette's syndrome and dyskenesia, comprising
the step of administering to a patient in need of such treatment an
effective amount of a compound of the invention including, for
example, a compound of formulas I, II, III, IV, V, VI, VII, VIII,
IX, X, XI, XII, and/or XIII. In certain preferred aspects, the
methods comprise the step of administering to said patient an
effective amount of a compound of formula IV:
##STR00049##
[1034] wherein: [1035] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1036] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1037] each R.sup.1 is
independently H, alkyl, or aryl; [1038] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1039] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1040] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1041] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1042] each k is independently 1,
2, or 3; [1043] p is 0, 1, 2 or 3; [1044] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1045] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1046] G is H or alkyl; [1047]
X.sup.2 is C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1048] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1049] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1050] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1051] In certain preferred embodiments, the present methods of
preventing or treating a motor disorder may further comprise the
administration to a patient of an effective amount of an agent for
the treatment of Parkinson's disease.
[1052] In another aspect, the invention is directed to methods for
treating a traumatic injury to the central nervous system,
including the spinal cord or brain, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and/or XIII. In certain preferred aspects, the methods
comprise the step of administering to said patient an effective
amount of a compound of formula IV:
##STR00050##
[1053] wherein: [1054] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1055] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1056] each R.sup.d is
independently H, alkyl, or aryl; [1057] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1058] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1059] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1060] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1061] each k is independently 1,
2, or 3; [1062] p is 0, 1, 2 or 3; [1063] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1064] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1065] G is H or alkyl; [1066]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1067] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1068] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1069] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1070] In another aspect, the invention is directed to methods for
preventing or treating stroke, comprising the step of administering
to a patient in need of such treatment an effective amount of a
compound of the invention including, for example, a compound of
formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and/or
XIII. In certain preferred aspects, the methods comprise the step
of administering to said patient an effective amount of a compound
of formula IV:
##STR00051##
[1071] wherein: [1072] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1073] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1074] each R.sup.d is
independently H, alkyl, or aryl; [1075] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1076] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1077] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1078] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1079] each k is independently 1,
2, or 3; [1080] p is 0, 1, 2 or 3; [1081] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1082] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1083] G is H or alkyl; [1084]
X.sup.2 is C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1085] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1086] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1087] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1088] In another aspect, the invention is directed to methods for
preventing or treating cardiac arrhythmia, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and/or XIII. In certain preferred aspects, the methods
comprise the step of administering to said patient an effective
amount of a compound of formula IV:
##STR00052##
[1089] wherein: [1090] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1091] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1092] each R.sup.d is
independently H, alkyl, or aryl; [1093] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1094] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1095] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1096] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1097] each k is independently 1,
2, or 3; [1098] p is 0, 1, 2 or 3; [1099] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1100] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1101] G is H or alkyl; [1102]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1103] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and
[1104] J.sup.2 forms a 6- to 10-membered aryl or a 5- to
10-membered heteroaryl ring when taken together with the carbon
atoms to which it is attached; [1105] or a stereoisomer, prodrug,
pharmaceutically acceptable salt, hydrate, solvate, acid salt
hydrate, or N-oxide thereof.
[1106] In another aspect, the invention is directed to methods for
preventing or treating glaucoma, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and/or XIII. In certain preferred aspects, the methods
comprise the step of administering to said patient an effective
amount of a compound of formula IV:
##STR00053##
[1107] wherein: [1108] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1109] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1110] each R.sup.d is
independently H, alkyl, or aryl; [1111] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1112] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1113] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1114] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1115] each k is independently 1,
2, or 3; [1116] p is 0, 1, 2 or 3; [1117] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1118] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1119] G is H or alkyl; [1120]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1121] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1122] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1123] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1124] In another aspect, the invention is directed to methods for
preventing or treating sexual dysfunction, including premature
ejaculation, comprising the step of administering to a patient in
need of such treatment an effective amount of a compound of the
invention including, for example, a compound of formulas I, II,
III, IV, V, VI, VII, VIII, IX, X, XI, XII, and/or XIII. In certain
preferred aspects, the methods comprise the step of administering
to said patient an effective amount of a compound of formula
IV:
##STR00054##
[1125] wherein: [1126] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1127] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1128] each R.sup.d is
independently H, alkyl, or aryl; [1129] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1130] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1131] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1132] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1133] each k is independently 1,
2, or 3; [1134] p is 0, 1, 2 or 3; [1135] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1136] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1137] G is H or alkyl; [1138]
X.sup.2 is C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1139] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1140] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1141] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1142] In another aspect, the invention is directed to methods for
treating a condition selected from the group consisting of shock,
brain edema, cerebral ischemia, cerebral deficits subsequent to
cardiac bypass surgery and grafting, systemic lupus erythematosus,
Hodgkin's disease, Sjogren's disease, epilepsy, and rejection in
organ transplants and skin grafts, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and/or XIII. In certain preferred aspects, the methods
comprise the step of administering to said patient an effective
amount of a compound of formula IV:
##STR00055##
[1143] wherein: [1144] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1145] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1146] each R.sup.d is
independently H, alkyl, or aryl; [1147] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1148] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1149] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1150] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1151] each k is independently 1,
2, or 3; [1152] p is 0, 1, 2 or 3; [1153] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1154] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1155] G is H or alkyl; [1156]
X.sup.2 is C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1157] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1158] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1159] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1160] In another aspect, the invention is directed to methods for
treating substance addiction, including addictions to alcohol,
nicotine or drugs such as opioids, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and/or XIII. In certain preferred aspects, the methods
comprise the step of administering to said patient an effective
amount of a compound of formula IV:
##STR00056##
[1161] wherein: [1162] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1163] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1164] each R.sup.d is
independently H, alkyl, or aryl; [1165] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1166] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1167] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1168] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1169] each k is independently 1,
2, or 3; [1170] p is 0, 1, 2 or 3; [1171] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1172] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1173] G is H or alkyl; [1174]
X is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.d)--;
[1175] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1176] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1177] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1178] In another aspect, the invention is directed to methods for
improving organ and cell survival, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and/or XIII. In certain preferred aspects, the methods
comprise the step of administering to said patient an effective
amount of a compound of formula IV:
##STR00057##
[1179] wherein: [1180] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1181] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1182] each R.sup.d is
independently H, alkyl, or aryl; [1183] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1184] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1185] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1186] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1187] each k is independently 1,
2, or 3; [1188] p is 0, 1, 2 or 3, [1189] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1190] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1191] G is H or alkyl; [1192]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1193] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1194] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1195] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1196] Techniques for evaluating and/or employing the present
compounds in methods for improving organ and cell survival and
organ preservation are described, for example, in C. V. Borlongan
et al., Frontiers in Bioscience (2004), 9(Suppl.), 3392-3398, Su,
Journal of Biomedical Science (Basel) (2000), 7(3), 195-199, and
U.S. Pat. No. 5,656,420, the disclosures of each of which are
hereby incorporated herein by reference in their entireties.
[1197] In another aspect, the invention is directed to methods for
providing cardioprotection following myocardial infarction,
comprising the step of administering to a patient in need of such
treatment an effective amount of a compound of the invention
including, for example, a compound of formulas I, II, III, IV, V,
VI, VII, VIII, IX, X, XI, XII, and/or XIII. In certain preferred
aspects, the methods comprise the step of administering to said
patient an effective amount of a compound of formula IV:
##STR00058##
[1198] wherein: [1199] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1200] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1201] each R.sup.d is
independently H, alkyl, or aryl; [1202] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1203] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1204] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1205] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1206] each k is independently 1,
2, or 3; [1207] p is 0, 1, 2 or 3; [1208] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1209] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1210] G is H or alkyl; [1211]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1212] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1213] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1214] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1215] In another aspect, the invention is directed to methods for
reducing the need for anesthesia, comprising the step of
administering to a patient in need of such treatment an effective
amount of a compound of the invention including, for example, a
compound of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI,
XII, and/or XIII. In certain preferred aspects, the methods
comprise the step of administering to said patient an effective
amount of a compound of formula IV:
##STR00059##
[1216] wherein: [1217] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1218] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1219] each R.sup.d is
independently H, alkyl, or aryl; [1220] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1221] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1222] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1223] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1224] each k is independently 1,
2, or 3; [1225] p is 0, 1, 2 or 3; [1226] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1227] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1228] G is H or alkyl; [1229]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1230] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1231] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1232] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1233] In another aspect, the invention is directed to methods of
producing or maintaining an anesthetic state, comprising the step
of administering to a patient in need of such treatment an
effective amount of a compound of the invention including, for
example, a compound of formulas I, II, III, IV, V, VI, VII, VIII,
IX, X, XI, XII, and/or XIII. The method may further comprise the
step of administering to said patient an anesthetic agent, which
may be co-administered with compound(s) of the invention. Suitable
anesthetic agents include, for example, an inhaled anaesthetic, a
hypnotic, an anxiolytic, a neuromuscular blocker and an opioid.
Thus, in the present embodiment, compounds of the invention may be
useful as analgesic agents for use during general anesthesia and
monitored anesthesia care. Combinations of agents with different
properties may be used to achieve a balance of effects needed to
maintain the anaesthetic state. In certain preferred aspects, the
methods comprise the step of administering to said patient an
effective amount of a compound of formula IV:
##STR00060##
[1234] wherein: [1235] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1236] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1237] each R.sup.d is
independently H, alkyl, or aryl; [1238] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1239] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1240] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1241] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1242] each k is independently 1,
2, or 3; [1243] p is 0, 1, 2 or 3; [1244] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1245] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1246] G is H or alkyl; [1247]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1248] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1249] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1250] or a
stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,
solvate, acid salt hydrate, or N-oxide thereof.
[1251] Additional diseases and/or disorders which may be treated
and/or prevented with the compounds and pharmaceutical compositions
of the present invention include those described, for example, in
WO2004/062562 A2, WO 2004/063157 A1, WO 2004/063193 A1, WO
2004/041801 A1, WO 2004/041784 A1, WO 2004/041800 A1, WO
2004/060321 A2, WO 2004/035541 A1, WO 2004/035574 A2, WO 2004041802
A1, US 2004082612 A1, WO 2004026819 A2, WO 2003057223 A1, WO
2003037342 A1, WO 2002094812 A1, WO 2002094810 A1, WO 2002094794
A1, WO 2002094786 A1, WO 2002094785 A1, WO 2002094784 A1, WO
2002094782 A1, WO 2002094783 A1, WO 2002094811 A1, the disclosures
of each of which are hereby incorporated herein by reference in
their entireties.
[1252] In certain aspects, the present invention is directed to
radiolabeled derivatives and isotopically labeled derivatives of
compounds of the invention including, for example, compounds of
formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and/or
XIII. Suitable labels include, for example, .sup.2H, .sup.3H,
.sup.11C, .sup.13C, .sup.13N, .sup.15N, .sup.15O, .sup.18O,
.sup.18F and .sup.34S. Such labeled derivatives may be useful for
biological studies, for example, using positron emission
tomography, for metabolite identification studies and the like.
Such diagnostic imaging methods may comprise, for example,
administering to a patient a radiolabeled derivative or
isotopically labeled derivative of a compound of the invention, and
imaging the patient, for example, by application of suitable
energy, such as in positron emission tomography. Isotopically- and
radio-labeled derivatives may be prepared utilizing techniques well
known to the ordinarily skilled artisan. In certain preferred
aspects, the radiolabeled derivatives and the isotopically labeled
derivatives of the invention are compounds of formula IV:
##STR00061##
[1253] wherein: [1254] Y.sup.2 is a single bond or
--[C(R.sup.c)(R.sup.d)].sub.k--; [1255] each R.sup.c, R.sup.e, and
R.sup.f is independently H or alkyl; [1256] each R.sup.d is
independently H, alkyl, or aryl; [1257] W.sup.2 is aryl, alkaryl,
heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl,
or alkylheteroarylaryl; [1258] R.sup.23 and R.sup.24 are each
independently H, alkyl, alkenyl, alkynyl, or aryl, or R.sup.23 and
R.sup.24 when taken together with the atoms through which they are
connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl
ring; [1259] Z is --N(R.sup.25)--, --C(.dbd.O)--, --CH(OH)--,
--CH(N(R.sup.c)(R.sup.d))--, or --O--; [1260] R.sup.25 is H, alkyl,
alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or
heteroarylalkyl, or R.sup.23 and R.sup.25 when taken together with
the atoms through which they are connected, form a 4- to 8-membered
heterocycloalkyl ring, or R.sup.24 and R.sup.25 when taken together
with the atoms through which they are connected, form a 4- to
8-membered heterocycloalkyl ring; [1261] each k is independently 1,
2, or 3; [1262] p is 0, 1, 2 or 3; [1263] s is 0, 1, 2 or 3,
provided that the sum of p and s is .ltoreq.4; [1264] A.sup.2 and
B.sup.2 are each independently H, fluoro, or alkyl, or together
form a double bond or --CH.sub.2--; [1265] G is H or alkyl; [1266]
X.sup.2 is --C(R.sup.c)(R.sup.d)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --C(.dbd.O)--, --CH(OH)-- or --N(R.sup.26)--;
[1267] R.sup.26 is H, alkyl, cycloalkyl, --(CH.sub.2)-alkenyl,
--(CH.sub.2)-alkynyl, aryl, --C(.dbd.O)R.sup.d, or
--S(.dbd.O).sub.2R.sup.d; and [1268] J.sup.2 forms a 6- to
10-membered aryl or a 5- to 10-membered heteroaryl ring when taken
together with the carbon atoms to which it is attached; [1269]
provided that when: [1270] (a) J.sup.2 taken together with the
carbon atoms to which it is attached forms a 6- to 10-membered aryl
ring substituted with 0-3 groups selected from the group consisting
of: [1271] halogen, [1272] hydroxy, [1273] --SH, [1274]
--C(.dbd.O)--H [1275] --S--C.sub.4 alkyl, [1276]
--NHS(.dbd.O).sub.2--C.sub.1-4 alkyl, [1277]
--NHS(.dbd.O).sub.2--H, [1278] --N(C.sub.1-4
alkyl)S(.dbd.O).sub.2--H, [1279] C.sub.1-4alkyl, and [1280]
C.sub.1-4 alkoxy, the latter two optionally substituted with one or
more halogens or with C.sub.1-4 alkoxy; [1281] W.sup.2 is phenyl
substituted with 0-3 groups selected from the group consisting of:
[1282] halogen, [1283] cyano, [1284] hydroxy, [1285] C.sub.1-6
alkyl optionally substituted with one or more halogens, [1286]
C.sub.1-6 alkoxy optionally substituted with one or more halogens
or with C.sub.3-6 cycloalkyl, [1287] C.sub.2-6 alkenyloxy, [1288]
C.sub.2-6 alkynyloxy, [1289] C.sub.3-6 cycloalkyloxy, [1290]
C.sub.6-12 aryloxy, [1291] aralkoxy, [1292] heteroaryloxy, [1293]
heteroaralkoxy, [1294] heterocycloalkyl substituted with alkoxy,
[1295] --SH, [1296] --S--C.sub.1-4 alkyl, [1297] --NH.sub.2, [1298]
--N.dbd.C(aryl).sub.2, [1299] --N(H)C.sub.1-14 alkyl, [1300]
--N(C.sub.1-4 alkyl).sub.2, [1301] --OS(.dbd.O).sub.2--C.sub.1-4
alkyl optionally substituted with one or more halogens, [1302]
--OS(.dbd.O).sub.2--C.sub.6-12 aryl optionally substituted with
C.sub.1-4 alkyl, [1303] --NHS(.dbd.O).sub.2--C.sub.1-4 alkyl,
[1304] --N(C.sub.1-4 alkyl)S(.dbd.O).sub.2--C.sub.1-4 alkyl, [1305]
--NHS(.dbd.O).sub.2--H, and [1306] --N(C.sub.1-4
alkyl)S(.dbd.O).sub.2--H; [1307] p and s are each 1, [1308]
R.sup.e, R.sup.f, R.sup.23, R.sup.24, and G are each H, [1309]
A.sup.2 and B.sup.2 together form a double bond which incorporates
the atoms to [1310] which they are attached, [1311] Y.sup.2 is a
single bond; and [1312] X.sup.2 is --O--; [1313] then Z is other
than:
##STR00062##
[1313] wherein t is an integer from 1 to 20; and [1314] provided
that when: [1315] (b) J.sup.2 taken together with the carbon atoms
to which it is attached forms a phenyl ring substituted with 0-3
groups selected from the group consisting of: [1316] halogen,
[1317] hydroxy, [1318] --S--C.sub.1-4 alkyl, [1319] C.sub.1-4
alkyl, and [1320] C.sub.1-4 alkoxy, the latter two optionally
substituted with one or more halogens or with C.sub.1-4 alkoxy;
[1321] W.sup.2 is unsubstituted naphthyl, or phenyl substituted
with 0-3 groups selected from the group consisting of: [1322]
halogen, [1323] C.sub.1-6 alkyl, [1324] C.sub.1-6 alkoxy, [1325]
phenyl, [1326] phenoxy, [1327] 1,3-benzodioxazolyl, or
2,2-difluoro-1,3-benzodioxazolyl fluoro, [1328] --NH.sub.2, [1329]
--N(C.sub.4 alkyl).sub.2, and [1330] pyrrolyl; [1331] p and s are
each 1, [1332] R.sup.e, R.sup.f, R.sup.23, R.sup.24, and G are each
H, [1333] A.sup.2 and B.sup.2 together form a double bond which
incorporates the atoms to which they are attached, [1334] Y.sup.2
is a single bond; and [1335] X.sup.2 is --O--; [1336] then Z is
other than:
##STR00063##
[1336] and [1337] provided that when: [1338] (c) J.sup.2 taken
together with the carbon atoms to which it is attached forms
unsubstituted phenyl, [1339] W.sup.2 is phenyl substituted with 0-3
groups selected from the group consisting of: [1340] fluoro, [1341]
hydroxy, [1342] C.sub.1-6 alkoxy optionally substituted with one or
more fluoro, [1343] C.sub.2-6 alkenyloxy, and [1344] --S--C.sub.1-4
alkyl, [1345] p and s are each 1, [1346] R.sup.e, R.sup.f,
R.sup.23, R.sup.24, and G are each H, [1347] A.sup.2 and B.sup.2
together form a double bond which incorporates the atoms to which
they are attached, [1348] Y.sup.2 is a single bond; and [1349]
X.sup.2 is --O--; [1350] then Z is other than:
##STR00064##
[1350] and [1351] provided that when: [1352] (d) J.sup.2 taken
together with the carbon atoms to which it is attached forms a
6-membered aryl ring substituted with:
##STR00065##
[1352] then Z is other than --N(R.sup.25)-- or --CH(NH.sub.2)--;
[1353] or a stereoisomer, prodrug, pharmaceutically acceptable
salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.
[1354] The present invention will now be illustrated by reference
to the following specific, non-limiting examples. Those skilled in
the art of organic synthesis may be aware of still other synthetic
routes to the invention compounds. The reagents and intermediates
used herein are commercially available or may be prepared according
to standard literature procedures.
Methods Of Preparation
[1355] The examples listed in Table 1 were prepared according to
Schemes 1-37. The synthesis of compounds 1A-1U is outlined in
Scheme 1. The 2'-hydroxyacetophenone derivatives 1.1a-1.1m were
condensed with 1-Boc-4-piperidone 1.2 in neat pyrrolidine (method
1A) at room temperature or in refluxing methanol in the presence of
pyrrolidine (method 1B) to provide
N-Boc-spiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one derivatives
1.3. Conversion of the ketones 1.3 to the enol triflate derivatives
1.5 was achieved using N-phenylbis(trifluoromethanesulphonimide)
1.4 as triflating reagent. Suzuki type coupling of the enol
triflate derivatives 1.5 with either
4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 (commercially
available from Combi-Blocks Inc.) or
2-(N,N-diethylaminocarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2--
yl)pyridine 1.7 in ethylene glycol dimethyl ether in the presence
of tetrakis triphenylphosphine palladium (0) (method 1C) or
palladium, 10 wt. % (dry basis) on activated carbon (method 1D),
lithium chloride, and an aqueous solution of sodium carbonate
afforded compounds 1.8 which were converted to the final products
(compounds 1A-1T) under acidic conditions (method 1E: anhydrous
HCl, diethyl ether, room temperature or method 1F: neat
trifluoroacetic acid, room temperature). Demethylation of compound
1G using boron tribromide provided the corresponding phenolic
derivative (compound 1U). The boronate derivative 1.7 was prepared
in 4 steps from 2,5-dibromopyridine 1.9. Treatment of
2,5-dibromopyridine with n-butyllithium provided the corresponding
lithiated derivative, which reacted with carbon dioxide to provide
5-bromopyridine-2-carboxylic acid 1.10. Treatment of the carboxylic
acid derivative 1.10 with oxalyl chloride furnished the acyl
chloride 1.11, which reacted with diethylamine 1.12 to provide
5-bromo-2-(N,N-diethylaminocarbonyl)-pyridine 1.13. Conversion of
the aryl bromide 1.13 to the corresponding boron derivative 1.7 was
achieved using
4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
-1,3,2-dioxaborolane 1.14 and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct, abbreviated as
[Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2].
[1356] The synthesis of compounds 2A-2F is outlined in Scheme 2.
The 2'-5'-dihydroxyacetophenone derivative 2.1 was condensed with
1-Boc-4-piperidone 1.2 in refluxing methanol in the presence of
pyrrolidine to provide
N-Boc-spiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one derivative
2.2 which was converted to the silyl ether derivative 2.4 using
tert-butyldimethylsilyl chloride 2.3. Conversion of the ketone 2.4
to the enol triflate derivative 2.5 was achieved using
N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating
reagent. Suzuki type coupling of the enol triflate derivative 2.5
with either 4-(N,N-diethylaminocarbonyl)-phenyl boronic acid 1.6 or
2-(N,N-diethylaminocarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2--
yl)pyridine 1.7 in ethylene glycol dimethyl ether in the presence
of tetrakis triphenylphosphine palladium (0) (method 1C) or
palladium, 10 wt. % (dry basis) on activated carbon (method 1D),
lithium chloride, and an aqueous solution of sodium carbonate
afforded compounds 2.6. Removal of the silyl protecting group of
2.6 using a solution of tetrabutylammonium fluoride (TBAF) in
tetrahydrofuran gave the phenolic derivatives 2.7 which were
converted to the final products compounds 2A and 2B under acidic
conditions. Preparation of each of the ether derivatives 2.9 from
the phenols 2.7 was achieved by alkylation reaction using the
appropriate alkyl bromide (2.8a, 2.8b) (method 2A) or alkyl iodide
(2.8c) reagent (method 2C). In some instances, the ether
derivatives 2.9 were also obtained from the phenols 2.7 using the
Mitsunobu conditions, i.e., condensation of the phenols 2.7 with
the appropriate alcohol (2.8d, 2.8e) in the presence of
triphenylphosphine and diisopropyl azodicarboxylate (DIAD) (method
2B). Treatment of the Boc derivatives 2.9 with hydrochloric acid
provided the final compounds 2C-F.
[1357] The synthesis of compounds 3A-AC is outlined in Scheme 3.
Conversion of the phenols 2.7 to the triflate derivatives 3.1 was
achieved using the triflating reagent
N-phenylbis(trifluoromethanesulphonimide) 1.4. Palladium catalyzed
carbonylation of 3.1, conducted in methanol or in a mixture
dimethylsulfoxide/methanol using palladium (II) acetate,
1,1'-bis(diphenylphosphino)ferrocene (dppf) and carbon monoxide,
provided the methyl esters 3.2 which were hydrolyzed under basic
conditions to give the carboxylic acid derivatives 3.3. Coupling of
the carboxylic acids 3.3 with various amines (3.4a-3.4q) using
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) as coupling agent afforded the primary, secondary, and
tertiary amides 3.5. Treatment of the Boc derivatives 3.2, 3.3 and
3.5 with hydrochloric acid provided the final compounds 3A-3Y.
Suzuki type coupling of the triflate derivative 3.1a (X.dbd.CH)
with various organoboron reagents (3.6a-3.6d) in ethylene glycol
dimethyl ether in the presence of tetrakis triphenylphosphine
palladium (0), and/or dichloro[1,1'-bis(diphenylphosphino)
ferrocene]palladium(II)dichloromethane, [Pd(dppf)Cl.sub.2
CH.sub.2Cl.sub.2], lithium chloride, and an aqueous solution of
sodium carbonate afforded compounds 3.7 which were converted to the
final products (compounds 3Z-3AC) under acidic conditions.
[1358] The synthesis of compounds 4A-4I is outlined in Scheme 4.
Treatment of compound 1A with trifluoroacetic anhydride in
tetrahydrofuran in the presence of triethylamine provided the
trifluoroacetamide derivative 4.2 which was converted to the
sulfonyl chloride 4.4 using sulfur trioxide N,N-dimethylformamide
complex (4.3) as sulfating agent. Condensation of 4.4 with various
primary and secondary amines (3.4, 4.5) afforded the sulfonamide
derivatives 4.6 which were converted to the compounds 4A-4G under
basic conditions. Treatment of the sulfonyl chloride 4.4 with
ammonium hydroxide in acetonitrile provided the sulfonamide
compound 4H, which was further protected as its
tert-butyloxycarbonyl (Boc) derivative 4.8 buy treatment with
tert-butyloxycarbonyl anhydride (4.7). Acetylation of 4.8 using
acetic anhydride (4.9) gave the acetylsulfonamide derivative 4.10
which was converted to compound 4I by treatment with
iodotrimethylsilane.
[1359] The synthesis of compound 5A is described in Scheme 5.
Condensation of hydrazine hydrate (5.1) with the sulfonyl chloride
derivative 4.4 provided the sulfonyl hydrazide 5.2, which was
converted to the sulfone 5.3 by treatment with methyl iodide (2.8c)
in the presence of sodium acetate. Deprotection of the
trifluoroacetamide protecting group of 5.3 under basic conditions
(potassium carbonate, methanol/tetrahydrofuran/water) provided the
final compound 5A.
[1360] The synthesis of compounds 6A-6E is described in Scheme 6.
Nitration of the trifluoroacetamide 4.2 using nitronium
tetrafluoroborate complex (6.1) as nitrating reagent provided
predominantly the mono-nitro isomer 6.2. Reduction of the nitro
functionality of 6.2 using tin(II) chloride dihydrate (6.3) gave
the aniline derivative 6.4, which reacted with the sulfonyl
chloride derivatives 6.5 or with acetyl chloride (6.7) to provide
the sulfonamides 6.6 or the acetamide 6.8, respectively.
Deprotection of the trifluoroacetamide protecting group of 6.2,
6.4, 6.6 and 6.8 under basic conditions (potassium carbonate,
methanol/tetrahydrofuran/water) provided the final compounds
(compounds 6A-6E).
[1361] The synthesis of compounds 7A-7C is described in Scheme 7.
Buchwald type coupling of the triflate derivative 3.1a with
diphenylmethanimine (7.1) in toluene in the presence of
tris(dibenzylideneacetone)dipalladium (0) [Pd.sub.2(dba).sub.3],
1,1'-bis(diphenylphosphino)ferrocene (dppf) and sodium
tert-butoxide afforded the benzophenone imine derivative 7.2, which
was converted to the aniline 7.3 by treatment with hydroxylamine
hydrochloride in the presence of sodium acetate. Treatment of 7.3
with methanesulfonyl chloride (7.4) in dichloromethane in the
presence of triethylamine provided the bis-methanesulfonamide 7.5,
which was hydrolyzed to the mono methanesulfonamide derivative 7.6
under basic conditions. Deprotection of the tert-butyloxycarbonyl
protecting group of 7.6 under acidic conditions provided the final
compound 7A. Compound 7B was obtained in two steps from 7.6.
Alkylation of 7.6 with methyl iodide (2.8c) in tetrahydrofuran in
the presence of sodium hydride provided the N-methylsulfonamide
7.7, which was converted to compound 7B under acidic conditions.
Treatment of the aniline derivative 6.4 with methanesulfonyl
chloride (7.4) in dichloromethane in the presence of triethylamine
provided the bis-methanesulfonamide 7.8, which was hydrolyzed to
the mono-methanesulfonamide derivative compound 7A under basic
conditions. During the course of this reaction, the N-methyl
piperidine derivative compound 7C was identified as a side product.
The separation of the mixture containing compounds 7A and 7C was
achieved by first treating the mixture of compounds 7A/7C with
tert-butyloxycarbonyl anhydride (4.7) which provided the Boc
derivative 7.6 and unreacted compound 7C, followed by purification
of compound 7C using flash column chromatography.
[1362] The synthesis of compounds 8A-8F is outlined in Scheme 8.
The 2'-3'-dihydroxyacetophenone derivative 8.1 was condensed with
1-Boc-4-piperidone 1.2 in refluxing methanol in the presence of
pyrrolidine to provide the
N-Boc-spiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one derivative
8.2 which was converted to the silyl ether derivative 8.3 using
tert-butyldimethylsilyl chloride 2.3. The ketone 8.3 was converted
to the enol triflate derivative 8.4 using the triflating reagent
N-phenylbis(trifluoromethanesulphonimide) 1.4. Suzuki type coupling
of the enol triflate derivative 8.4 with either
4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 or
2-(N,N-diethylaminocarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2--
yl)pyridine 1.7 in ethylene glycol dimethyl ether in the presence
of palladium, 10 wt. % (dry basis) on activated carbon, lithium
chloride, and an aqueous solution of sodium carbonate afforded
compounds 8.5. Removal of the silyl protecting group of 8.5 using a
solution of tetrabutylammonium fluoride (TBAF) in tetrahydrofuran
gave the phenolic derivatives 8.6 which were converted to the final
products (compounds 8A and 8B) under acidic conditions. Preparation
of the ether derivatives 8.7 from the phenols 8.6 was achieved by
alkylation using the appropriate alkyl bromide (2.8a) or methyl
iodide (2.8c) reagent. Treatment of the Boc derivatives 8.7 with
hydrochloric acid provided the final compounds 8C-8F.
[1363] The synthesis of compounds 9A-9B is outlined in Scheme 9.
The 2'-4'-dihydroxyacetophenone derivative 9.1 was condensed with
1-Boc-4-piperidone 1.2 in refluxing methanol in the presence of
pyrrolidine to provide the
N-Boc-spiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one derivative
9.2 which was converted to the silyl ether derivative 9.3 using
tert-butyldimethylsilyl chloride 2.3. Conversion of the ketone 9.3
to the enol triflate derivative 9.4 was achieved using
N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating
reagent. Suzuki type coupling of the enol triflate derivative 9.4
with 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 in
ethylene glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded the phenolic derivative 9.5
(simultaneous removal of the silyl protecting group occurred under
the Suzuki coupling conditions). Alkylation of the phenol 9.5 with
(bromomethyl)cyclopropane (2.8a) in acetone in the presence of
potassium carbonate provided the ether derivative 9.6 which was
converted to compound 9A under acidic conditions. Treatment of the
phenol 9.5 with methyl chlorodifluoroacetate (9.7) in
N,N-dimethylformamide in the presence of cesium carbonate provided
the ether derivative 9.8 which was converted to compound 9B under
acidic conditions.
[1364] The synthesis of compounds 10A-10J is outlined in Scheme 10.
Conversion of the phenol 9.5 to the triflate derivative 10.1 was
achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as
triflating reagent. Palladium catalyzed carbonylation of 10.1,
conducted in a mixture N,N-dimethylformamide/methanol using
palladium (II) acetate, 1,1'-bis(diphenylphosphino)ferrocene
(dppf), and carbon monoxide, provided the methyl ester 10.2 which
was hydrolyzed under basic conditions to give the carboxylic acid
derivative 10.3. Coupling of the carboxylic acid 10.3 with various
amines (3.4a, c, j, k, p; 1.12) using either
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) (method 101B) or
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) (method 10A) as coupling agents afforded the primary,
secondary, and tertiary amides 10.4. The dimethylamide derivative
10.4b (R.sub.1.dbd.H, R.sub.2.dbd.CH.sub.3) was obtained by heating
a mixture of the ester 10.2 with methylamine (3.4b) in methanol in
a sealed tube. Treatment of the Boc derivatives 10.2, 10.3 and 10.4
with hydrochloric acid provided the final compounds 10A-10I.
Treatment of the ester 10.2 with lithium borohydride in
tetrahydrofuran provided the primary alcohol 10.5 which was
converted to the compound 10J under acidic conditions.
[1365] The synthesis of compounds 11A-11F is outlined in Scheme 11.
The 2'-6'-dihydroxyacetophenone derivative 11.1 was condensed with
1-Boc-4-piperidone 1.2 in refluxing methanol in the presence of
pyrrolidine to provide the
N-Boc-spiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one derivative
11.2 which was converted to the methoxymethyl (MOM) ether
derivative 11.4 using chloro(methoxy)methane (11.3). Conversion of
the ketone 11.4 to the enol triflate derivative 11.5 was achieved
using N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating
reagent. Suzuki type coupling of the enol triflate derivative 11.5
with either 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 or
2-(N,N-diethylaminocarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2--
yl)pyridine 1.7 in ethylene glycol dimethyl ether in the presence
of tetrakis triphenylphosphine palladium (0), lithium chloride, and
an aqueous solution of sodium carbonate afforded compounds 11.6.
Removal of the MOM and the Boc protecting groups of 11.6 in
methanol at room temperature in the presence of hydrochloric acid
(anhydrous solution in dioxane) afforded the phenolic compounds 11A
and 11B which were converted to the corresponding Boc derivatives
11.7 by treatment with tert-butyloxycarbonyl anhydride (4.7).
Preparation of the ether derivatives 11.9a [X.dbd.CH;
R.dbd.CH.sub.2c(C.sub.3H.sub.5)], 11.9b [X.dbd.N;
R.dbd.CH.sub.2c(C.sub.3H.sub.5)] and 11.9d [X.dbd.N;
R=c(C.sub.5H.sub.9)] from the corresponding phenols 11.7a
[X.dbd.CH] or 11.7b [X.dbd.N] was achieved using the Mitsunobu
conditions, i.e., condensation of the phenols 11.7a or 11.7b with
cyclopropylmethanol (2.8e) or cyclopentanol (11.10) in
dichloromethane in the presence of triphenylphosphine and diethyl
azodicarboxylate (DEAD). The cyclobutyl ether 11.9c [X.dbd.CH;
R=c(C.sub.4H.sub.7)] was obtained by alkylation of the
corresponding phenol 11.7a [X.dbd.CH] with bromocyclobutane in
acetone in the presence of potassium carbonate. Treatment of the
Boc derivatives 11.9 with hydrochloric acid provided the final
compounds 11C-11F.
[1366] The synthesis of compounds 12A-12L is outlined in Scheme 12.
Conversion of the phenol 11.2 to the triflate derivative 12.1 was
achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as
triflating reagent. Palladium catalyzed Negishi-type coupling of
12.1 with methylzinc chloride (12.2a), propylzinc bromide (12.2b),
or butylzinc bromide (12.2c), conducted in tetrahydrofuran using
tetrakis triphenylphosphine palladium (0) as catalyst, provided the
ketones 12.3. Conversion of the ketones 12.3 to the enol triflate
derivatives 12.4 was achieved using
N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating
reagent. Suzuki type coupling of the enol triflate derivative 12.4
with 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 or
2-(N,N-diethylaminocarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2--
yl)pyridine 1.7 using either method 1C (tetrakis triphenylphosphine
palladium (0), lithium chloride, aqueous solution of sodium
carbonate, ethylene glycol dimethyl ether) or method 12A (tetrakis
triphenylphosphine palladium (0), potassium bromide, potassium
phosphate, dioxane) afforded compounds 12.5. Removal of the Boc
protecting group of 12.5 in dichloromethane at room temperature in
the presence of hydrochloric acid (anhydrous solution in diethyl
ether) afforded compounds 12A and 12H-12L. Palladium catalyzed
carbonylation of 12.1, conducted in a mixture
N,N-dimethylformamide/methanol using palladium (II) acetate,
1,3-bis(diphenylphosphino)propane (dppp) and carbon monoxide,
provided the methyl ester 12.6 which was hydrolyzed under basic
conditions (lithium hydroxide, methanol/tetrahydrofuran) to give
the carboxylic acid derivative 12.7. Coupling of the carboxylic
acid 12.7 with dimethylamine (3.4j) using
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) as coupling agent afforded the dimethylaminocarbonyl
derivative 12.8. Conversion of 12.8 to the enol triflate derivative
12.9 was achieved using N-phenylbis(trifluoromethanesulphonimide)
1.4 as triflating reagent. Suzuki type coupling of the enol
triflate derivative 12.9 with 4-(N,N-diethylaminocarbonyl)phenyl
boronic acid 1.6 in ethylene glycol dimethyl ether in the presence
of tetrakis triphenylphosphine palladium (0), lithium chloride, and
an aqueous solution of sodium carbonate afforded compound 12.10.
Removal of the Boc protecting group of 12.10 in dichloromethane at
room temperature in the presence of hydrochloric acid (anhydrous
solution in diethyl ether) afforded compound 12G
(R.sub.1.dbd.R.sub.2.dbd.CH.sub.3). Conversion of 12.6 to the enol
triflate derivative 12.11 was achieved using
N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating
reagent. Suzuki type coupling of the enol triflate derivative 12.11
with 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 in
ethylene glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded the ester 12.12 which was
hydrolyzed under basic conditions (potassium tert-butoxide, diethyl
ether, water) to give the carboxylic acid 12.13. Coupling of the
carboxylic acid 12.13 with various amines (12.15 or 3.4b-3.4d)
using O-benzotriazol-1-yl-N',N'-tetramethyluronium
tetrafluoroborate (TBTU) as coupling agent afforded the primary and
secondary aminocarbonyl derivatives 12.14. Treatment of the Boc
derivatives 12.13 and 12.14 with hydrochloric acid provided the
final compounds 12B-12F.
[1367] The synthesis of compounds 13A-13S is outlined in Scheme 13.
The 2'-hydroxyacetophenone derivative 1.1a was condensed with
1-Boc-4-piperidone 1.2 in refluxing methanol in the presence of
pyrrolidine to provide
N-Boc-spiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one 1.3a.
Conversion of 1.3a to the enol triflate derivative 1.5a was
achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as
triflating reagent. Suzuki type coupling of the enol triflate
derivative 1.5a with 4-(methoxycarbonyl)phenylboronic acid (13.1)
in ethylene glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded the ester 13.2 which was
hydrolyzed under basic conditions (lithium hydroxide,
methanol/tetrahydrofuran/water) to give the carboxylic acid 13.3.
Coupling of the carboxylic acid 13.3 with various amines
(3.4a-3.4c, 3.4e, 3.4j-3.4k, 3.4o-3.4q; 13.4a-13.4h) using
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) as coupling agent afforded the primary, secondary, and
tertiary aminocarbonyl derivatives 13.5. Treatment of the Boc
derivatives 13.3 and 13.5 with hydrochloric acid provided the final
compounds 13A-13R. Hydrolysis of compound 130 under basic
conditions (sodium hydroxide, ethanol/tetrahydrofuran) provided the
carboxylic acid compound 13S.
[1368] The synthesis of compounds 14A-14C is outlined in Scheme 14.
Suzuki type coupling of the enol triflate derivative 1.5a with
4-cyanophenylboronic acid (14.1) in ethylene glycol dimethyl ether
in the presence of tetrakis triphenylphosphine palladium (0),
lithium chloride, and an aqueous solution of sodium carbonate
afforded the cyanide 14.2 which was converted to the tetrazole 14.4
using sodium azide (14.3) and zinc bromide in a solution
isopropanol/water. Alkylation of 14.4 with methyl iodide (2.8c) in
N,N-dimethylformamide in the presence of triethylamine afforded the
two regioisomers 14.5 (major isomer) and 14.6 (minor isomer)
separated by silica gel column chromatography. The Boc protecting
group of 14.4, 14.5, and 14.6 was removed using hydrochloric acid
to generate the compounds 14A-14C. Alternatively, the Boc
protecting group of 14.4 was also removed using trifluoroacetic
acid to give 14A.
[1369] The synthesis of compounds 15A-15N is outlined in Scheme 15.
Alkylation of 14.4 with the alkyl bromide derivatives 15.1a-15.1e
in N,N-dimethylformamide in the presence of triethylamine afforded
the regioisomers 15.2 (major isomers) and 15.3 (minor isomers)
separated by silica gel column chromatography. The Boc protecting
group of 15.2 and 15.3 was removed using hydrochloric acid to
generate the compounds 15A-15J. Hydrolysis of compounds 15A or
15C-15E under basic conditions (sodium hydroxide, methanol (or
ethanol)/tetrahydrofuran/water) provided the corresponding
carboxylic acids compounds 15K-15N, respectively. In some
instances, compounds 15K-15N were also obtained in two steps from
15.2, i.e. by basic hydrolysis of the ester functionality of 15.2
followed by deprotection of the Boc derivatives 15.4 under acidic
conditions.
[1370] The synthesis of compounds 16A-16C is outlined in Scheme 16.
Suzuki type coupling of the enol triflate derivative 1.5a with
3-cyanophenylboronic acid (16.1) in ethylene glycol dimethyl ether
in the presence of tetrakis triphenylphosphine palladium (0),
lithium chloride, and an aqueous solution of sodium carbonate
afforded the cyanide 16.2 which was converted to the tetrazole 16.3
using sodium azide (14.3) and zinc bromide in a solution
isopropanol/water. Alkylation of 16.3 with methyl iodide (2.8c) in
N,N-dimethylformamide in the presence of triethylamine afforded the
two regioisomers 16.4 (major isomer) and 16.5 (minor isomer)
separated by silica gel column chromatography. The Boc protecting
group of 16.3, 16.4, and 16.5 was removed using hydrochloric acid
to generate the compounds 16A-16C.
[1371] The synthesis of compounds 17A-17F is outlined in Scheme 17.
Alkylation of 16.3 with the alkyl bromide derivatives 15.1a or
15.1c in N,N-dimethylformamide in the presence of triethylamine
afforded the regioisomers 17.1 (major isomers) and 17.2 (minor
isomers) separated by silica gel column chromatography. Alkylation
of 16.3 with 4-(2-bromoethyl)morpholine (17.3) in
N,N-dimethylformamide in the presence of triethylamine afforded the
isomer 17.4. The Boc protecting group of 17.1, 17.2, and 17.4 was
removed using hydrochloric acid to generate the compounds 17A-17D.
Hydrolysis of compounds 17A and 17B under basic conditions (sodium
hydroxide, methanol/tetrahydrofuran/water) provided the
corresponding carboxylic acids compound 17E and compound 17F,
respectively. In some instances compounds 17E and 17F could also be
obtained in two steps from 17.1, i.e. by basic hydrolysis of the
ester functionality of 17.1 followed by deprotection of the Boc
derivatives 17.5 under acidic conditions.
[1372] The synthesis of compounds 18A-18C is outlined in Scheme 18.
Coupling of the carboxylic acid 13.3 with ammonium chloride (3.4a)
in acetonitrile in the presence of diisopropylethylamine using
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) as coupling agent afforded the primary aminocarbonyl
derivative 13.5a which was converted to the thioamide 18.2 using
the Lawesson's reagent (18.1)
[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfi-
de]. Condensation of the thioamide 18.2 with
1-bromo-3,3-dimethylbutan-2-one (18.3a) or 2-bromo-1-phenylethanone
(18.3b) afforded the thiazole derivatives 18.4 which were converted
to the final compounds (compounds 18A and 18B) under acidic
conditions. Condensation of the nitrile derivative 14.2 with
hydroxylamine hydrochloride (18.5) in ethanol in the presence of
triethylamine afforded the N-hydroxybenzamidine derivative 18.6
which reacted with acetyl chloride (6.7) in refluxing pyridine to
give the 1,2,4-oxadiazole derivative 18.7. Deprotection of the Boc
functionality of 18.7 under acidic conditions afforded compound
18C.
[1373] The synthesis of compound 19A-19D is outlined in Scheme 19.
The 2'-hydroxyacetophenone 1.1a was condensed with benzyl
4-oxopiperidine-1-carboxylate (19.1) in refluxing methanol in the
presence of pyrrolidine to provide
N-Cbz-spiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one (19.2).
Conversion of the ketone 19.2 to the enol triflate derivative 19.3
was achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as
triflating reagent. Conversion of the enol triflate 19.3 to the
corresponding boron derivative 19.4 was achieved using
4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-
-dioxaborolane 1.14 and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct, abbreviated as
[Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2]. Suzuki type coupling of the
boronate derivative 19.4 with tert-butyl 4-bromophenylcarbamate
19.5 in ethylene glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded the tert-butyloxycarbonyl
(Boc) protected aniline derivative 19.6. Acidic hydrolysis of 19.6
provided the aniline derivative 19.7 which reacted with acyl
chlorides 19.8a, 19.8b, isopropylsulfonyl chloride (6.5b) or ethyl
isocyanate (19.11) to give the corresponding amide derivatives
19.9, sulfonamide derivative 19.10 or urea derivative 19.12,
respectively. The derivatives 19.9, 19.10 and 19.12 were converted
to compounds 19A-19D by treatment with iodotrimethylsilane.
[1374] The synthesis of compounds 20A-20R is outlined in Scheme 20.
The tertiary amine derivatives compounds 20A-20R were obtained from
the secondary amines of general formula 201, by reductive amination
methods (methods 20A or 20B) using the aldehydes 20.1a-20.1d and
sodium cyanoborohydride as reducing agent or by alkylation method
(method 20C) using the bromides 2.8a, 20.2a-e as the alkylating
reagent.
[1375] The synthesis of compounds 21A-21F is outlined in Scheme 21.
Condensation of 1-Boc-4-piperidone 1.2 with ethyl diazoacetate
(21.1) in the presence of boron trifluoride diethyl etherate
provided 1-tert-butyl 4-ethyl 3-oxoazepane-1,4-dicarboxylate in
equilibrium with its enol form (21.2). Ester hydrolysis followed by
decarboxylation of 21.2 under acidic conditions provided the
azepan-3-one (21.3), which was protected as its Boc derivative 21.4
by treatment with tert-butyloxycarbonyl anhydride (4.7). The
2'-hydroxyacetophenone 1.1a was condensed with 21.4 in refluxing
methanol in the presence of pyrrolidine to provide the racemic
ketone 21.5. Conversion of 21.5 to the enol triflate derivative
21.6 was achieved using the triflating reagent
N-phenylbis(trifluoromethanesulphonimide) 1.4. Suzuki type coupling
of the enol triflate derivative 21.6 with
4-(N,N-diethylaminocarbonyl)phenyl boronic acid (1.6) in ethylene
glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded the racemic derivative 21.7,
which was hydrolyzed under acidic conditions to give the compound
21A (racemic mixture). The two enantiomers derived from 21.7, i.e.
compounds 21.7a and 21.7b, were separated by chiral HPLC. The pure
enantiomers 21.7a and 21.7b were converted to compounds 21B and
21C, respectively under acidic conditions. Palladium catalyzed
hydrogenation of compounds 21B and 21C afforded compounds 21D
(diastereoisomeric mixture) and 21E (diastereoisomeric mixture),
respectively. Treatment of compound 21A with benzyl chloroformate
(21.8) in dichloromethane in the presence of triethylamine provided
the Cbz-protected derivative 21.9, which was converted to the
sulfonyl chloride 21.10 using sulfur trioxide N,N-dimethylformamide
complex (4.3) as sulfating agent. Condensation of 21.10 with
ethylamine (3.4c) in dichloromethane in the presence of
triethylamine, afforded the ethyl sulfonamide derivative 21.11
which was converted to compound 21F by treatment with
iodotrimethylsilane.
[1376] The synthesis of compounds 22A-22E is outlined in Scheme 22.
Treatment of compound 21B (most active enantiomer) with
trifluoroacetic anhydride (4.1) in tetrahydrofuran in the presence
of triethylamine provided the trifluoroacetamide derivative 22.1
which was converted to the sulfonyl chloride 22.2 using sulfur
trioxide N,N-dimethylformamide complex (4.3) as sulfating agent.
Condensation of 22.2 with various primary amines (3.4b, 3.4c, 3.4d,
3.4 g) afforded the sulfonamide derivatives 22.3 which were
converted to compounds 22A-22D under basic conditions. Condensation
of hydrazine hydrate (5.1) with the sulfonyl chloride derivative
22.2 provided the sulfonyl hydrazide 22.4, which was converted to
the sulfone 22.5 by treatment with methyl iodide (2.8c) in the
presence of sodium acetate. Deprotection of the trifluoroacetamide
protecting group of 22.5 under basic conditions (potassium
carbonate, methanol/tetrahydrofuran/water) provided the methyl
sulfonyl analog (compound 22E).
[1377] The synthesis of compounds 23A-23C is outlined in Scheme 23.
The 2'-hydroxyacetophenone 1.1a was condensed with tert-butyl
3-oxopyrrolidine-1-carboxylate (23.1a) or tert-butyl
3-oxopiperidine-1-carboxylate (23.1b) in refluxing methanol in the
presence of pyrrolidine to provide the racemic ketones 23.2a (n=0)
and 23.2b (n=1), respectively. Conversion of the ketones 23.2 to
the enol triflate derivatives 23.3 was achieved using
N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating
reagent. Suzuki type coupling of the enol triflate derivatives 23.3
with 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 in
ethylene glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded the Boc derivatives 23.4
which were converted to the final products compounds 23A and 23B
(racemic mixtures) under acidic conditions. The
2'-hydroxyacetophenone 1.1a was also condensed with
1-Boc-4-nortropinone (23.5) in refluxing methanol in the presence
of pyrrolidine to provide the ketone 23.6. Conversion of the ketone
23.6 to the enol triflate derivative 23.7 was achieved using
N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating
reagent. Suzuki type coupling of the enol triflate derivative 23.7
with 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 in
ethylene glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded the Boc derivative 23.8 which
was converted to the final product compound 23C under acidic
conditions.
[1378] The synthesis of compounds 24A-24G is outlined in Scheme 24.
The 2'-hydroxyacetophenone 1.1a was condensed with
1,4-cyclohexanedione mono-ethylene ketal (24.1) in refluxing
methanol in the presence of pyrrolidine to provide the ketone 24.2.
Conversion of the ketone 24.2 to the enol triflate derivative 24.3
was achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as
triflating reagent. Suzuki type coupling of the enol triflate
derivative 24.3 with 4-(N,N-diethylaminocarbonyl)phenyl boronic
acid 1.6 in ethylene glycol dimethyl ether in the presence of
tetrakis triphenylphosphine palladium (0), lithium chloride, and an
aqueous solution of sodium carbonate afforded the derivative 24.4
which was converted to the ketone compound 24A under acidic
conditions. The reduction of the ketone compound 24A, conducted in
tetrahydrofuran in the presence of sodium borohydride, provided the
corresponding alcohol derivatives compounds 24B and 24C. Treatment
of the ketone compound 24A with propylamine (3.4d) or dimethylamine
(3.4j) under reductive amination conditions using sodium
cyanoborohydride as reducing agent, provided the amines compounds
24D-24G.
[1379] The synthesis of compound 25A is outlined in Scheme 25. The
2'-hydroxyacetophenone 1.1a was also condensed with
tetrahydropyran-4-one (25.1) in refluxing methanol in the presence
of pyrrolidine to provide the ketone 25.2. Conversion of the ketone
25.2 to the enol triflate derivative 25.3 was achieved using
N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating
reagent. Suzuki type coupling of the enol triflate derivative 25.3
with 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 in
ethylene glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded compound 25A.
[1380] The synthesis of compounds 26A-26B is outlined in Scheme 26.
Palladium catalyzed Negishi-type coupling of 1.5a with
4-cyanobenzylzinc bromide (26.1) conducted in tetrahydrofuran using
tetrakis triphenylphosphine palladium (0) as catalyst, provided the
nitrile 26.2. Acidic hydroysis of the nitrile 26.2 provided the
carboxylic acid derivatives 26.3a and 26.3b (compounds 26.3a and
26.3b were separated by column chromatography; however, the
following step was conducted using the mixture 26.3a/26.3b).
Treatment of the mixture 26.3a/26.3b with methanol in the presence
of hydrochloric acid afforded the piperidine esters 26.4a/26.4b
which were converted to the corresponding Boc derivatives
26.5a/26.5b by treatment with tert-butyloxycarbonyl anhydride
(4.7). Hydrolysis of the esters 26.5a/26.5b in basic conditions
gave the carboxylic acid derivatives 26.6a/26.6b. Coupling of the
carboxylic acid derivatives 26.6a/26.6b with diethylamine (1.12)
using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU) as coupling agent afforded the
dimethylaminocarbonyl derivatives 26.7a/26.7b. Removal of the Boc
protecting group of 26.7a/26.7b in dichloromethane at room
temperature in the presence of hydrochloric acid (anhydrous
solution in dioxane) afforded compounds 26A and 26.8 which were
separated by column chromatography. Palladium catalyzed
hydrogenation of compound 26.8 afforded compound 26B.
[1381] The synthesis of compounds 27A-27W is outlined in Scheme 27.
The saturated derivatives (compounds 27A, 27D, 27G, 27H, 27K, 27N,
and 27W, as their racemic mixtures) were obtained by hydrogenation
of the unsaturated analogs (compounds 1A, 1D, 2C, 1N, 1O, 1S, and
1E), respectively, in methanol in the presence of palladium, 10 wt.
% (dry basis) on activated carbon (method 27A) or palladium
hydroxide, 20 wt. % Pd (dry basis) on carbon (Pearlman's catalyst
(method 27B)). Hydrogenation of 11.6a in methanol in the presence
of palladium hydroxide, 20 wt. % Pd (dry basis) on carbon
(Pearlman's catalyst) provided the saturated derivative 27.1.
Acidic hydrolysis of 27.1 provided compound 27T. Hydrolysis of 2.7a
in methanol in the presence of palladium, 10 wt. % (dry basis) on
activated carbon, provided the saturated derivative 27.6. Acidic
hydrolysis of 27.6 provided the compound 27Q. Chiral separation of
the enantiomers derived from 27.1 provided compounds 27.4 and 27.5.
The enantiomers 27.4 and 27.5 were converted to compounds 27U and
27V, respectively under acidic conditions. Chiral separation of the
enantiomers derived from each of the racemic compounds (compounds
27A, 27 D, 27G, 27H, 27K, 27N, 27Q and 27W) provided compounds 27B,
27E, 27I, 27L, 27O, 27R (pure enantiomer) and compounds 27C, 27F,
27J, 27M, 27P, 27S (pure enantiomer). Condensation of compound 27B
with (1S)-(+)-10-camphorsulfonyl chloride (27.2) (used as chiral
resolving agent) in dichloromethane in the presence of
triethylamine provided the chiral sulfonamide derivative 27.3. The
absolute configuration of 27.3 was determined by X-ray
crystallography, therefore establishing the absolute configuration
of compound 27B, and therefore by inference, its enantiomer,
compound 29C.
[1382] The synthesis of compounds 28A-28E is outlined in Scheme 28.
Condensation of benzyl 4-oxopiperidine-1-carboxylate (19.1) with
ethyl cyanoacetate (28.1) in the presence of acetic acid and
ammonium acetate gave the unsaturated ester 28.2. Compound 28.2 was
subjected to conjugate addition by reaction with organo cuprate
reagents derived from benzyl or methoxybenzyl magnesium chloride
(28.3a and 28.3b, respectively) and copper (I) cyanide to yield the
cyano esters 28.4. Treatment of the conjugate addition product
28.4a (R.sup.v.dbd.H) with concentrated sulfuric acid at 90.degree.
C. provided the amino ketone 28.5. Treatment of 28.5 with benzyl
chloroformate (21.8) in dichloromethane in the presence of
triethylamine provided the corresponding Cbz-protected derivative
28.6a (R.sup.v.dbd.H). Decarboxylation of 28.4b
(R.sup.v.dbd.OCH.sub.3) by treatment with sodium chloride in
dimethylsulfoxide containing small amount of water at 160.degree.
C. afforded the nitrile 28.9. Hydrolysis of the nitrile
functionality of 28.9 to the methyl ester group by treatment with
methanol in the presence of sulfuric acid provided the
corresponding piperidine derivative (Cleavage of the Cbz protecting
group of 28.9 occurred during the course of the hydrolysis).
Treatment of the piperidine derivative with benzyl chloroformate
afforded the compound 28.10. The ester 28.10 was hydrolyzed with
lithium hydroxide to furnish the carboxylic acid 28.11. Treatment
of the acid 28.11 with oxalyl chloride followed by reaction of the
resulting acyl chloride with aluminum chloride yielded the
corresponding spiro piperidine derivative which was further
protected as its CBz derivative 28.6b (R.sup.v.dbd.OCH.sub.3) by
treatment with benzylchloroformate. Conversion of the ketones 28.6
to the enol triflate derivatives 28.7 was achieved using
N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating
reagent. Suzuki type coupling of the enol triflate derivatives 28.7
with 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 in
ethylene glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded the derivatives 28.8 which
were converted to the compounds 28A and 28B by treatment with
iodotrimethylsilane. The compounds 28C and 28D (racemic mixtures)
were obtained by hydrogenation of unsaturated derivatives 28.8 in
methanol in the presence of palladium, 10 wt. % (dry basis) on
activated carbon. Suzuki type coupling of the enol triflate
derivative 28.7a (R.sup.v.dbd.H) with
2-(N,N-diethylaminocarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2--
yl)pyridine 1.7 in ethylene glycol dimethyl ether in the presence
of tetrakis triphenylphosphine palladium (0), lithium chloride, and
an aqueous solution of sodium carbonate afforded the derivative
28.12 which was converted to the compound 28E by treatment with
iodotrimethylsilane.
[1383] The synthesis of compounds 29A-29D is outlined in Scheme 29.
The Negishi coupling of the enol triflate 28.7a with
4-(ethoxycarbonyl)phenylzinc iodide (29.1) in tetrahydrofuran in
the presence of tetrakis triphenylphosphine palladium (0) gave the
ester 29.2, which was hydrolyzed with lithium hydroxide to afford
the carboxylic acid 29.3. Coupling of the carboxylic acid 29.3 with
isopropylamine (3.4h) or 1-ethylpropylamine (29.4) using
2-chloro-1-methylpyridinium iodide (Mukaiyama acylating reagent) as
coupling agent afforded the secondary aminocarbonyl derivatives
29.5, which were converted to the compounds 29A and 29B by
treatment with iodotrimethylsilane. Curtius rearrangement of the
carboxylic acid 29.3 by reaction with diphenylphosphoryl azide
(29.6) in the presence of tert-butyl alcohol provided the
tert-butyloxycarbonyl (Boc) protected aniline derivative 29.7.
Acidic hydrolysis of 29.7 provided the aniline derivative 29.8
which reacted with propionyl chloride 29.9 or methanesulfonyl
chloride (7.4) to give the corresponding amide derivative 29.10 or
sulfonamide derivative 29.11, respectively. The derivatives 29.10
and 29.11 were converted to compounds 29C and 29D, respectively, by
treatment with iodotrimethylsilane.
[1384] The synthesis of compound 30A is outlined in Scheme 30.
Wittig type condensation of 1-benzoyl-4-piperidone (30.1) with
methyl(triphenylphosphoranylidene)acetate (30.2) in toluene gave
the unsaturated ester 30.3. Compound 30.3 was subjected to
conjugate addition by reaction with benzenethiol (30.4) to yield
the thioether 30.5. Treatment of the conjugate addition product
30.5 with concentrated sulfuric acid provided the cyclized product
30.6, which was converted to the sulfone 30.7 by oxidation using a
solution of hydrogen peroxide in glacial acetic acid. Acidic
hydrolysis of 30.7 provided the amine 30.8, which was treated with
tert-butyloxycarbonyl anhydride (4.7) to give the Boc protected
derivative 30.9. Conversion of the ketone 30.9 to the enol triflate
derivative 30.10 was achieved using
N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating
reagent. Suzuki type coupling of the enol triflate derivative 30.10
with 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 in
ethylene glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded the derivative 30.11 which
was converted to compound 30A under acidic conditions.
[1385] The synthesis of compounds 31A-31AA is outlined in Scheme
31. Suzuki type coupling of the enol triflate derivative 1.5a with
the commercially available boronic acid derivatives 13.1, 14.1,
16.1 or 31.1a-31.1u in ethylene glycol dimethyl ether in the
presence of tetrakis triphenylphosphine palladium (0), lithium
chloride, and an aqueous solution of sodium carbonate afforded
compounds 13.2, 14.2, 16.2 and 31.2, respectively. Compounds 13.2,
14.2, 16.2 and 31.2 were converted to the final products compounds
31A-31X under acidic conditions (method 1E: anhydrous HCl, diethyl
ether, room temperature or method 1F: neat trifluoroacetic acid
(with optional dichloromethane), room temperature or method 31A:
anhydrous HCl, methanol, dioxane, reflux). Treatment of the nitrile
16.2 with lithium aluminum hydride in tetrahydrofuran provided the
diamine compound 31Y, which reacted with acetyl chloride (6.7) or
methanesulfonyl chloride (7.4) to give the corresponding amide
derivative compounds 31Z or the sulfonamide derivative compound
31AA, respectively.
[1386] The synthesis of compounds 32A-32Z is outlined in Scheme 32.
Conversion of the enol triflate 1.5a to the corresponding boron
derivative 32.1 was achieved using
4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-
-dioxaborolane 1.14 and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct, abbreviated as
[Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2]. Suzuki type coupling of the
boronate derivative 32.1 with various aryl bromide derivatives 32.2
under different conditions [method 1C: ethylene glycol dimethyl
ether, tetrakis triphenylphosphine palladium (0), lithium chloride,
aqueous solution of sodium carbonate; method 1D: ethylene glycol
dimethyl ether, palladium, 10 wt. % (dry basis) on activated
carbon, lithium chloride, aqueous solution of sodium carbonate;
method 12A: tetrakis triphenylphosphine palladium (0), potassium
bromide, potassium phosphate, dioxane] afforded the derivatives
32.3, which were converted to compounds 32A-32I or 32K-32Z under
acidic conditions. The tert-butyl sulfonamide derivative compound
32.3b was converted to the sulfonamide compound 32J by treatment
with trifluoroacetic acid. The derivatives 32.2 used in the Suzuki
coupling step were prepared as follows. Coupling of the carboxylic
acid 32.4 with diethylamine (1.12) using
2-chloro-1-methylpyridinium iodide (Mukaiyama acylating reagent) as
coupling agent afforded 2-(4-bromophenyl)-N,N-diethylacetamide
(32.2a). The sulfone derivatives 32.2j-32.2p were obtained in two
steps from 4-bromobenzenethiol (32.7). Alkylation of 32.7 with the
alkyl bromide derivatives 20.2, 2.8 or 32.8 in acetonitrile in the
presence of triethylamine (method 32A) or in N,N-dimethylformamide
in the presence of sodium hydride (method 32B) provided the
thioether derivatives 32.9, which were oxidized to the sulfone
derivatives 32.2j-32.2p in glacial acetic acid in the presence of
an aqueous solution of hydrogen peroxide. Coupling of
4-bromobenzene-1-sulfonyl chloride (32.5) with various amines (3.4,
1.12, 13.4 or 32.6) in tetrahydrofuran in the presence of
triethylamine provided the sulfonamides 32.2b-32.2i. Acylation of
N-methyl-4-bromoaniline (32.10) with various acyl chloride
derivatives (19.8, 32.11 or 6.7) in dichloromethane in the presence
of triethylamine provided the amides 32.2q-32.2u, 32.2x, 32.2y. The
aryl bromides 32.2v and 32.2w are commercially available.
[1387] The synthesis of compounds 33A-33L is outlined in Scheme 33.
Suzuki type coupling of the boronate derivative 32.1 with various
aryl bromide derivatives 33.1 under different conditions [method
1C: ethylene glycol dimethyl ether, tetrakis triphenylphosphine
palladium (0), lithium chloride, aqueous solution of sodium
carbonate; method 1D: ethylene glycol dimethyl ether, palladium, 10
wt. % (dry basis) on activated carbon, lithium chloride, aqueous
solution of sodium carbonate; method 33A: ethylene glycol dimethyl
ether, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct, abbreviated as
[Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2], lithium chloride, potassium
phosphate] afforded the derivatives 33.2, which were converted to
compounds 33A-33K under acidic conditions. The derivatives 33.1
used in the Suzuki coupling step were either obtained from
commercial sources (33.1 a-e) or prepared as follows. Coupling of
5-bromopyridine-3-carboxylic acid (33.3) or
6-bromopyridine-2-carboxylic acid (33.4) with diethylamine (1.12)
using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU) as coupling agent afforded the
diethylaminocarbonyl derivative derivatives 33.1f and 33.1g,
respectively. Treatment of 2,5-dibromopyridine (1.9) with
n-butyllithium provided the corresponding lithiated derivative,
which reacted with carbon dioxide to provide
5-bromopyridine-2-carboxylic acid 1.10. The carboxylic acid 1.10
was also obtained by acidic hydrolysis of commercially available
5-bromopyridine-2-carbonitrile (33.1e). Treatment of the carboxylic
acid derivative 1.10 with oxalyl chloride furnished the acyl
chloride 1.11, which reacted with dimethylamine (3.4j), ethylamine
(3.4c) or methylamine (3.4b) to provide the corresponding
aminocarbonyl derivatives 33.1h, 33.1i and 33.1j, respectively.
Treatment of commercially available 5-bromo-2-iodopyrimidine (33.5)
with n-butyllithium provided the corresponding lithiated
derivative, which reacted with carbon dioxide to provide
5-bromopyrimidine-2-carboxylic acid (33.6). Treatment of the
carboxylic acid derivative 33.6 with oxalyl chloride furnished the
acyl chloride 33.7, which reacted with diethylamine 1.12 to provide
5-bromo-2-(N,N-diethylaminocarbonyl)-pyrimidine 33.1k.
[1388] Hydrolysis of the nitrile derivative 33.2a under acidic
conditions provided the carboxylic acid derivative compound 33E and
compound 33L. Compound 33E and compound 33L were readily separated
by column chromatography.
[1389] The synthesis of compounds 34A-34P is outlined in Scheme 34.
Suzuki type coupling of the boronate derivative 32.1 with various
aryl bromide derivatives 34.1 in ethylene glycol dimethyl ether in
the presence of tetrakis triphenylphosphine palladium (0), lithium
chloride, and an aqueous solution of sodium carbonate afforded
compounds 34.2 which were converted to the final products compounds
34A-34P under acidic conditions. The derivatives 34.1 used in the
Suzuki coupling step were prepared as follow. Coupling of
6-bromopyridine-3-carboxylic acid (34.3),
5-bromothiophene-2-carboxylic acid (34.4),
4-bromothiophene-2-carboxylic acid (34.7) or
5-bromofuran-2-carboxylic acid (34.6) with diethylamine (1.12) or
diisopropylamine (3.4o) using
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) as coupling agent afforded the diethylaminocarbonyl
derivatives 34.1 a-d, f-i. Coupling of 5-bromothiophene-2-sulfonyl
chloride (34.5) with diethylamine (1.12) in acetonitrile in the
presence of triethylamine provided the sulfonamide 34.1e. Coupling
of the commercially available carboxylic acid derivatives
34.8a-34.8f and 34.9 with diethylamine (1.12) using
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) as coupling agent afforded the corresponding
diethylaminocarbonyl derivatives 34.1j-34.1o and 34.1p.
[1390] The synthesis of compounds 35A and 35B is outlined in Scheme
35. Iodination of 3-hydroxybenzoic acid (35.1) afforded
3-hydroxy-4-iodobenzoic acid (35.2), which was converted to the
methyl ester 35.3 under standard esterification conditions.
Alkylation of the phenolic derivative 35.3 with methyl iodide
(2.8c) in acetone in the presence of potassium carbonate afforded
the methyl ether 35.4, which was converted to the carboxylic acid
35.5 in the presence of lithium hydroxide. Coupling of the
carboxylic acid derivatives 35.5 with diethylamine (1.12) using
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) as coupling agent afforded the corresponding
diethylaminocarbonyl derivative 35.6. Demethylation of 35.6 using
boron tribromide afforded the phenolic derivative 35.7 which was
converted to the methyloxymethyl (MOM) ether derivative 35.8 using
chloro(methoxy)methane 11.3. Suzuki type coupling of the boronate
derivative 32.1 with 35.6 in ethylene glycol dimethyl ether in the
presence of tetrakis triphenylphosphine palladium (0), lithium
chloride, and an aqueous solution of sodium carbonate afforded
compound 35.9 which was converted to the final product compound 35A
under acidic conditions. Suzuki type coupling of the boronate
derivative 32.1 with 35.8 in ethylene glycol dimethyl ether in the
presence of palladium, 10 wt. % (dry basis) on activated carbon,
lithium chloride, and an aqueous solution of sodium carbonate
afforded compound 35.10 which was converted to the final product
compound 35B under acidic conditions.
[1391] The synthesis of compounds 36A and 36B is outlined in Scheme
36. Coupling of 4-bromo-2-hydroxybenzoic acid (36.3) [obtained from
4-amino-2-hydroxybenzoic acid (36.1) under Sandmeyer conditions]
with diethylamine (1.12) using
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) as coupling agent afforded the
corresponding diethylaminocarbonyl derivative 36.4. Suzuki type
coupling of the boronate derivative 32.1 with 36.4 in ethylene
glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded compound 36.5 which was
converted to the final product (compound 36A) under acidic
conditions. Compound 36B was obtained in 7 steps from
2-(3-methoxyphenyl)ethanamine (36.6). Coupling of 36.6 with ethyl
chloroformate (36.7) afforded the ethyl carbamate derivative 36.8
which was cyclized to 3,4-dihydro-6-methoxyisoquinolin-1-(2H)-one
(36.9) in the presence of polyphosphoric acid. Alkylation of 36.9
with ethyl iodide (36.10) in tetrahydrofuran in the presence of
sodium hydride, afforded the methyl ether 36.11, which was
converted to the phenolic derivative 36.12 by treatment with boron
tribromide. Condensation of 36.12 with trifluoromethanesulfonic
anhydride (36.13) in dichloromethane in the presence of pyridine
afforded the triflate derivative 36.14. Suzuki type coupling of the
boronate derivative 32.1 with 36.14 in N,N-dimethylformamide in the
presence of
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct, abbreviated as
[Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2], and potassium acetate afforded
compound 36.15 which was converted to the final product (compound
36B) under acidic conditions.
[1392] The synthesis of compounds 37A-37B is outlined in Scheme 37.
The 2'-hydroxyacetophenone 1.1a was condensed with
1-benzyl-3-methylpiperidin-4-one (37.1) (racemic mixture) in
refluxing methanol in the presence of pyrrolidine to provide the
racemic ketones 37.2 and 37.3. The diastereoisomers 37.2 and 37.3
were separated by column chromatography. Palladium catalyzed
hydrogenation of 37.2 afforded the piperidine derivative 37.4,
which was converted to 37.5 by treatment with tert-butyloxycarbonyl
anhydride (4.7). Conversion of the ketone 37.5 to the enol triflate
derivative 37.6 was achieved using
N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating
reagent. Suzuki type coupling of the enol triflate derivative 37.6
with 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 in
ethylene glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded the Boc derivative 37.7,
which was converted to the final product compound 37A (racemic
mixture) under acidic conditions. Similarly, palladium catalyzed
hydrogenation of 37.3 afforded the piperidine derivative 37.8,
which was converted to 37.9 by treatment with tert-butyloxycarbonyl
anhydride (4.7). Conversion of the ketone 37.9 to the enol triflate
derivative 37.10 was achieved using
N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating
reagent. Suzuki type coupling of the enol triflate derivative 37.10
with 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 in
ethylene glycol dimethyl ether in the presence of tetrakis
triphenylphosphine palladium (0), lithium chloride, and an aqueous
solution of sodium carbonate afforded the Boc derivative 37.11,
which was converted to the final product compound 37B (racemic
mixture) under acidic conditions.
##STR00066## ##STR00067## ##STR00068## ##STR00069##
##STR00070## ##STR00071##
##STR00072## ##STR00073## ##STR00074##
##STR00075## ##STR00076##
##STR00077##
##STR00078##
##STR00079## ##STR00080##
##STR00081## ##STR00082##
##STR00083## ##STR00084##
##STR00085## ##STR00086##
##STR00087## ##STR00088##
##STR00089## ##STR00090## ##STR00091##
##STR00092## ##STR00093##
##STR00094##
##STR00095##
##STR00096##
##STR00097##
##STR00098## ##STR00099##
##STR00100## ##STR00101## ##STR00102##
##STR00103##
##STR00104## ##STR00105## ##STR00106##
##STR00107## ##STR00108## ##STR00109##
##STR00110## ##STR00111## ##STR00112##
##STR00113##
##STR00114##
##STR00115## ##STR00116##
##STR00117## ##STR00118## ##STR00119##
##STR00120## ##STR00121## ##STR00122##
##STR00123## ##STR00124##
##STR00125## ##STR00126## ##STR00127##
##STR00128## ##STR00129## ##STR00130## ##STR00131##
##STR00132##
##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137##
##STR00138## ##STR00139## ##STR00140##
##STR00141## ##STR00142## ##STR00143## ##STR00144##
##STR00145## ##STR00146## ##STR00147## ##STR00148##
##STR00149##
##STR00150##
##STR00151## ##STR00152## ##STR00153##
##STR00154## ##STR00155##
[1393] 37A and 37B are diastereomeric with respect to one another,
but each is a racemic mixture of its two possible enantiomers.
Their absolute stereochemistry has not been conclusively
established.
TABLE-US-00001 TABLE 1 C. EXAMPLES CLAIMED IN THE PRESENT INVENTION
[M + H] Example Structure + 1A ##STR00156## 377.4 1B ##STR00157##
407.1 1C ##STR00158## 411.2 1D ##STR00159## 395.2 1E ##STR00160##
391.3 1F ##STR00161## 407.2 1G ##STR00162## 407.1 1H ##STR00163##
427.4 1I ##STR00164## 427.4 1J ##STR00165## 405.4 1K ##STR00166##
413.2 1L ##STR00167## 405.4 1M ##STR00168## 391.0 1N ##STR00169##
378.4 1O ##STR00170## 396.3 1P ##STR00171## 392.3 1Q ##STR00172##
408.3 1R ##STR00173## 428.3 1S ##STR00174## 406.3 1T ##STR00175##
406.4 1U ##STR00176## 393.2 2A ##STR00177## 393.3 2B ##STR00178##
394 2C ##STR00179## 447.1 2D ##STR00180## 461.1 2E ##STR00181##
448.3 2F ##STR00182## 408.3 3A ##STR00183## 435.0 3B ##STR00184##
421.0 3C ##STR00185## 422.2 3D ##STR00186## 420.0 3E ##STR00187##
434.3 3F ##STR00188## 448.4 3G ##STR00189## 462.4 3H ##STR00190##
476.5 3I ##STR00191## 490.6 3J ##STR00192## 474.4 3K ##STR00193##
462.5 3L ##STR00194## 490.5 3M ##STR00195## 448.4 3N ##STR00196##
474.5 3O ##STR00197## 490.3 3P ##STR00198## 490.5 3Q ##STR00199##
502.5 3R ##STR00200## 476.5 3S ##STR00201## 504.4 3T ##STR00202##
490.1 3U ##STR00203## 488.4 3V ##STR00204## 421.3 3W ##STR00205##
435.3 3X ##STR00206## 449.3 3Y ##STR00207## 449.3 3Z ##STR00208##
454.0 3AA ##STR00209## 459.3 3AB ##STR00210## 454.4 3AC
##STR00211## 455.4 4A ##STR00212## 470.2 4B ##STR00213## 484.3 4C
##STR00214## 498.3 4D ##STR00215## 510.3 4E ##STR00216## 498.3 4F
##STR00217## 484.1 4G ##STR00218## 496.2 4H ##STR00219## 456.0 4I
##STR00220## 498.3 5A ##STR00221## 455.2 6A ##STR00222## 422.3 6B
##STR00223## 392.2 6C ##STR00224## 484.2 6D ##STR00225## 498.2 6E
##STR00226## 434.2 7A ##STR00227## 470.4 7B ##STR00228## 484.2 7C
##STR00229## 484.2 8A ##STR00230## 393.4 8B ##STR00231## 394.2 8C
##STR00232## 447.3 8D ##STR00233## 407.3 8E ##STR00234## 448.3 8F
##STR00235## 408.4 9A ##STR00236## 447.3 9B ##STR00237## 443.4 10A
##STR00238## 435.3 10B ##STR00239## 421.3 10C ##STR00240## 420.3
10D ##STR00241## 434.3 10E ##STR00242## 448.3 10F ##STR00243##
448.3 10G ##STR00244## 476.2 10H ##STR00245## 474.3 10I
##STR00246## 490.2 10J ##STR00247## 407.4 11A ##STR00248## 393.0
11B ##STR00249## 394.3 11C ##STR00250## 447.4 11D ##STR00251##
448.4 11E ##STR00252## 447.3 11F ##STR00253## 462.4 12A
##STR00254## 391.4 12B ##STR00255## 421.3 12C ##STR00256## 420.3
12D ##STR00257## 434.3 12E ##STR00258## 448.4 12F ##STR00259##
462.4 12G ##STR00260## 448.4 12H ##STR00261## 392.4 12I
##STR00262## 419.4 12J ##STR00263## 433.4 12K ##STR00264## 420.4
12L ##STR00265## 434.3 13A ##STR00266## 322.1 13B ##STR00267##
321.1 13C ##STR00268## 335.2 13D ##STR00269## 349.2 13E
##STR00270## 377.2 13F ##STR00271## 349.1 13G ##STR00272## 375.1
13H ##STR00273## 405.3 13I ##STR00274## 391.1 13J ##STR00275##
389.1 13K ##STR00276## 403.3 13L ##STR00277## 423.1
13M ##STR00278## 417.2 13N ##STR00279## 425.2 13O ##STR00280##
461.2 13P ##STR00281## 421.2 13Q ##STR00282## 404.3 13R
##STR00283## 501.2 13S ##STR00284## 433.1 14A ##STR00285## 346.1
14B ##STR00286## 360.1 14C ##STR00287## 360.2 15A ##STR00288##
418.1 15B ##STR00289## 432.2 15C ##STR00290## 460.2 15D
##STR00291## 474.2 15E ##STR00292## 488.2 15F ##STR00293## 418.2
15G ##STR00294## 432.1 15H ##STR00295## 460.2 15I ##STR00296##
474.3 15J ##STR00297## 488.3 15K ##STR00298## 404.1 15L
##STR00299## 432.1 15M ##STR00300## 446.2 15N ##STR00301## 460.2
16A ##STR00302## 346.1 16B ##STR00303## 360.1 16C ##STR00304##
360.1 17A ##STR00305## 418.1 17B ##STR00306## 460.2 17C
##STR00307## 418.1 17D ##STR00308## 459.2 17E ##STR00309## 404.1
17F ##STR00310## 432.1 18A ##STR00311## 417.3 18B ##STR00312##
437.1 18C ##STR00313## 360.3 19A ##STR00314## 363.4 19B
##STR00315## 391.4 19C ##STR00316## 399.3 19D ##STR00317## 364.4
20A ##STR00318## 391.2 20B ##STR00319## 407.3 20C ##STR00320##
408.3 20D ##STR00321## 434.4 20E ##STR00322## 448.5 20F
##STR00323## 462.5 20G ##STR00324## 435.4 20H ##STR00325## 470.3
20I ##STR00326## 405.4 20J ##STR00327## 419.4 20K ##STR00328##
447.5 20L ##STR00329## 445.4 20M ##STR00330## 431.0 20N
##STR00331## 405.0 20O ##STR00332## 419.1 20P ##STR00333## 467.3
20Q ##STR00334## 481.3 20R ##STR00335## 495.3 21A ##STR00336##
391.2 21B ##STR00337## 391.3 21C ##STR00338## 391.3 21D
##STR00339## 393.3 21E ##STR00340## 393.3 21F ##STR00341## 498.5
22A ##STR00342## 484.2 22B ##STR00343## 498.3 22C ##STR00344##
512.4 22D ##STR00345## 524.3 22E ##STR00346## 469.2 23A
##STR00347## 363.2 23B ##STR00348## 377.0 23C ##STR00349## 403.2
24A ##STR00350## 390.2 24B ##STR00351## 392.2 24C ##STR00352##
392.2 24D ##STR00353## 433.2 24E ##STR00354## 433.2 24F
##STR00355## 419.2 24G ##STR00356## 419.2 25A ##STR00357## 378.2
26A ##STR00358## 391.0 26B ##STR00359## 393.0 27A ##STR00360##
379.1 27B ##STR00361## 379.4 27C ##STR00362## 379.4 27D
##STR00363## 397.3 27E ##STR00364## 397.4 27F ##STR00365## 397.3
27G ##STR00366## 449.3 27H ##STR00367## 380.2 27I ##STR00368##
380.2 27J ##STR00369## 380.2 27K ##STR00370## 398.3 27L
##STR00371## 398.3 27M ##STR00372## 398.3 27N ##STR00373## 408.3
27O ##STR00374## 408.3 27P ##STR00375## 408.3 27Q ##STR00376##
395.4 27R ##STR00377## 395.1 27S ##STR00378## 395.1 27T
##STR00379## 395.3 27U ##STR00380## 395.1 27V ##STR00381## 395.1
27W ##STR00382## 393.4 28A ##STR00383## 375.1 28B ##STR00384##
405.1 28C ##STR00385## 377.1 28D ##STR00386## 407.3 28E
##STR00387## 376.4 29A ##STR00388## 361.0 29B ##STR00389## 389.1
29C ##STR00390## 347.0 29D ##STR00391## 368.9 30A ##STR00392##
425.3 31A ##STR00393## 336.0 31B ##STR00394## 303.1 31C
##STR00395## 303.1 31D ##STR00396## 377.4 31E ##STR00397## 356.1
31F ##STR00398## 317.0 31G ##STR00399## 308.0 31H ##STR00400##
292.1 31I ##STR00401## 346.1 31J ##STR00402## 278.1 31K
##STR00403## 294.0
31L ##STR00404## 308.0 31M ##STR00405## 294.0 31N ##STR00406##
414.1 31O ##STR00407## 308.0 31P ##STR00408## 294.0 31Q
##STR00409## 333.9 31R ##STR00410## 318.1 31S ##STR00411## 279.1
31T ##STR00412## 283.9 31U ##STR00413## 284.1 31V ##STR00414##
268.1 31W ##STR00415## 457.1 31X ##STR00416## 308.8 31Y
##STR00417## 321.1 31Z ##STR00418## 363.1 31AA ##STR00419## 399.1
32A ##STR00420## 391.3 32B ##STR00421## 454.0 32C ##STR00422##
385.3 32D ##STR00423## 413.3 32E ##STR00424## 459.3 32F
##STR00425## 413.3 32G ##STR00426## 399.4 32H ##STR00427## 441.4
32I ##STR00428## 453.3 32J ##STR00429## 357.4 32K ##STR00430##
370.2 32L ##STR00431## 384.2 32M ##STR00432## 396.2 32N
##STR00433## 412.2 32O ##STR00434## 412.2 32P ##STR00435## 384.2
32Q ##STR00436## 426.2 32R ##STR00437## 377.3 32S ##STR00438##
405.4 32T ##STR00439## 391.3 32U ##STR00440## 349.2 32V
##STR00441## 405.3 32W ##STR00442## 361.2 32X ##STR00443## 361.3
32Y ##STR00444## 377.4 32Z ##STR00445## 391.4 33A ##STR00446##
284.9 33B ##STR00447## 279.9 33C ##STR00448## 282.0 33D
##STR00449## 362.9 33E ##STR00450## 303.9 33F ##STR00451## 378.3
33G ##STR00452## 378.2 33H ##STR00453## 350.2 33I ##STR00454##
350.2 33J ##STR00455## 336.2 33K ##STR00456## 379.3 33L
##STR00457## 321.9 34A ##STR00458## 378.4 34B ##STR00459## 406.4
34C ##STR00460## 383.3 34D ##STR00461## 411.4 34E ##STR00462##
419.2 34F ##STR00463## 367.3 34G ##STR00464## 395.5 34H
##STR00465## 383.4 34I ##STR00466## 411.4 34J ##STR00467## 395.0
34K ##STR00468## 395.0 34L ##STR00469## 391.0 34M ##STR00470##
391.0 34N ##STR00471## 413.0 34O ##STR00472## 411.0 34P
##STR00473## 377.4 35A ##STR00474## 407.0 35B ##STR00475## 393.3
36A ##STR00476## 393.4 36B ##STR00477## 375.3 37A ##STR00478##
391.3 37B ##STR00479## 391.3
[1394] 21B and 21C are enantiomeric with respect to one another,
but their absolute stereochemistry has not been conclusively
established.
[1395] 21D and 21E are diastereomeric with respect to one another,
but their absolute stereochemistry has not been conclusively
established.
[1396] 24B and 24C are geometric isomers with respect to one
another (wherein the hydroxyl is either equatorial or axial), but
the conformation of each has not been conclusively established.
[1397] 24D and 24E are geometric isomers with respect to one
another (wherein the hydroxyl is either equatorial or axial), but
the conformation of each has not been conclusively established.
[1398] 24F and 24G are geometric isomers with respect to one
another (wherein the hydroxyl is either equatorial or axial), but
the conformation of each has not been conclusively established.
[1399] 27B and 27C are enantiomeric with respect to one another,
and their absolute stereochemistry has been conclusively
established using X-ray crystallography.
[1400] 27E and 27F are enantiomeric with respect to one another,
but their absolute stereochemistry has not been conclusively
established.
[1401] 27I and 27J are enantiomeric with respect to one another,
but their absolute stereochemistry has not been conclusively
established.
[1402] 27L and 27M are enantiomeric with respect to one another,
but their absolute stereochemistry has not been conclusively
established.
[1403] 27O and 27P are enantiomeric with respect to one another,
but their absolute stereochemistry has not been conclusively
established.
[1404] 27R and 27S are enantiomeric with respect to one another,
but their absolute stereochemistry has not been conclusively
established.
[1405] 27U and 27V are enantiomeric with respect to one another,
but their absolute stereochemistry has not been conclusively
established.
[1406] 37A and 37B are diastereomeric with respect to one another,
but each is a racemic mixture of its two possible enantiomers.
Their absolute stereochemistry has not been conclusively
established.
Biological Methods
[1407] In Vitro Assays
[1408] The potencies of the compounds listed in Table 1 were
determined by testing the ability of a range of concentrations of
each compound to inhibit the binding of the non-selective opioid
antagonist, [.sup.3H]diprenorphine, to the cloned human .mu.,
.kappa., and .delta. opioid receptors, expressed in separate cell
lines. IC.sub.50 values were obtained by nonlinear analysis of the
data using GraphPad Prism version 3.00 for Windows (GraphPad
Software, San Diego). K.sub.i values were obtained by Cheng-Prusoff
corrections of IC.sub.50 values.
[1409] Receptor Binding
[1410] The receptor binding method (DeHaven and DeHaven-Hudkins,
1998) was a modification of the method of Raynor et al. (1994).
After dilution in buffer A and homogenization as before, membrane
proteins (10-80 .mu.g) in 250 .mu.L were added to mixtures
containing test compound and [.sup.3H]diprenorphine (0.5 to 1.0 nM,
40,000 to 50,000 dpm) in 250 .mu.L of buffer A in 96-well deep-well
polystyrene titer plates (Beckman). After incubation at room
temperature for one hour, the samples were filtered through GF/B
filters that had been presoaked in a solution of 0.5% (w/v)
polyethylenimine and 0.1% (w/v) bovine serum albumin in water. The
filters were rinsed 4 times with 1 mL of cold 50 mM Tris HCl, pH
7.8 and radioactivity remaining on the filters determined by
scintillation spectroscopy. Nonspecific binding was determined by
the minimum values of the titration curves and was confirmed by
separate assay wells containing 10 .mu.M naloxone. K.sub.i values
were determined by Cheng-Prusoff corrections of IC.sub.50 values
derived from nonlinear regression fits of 12 point titration curves
using GraphPad Prism.RTM. version 3.00 for Windows (GraphPad
Software, San Diego, Calif.).
[1411] To determine the equilibrium dissociation constant for the
inhibitors (K.sub.i), radioligand bound (cpm) in the presence of
various concentrations of test compounds was measured. The
concentration to give half-maximal inhibition (EC.sub.50) of
radioligand binding was determined from a best nonlinear regression
fit to the following equation,
Y = Bottom + ( Top - Bottom ) 1 + 10 X - LogEC 50 ##EQU00001##
where Y is the amount of radioligand bound at each concentration of
test compound, Bottom is the calculated amount of radioligand bound
in the presence of an infinite concentration of test compound, Top
is the calculated amount of radioligand bound in the absence of
test compound, X is the logarithm of the concentration of test
compound, and LogEC.sub.50 is the log of the concentration of test
compound where the amount of radioligand bound is half-way between
Top and Bottom. The nonlinear regression fit was performed using
the program Prism.RTM. (GraphPad Software, San Diego, Calif.). The
K.sub.i values were then determined from the EC.sub.50 values by
the following equation,
K i = EC 50 1 + [ ligand ] K d ##EQU00002##
where [ligand] is the concentration of radioligand and K.sub.d is
the equilibrium dissociation constant for the radioligand.
[1412] Receptor-Mediated [.sup.35S]GTP.gamma.S Binding
[1413] The potency and efficacy of compounds at each of the
receptors are assessed by modifications of the methods of Selley et
al., 1997 and Traynor and Nahorski, 1995 using receptor-mediated
[35S]GTP.gamma.S binding in the same membrane preparations used to
measure receptor binding. Assays are carried out in 96-well
FlashPlates.RTM. (Perkin Elmer Life Sciences, Inc, Boston, Mass.).
Membranes prepared from CHO cells expressing the appropriate
receptor (50-100 .mu.g of protein) are added to assay mixtures
containing agonist with or without antagonists, 100 .mu.M
[.sup.35S]GTP.gamma.S (approx. 100,000 dpm), 3.0 .mu.M GDP, 75 mM
NaCl, 15 mM MgCl.sub.2, 1.0 mM ethylene
glycol-bis(.beta.-aminoethyl ether)-N,N,N',N'-tetracetic acid, 1.1
mM dithiothreitol, 10 .mu.g/mL leupeptin, 10 .mu.g/mL pepstatin A,
200 .mu.g/mL bacitracin, and 0.5 .mu.g/mL aprotinin in 50 mM
Tris-HCl buffer, pH 7.8. After incubation at room temperature for
one hour, the plates are sealed, centrifuged at 800.times.g in a
swinging bucket rotor for 5 min and bound radioactivity determined
with a TopCount microplate scintillation counter (Packard
Instrument Co., Meriden, Conn.).
[1414] EC.sub.50 values for agonists are determined from nonlinear
regression fits of 8- or 12-point titration curves to the
4-parameter equation for a sigmoidal dose-response with a slope
factor of 1.0 using GraphPad Prism.RTM. version 3.00 for Windows
(GraphPad Software, San Diego, Calif.).
[1415] The potencies of the compounds were determined by testing
the ability of a range of concentrations of each compound to
inhibit the binding of the non-selective opioid antagonist,
[.sup.3H]diprenorphine, to the cloned human .mu., .kappa., and
.delta. opioid receptors, expressed in separate cell lines. All the
compounds tested (compounds included in Table 1) bind with affinity
to the human cloned .delta. opioid receptor less than 2 .mu.M
(K.sub.i values). These compounds display high selectivity
.delta./.kappa. and .delta./.mu. (at least 10-fold). The potencies
of the agonists were assessed by their abilities to stimulated
[.sup.35S]GTP.gamma.S binding to membranes containing the cloned
human .delta. opioid receptors. All the compounds listed in Table 1
were agonists at the .delta. opioid receptor.
[1416] As example, 1A (Table 1) binds to the delta, mu, and kappa
opioid receptors with affinity (expressed as K.sub.i value) of 0.93
nM, 980 nM and >1000 nM, respectively). Furthermore, 1A
displayed potent in vitro agonist activity (EC.sub.50=9.1 nM).
[1417] In Vivo Assays
[1418] Freunds Complete Adjuvant (FCA)-Induced Hyperalgesia
[1419] Rats were injected intraplantar with FCA and 24 h later
treated with tested compounds administered orally. Paw Pressure
Thresholds (PPT) was assessed 30, 60, 120, and 240 minutes after
drug treatment. 1A significantly increased PPT by 170-180% in the
inflamed paw 1-2 h after oral administration (ED.sub.50=2.5 mg/kg
p.o.). 1A produced a similar increase in PPT in the uninflamed paw
at the 2 h time point, a change that is generally associated with
effects mediated within the central nervous system.
[1420] Acetic Acid-Induced Writhing
[1421] Male ICR mice weighing 20-25 g are injected s.c. with either
vehicle or test compound 15 min before they are injected
intraperitoneally with 0.6% acetic acid. At minutes after treatment
with acetic acid, the number of writhes is counted for 10 minutes.
Dose response curves are expressed as the percent inhibition of
acetic acid induced writhing, when compared to the mean number of
writhes observed in the vehicle-treated mice. The mean percent
inhibition (% I) of acetic acid-induced writhing for drug-treated
mice is calculated according to the following formula:
% I = ( Mean vehicle response - Mean individual response ) .times.
100 ( Mean vehicle response ) ##EQU00003##
[1422] The mean individual response is the mean number of writhes
in mice treated with test compound. The mean vehicle response is
the mean number of writhes in mice treated with vehicle.
[1423] 1A produces 69% inhibition of acetic acid-induced writhing
at 30 mg/kg (s.c.)
[1424] Castor Oil-Induced Diarrhea
[1425] Mice were fasted overnight with water ad libitum. Mice were
weighed, dosed orally with 0.6 mL of castor oil and placed in
individual cubicles (11 cm.times.10 cm) lined with a pre-weighed
sheet of absorbent paper. Thirty min after receiving castor oil,
mice were injected s.c with tested compound. Seventy-five min after
dosing with castor oil, the mice and absorbent paper were reweighed
and the number of mice with diarrhea (defined as wet, unformed
stool) was determined.
[1426] Percent inhibition by tested compounds in castor oil-induced
diarrhea assay was determined by the following formula:
1 - ( agonist response ) .times. 100 ( vehicle response )
##EQU00004##
[1427] 1A reduced incidence of diarrhea in a time-dependent manner:
ED.sub.50 (s.c.)=8.7 mg/kg.
[1428] Forced Swim Assay
[1429] Male Sprague-Dawley rats (approximately 200 g) are placed in
a tank of room temperature water for a fifteen min practice swim.
Every five sec during the first five min of the practice swim, the
rats are rated as immobile (floating with motion needed to keep
head above the water), swimming (movement across the swim), or
climbing (actively trying to climb out of the tank of water, upward
directed movements of the forepaws). The percentage of time the
rats spent in each of these responses is calculated.
[1430] Approximately 24 h after the practice swim, the rats are
treated with vehicle or test compound and placed in the tank for a
5 min swim. As was the case with the practice swim, the rats are
rated as immobile, swimming, or climbing during the test swim and
the percentage of time spent in each of these responses is
calculated. The data is analyzed by one-way ANOVA with post-hoc
analysis to compare the behavioral response after vehicle treatment
to the behavioral response after drug treatment for each of the
three behavioral responses. The level of significance is set at
p<0.05.
[1431] Data for 1A (presented as percent change .+-.SEM, relative
to vehicle-treated rats)
TABLE-US-00002 RESPONSE 3 mg/kg p.o. 30 mg/kg p.o. IMMOBILITY (%
Decrease) 17 .+-. 10 43 .+-. 13* SWIMMING (% Increase) 37 .+-. 17
137 .+-. 35* *Values significantly different (p < 0.05) than
vehicle-treated rats
Experimental Section
Introduction
[1432] Materials: All chemicals were reagent grade and used without
further purification. Analytical: Thin-layer chromatography (TLC)
was performed on silica gel 60 flexible backed plates (250 microns)
from Alltech and visualized by UV 254 irradiation and iodine. Flash
chromatography was conducted using the ISCO CombiFlash with RediSep
silica gel cartridges (4 g, 12 g, 40 g, 120 g). Flash
chromatography was also conducted with silica gel (200-400 mesh,
60A, Aldrich). Chromatographic elution solvent systems are reported
as volume:volume ratios. All .sup.1H NMR spectra were recorded at
ambient temperature on a Bruker-400 MHz spectrometer. They are
reported in ppm on the .delta. scale, from TMS. LC-MS data were
obtained using a Thermo-Finnigan Surveyor HPLC and a
Thermo-Finnigan AQA MS using either positive or negative
electrospray ionization. Program (positive) Solvent A: 10 mM
ammonium acetate, pH 4.5, 1% acetonitrile; solvent B: acetonitrile;
column: Michrom Bioresources Magic C18 Macro Bullet, detector: PDA
.lamda.=220-300 nm. Gradient: 96% A-100% B in 3.2 minutes, hold
100% B for 0.4 minutes. Program (negative) Solvent A: 1 mM ammonium
acetate, pH 4.5, 1% acetonitrile; solvent B: acetonitrile; column:
Michrom Bioresources Magic C18 Macro Bullet, detector: PDA
.lamda.=220-300 nm. Gradient: 96% A-100% B in 3.2 minutes, hold
100% B for 0.4 minutes.
Example 1A
Preparation of 1.3a
[1433] Method 1A: Pyrrolidine (6.12 mL, 73.38 mmol, 2.0 eq) was
added at room temperature to 1.2 (7.31 g, 36.69 mmol, 1.0 eq) and
1.1a (5.00 g, 36.69 mmol, 1.0 eq). The solution was stirred
overnight at room temperature and then concentrated under reduced
pressure. Diethyl ether (500 mL) was added. The organic mixture was
washed with a 1N aqueous solution of hydrochloric acid, a 1N
aqueous solution of sodium hydroxide, brine and dried over sodium
sulfate. Hexane (300 mL) was added to the mixture. The resulting
precipitate was collected by filtration, washed with hexane and
used for the next step without further purification.
[1434] Yield: 68%
[1435] Method 1B: Pyrrolidine (42 mL, 73.38, 2.0 eq) was added drop
wise at room temperature to a solution of 1.2 (49.8 g, 0.249 mol,
1.0 eq) and 1.1a (34 g, 0.184 mol, 1.0 eq) in anhydrous methanol
(400 mL). The solution was refluxed overnight and then concentrated
under reduced pressure. Diethyl ether (500 mL) was added. The
organic mixture was washed with a 1N aqueous solution of
hydrochloric acid, a 1N aqueous solution of sodium hydroxide, brine
and dried over sodium sulfate. Hexane (300 mL) was added to the
mixture. The resulting precipitate was collected by filtration,
washed with hexane, and used for the next step without further
purification.
[1436] Yield: 72%
[1437] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.86 (d, 1H), 7.50
(t, 1H), 7.00 (m, 2H), 3.87 (m, 2H), 3.22 (m, 2H), 2.72 (s, 2H),
2.05 (d, 2H), 1.61 (m, 2H), 1.46 (s, 9H)
[1438] Mass Spectral Analysis m/z=318.0 (M+H).sup.+
Preparation of 1.5a
[1439] To a solution of 1.3a (25 g, 0.078 mol, 1.0 eq) in
tetrahydrofuran (250 mL) at -78.degree. C. under nitrogen was added
drop wise a 1.0M solution of lithium bis(trimethylsilyl)amide in
tetrahydrofuran (94.5 mL, 0.095 mol, 1.2 eq). The mixture was
stirred for 1 h at -78.degree. C. A solution of 1.4 (33.8 g, 0.095
mol, 1.2 eq) in tetrahydrofuran (150 mL) was added drop wise. The
mixture was warmed slowly to room temperature and stirring was
continued for a further 12 h. The mixture was then poured into ice
water and the two phases were separated. The organic phase was
washed with a 1N aqueous solution of hydrochloric acid, a 1N
aqueous solution of sodium hydroxide, brine and dried over sodium
sulfate. The crude product was purified by column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity).
[1440] Yield: 70%
[1441] .sup.1H NMR (400 MHz, DMSO d.sub.6) .quadrature. 7.45-7.20
(m, 2H), 7.00 (m, 2H), 6.15 (s, 1H), 3.70 (m, 2H), 3.20 (m, 2H),
1.90 (m, 2H), 1.75 (m, 2H), 1.40 (s, 9H)
[1442] Mass Spectral Analysis m/z=450.1 (M+H).sup.+
Preparation of 1.8a
[1443] Method 1C: To a solution of 1.5a (15 g, 33.37 mmol, 1.0 eq)
in dimethoxyethane (100 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (50.06 mL, 100.12 mmol, 3.0 eq),
lithium chloride (4.24 g, 100.12 mmol, 3.0 eq), 1.6 (8.12 g, 36.71
mmol, 1.1 eq) and tetrakis(triphenylphosphine)palladium(0) (0.77 g,
0.67 mmol, 0.02 eq). The mixture was refluxed for 10 h under
nitrogen. The mixture was then cooled to room temperature and water
(250 mL) was added. The mixture was extracted with ethyl acetate.
The organic layer was further washed with brine and dried over
sodium sulfate. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[1444] Yield: 73%
[1445] Method 1D: To a solution of 1.5a (10 g, 22.25 mmol, 1.0 eq)
in dimethoxyethane (67 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (33.37 mL, 66.75 mmol, 3.0 eq),
lithium chloride (2.83 g, 66.75 mmol, 3.0 eq), 1.6 (4.40 g, 24.47
mmol, 1.1 eq) and palladium, 10 weight % (dry basis) on activated
carbon, wet, Degussa type E101 NE/W (0.24 g, 0.11 mmol, 0.005 eq).
The mixture was refluxed for 2 h under nitrogen. The mixture was
then cooled to room temperature and diluted with dichloromethane
(350 mL). The mixture was filtered through a celite plug and dried
over sodium sulfate, filtered and concentrated under reduced
pressure. The crude product was triturated with diethyl ether. The
precipitate was collected by filtration.
[1446] Yield: 60%
[1447] .sup.1H NMR (400 MHz, CDCl.sub.3) .quadrature. 7.35 (m, 4H),
7.15 (t, 1H), 7.00-6.80 (m, 3H), 5.55 (s, 1H), 3.85 (m, 2H), 3.55
(m, 2H), 3.30 (m, 4H), 2.00 (m, 2H), 1.65 (m, 2H), 1.40 (s, 9H);
1.20 (m, 6H)
[1448] Mass Spectral Analysis m/z=477.2 (M+H).sup.+
Preparation of 1A
[1449] Method 1E: A 2.0M solution of hydrochloric acid in diethyl
ether (34.6 mL, 69.24 mmol, 5.5 eq) was added drop wise to a cooled
(0.degree. C.) solution of 1.8a (6.00 g, 12.59 mmol, 1.0 eq) in
anhydrous dichloromethane (70 mL). The mixture was warmed to room
temperature and stirring was continued for an additional 10 h.
Diethyl ether (100 mL) was added to the solution and the resulting
precipitate was collected by filtration and washed with diethyl
ether.
[1450] Yield: 99%
[1451] Method 1F: Trifluoroacetic acid (10.33 mL, 134.09 mmol, 5.5
eq) was added drop wise to a cold (0.degree. C.) solution of 1.8a
(11.62 g, 24.38 mmol, 1.0 eq) in anhydrous dichloromethane (50 mL).
The mixture was warmed to room temperature and stirring was
continued for an additional 10 h. The mixture was then concentrated
under reduced pressure. A saturated solution of sodium bicarbonate
(100 mL) was added to the mixture, which was extracted with
dichloromethane. The organic phase was separated, washed with
brine, dried over sodium sulfate and concentrated under reduced
pressure. To a cold (0.degree. C.) solution of the resulting oil in
anhydrous dichloromethane was added drop wise a 2.0M solution of
anhydrous hydrochloric acid in diethyl ether (36.5 mL, 0.073 mol,
3.0 eq). The mixture was then stirred for 1 h at room temperature
and concentrated under reduced pressure. Diethyl ether was added.
The resulting precipitate was collected by vacuum filtration and
washed with diethyl ether.
[1452] Yield: 99%
[1453] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.06 (m, 2H),
7.43 (s, 4H), 7.27 (t, 1H), 7.00 (m, 3H), 5.95 (s, 1H), 3.45 (m,
2H), 3.23 (m, 6H), 2.00 (m, 4H), 1.12 (m, 6H)
[1454] Mass Spectral Analysis m/z=377.4 (M+H).sup.+
[1455] Elemental analysis:
[1456] C.sub.24H.sub.28N.sub.2O.sub.2, 1HCl
[1457] Theory: % C, 69.80; % H, 7.08; % N, 6.78.
[1458] Found: % C, 69.73; % H, 7.04; % N, 6.81.
Example 1B
[1459] 1B was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1b and Method 1B was used. Step
1.3: Method 1C was used. Step 1.4: Method 1E was used.
[1460] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.97 (m, 2H),
7.42 (m, 4H), 6.98 (m, 1H), 6.86 (m, 1H), 6.49 (m, 1H), 5.99 (s,
1H), 3.62 (m, 3H), 3.50 (m, 2H), 3.21 (m, 6H), 2.06 (m, 4H), 1.11
(m, 6H)
[1461] Mass Spectral Analysis m/z=407.1 (M+H).sup.+
[1462] Elemental analysis:
[1463] C.sub.25H.sub.30N.sub.2O.sub.3, 1HCl, 1.25H.sub.2O
[1464] Theory: % C, 64.51; % H, 7.25; % N, 6.02.
[1465] Found: % C, 64.53; % H, 7.11; % N, 5.89.
Example 1C
[1466] 1C was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1c and Method 1A was used. Step
1.3: Method 1C was used. Step 1.4: Method 1E was used.
[1467] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.05 (m, 1.5H),
7.45 (s, 4H), 7.30 (d, 1H), 7.10 (d, 1H), 6.90 (s, 1H), 6.00 (s,
1H), 3.1-3.55 (m, 8H), 2.05 (m, 4H), 1.10 (m, 6H)
[1468] Mass Spectral Analysis m/z=411.2 (M+H).sup.+
Example 1D
[1469] 1D was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1d and Method 1B was used. Step
1.3: Method 1D was used. Step 1.4: Method 1E was used.
[1470] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.95 (m, 1H),
7.40 (s, 4H), 7.10 (m, 2H), 6.70 (m, 1H), 6.05 (s, 1H), 3.10-3.50
(m, 8H), 2.00 (m, 4H), 1.10 (m, 6H)
[1471] Mass Spectral Analysis m/z=395.2 (M+H).sup.+
Example 1E
[1472] 1E was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1e and Method 1A was used. Step
1.3: Method 1D was used. Step 1.4: Method 1E was used.
[1473] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.92 (brm, 1H),
7.42 (s, 4H), 7.07 (dd, 1H), 6.94 (d, 1H), 6.79 (d, 1H), 5.92 (s,
1H), 3.45 (brs, 2H), 3.22 (brm, 6H), 2.18 (s, 3H), 2.08 (m, 2H),
1.97 (m, 2H), 1.12 (brd, 6H)
[1474] Mass Spectral Analysis m/z=391.3 (M+H).sup.+
[1475] Elemental analysis:
[1476] C.sub.25H.sub.30N.sub.2O.sub.2, 1HCl, 1.5H.sub.2O
[1477] Theory: % C, 66.13; % H, 7.55; % N, 6.17.
[1478] Found: % C, 65.73; % H, 7.38; % N, 6.05.
Example 1F
[1479] 1F was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1f and Method 1B was used. Step
1.3: Method 1C was used. Step 1.4: Method 1F was used.
[1480] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.90 (m, 2H),
7.25 (m, 5H), 6.71 (m, 1H), 6.64 (m, 1H), 5.81 (s, 1H), 3.45 (m,
2H), 3.39 (m, 3H), 3.20 (m, 6H), 2.00 (m, 4H), 1.09 (m, 6H)
[1481] Mass Spectral Analysis m/z=407.2 (M+H).sup.+
[1482] Elemental analysis:
[1483] C.sub.25H.sub.30N.sub.2O.sub.3, 1HCl, 2H.sub.2O
[1484] Theory: % C, 62.69; % H, 7.36; % N, 5.85.
[1485] Found: % C, 62.78; % H, 6.90; % N, 5.61.
Example 1G
[1486] 1G was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1g and Method 1B was used. Step
1.3: Method 1C was used. Step 1.4: Method 1E was used.
[1487] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.95 (m, 1H),
8.85 (m, 1H), 7.38 (m, 4H), 6.89 (m, 1H), 6.68 (m, 1H), 6.54 (m,
1H), 5.78 (s, 1H), 3.76 (m, 3H), 3.45 (m, 2H), 3.21 (m, 6H), 2.09
(m, 2H), 1.98 (m, 2H), 1.11 (m, 6H)
[1488] Mass Spectral Analysis m/z=407.1 (M+H).sup.+
[1489] Elemental analysis:
[1490] C.sub.25H.sub.30N.sub.2O.sub.3, 1HCl, 0.5H.sub.2O
[1491] Theory: % C, 66.43; % H, 7.14; % N, 6.20.
[1492] Found: % C, 66.25; % H, 7.19; % N, 6.11.
Example 1H
[1493] 1H was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1h and Method 1B was used. Step
1.3: Method 1D was used. Step 1.4: Method 1E was used.
[1494] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.80 (brm, 1H),
8.33 (d, 1H), 7.90 (m, 1H), 7.58 (m, 2H), 7.51 (d, 1H), 7.46 (d,
4H), 7.16 (d, 1H), 5.97 (s, 1H), 3.46 (brs, 2H), 3.30 (brm, 6H),
2.25 (d, 2H), 2.05 (m, 2H), 1.13 (brd, 6H)
[1495] Mass Spectral Analysis m/z=427.4 (M+H).sup.+
[1496] Elemental analysis:
[1497] C.sub.28H.sub.30N.sub.2O.sub.2, 1HCl, 1.5H.sub.2O
[1498] Theory: % C, 68.63; % H, 6.99; % N, 5.72.
[1499] Found: % C, 68.96; % H, 6.82; % N, 5.75.
Example 1I
[1500] 1I was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1i and Method 1B was used. Step
1.3: Method 1D was used. Step 1.4: Method 1E was used.
[1501] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.90 (brm, 1H),
7.94 (d, 1H), 7.87 (d, 1H), 7.37 (m, 3H), 7.28 (t, 1H), 7.24 (d,
2H), 7.10 (t, 1H), 6.96 (d, 1H), 6.04 (s, 1H), 3.44 (brs, 2H), 3.23
(brs, 6H), 2.09 (brm, 4H), 1.12 (brd, 6H)
[1502] Mass Spectral Analysis m/z=427.4 (M+H).sup.+
[1503] Elemental analysis:
[1504] C.sub.28H.sub.30N.sub.2O.sub.2, 1HCl, 0.67H.sub.2O
[1505] Theory: % C, 70.80; % H, 6.86; % N, 5.90.
[1506] Found: % C, 70.57; % H, 6.72; % N, 5.83.
Example 1J
[1507] 1J was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1j and Method 1A was used. Step
1.3: Method 1D was used. Step 1.4: Method 1E was used.
[1508] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.09 (brm, 1H),
7.41 (s, 4H), 6.87 (s, 1H), 6.75 (s, 1H), 5.84 (s, 1H), 3.45 (brs,
2H), 3.20 (brm, 6H), 2.19 (s, 3H), 2.08 (s, 3H), 2.05 (m, 2H), 1.97
(m, 2H), 1.12 (brd, 6H)
[1509] Mass Spectral Analysis m/z=405.4 (M+H).sup.+
[1510] Elemental analysis:
[1511] C.sub.26H.sub.32N.sub.2O.sub.2, 1HCl, 0.5H.sub.2O
[1512] Theory: % C, 69.39; % H, 7.62; % N, 6.22.
[1513] Found: % C, 69.22; % H, 7.49; % N, 6.24.
Example 1K
[1514] 1K was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1k and Method 1B was used. Step
1.3: Method 1C was used. Step 1.4: Method 1F was used.
[1515] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.25 (m, 1H),
7.40 (m, 4H), 7.35 (m, 1H), 6.61 (s, 1H), 3.25 (m, 8H), 2.06 (m,
4H), 1.02 (m, 6H)
[1516] Mass Spectral Analysis m/z=413.2 (M+H).sup.+
Example 1L
[1517] 1L was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1l and Method 1B was used. Step
1.3: Method 1D was used. Step 1.4: Method 1E was used.
[1518] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.84 (brs, 1H),
7.41 (d, 4H), 6.96 (s, 1H), 6.61 (s, 1H), 5.86 (s, 1H), 3.45 (brs,
2H), 3.20 (brm, 6H), 2.23 (s, 3H), 2.13 (s, 3H), 2.08 (m, 2H), 1.96
(m, 2H), 1.12 (brd, 6H)
[1519] Mass Spectral Analysis m/z=405.4 (M+H).sup.+
[1520] Elemental analysis:
[1521] C.sub.26H.sub.32N.sub.2O.sub.2, 1HCl, 0.5H.sub.2O
[1522] Theory: % C, 69.39; % H, 7.62; % N, 6.22.
[1523] Found: % C, 69.69; % H, 7.56; % N, 6.28.
Example 1M
[1524] 1M was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1m and Method 1B was used. Step
1.3: Method 1C was used. Step 1.4: Method 1E was used.
[1525] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.05 (m, 2H),
7.46 (m, 2H), 7.20 (m, 3H), 7.01 (m, 1H), 6.82 (m, 1H), 6.48 (m,
1H), 3.45 (m, 2H), 3.28 (m, 6H), 2.24 (m, 2H), 2.06 (m, 2H), 1.60
(m, 3H), 1.12 (m, 6H)
[1526] Mass Spectral Analysis m/z=391.0 (M+H).sup.+
[1527] Elemental analysis:
[1528] C.sub.25H.sub.30N.sub.2O.sub.2, 1HCl, 0.25H.sub.2O
[1529] Theory: % C, 69.59; % H, 7.36; % N, 6.49.
[1530] Found: % C, 69.25; % H, 7.29; % N, 6.58.
Example 1N
Preparation of 1.10
[1531] To an oven-dried 2-necked 500 mL flask charged with
anhydrous toluene (90 mL) at -78.degree. C. was added n-butyl
lithium (2.5 M solution in hexane, 40 mL, 0.1 mol, 1.0 eq). A
solution of 2,5-dibromo-pyridine (1.9) (23.69 g, 0.1 mol, 1.0 eq)
in anhydrous toluene (50 mL) was added dropwise. The reaction
mixture was stirred at -78.degree. C. for 2 h and then poured onto
freshly crushed dry-ice (.about.500 g). The dry-ice mixture was
then left at room temperature for 10 h. The volatiles were removed
under reduced pressure and the residue was dissolved in water. The
insoluble solids were filtered and the filtrate was acidified to pH
2, at which point a light brown solid precipitated out. The solids
were collected by filtration and recrystallized from acetic acid
(500 mL). This provided 1.10 isolated as its acetic acid salt.
[1532] Yield: 74%
[1533] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.84 (d, 1H),
8.25 (dd, 1H), 7.98 (d, 1H)
[1534] Mass Spectral Analysis m/z=202.06 (M+H).sup.+
Preparation of 1.11
[1535] To a suspension of 5-bromo-pyridine-2-carboxylic acid (1.10)
(808 mg, 3.01 mmol, 1.0 eq) in dry dichloromethane (5 mL) was added
oxalyl chloride (0.34 mL, 3.96 mmol, 1.3 eq) followed by 2 drops of
N,N-dimethylformamide. The reaction mixture was heated under reflux
for 1 h. After cooling to room temperature, the mixture was
concentrated under reduced pressure to provide the crude product
1.11, which was used for the next step without purification.
Preparation of 1.13
[1536] To a suspension of 1.11 (crude, as of 3.01 mmol, 1.0 eq) in
dry tetrahydrofuran (5 mL) was added N,N-diethylamine (1.12) (1.56
mL, 15.08 mmol, 5.0 eq) drop wise. The reaction mixture was stirred
at room temperature for 2 h. Ethyl acetate (20 mL) was added and
the mixture was washed with water (20 mL), saturated aqueous sodium
bicarbonate (30 mL), 1M aqueous hydrochloric acid (20 mL) and
brine. The organics were dried over sodium sulfate, filtered and
concentrated under reduced pressure to give a red/brown crystalline
solid.
[1537] Yield: 88% over two steps
[1538] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.64 (d, 1H), 7.91
(dd, 1H), 7.53 (d, 1H), 3.56 (q, 2H), 3.39 (q, 2H), 1.27 (t, 3H),
1.17 (t, 3H)
[1539] Mass Spectral Analysis m/z=257.15 (M+H).sup.+
Preparation of 1.7
[1540] To a solution of bis(pinacolato)diboron (1.14) (2.18 g, 8.6
mmol, 1.2 eq) in N,N-dimethylformamide (10 mL) at 0.degree. C. was
added potassium acetate (2.3 g, 23.4 mmol, 3.0 eq),
1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride complex
with dichloromethane (171 mg, 0.23 mmol, 0.03 eq). The reaction
mixture was heated at 80.degree. C. at which point a solution of
1.13 (2.0 g, 7.8 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL) was
added dropwise. The reaction mixture was stirred at 80.degree. C.
for another 10 h. Ethyl acetate (75 mL) and water (50 mL) were
added and the two phases were separated. The organic phase was
washed with brine (50 mL), dried over sodium sulfate, filtered, and
concentrated under reduced pressure to give a dark brown oil, which
solidified to needles. The crude product was triturated with
hexane. The resulting solid was collected by filtration.
[1541] Yield: 52% .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.92
(d, 1H), 8.14 (dd, 1H), 7.53 (d, 1H), 3.55 (q, 2H), 3.32 (q, 2H),
1.36 (s, 12H), 1.27 (t, 3H), 1.12 (t, 3H)
Preparation of 1.8b
[1542] To a solution of 1.5a (1.48 g, 3.29 mmol, 1.0 eq) in
dimethoxyethane (DME) (20 mL) under nitrogen was added sequentially
a 2M aqueous solution of sodium carbonate (4.94 mL, 9.87 mmol, 3.0
eq), lithium chloride (0.42 g, 9.87 mmol, 3.0 eq), palladium (70
mg, 10 wt. % (dry basis) on activated carbon, 0.033 mmol, 0.01 eq),
and 1.7 (1.0 g, 3.29 mmol, 1.0 eq). The mixture was heated under
reflux for 10 h. Dichloromethane (200 mL) was added to dilute the
reaction mixture and palladium(0) on carbon was filtered off on a
celite pad. The filtrate was washed with brine, dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography (eluent:
hexane/ethyl acetate mixtures of increasing polarity).
[1543] Yield: 76%
[1544] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.56 (dd, 1H),
7.75 (dd, 1H), 7.64 (dd, 1H), 7.22 (m, 1H), 6.99-6.85 (m, 3H), 5.62
(s, 1H), 3.88 (m, 2H), 3.59 (q, 2H), 3.45 (q, 2H), 3.34 (m, 2H),
2.06 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H), 1.29 (t, 3H), 1.20 (t,
3H)
[1545] Mass Spectral Analysis m/z=478.0 (M+H).sup.+
Preparation of 1N
[1546] To a cold (0.degree. C.) solution of 1.8b (2 g, 4.18 mmol,
1.0 eq) in anhydrous dichloromethane (20 mL) was slowly added a 4.0
M solution of hydrogen chloride in dioxane (5.2 mL, 20.8 mmol, 5.0
eq). The reaction mixture was stirred at room temperature for 10 h
and then concentrated under reduced pressure. The resulting foamy
solids were soaked in diethyl ether to give the fine powders, which
were collected by filtration and washed sequentially with ethyl
acetate and diethyl ether.
[1547] Yield: 95%
[1548] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.99 (m, 2H),
8.60 (d, 1H), 7.90 (dd, 1H), 7.61 (d, 1H), 7.29 (m, 1H), 7.06 (d,
1H), 6.98 (m, 2H), 6.09 (s, 1H), 3.47 (q, 2H), 3.35-3.13 (m, 6H),
2.06 (m, 4H), 1.17 (t, 3H), 1.11 (t, 3H)
[1549] Mass Spectral Analysis m/z=378.4 (M+H).sup.+
[1550] Elemental analysis:
[1551] C.sub.23H.sub.27N.sub.3O.sub.2, 2HCl, 0.5H.sub.2O
[1552] Theory: % C, 60.13; % H, 6.58; % N, 9.15.
[1553] Found: % C, 60.34; % H, 6.60; % N, 9.10.
Example 1O
[1554] 1O was obtained according to a procedure similar to the one
described for 1N, with the following exception:
Step 1.1: 1.1a was replaced by 1.1d.
[1555] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.96 (m, 1H),
8.62 (d, 1H), 7.92 (dd, 1H), 7.61 (d, 1H), 7.12 (m, 2H), 6.78 (dd,
1H), 6.20 (s, 1H), 3.47 (q, 2H), 3.30 (q, 2H), 3.24 (m, 4H), 2.05
(m, 4H), 1.17 (t, 3H), 1.11 (t, 3H)
[1556] Mass Spectral Analysis m/z=396.3 (M+H).sup.+
[1557] Elemental analysis:
[1558] C.sub.23H.sub.26FN.sub.3O.sub.2, 1.05HCl, 1H.sub.2O
[1559] Theory: % C, 61.15; % H, 6.48; % N, 9.30; % Cl, 8.24.
[1560] Found: % C, 61.11; % H, 6.44; % N, 9.18; % Cl, 8.28.
Example 1P
[1561] 1P was obtained according to a procedure similar to the one
described for 1N, with the following exception:
Step 1.1: 1.1a was replaced by 1.1e.
[1562] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.93 (brm, 1H),
8.60 (d, 1H), 7.89 (dd, 1H), 7.61 (d, 1H), 7.09 (dd, 1H), 6.96 (d,
1H), 6.77 (s, 1H), 6.07 (s, 1H), 3.47 (q, 2H), 3.30 (q, 2H), 2.21
(brm, 4H), 2.18 (s, 3H), 2.04 (brm, 4H), 1.17 (t, 3H), 1.11 (t,
3H)
[1563] Mass Spectral Analysis m/z=392.3 (M+H).sup.+
[1564] Elemental analysis:
[1565] C.sub.24H.sub.29N.sub.3O.sub.2, 2HCl
[1566] Theory: % C, 62.07; % H, 6.73; % N, 9.05; % Cl, 15.27.
[1567] Found: % C, 61.81; % H, 6.69; % N, 8.95; % Cl, 15.42.
Example 1Q
[1568] 1Q was obtained according to a procedure similar to the one
described for 1N, with the following exceptions:
Step 1.1: 1.1a was replaced by 1.1f and Method 1A was used.
[1569] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.20 (m, 2H),
8.38 (m, 1H), 7.69 (m, 1H), 7.48 (m, 1H), 7.28 (m, 1H), 6.75 (m,
1H), 6.69 (m, 1H), 5.99 (s, 1H), 3.40 (m, 5H), 3.26 (m, 6H), 2.08
(m, 4H), 1.20 (m, 3H), 1.10 (m, 3H)
[1570] Mass Spectral Analysis m/z=408.3 (M+H).sup.+
[1571] Elemental analysis:
[1572] C.sub.24H.sub.29N.sub.3O.sub.3, 1HCl, 0.25H.sub.2O
[1573] Theory: % C, 64.28; % H, 6.85; % N, 9.37; % Cl, 7.91.
[1574] Found: % C, 64.07; % H, 6.84; % N, 9.23; % Cl, 8.18.
Example 1R
[1575] 1R was obtained according to a procedure similar to the one
described for 1N, with the following exception:
Step 1.1: 1.1a was replaced by 1.1h.
[1576] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.06 (brs,
0.5H), 8.90 (brs, 0.5H), 8.65 (d, 1H), 8.33 (d, 1H), 7.95 (dd, 1H),
7.91 (m, 1H), 7.64 (d, 1H), 7.59 (m, 2H), 7.53 (d, 1H), 7.14 (d,
1H), 6.11 (s, 1H), 3.48 (q, 2H), 3.32 (brm, 6H), 2.26 (d, 2H), 2.10
(m, 2H), 1.18 (t, 3H), 1.12 (t, 3H)
[1577] Mass Spectral Analysis m/z=428.3 (M+H).sup.+
[1578] Elemental analysis:
[1579] C.sub.27H.sub.29N.sub.3O.sub.2, 1.8HCl, 1H.sub.2O
[1580] Theory: % C, 63.44; % H, 6.47; % N, 8.22; % Cl, 12.48.
[1581] Found: % C, 63.36; % H, 6.22; % N, 8.14; % Cl, 12.87.
Example 1S
[1582] 1S was obtained according to a procedure similar to the one
described for 1N, with the following exception:
Step 1.1: 1.1a was replaced by 1.1j.
[1583] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.89 (brm, 2H),
8.59 (d, 1H), 7.88 (dd, 1H), 7.61 (d, 1H), 6.89 (s, 1H), 6.73 (s,
1H), 5.99 (s, 1H), 3.47 (q, 2H), 3.30 (q, 2H), 3.20 (brm, 4H), 2.20
(s, 3H), 2.09 (s, 3H), 2.06 (m, 2H), 1.97 (m, 2H), 1.17 (t, 3H),
1.11 (t, 3H)
[1584] Mass Spectral Analysis m/z=406.3 (M+H).sup.+
[1585] Elemental analysis:
[1586] C.sub.25H.sub.31N.sub.3O.sub.2, 2HCl, 2H.sub.2O
[1587] Theory: % C, 58.36; % H, 7.25; % N, 8.17; % Cl, 13.78.
[1588] Found: % C, 58.45; % H, 7.16; % N, 8.16; % Cl, 13.68.
Example 1T
[1589] 1T was obtained according to a procedure similar to the one
described for 1N, with the following exception:
Step 1.1: 1.1a was replaced by 1.11.
[1590] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.02 (brm, 1H),
8.56 (d, 1H), 7.87 (dd, 1H), 7.61 (d, 1H), 6.98 (s, 1H), 6.59 (s,
1H), 6.01 (s, 1H), 3.47 (q, 2H), 3.30 (q, 2H), 3.25 (m, 2H), 3.14
(brs, 2H), 2.24 (s, 3H), 2.15 (s, 3H), 2.09 (m, 2H), 2.02 (m, 2H),
1.17 (t, 3H), 1.11 (t, 3H)
[1591] Mass Spectral Analysis m/z=406.4 (M+H).sup.+
[1592] Elemental analysis:
[1593] C.sub.25H.sub.31N.sub.3O.sub.2, 1.9HCl, 0.5H.sub.2O
[1594] Theory: % C, 62.06; % H, 7.06; % N, 8.69; % Cl, 13.92.
[1595] Found: % C, 61.90; % H, 7.03; % N, 8.45; % Cl, 13.85.
Example 1U
Preparation of 1U
[1596] A solution of 1G (1.00 g, 2.46 mmol, 1.0 eq) in
dichloromethane (12 mL) was added drop wise to a cold (-78.degree.
C.) solution of boron tribromide, 1.0M, in anhydrous
dichloromethane (13.53 mL, 13.53 mmol, 5.5 eq). The mixture was
warmed to room temperature and stirring was continued for an
additional 1 h. Water (1.2 mL) was added drop wise to the cooled
(0.degree. C.) reaction mixture and then a saturated solution of
sodium bicarbonate (3.7 mL) was added. The resulting mixture was
stirred for 1 h at room temperature. A saturated solution of sodium
bicarbonate was added to the mixture until the solution was basic
when tested with pH paper. The phases were separated and the
aqueous phase was extracted with dichloromethane. The organic
phases were combined and washed with brine. A gummy residue stuck
to the walls of the separatory funnel. It was dissolved in methanol
and combined with the dichloromethane extracts. The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: dichloromethane/methanol mixtures
of increasing polarity).
[1597] Yield: 79%
[1598] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.66 (m, 1H),
7.37 (m, 4H), 6.77 (m, 1H), 6.32 (m, 2H), 5.62 (s, 1H), 3.32 (m,
5H), 2.89 (m, 2H), 2.76 (m, 2H), 1.78 (m, 2H), 1.67 (m, 2H), 1.11
(m, 6H)
[1599] Mass Spectral Analysis m/z=393.2 (M+H).sup.+
[1600] Elemental analysis:
[1601] C.sub.24H.sub.28N.sub.2O.sub.3, 0.5H.sub.2O
[1602] Theory: % C, 71.80; % H, 7.28; % N, 6.98.
[1603] Found: % C, 71.79; % H, 7.13; % N, 6.94.
Example 2A
Preparation of 2.2
[1604] Pyrrolidine (104 mL, 1.256 mol, 2.0 eq) was added at room
temperature to 1.2 (125.2 g, 0.628 mol, 1.0 eq) and 2.1 (95.6 g,
0.628 mol, 1.0 eq). The solution was stirred at 70.degree. C. for
30 min and then cooled to room temperature and stirred for 48 h.
The mixture was then concentrated under reduced pressure and ethyl
acetate (800 mL) was added. The organic mixture was washed with a
1N aqueous solution of hydrochloric acid, water, brine and dried
over sodium sulfate. Diethyl ether (500 mL) was added to the
organics and the mixture was stirred overnight at room temperature.
The resulting precipitate was collected by filtration, washed with
hexane and used for the next step without further purification.
[1605] Yield: 75%
[1606] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.31 (d, 1H), 7.08
(m, 1H), 6.87 (d, 1H), 6.06 (s, 1H), 3.86 (br s, 2H), 3.19 (br s,
2H), 2.69 (s, 2H), 2.02 (m, 2H), 1.58 (m, 2H), 1.47 (s, 9H)
[1607] Mass Spectral Analysis m/z=332.4 (M-H).sup.-
Preparation of 2.4
[1608] To a solution of 2.3 (2.17 g, 14.4 mmol, 1.2 eq) and
imidazole (2.04 g, 30.03 mmol, 2.5 eq) in dimethylformamide (20 mL)
at room temperature under nitrogen was added drop wise a solution
of 2.2 (4 g, 12.01 mmol, 1.0 eq) in dimethylformamide (15 mL). The
mixture was stirred overnight at room temperature and then diluted
with ethyl acetate. The organics were washed with water, dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The crude product was triturated with methanol and then isolated
using vacuum filtration and used without further purification.
[1609] Yield: 76%
[1610] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.10 (m, 2H),
6.99 (d, 1H), 3.70 (m, 2H), 3.11 (brs, 2H), 2.81 (s, 2H), 1.84 (m,
2H), 1.60 (m, 2H), 1.40 (s, 9H), 0.94 (s, 9H), 0.17 (s, 6H)
Preparation of 2.5
[1611] To a solution of 2.4 (4 g, 8.94 mmol, 1.0 eq) in
tetrahydrofuran (20 mL) at -78.degree. C. under nitrogen was added
drop wise a 1.0M solution of lithium bis(trimethylsilyl)amide in
tetrahydrofuran (6.2 mL, 10.72 mmol, 1.2 eq). The mixture was
stirred for 1 h at -78.degree. C. A solution of 1.4 (3.83 g, 10.72
mmol, 1.2 eq) in tetrahydrofuran (20 mL) was added drop wise. The
mixture was stirred and allowed to warm slowly to room temperature.
The reaction was concentrated under reduced pressure. The crude
product was purified by column chromatography (eluent: hexane/ethyl
acetate mixtures of increasing polarity).
[1612] Yield: 90.5%
[1613] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.76 (m, 3H), 5.56
(s, 1H), 3.85 (br s, 2H), 3.26 (m, 2H), 2.05 (m, 2H), 1.65 (m, 2H),
1.47 (s, 9H), 0.97 (s, 9H), 0.18 (s, 6H)
Preparation of 2.6a
[1614] To a solution of 2.5 (4.47 g, 7.71 mmol, 1.0 eq) in
dimethoxyethane (35 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (11.6 mL, 23.13 mmol, 3.0 eq), lithium
chloride (0.98 g, 23.13 mmol, 3.0 eq), 1.6 (1.87 g, 8.48 mmol, 1.1
eq) and tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.15
mmol, 0.02 eq). The mixture was refluxed for 4 h under nitrogen.
The mixture was then cooled to room temperature and water was
added. The mixture was extracted with ethyl acetate. The organic
layer was further washed with a 2N aqueous solution of sodium
hydroxide, brine and dried over sodium sulfate. The crude product
was triturated with hexanes and used without further
purification.
[1615] Yield: 84%
[1616] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.39 (m, 4H),
6.87 (d, 1H), 6.69 (m, 1H), 6.37 (d, 1H), 5.89 (s, 1H), 3.71 (m,
2H), 3.45 (brs, 2H), 3.23 (m, 4H), 1.85 (m, 2H), 1.70 (m, 2H), 1.41
(s, 9H); 1.10 (m, 6H), 0.87 (s, 9H), 0.08 (s, 6H)
[1617] Mass Spectral Analysis m/z=607.0 (M+H).sup.+
Preparation of 2.7a
[1618] To a solution of 2.6a (0.50 g, 0.82 mmol, 1.0 eq) in
tetrahydrofuran (10 mL) was added a 1N solution of
tetrabutylammonium fluoride (2.5 mL, 2.47 mmol, 3.0 eq) in
tetrahydrofuran at 0.degree. C. The mixture was stirred for 1 h at
room temperature under nitrogen. The mixture was diluted with ethyl
acetate. The organic layer was washed with a saturated solution of
aqueous sodium bicarbonate, brine, a 1N solution of hydrochloric
acid and brine. The solution was then dried over sodium sulfate,
filtered and concentrated under reduced pressure. The crude product
was triturated with a diethyl ether/hexanes mixture (3:7) and used
without further purification.
[1619] Yield: 74%
[1620] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.34 (s, 4H), 6.80
(d, 1H), 6.67 (m, 1H), 6.49 (d, 1H), 5.87 (s, 1H), 5.57 (s, 1H),
3.84 (brs, 2H), 3.56 (brs, 2H), 3.30 (brs, 4H), 2.00 (m, 2H), 1.64
(m, 2H), 1.47 (s, 9H), 1.20 (m, 6H)
[1621] Mass Spectral Analysis m/z=493.0 (M+H).sup.+
Preparation of 2A
[1622] A 2.0M solution of hydrochloric acid in diethyl ether (1.7
mL, 3.35 mmol, 5.5 eq) was added drop wise to a cooled (0.degree.
C.) solution of 2.7a (0.30 g, 0.61 mmol, 1.0 eq) in anhydrous
dichloromethane (5 mL). The mixture was warmed to room temperature
and stirring was continued for an additional 10 h. Diethyl ether
(100 mL) was added to the solution. The resulting precipitate was
collected by filtration and washed with diethyl ether. The crude
product was purified by column chromatography (eluent:
dichloromethane/methanol mixtures of increasing polarity).
[1623] Yield: 50%
[1624] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.03 (m, 2H),
7.42 (s, 4H), 6.85 (d, 1H), 6.64 (m, 1H), 6.42 (d, 1H), 5.91 (s,
1H), 3.49 (m, 4H), 3.21 (m, 5H), 2.08 (m, 2H), 1.96 (m, 2H), 1.13
(m, 6H)
[1625] Mass Spectral Analysis m/z=393.3 (M+H).sup.+
[1626] Elemental analysis:
[1627] C.sub.24H.sub.28N.sub.2O.sub.2, 1HCl, 1H.sub.2O
[1628] Theory: % C, 64.49; % H, 6.99; % N, 6.27.
[1629] Found: % C, 64.59; % H, 6.67; % N, 6.26.
Example 2B
[1630] 2B was obtained according to a procedure similar to the one
described for 2A, with the following exception:
Step 2.4: 1.6 was replaced by 1.7.
[1631] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.94 (brm, 2H),
8.59 (s, 1H), 7.90 (dd, 1H), 7.62 (d, 1H), 6.88 (d, 1H), 6.67 (dd,
1H), 6.38 (d, 1H), 6.06 (s, 1H), 3.47 (q, 2H), 3.22 (m, 6H), 2.07
(m, 2H), 1.97 (m, 2H), 1.17 (t, 3H), 1.11 (t, 3H)
[1632] Mass Spectral Analysis m/z=394 (M+H).sup.+
[1633] Elemental analysis:
[1634] C.sub.23H.sub.27N.sub.3O.sub.3, 2HCl, 1.25H.sub.2O
[1635] Theory: % C, 56.50; % H, 6.49; % N, 8.59; % Cl, 14.50.
[1636] Found: % C, 56.55; % H, 6.46; % N, 8.39; % Cl, 14.49.
Example 2C
Preparation of 2.9a
[1637] A mixture of 2.7a (0.210 g, 0.00042 mol, 1.0 eq),
cyclopropylmethyl bromide (2.8a) (0.12 mL, 0.0012 mol, 2.95 eq) and
potassium carbonate (0.350 g, 0.0025 mole, 6.0 eq) in
N,N-dimethylformamide (5 mL) was stirred for 48 h at 80.degree. C.
The mixture was cooled to room temperature, poured into water (50
mL) and extracted with ethyl acetate. The organic phase was washed
with brine, dried over sodium sulfate, filtered and concentrated
under reduced pressure. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[1638] Yield: 96%
[1639] Mass Spectral Analysis m/z=547.12 (M+H).sup.+
Preparation of 2C
[1640] To a cold (0.degree. C.) solution of 2.9a (0.200 g, 0.00036
mol, 1.0 eq) in anhydrous dichloromethane (10 mL) was added drop
wise a 2.0 M solution of anhydrous hydrochloric acid in diethyl
ether (1.8 mL, 0.0036 mole, 10.0 eq). The mixture was warmed slowly
to room temperature and stirring was continued for 12 h at room
temperature. The mixture was concentrated under reduced pressure.
Diethyl ether was then added to the mixture, which was stirred for
1 h at room temperature. The precipitate was collected by
filtration, washed with diethyl ether and dried under vacuum.
[1641] Yield: 63%
[1642] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.85 (m, 1H),
7.40 (s, 4H), 6.97 (d, 1H), 6.80 (m, 1H), 6.45 (d, 1H), 5.95 (s,
1H), 3.65 (d, 2H), 3.10-3.50 (m, 8H), 2.00 (m, 4H), 1.10 (m, 7H),
0.50 (m, 2H), 0.20 (m, 2H)
[1643] Mass Spectral Analysis m/z=447.1 (M+H).sup.+
Example 2D
[1644] 2D was obtained according to a procedure similar to the one
described for 2C, with the following exception:
Step 2.7: 2.8a was replaced by 2.8b (method 2A).
[1645] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.00 (s, 1H),
7.45 (s, 4H), 7.00 (m, 1H), 6.80 (m, 1H), 6.45 (m, 1H), 6.00 (s,
1H), 4.55 (m, 1H), 3.10-3.55 (m, 8H), 2.00 (m, 4H), 1.80 (m, 2H),
1.60 (m, 4H), 1.50 (m, 2H), 1.10 (m, 6H)
[1646] Mass Spectral Analysis m/z=461.1 (M+H).sup.+
Example 2E
Preparation of 2.7b
[1647] Intermediate 2.7b was obtained according to a procedure
similar to the one described for 2.7a (see 2A), except 1.6 was
replaced by 1.7 in Step 2.4.
Preparation of 2.9b
[1648] To a solution of 2.7b (1.0 g, 2.03 mmol, 1.0 eq), 2.8e (0.29
g, 4.06 mmol, 2.0 eq), triphenylphosphine (1.06 g, 4.06 mmol, 2.0
eq) and triethylamine (0.82 g, 8.12 mmol, 4.0 eq) in
tetrahydrofuran (50 mL) at 0.degree. C. was added diisopropyl
azodicarboxylate (DIAD) (0.82 g, 4.06 mmol, 2.0 eq). The mixture
was warmed to room temperature and stirred for 48 h at room
temperature. Methylene chloride was added and the crude mixture was
washed with water, concentrated under reduced pressure and purified
by column chromatography (eluent: hexane/ethyl acetate mixtures of
increasing polarity).
[1649] Yield: 45%
[1650] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.56 (s, 1H), 7.76
(dd, 1H), 7.64 (d, 1H), 6.89 (d, 1H), 6.78 (m, 1H), 6.50 (d, 1H),
5.65 (s, 1H), 3.86 (brm, 2H), 3.62 (m, 4H), 3.45 (q, 2H), 3.32
(brm, 2H), 2.05 (brm, 2H), 1.67 (brm, 2H), 1.48 (s, 9H), 1.30 (m,
4H), 1.21 (t, 3H), 0.60 (m, 2H), 0.30 (m, 2H)
[1651] Mass Spectral Analysis m/z=548.4 (M+H).sup.+
Preparation of 2E
[1652] To a solution of 2.9b (0.50 g, 0.913 mmol, 1.0 eq) in
methylene chloride (3 mL) was slowly added an excess of a 1.0M
solution of anhydrous hydrochloric acid in diethyl ether. The
mixture was stirred for 16 h at room temperature and then
concentrated under reduced pressure. This mixture (0.41 g) was
purified by HPLC using a 20.times.150 mm XTerra Reversed Phase-HPLC
column (eluent: 95:5 A:B to 1:99 A:B where A is 0.1% ammonia in
Milli-Q water and B is acetonitrile). After HPLC purification, the
pure product (0.10 g, 0.22 mmol, 1.0 eq) was obtained as the free
amine, which was dissolved in methanol (10 mL) at 0.degree. C.
under nitrogen and treated with a 1.0M solution of anhydrous
hydrochloric acid in diethyl ether (0.47 mL, 0.47 mmol, 2.1 eq).
The mixture was stirred at 0.degree. C. for 30 min. The mixture was
concentrated under reduced pressure and dried under vacuum.
[1653] Yield: 26%
[1654] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.75 (brs, 1H),
9.33 (brs, 1H), 9.18 (s, 1H), 8.45 (brd, 1H), 7.96 (brd, 1H), 6.94
(d, 1H), 6.80 (m, 1H), 6.42 (brm, 2H), 3.66 (brm, 4H), 3.46 (brm,
6H), 2.30 (brm, 4H), 1.35 (t, 3H), 1.22 (brm, 4H), 0.62 (m, 2H),
0.31 (m, 2H)
[1655] Mass Spectral Analysis m/z=448.3 (M+H).sup.+
[1656] Elemental analysis:
[1657] C.sub.27H.sub.33N.sub.3O.sub.3, 1.75HCl, 1.5H.sub.2O
[1658] Theory: % C, 60.23; % H, 7.07; % N, 7.80; % Cl, 11.52.
[1659] Found: % C, 60.50; % H, 6.99; % N, 7.77; % Cl, 11.38.
Example 2F
[1660] 2F was obtained according to a procedure similar to the one
described for 2E, with the following exception:
Step 2.7: 2.8e was replaced by 2.8d.
[1661] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.10 (brs, 2H),
8.62 (d, 1H), 7.93 (dd, 1H), 7.61 (d, 1H), 7.03 (d, 1H), 6.89 (dd,
1H), 6.47 (d, 1H), 6.13 (s, 1H), 3.64 (s, 3H), 3.47 (q, 2H), 3.24
(m, 6H), 2.05 (brm, 4H), 1.17 (t, 3H), 1.11 (t, 3H)
[1662] Mass Spectral Analysis m/z=408.3 (M+H).sup.+
[1663] Elemental analysis:
[1664] C.sub.24H.sub.29N.sub.3O.sub.3, 1.25HCl, 1.25H.sub.2O
[1665] Theory: % C, 60.61; % H, 6.94; % N, 8.84; % Cl, 9.32.
[1666] Found: % C, 60.69; % H, 6.87; % N, 8.66; % Cl, 9.35.
Note: 2F was also obtained according to a procedure similar to the
one described for 2C with the following exceptions: Step 2.7: 2.8a
was replaced by 2.8c and method 2C was used (alkylation reaction
conducted in acetone instead of N,N-dimethylformamide).
Example 3A
Preparation of 3.1a
[1667] To a cold (0.degree. C.) solution of 2.7a (2.5 g, 0.0050
mol, 1.0 eq) in anhydrous dichloromethane (100 mL), was added
N-triphenyltrifluoromethane sulfonimide (1.4) (2 g, 0.0055 mol, 1.1
eq) followed by addition of triethylamine (0.85 mL, 0.060 mol, 1.2
eq). The mixture was allowed to warm slowly to room temperature and
stirring was continued for 12 h. The mixture was diluted with ethyl
acetate and washed successively with water, aqueous 1N NaOH, water,
and brine. The organic layer was dried over sodium sulfate,
filtered and concentrated under vacuum. The crude product was
purified by column chromatography (eluent: hexane/ethyl acetate
mixtures of increasing polarity).
[1668] Yield: 78%
[1669] Mass Spectral Analysis m/z=666.06 (M+H+CH.sub.3CN).sup.+
Preparation of 3.2a
[1670] To a stirred solution of 3.1a (2.5 g, 0.040 mol, 1.0 eq) in
a mixture of methanol (30 mL) and dimethylsulfoxide (40 mL) was
added triethylamine (1.23 mL, 0.088 mol, 2.2 eq). Carbon monoxide
gas was bubbled through the mixture for 5 min. To the mixture was
added palladium (II) acetate (0.090 g, 0.00040 mol, 0.1 eq)
followed by 1,1'-bis(diphenylphosphino)ferrocene (0.443 g, 0.00080
mol, 0.2 eq). Carbon monoxide gas was bubbled through the mixture
for 15 min and the mixture was then stirred under an atmosphere of
carbon monoxide and heated at 65.degree. C. overnight. The mixture
was cooled to room temperature and poured into water. The mixture
was extracted with ethyl acetate. The combined organic extracts
were washed with water, brine, dried over sodium sulfate and
filtered. Evaporation of the solvent under reduced pressure
afforded a dark oil. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[1671] Yield: 75%
[1672] Mass Spectral Analysis m/z=576.08 (M+H+CH.sub.3CN).sup.+
Preparation of 3A
[1673] To a cold (0.degree. C.) solution of 3.2a (0.140 g, 0.00026
mole, 1.0 eq) in anhydrous dichloromethane (10 mL) was added drop
wise a 2.0 M solution of anhydrous hydrochloric acid in diethyl
ether (2.6 mL, 0.0026 mole, 10.0 eq). The mixture was warmed slowly
to room temperature and stirring was continued for 12 h at room
temperature. An additional 1.0 mL of a 2.0 M solution of anhydrous
hydrochloric acid in diethyl ether was added to the reaction
mixture, which was allowed to stir for an additional 12 h at room
temperature. The mixture was concentrated under reduced pressure.
Diethyl ether was then added to the mixture, which was stirred for
2 h at room temperature. The resulting precipitate was collected by
filtration, washed with diethyl ether and dried under vacuum.
[1674] Yield: 53%
[1675] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.08 (m, 2H),
7.90 (d, 1H), 7.60 (s, 1H), 7.40 (s, 4H), 7.15 (d, 1H), 6.00 (s,
1H), 3.70 (s, 3H), 3.10-3.50 (m, 8H), 2.1 (m, 4H), 1.10 (m, 6H)
[1676] Mass Spectral Analysis m/z=435.0 (M+H).sup.+
Example 3B
Preparation of 3.3a
[1677] To a cold (0.degree. C.) solution of 3.2a (1.41 g, 0.0026
mol, 1.0 eq) in tetrahydrofuran (20 mL), was added a solution of
lithium hydroxide monohydrate (0.332 g, 0.0079 mole, 3.0 eq) in
water (3 mL). Methanol (6 mL) was then added to the reaction
mixture, which was stirred at room temperature for 12 h. A solution
of lithium hydroxide monohydrate (0.165 g, 0.0058 mole, 1.5 eq) in
water (3 mL) was added to the reaction mixture, which was stirred
for an additional 12 h at room temperature. The mixture was
concentrated under reduced pressure and the residue was dissolved
in ethyl acetate. The organic solution was dried over sodium
sulfate and filtered. Evaporation of the filtrate provided a solid,
which was triturated in hexane. The precipitate was collected by
filtration.
[1678] Yield: 85%
[1679] Mass Spectral Analysis m/z=562.08 (M+H+CH.sub.3CN).sup.+
Preparation of 3B
[1680] To a cold (0.degree. C.) solution of 3.3a (0.200 g, 0.00038
mole, 1.0 eq) in anhydrous dichloromethane (10 mL) was added drop
wise a 2.0 M solution of anhydrous hydrochloric acid in diethyl
ether (1.9 mL, 0.0038 mole, 10 eq). The mixture was warmed slowly
to room temperature and stirring was continued for 12 h at room
temperature. The desired product precipitates from the reaction
mixture. The precipitate was collected by filtration, washed with
diethyl ether and dried under vacuum.
[1681] Yield: 60%
[1682] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.10 (m, 1.5H),
7.85 (d, 1H), 7.60 (s, 1H), 7.40 (s, 4H), 7.10 (d, 1H), 6.00 (s,
1H), 3.10-3.55 (m, 8H), 2.10 (m, 4H), 1.10 (m, 6H)
[1683] Mass Spectral Analysis m/z=421.0 (M+H).sup.+
Example 3C
[1684] 3C was obtained according to a procedure similar to the one
described for 3B, with the following exception:
Step 3.1: 2.7a (X.dbd.H) was replaced by 2.7b (X.dbd.N).
[1685] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.02 (brm, 2H),
8.64 (d, 1H), 7.94 (dd, 1H), 7.87 (dd, 1H), 7.66 (d, 1H), 7.52 (d,
1H), 7.16 (d, 1H), 6.19 (s, 1H), 3.48 (q, 2H), 3.25 (brm, 6H), 2.10
(brm, 4H), 1.18 (t, 3H), 1.11 (t, 3H)
[1686] Mass Spectral Analysis m/z=422.2 (M+H).sup.+
Example 3D
[1687] 3D was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4a.
[1688] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.33 (m, 2H),
7.83 (m, 2H), 7.54 (m, 1H), 7.42 (m, 4H), 7.22 (m, 1H), 7.10 (m,
1H), 6.01 (s, 1H), 5.60 (m, 2H), 3.42 (m, 2H), 3.25 (m, 4H), 2.11
(m, 4H), 1.10 (m, 6H)
[1689] Mass Spectral Analysis m/z=420.0 (M+H).sup.+
[1690] Elemental analysis:
[1691] C.sub.25H.sub.29N.sub.3O.sub.3, 1HCl, 3H.sub.2O
[1692] Theory: % C, 58.87; % H, 7.11; % N, 8.24.
[1693] Found: % C, 58.85; % H, 6.74; % N, 8.03.
Example 3E
Preparation of 3.5a
[1694] O-Benzotriazol-1-yl-N,N,N'N'-tetramethyluronium
tetrafluoroborate (TBTU) (244.2 mg, 0.76 mmol, 1.1 eq) was added to
a cooled (0.degree. C.) solution of 3.3a (360.0 mg, 0.69 mmol, 1.0
eq), 3.4b (256.8 mg, 3.80 mmol, 5.5 eq), and
N,N-diisopropylethylamine (1.06 mL, 6.08 mmol, 7.7 eq) in
acetonitrile (8 mL). The solution was stirred overnight at room
temperature and then concentrated under reduced pressure. Ethyl
acetate (10 mL) and a saturated aqueous solution of sodium
bicarbonate (10 mL) were added to the crude product and the mixture
was stirred for 20 min. The phases were separated and the organic
phase was washed with an aqueous saturated solution of sodium
bicarbonate and brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: hexane/ethyl acetate mixtures of
increasing polarity).
[1695] Yield: 68%
[1696] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.28 (m, 1H),
7.70 (m, 1H), 7.50 (m, 1H), 7.42 (m, 4H), 7.04 (d, 1H), 5.94 (s,
1H), 3.72 (m, 2H), 3.45 (br s, 2H), 3.25 (m, 4H), 2.70 (d, 3H),
1.89 (m, 2H), 1.74 (m, 2H), 1.42 (s, 9H), 1.12 (m, 6H)
[1697] Mass Spectral Analysis m/z=534.3 (M+H).sup.+
Preparation of 3E
[1698] A 2.0M solution of hydrochloric acid in diethyl ether (1.30
mL, 2.57 mmol, 5.5 eq) was added drop wise to a cooled (0.degree.
C.) solution of 3.5a (0.25 g, 0.47 mmol, 1.0 eq) in anhydrous
dichloromethane (5 mL). The mixture was warmed to room temperature
and stirring was continued for an additional 10 h. Diethyl ether
(100 mL) was added to the solution. The resulting precipitate was
collected by filtration and washed with diethyl ether.
[1699] Yield: 99%
[1700] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.14 (m, 2H),
8.34 (m, 1H), 7.77 (d, 1H), 7.54 (s, 1H), 7.44 (s, 4H), 7.12 (d,
1H), 6.01 (s, 1H), 3.63 (brs, 2H), 3.45 (brs, 2H), 3.24 (m, 4H),
2.69 (d, 3H), 2.09 (m, 4H), 1.11 (m, 6H)
[1701] Mass Spectral Analysis m/z=434.3 (M+H).sup.+
[1702] Elemental analysis:
[1703] C.sub.26H.sub.31N.sub.3O.sub.3, 1HCl, 1.25H.sub.2O
[1704] Theory: % C, 63.40; % H, 7.06; % N, 8.53.
[1705] Found: % C, 63.13; % H, 6.94; % N, 8.39.
Example 3F
[1706] 3F was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4c.
[1707] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.20 (m, 2H),
8.37 (m, 1H), 7.79 (m, 1H), 7.55 (m, 1H), 7.44 (m, 4H), 7.10 (m,
1H), 6.01 (s, 1H), 3.61 (m, 2H), 3.45 (m, 2H), 3.22 (m, 6H), 2.10
(m, 4H), 1.10 (m, 9H)
[1708] Mass Spectral Analysis m/z=448.4 (M+H).sup.+
[1709] Elemental analysis:
[1710] C.sub.27H.sub.33N.sub.3O.sub.3, 1HCl, 1H.sub.2O
[1711] Theory: % C, 64.59; % H, 7.23; % N, 8.37.
[1712] Found: % C, 64.70; % H, 7.16; % N, 8.30.
Example 3G
[1713] 3G was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4d.
[1714] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.16 (m, 2H),
8.36 (m, 1H), 7.78 (m, 1H), 7.55 (m, 1H), 7.44 (m, 4H), 7.10 (m,
1H), 6.00 (s, 1H), 3.44 (m, 2H), 3.20 (m, 8H), 2.10 (m, 4H), 1.45
(m, 2H), 1.12 (m, 6H), 0.80 (m, 3H)
[1715] Mass Spectral Analysis m/z=462.4 (M+H).sup.+
[1716] Elemental analysis:
[1717] C.sub.28H.sub.35N.sub.3O.sub.3, 1HCl, 1.5H.sub.2O
[1718] Theory: % C, 64.05; % H, 7.49; % N, 8.00.
[1719] Found: % C, 63.76; % H, 7.41; % N, 7.76.
Example 3H
[1720] 3H was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4e.
[1721] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.23 (m, 2H),
8.36 (m, 1H), 7.79 (m, 1H), 7.55 (m, 1H), 7.45 (m, 4H), 7.12 (m,
1H), 6.01 (s, 1H), 3.45 (m, 2H), 3.24 (m, 6H), 3.01 (m, 2H), 2.06
(m, 4H), 1.76 (m, 1H), 1.11 (m, 6H), 0.81 (m, 6H)
[1722] Mass Spectral Analysis m/z=476.5 (M+H).sup.+
[1723] Elemental analysis:
[1724] C.sub.29H.sub.37N.sub.3O.sub.3, 1HCl, 1.5H.sub.2O
[1725] Theory: % C, 64.61; % H, 7.67; % N, 7.79.
[1726] Found: % C, 64.94; % H, 7.39; % N, 7.77.
Example 3I
[1727] 3I was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4f.
[1728] .sup.1H NMR (400 MHz, DMSO d.sub.6) 9.14 (brs, 2H), 8.23 (m,
1H), 7.80 (m, 1H), 7.54 (m, 1H), 7.44 (m, 4H), 7.11 (m, 1H), 6.02
(s, 1H), 3.45 (m, 2H), 3.23 (m, 6H), 3.01 (m, 2H), 2.10 (m, 4H),
1.12 (m, 6H), 0.83 (m, 9H)
[1729] Mass Spectral Analysis m/z=490.6 (M+H).sup.+
[1730] Elemental analysis:
[1731] C.sub.30H.sub.39N.sub.3O.sub.3, 1HCl, 0.75H.sub.2O
[1732] Theory: % C, 66.77; % H, 7.75; % N, 7.79.
[1733] Found: % C, 66.63; % H, 7.64; % N, 7.77.
Example 3J
[1734] 3J was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4g.
[1735] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.21 (m, 2H),
8.45 (m, 1H), 7.80 (m, 1H), 7.54 (m, 1H), 7.44 (m, 4H), 7.11 (m,
1H), 6.01 (s, 1H), 3.45 (m, 2H), 3.24 (m, 6H), 3.09 (m, 2H), 2.11
(m, 4H), 1.12 (m, 6H), 0.96 (m, 1H), 0.36 (m, 2H), 0.16 (m, 2H)
[1736] Mass Spectral Analysis m/z=474.4 (M+H).sup.+
[1737] Elemental analysis:
[1738] C.sub.29H.sub.35N.sub.3O.sub.3, 1HCl, 1.75H.sub.2O
[1739] Theory: % C, 64.31; % H, 7.35; % N, 7.76.
[1740] Found: % C, 64.69; % H, 7.17; % N, 7.66.
Example 3K
[1741] 3K was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4h.
[1742] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.36 (m, 2H),
8.13 (m, 1H), 7.82 (m, 1H), 7.54 (m, 1H), 7.44 (m, 4H), 7.11 (m,
1H), 6.00 (s, 1H), 4.01 (m, 1H), 3.45 (m, 2H), 3.22 (m, 6H), 2.10
(m, 4H), 1.15 (m, 12H)
[1743] Mass Spectral Analysis m/z=462.5 (M+H).sup.+
[1744] Elemental analysis:
[1745] C.sub.28H.sub.35N.sub.3O.sub.3, 1HCl, 2.25H.sub.2O
[1746] Theory: % C, 62.44; % H, 7.58; % N, 7.80.
[1747] Found: % C, 62.42; % H, 7.58; % N, 8.08.
Example 3L
[1748] 3L was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4i.
[1749] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.20 (m, 2H),
8.34 (m, 1H), 7.78 (m, 1H), 7.54 (m, 1H), 7.44 (m, 4H), 7.11 (m,
1H), 6.00 (s, 1H), 3.45 (m, 2H), 3.20 (m, 8H), 2.08 (m, 4H), 1.45
(m, 2H), 1.25 (m, 4H), 1.11 (m, 6H), 0.84 (m, 3H)
[1750] Mass Spectral Analysis m/z=490.5 (M+H).sup.+
[1751] Elemental analysis:
[1752] C.sub.30H.sub.39N.sub.3O.sub.3, 1HCl, 1.5H.sub.2O
[1753] Theory: % C, 65.14; % H, 7.84; % N, 7.60.
[1754] Found: % C, 65.38; % H, 7.60; % N, 7.64.
Example 3M
[1755] 3M was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4j.
[1756] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.11 (m, 2H),
7.41 (m, 4H), 7.30 (m, 1H), 7.09 (m, 1H), 6.99 (m, 1H), 6.00 (s,
1H), 3.45 (m, 2H), 3.20 (m, 6H), 2.91 (m, 6H), 2.10 (m, 4H), 1.12
(m, 6H)
[1757] Mass Spectral Analysis m/z=448.4 (M+H).sup.+
[1758] Elemental analysis:
[1759] C.sub.27H.sub.33N.sub.3O.sub.3, 1HCl, 1.25H.sub.2O
[1760] Theory: % C, 64.02; % H, 7.26; % N, 8.30.
[1761] Found: % C, 64.03; % H, 7.21; % N, 8.23.
Example 3N
[1762] 3N was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4k.
[1763] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.21 (m, 2H),
7.44 (m, 5H), 7.09 (m, 2H), 5.99 (s, 1H), 3.41 (m, 2H), 3.36 (m,
4H), 3.21 (m, 6H), 2.10 (m, 4H), 1.78 (m, 4H), 1.10 (m, 6H)
[1764] Mass Spectral Analysis m/z=474.5 (M+H).sup.+
[1765] Elemental analysis:
[1766] C.sub.29H.sub.35N.sub.3O.sub.3, 1HCl, 1.25H.sub.2O
[1767] Theory: % C, 65.40; % H, 7.29; % N, 7.89.
[1768] Found: % C, 65.48; % H, 7.08; % N, 7.90.
Example 3O
[1769] 3O was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.41.
[1770] .sup.1H NMR (400 MHz, DMSO d.sub.6) 9.03 (brs, 2H), 7.44 (m,
5H), 7.13 (m, 2H), 6.01 (s, 1H), 4.96 (m, 1H), 4.24 (m, 1H), 3.44
(m, 6H), 3.22 (m, 6H), 2.09 (m, 4H), 1.86 (m, 1H), 1.75 (m, 1H),
1.12 (m, 6H)
[1771] Mass Spectral Analysis m/z=490.3 (M+H).sup.+
Example 3P
[1772] 3P was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4m.
[1773] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.25 (m, 2H),
7.44 (m, 5H), 7.10 (m, 2H), 6.00 (s, 1H), 4.93 (m, 1H), 4.24 (m,
1H), 3.45 (m, 6H), 3.21 (m, 6H), 2.11 (m, 4H), 1.88 (m, 1H), 1.76
(m, 1H), 1.11 (m, 6H)
[1774] Mass Spectral Analysis m/z=490.5 (M+H).sup.+
[1775] Elemental analysis:
[1776] C.sub.29H.sub.35N.sub.3O.sub.4, 1HCl, 1.5H.sub.2O
[1777] Theory: % C, 62.98; % H, 7.11; % N, 7.60.
[1778] Found: % C, 62.79; % H, 6.98; % N, 7.58.
Example 3Q
[1779] 3Q was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4n.
[1780] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.25 (m, 2H),
7.40 (m, 5H), 7.09 (m, 1H), 6.99 (m, 1H), 6.01 (s, 1H), 4.10 (m,
2H), 3.45 (m, 2H), 3.25 (m, 6H), 2.11 (m, 6H), 2.51 (m, 2H), 1.19
(m, 9H), 0.80 (m, 3H)
[1781] Mass Spectral Analysis m/z=502.5 (M+H).sup.+
[1782] Elemental analysis:
[1783] C.sub.31H.sub.39N.sub.3O.sub.3, 1HCl, 2H.sub.2O
[1784] Theory: % C, 64.85; % H, 7.72; % N, 7.32.
[1785] Found: % C, 64.54; % H, 7.37; % N, 7.35.
Example 3R
[1786] 3R was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 1.12.
[1787] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.21 (m, 2H),
7.41 (m, 4H), 7.29 (m, 1H), 7.08 (m, 1H), 6.89 (m, 1H), 5.98 (s,
1H), 3.41 (m, 2H), 3.22 (m, 10H), 2.10 (m, 4H), 1.02 (m, 12H)
[1788] Mass Spectral Analysis m/z=476.5 (M+H).sup.+
[1789] Elemental analysis:
[1790] C.sub.29H.sub.37N.sub.3O.sub.3, 1HCl, 1.25H.sub.2O
[1791] Theory: % C, 65.15; % H, 7.64; % N, 7.86.
[1792] Found: % C, 64.85; % H, 7.26; % N, 7.79.
Example 3S
[1793] 3S was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4o.
[1794] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.67 (m, 1H),
8.55 (m, 1H), 7.43 (m, 4H), 7.22 (m, 1H), 7.09 (m, 1H), 6.82 (m,
1H), 6.01 (s, 1H), 3.66 (m, 2H), 3.44 (m, 2H), 3.23 (m, 6H), 2.10
(m, 2H), 1.98 (m, 2H), 1.16 (m, 18H)
[1795] Mass Spectral Analysis m/z=504.4 (M+H).sup.+
Example 3T
[1796] 3T was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4p.
[1797] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.00 (m, 1.3H),
7.45 (s, 4H), 7.32 (d, 1H), 7.10 (d, 1H), 7.00 (s, 1H), 6.00 (s,
1H), 4.10 (m, 4H), 3.35-3.60 (m, 8H), 3.20 (m, 4H), 2.10 (m, 4H),
1.10 (m, 6H)
[1798] Mass Spectral Analysis m/z=490.1 (M+H).sup.+
Example 3U
[1799] 3U was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.4b was replaced by 3.4q.
[1800] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.23 (brs, 2H),
7.44 (m, 4H), 7.30 (m, 1H), 7.12 (m, 1H), 6.96 (m, 1H), 6.01 (s,
1H), 3.40 (m, 6H), 3.22 (m, 6H), 2.11 (m, 4H), 1.56 (m, 2H), 1.43
(m, 4H), 1.12 (m, 6H)
[1801] Mass Spectral Analysis m/z=488.4 (M+H).sup.+
[1802] Elemental analysis:
[1803] C.sub.30H.sub.37N.sub.3O.sub.3, 1HCl, 1.75H.sub.2O
[1804] Theory: % C, 64.85; % H, 7.53; % N, 7.56.
[1805] Found: % C, 64.99; % H, 7.37; % N, 7.46.
Example 3V
[1806] 3V was obtained according to a procedure similar to the one
described for 3E, with the following exceptions:
Step 3.5: 3.3a (X.dbd.CH) was replaced by 3.3b (X.dbd.N). Step 3.5:
3.4b was replaced by 3.4a.
[1807] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.20 (brm, 2H),
8.63 (d, 1H), 7.92 (m, 2H), 7.83 (dd, 1H), 7.64 (d, 1H), 7.53 (d,
1H), 7.25 (brs, 1H), 7.12 (d, 1H), 6.16 (s, 1H), 3.48 (q, 2H), 3.31
(q, 2H), 3.22 (brm, 4H), 2.10 (brm, 4H), 1.18 (t, 3H), 1.12 (t,
3H)
[1808] Mass Spectral Analysis m/z=421.3 (M+H).sup.+
[1809] Elemental analysis:
[1810] C.sub.24H.sub.28N.sub.4O.sub.3, 1.6HCl, 1.4H.sub.2O
[1811] Theory: % C, 57.19; % H, 6.48; % N, 11.12; % Cl, 11.25.
[1812] Found: % C, 57.14; % H, 6.41; % N, 10.98; % Cl, 11.00.
Example 3W
[1813] 3W was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.3a was replaced by 3.3b.
[1814] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.21 (brm, 2H),
8.63 (d, 1H), 8.36 (m, 1H), 7.93 (dd, 1H), 7.79 (dd, 1H), 7.64 (d,
1H), 7.49 (d, 1H), 7.13 (d, 1H), 6.16 (s, 1H), 3.48 (q, 2H), 3.25
(brm, 6H), 2.71 (d, 3H), 2.10 (m, 4H), 1.18 (t, 3H), 1.12 (t,
3H)
[1815] Mass Spectral Analysis m/z=435.3 (M+H).sup.+
[1816] Elemental analysis:
[1817] C.sub.25H.sub.30N.sub.4O.sub.3, 1.8HCl, 2H.sub.2O
[1818] Theory: % C, 56.00; % H, 6.73; % N, 10.45; % Cl, 11.90.
[1819] Found: % C, 56.16; % H, 6.72; % N, 10.47; % Cl, 12.23.
Example 3X
[1820] 3X was obtained according to a procedure similar to the one
described for 3E, with the following exceptions:
Step 3.5: 3.3a was replaced by 3.3b. Step 3.5: 3.4b was replaced by
3.4c.
[1821] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.23 (brm, 2H),
8.63 (d, 1H), 8.40 (t, 1H), 7.93 (dd, 1H), 7.81 (dd, 1H), 7.64 (d,
1H), 7.49 (d, 1H), 7.13 (d, 1H), 6.16 (s, 1H), 3.48 (q, 2H), 3.25
(brm, 8H), 2.10 (brm, 4H), 1.18 (t, 3H), 1.12 (t, 3H), 1.05 (t,
3H)
[1822] Mass Spectral Analysis m/z=449.3 (M+H).sup.+
[1823] Elemental analysis:
[1824] C.sub.26H.sub.32N.sub.4O.sub.3, 2HCl, 1.5H.sub.2O
[1825] Theory: % C, 56.93; % H, 6.80; % N, 10.21; % Cl, 12.93.
[1826] Found: % C, 56.64; % H, 6.86; % N, 10.13; % Cl, 12.59.
Example 3Y
[1827] 3Y was obtained according to a procedure similar to the one
described for 3E, with the following exceptions:
Step 3.5: 3.3a was replaced by 3.3b. Step 3.5: 3.4b was replaced by
3.4j.
[1828] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.06 (brs, 2H),
8.62 (d, 1H), 7.92 (dd, 1H), 7.63 (d, 1H), 7.36 (dd, 1H), 7.11 (d,
1H), 6.98 (d, 1H), 6.16 (s, 1H), 3.47 (q, 2H), 3.25 (brm, 6H), 2.91
(s, 6H), 2.10 (brm, 4H), 1.17 (t, 3H), 1.11 (t, 3H)
[1829] Mass Spectral Analysis m/z=449.3 (M+H).sup.+
[1830] Elemental analysis:
[1831] C.sub.26H.sub.32N.sub.4O.sub.3, 1.75HCl, 1.25H.sub.2O
[1832] Theory: % C, 58.38; % H, 6.83; % N, 10.47; % Cl, 11.60.
[1833] Found: % C, 58.37; % H, 6.94; % N, 10.21; % Cl, 11.35.
Example 3Z
[1834] 3Z was obtained according to a procedure similar to the one
described for 3AC, with the following exception:
Step 3.8: 3.6d was replaced by 3.6a;
tetrakis(triphenylphosphine)palladium(0) was used.
[1835] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.21 (brm, 2H),
9.01 (s, 1H), 8.73 (d, 1H), 8.47 (d, 1H), 7.87 (m, 1H), 7.76 (dd,
1H), 7.53 (d, 2H), 7.44 (d, 2H), 7.38 (d, 1H), 7.28 (d, 1H), 6.07
(s, 1H), 3.44 (m, 2H), 3.23 (brm, 6H), 2.11 (brm, 4H), 1.12 (brd,
6H)
[1836] Mass Spectral Analysis m/z=454.0 (M+H).sup.+
Example 3AA
[1837] 3AA was obtained according to a procedure similar to the one
described for 3AC, with the following exception:
Step 3.8: 3.6d was replaced by 3.6b;
tetrakis(triphenylphosphine)palladium(0) was used.
[1838] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.84 (brm, 2H),
7.58 (dd, 1H), 7.46 (m, 5H), 7.27 (d, 1H), 7.18 (d, 1H), 7.12 (d,
1H), 7.06 (m, 1H), 6.04 (s, 1H), 3.46 (m, 2H), 3.23 (brm, 6H), 2.13
(m, 2H), 2.01 (m, 2H), 1.12 (brd, 6H)
[1839] Mass Spectral Analysis m/z=459.3 (M+H).sup.+
[1840] Elemental analysis:
[1841] C.sub.28H.sub.30N.sub.2O.sub.2S, 1HCl, 0.5H.sub.2O
[1842] Theory: % C, 66.71; % H, 6.40; % N, 5.56; % Cl, 7.03.
[1843] Found: % C, 66.76; % H, 6.27; % N, 5.50; % Cl, 7.34.
Example 3AB
[1844] 3AB was obtained according to a procedure similar to the one
described for 3AC, with the following exception:
Step 3.8: 3.6d was replaced by 3.6c;
tetrakis(triphenylphosphine)palladium(0) was used.
[1845] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.39 (b, 1H),
9.32 (b, 1H), 8.83 (d, 2H), 8.16 (d, 2H), 7.98 (d, 1H), 7.49 (m,
3H), 7.46 (d, 2H), 7.34 (d, 1H), 6.14 (s, 1H), 3.3-3.7 (m, 8H),
2.12 (m, 4H), 1.05-1.2 (b, 6H)
[1846] Mass Spectral Analysis m/z=454.4 (M+H).sup.+
[1847] Elemental analysis:
[1848] C.sub.29H.sub.33Cl.sub.2N.sub.3O.sub.2, 2HCl,
2.75H.sub.2O
[1849] Theory: % C, 60.47; % H, 6.74; % N, 7.29.
[1850] Found: % C, 60.35; % H, 6.46; % N, 7.32.
Example 3AC
Preparation of 3.7a
[1851] To a solution of 3.1a (1.50 g, 2.40 mmol, 1.0 eq) in
dimethoxyethane (DME) (20 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (3.6 mL, 7.20 mmol, 3.0 eq), lithium
chloride (0.305 g, 7.20 mmol, 3.0 eq), 3.6d (0.357 g, 2.88 mmol,
1.2 eq) and tetrakis(triphenylphosphine)palladium(0) (0.277 g, 0.24
mmol, 0.10 eq). The mixture was heated at 120.degree. C. for 16 h.
After this time, only starting material 3.1a was observed by LC/MS.
Therefore, additional quantities of 3.6d (0.10 g, 0.81 mmol, 0.34
eq), tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.087 mmol,
0.036 eq) and [1,1'-bis(diphenylphosphino)ferrocene palladium (II)
chloride, dichloromethane complex] (0.50 g, 0.68 mmol, 0.28 eq)
were added to the reaction mixture, which was heated at 120.degree.
C. for 5 h. The crude mixture was cooled to room temperature,
dissolved in ethyl acetate and the mixture was washed with water.
The organic extract was dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude product was purified
column chromatography (eluent: hexane/ethyl acetate mixtures of
increasing polarity), and the product was used without further
purification.
[1852] Yield: 20%
[1853] Mass Spectral Analysis m/z=555.5 (M+H).sup.+
Preparation of 3AC
[1854] To a solution of 3.7a (0.3 g, purity: 90%, 0.489 mmol, 1.0
eq) in methylene chloride (10 mL) was added an excess of a 1.0M
solution of anhydrous hydrochloric acid in diethyl ether (10 mL).
The mixture was stirred for 16 h at room temperature, concentrated
under reduced pressure and purified by column chromatography
(eluent: methylene chloride/methanol mixtures of increasing
polarity).
[1855] Yield: 90%
[1856] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.26 (brs, 2H),
9.13 (s, 1H), 8.99 (s, 2H), 7.72 (d, 1H), 7.53 (d, 2H), 7.44 (d,
2H), 7.34 (s, 1H), 7.25 (d, 1H), 6.07 (s, 1H), 3.44 (brs, 2H), 3.23
(brm, 6H), 2.12 (brm, 4H), 1.12 (brd, 6H)
[1857] Mass Spectral Analysis m/z=455.4 (M+H).sup.+
[1858] Elemental analysis:
[1859] C.sub.28H.sub.30N.sub.4O.sub.2, 2HCl, 2.75H.sub.2O
[1860] Theory: % C, 58.28; % H, 6.55; % N, 9.71.
[1861] Found: % C, 58.53; % H, 6.27; % N, 9.74.
Example 4A
Preparation of 4.2
[1862] To a suspension of 1A (21.9 g, 52.45 mmol, 1.0 eq) in
tetrahydrofuran (200 mL) at 0.degree. C. was added triethylamine
(18.3 mL, 131 mmol, 2.5 eq), followed by trifluoroacetic anhydride
(4.1) (8.75 ml, 63 mmol, 1.2 eq) dropwise. The reaction mixture was
slowly warmed up to and stirred at room temperature for 10 h. Ethyl
acetate (500 mL) was added and the organic layer was washed with a
1M aqueous solution of hydrochloric acid (5.times.100 mL) and
brine, dried over sodium sulfate and filtered. The crude product
was concentrated under reduced pressure and purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[1863] Yield: 93%
[1864] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.42 (m, 2H), 7.36
(m, 2H), 7.22 (m, 1H), 7.02 (m, 1H), 6.96 (m, 1H), 6.90 (m, 1H),
5.54 (s, 1H), 4.39 (m, 1H), 3.87 (m, 1H), 3.71 (m, 1H), 3.58 (m,
2H), 3.35 (m, 3H), 2.22 (m, 2H), 1.74 (m, 2H), 1.22 (m, 6H)
[1865] Mass Spectral Analysis m/z=473.3 (M+H).sup.+
Preparation of 4.4
[1866] To a solution of 4.2 (4.0 g, 8.47 mmol, 1.0 eq) in dry
dichloroethane (100 mL) was added sulfur trioxide
N,N-dimethylformamide complex (4.3) (1.98 g, 12.9 mmol, 1.5 eq)
portionwise. The reaction mixture was heated under reflux for 10 h
and then cooled down to 0-10.degree. C. at which point oxalyl
chloride (1.2 mL, 13.55 mmol, 1.6 eq) was added drop wise. The
reaction mixture was then stirred at 70.degree. C. for another 3 h.
The reaction was quenched with ice/water (100 mL). Dichloromethane
(100 mL) was added and the two phases were separated. The aqueous
phase was extracted with dichloromethane (3.times.50 mL) and the
combined organic layers were dried over sodium sulfate, filtered,
and concentrated under reduced pressure. The crude product was
purified by column chromatography (eluent: hexane/ethyl acetate
mixtures of increasing polarity).
[1867] Yield: 79%
[1868] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.90 (dd, 1H),
7.72 (d, 1H), 7.49 (m, 2H), 7.36 (m, 2H), 7.13 (d, 1H), 5.68 (s,
1H), 4.44 (m, 1H), 3.92 (m, 1H), 3.70 (m, 1H), 3.58 (m, 2H), 3.35
(m, 3H), 2.25 (m, 2H), 1.83 (m, 2H), 1.22 (m, 6H)
[1869] Mass Spectral Analysis m/z=571.2 (M+H).sup.+
Preparation of 4.6a
[1870] To a solution of 4.4 (0.7 g, 1.22 mmol, 1.0 eq) in dry
dichloromethane (30 mL) at 0.degree. C. was added triethylamine
(0.85 mL, 6.10 mmol, 5.0 eq) and methylamine (3.4b) hydrochloride
salt (0.25 g, 3.66 mmol, 3.0 eq) in one portion. The reaction
mixture was slowly warmed up to room temperature and stirred at
room temperature for 10 h. Water (50 mL) and chloroform (50 mL)
were added and the two phases were separated. The aqueous phase was
extracted with chloroform (3.times.50 mL) and the combined organic
layers were dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[1871] Yield: 86%
[1872] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.73 (dd, 1H),
7.53 (d, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.07 (d, 1H), 5.63 (s,
1H), 4.42 (m, 1H), 4.29 (q, 1H), 3.90 (m, 1H), 3.69 (m, 1H), 3.58
(m, 2H), 3.35 (m, 3H), 2.63 (d, 3H), 2.22 (m, 2H), 1.79 (m, 2H),
1.22 (m, 6H)
[1873] Mass Spectral Analysis m/z=566.2 (M+H).sup.+
Preparation of 4A
[1874] To a solution of 4.6a (0.63 g, 1.11 mmol, 1.0 eq) in a
mixture of methanol (20 mL) and water (5 mL) at 0.degree. C. was
added potassium carbonate (0.92 g, 6.66 mmol, 6.0 eq) portionwise.
The reaction mixture was warmed up to room temperature and stirred
at room temperature for 10 h. Brine (50 mL) and chloroform (50 mL)
were added and the two phases were separated. The aqueous phase was
extracted with chloroform (3.times.50 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The crude product was purified by column
chromatography (eluent: dichloromethane/methanol mixtures of
increasing polarity). The desired fractions were combined and
concentrated under reduced pressure. To a cold (0.degree. C.)
solution of the resulting oil in anhydrous dichloromethane was
added a 2.0M solution of hydrogen chloride in diethyl ether (1.11
mL, 2.22 mmol, 2 eq) drop wise. The mixture was then stirred for 1
h at room temperature, concentrated under reduced pressure, and
dried under reduced pressure.
[1875] Yield: 85%
[1876] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.99 (m, 2H),
7.66 (dd, 1H), 7.49-7.37 (m, 6H), 7.25 (d, 1H), 6.10 (s, 1H), 3.45
(m, 2H), 3.22 (m, 6H), 2.36 (d, 3H), 2.01 (m, 4H), 1.12 (m, 6H)
[1877] Mass Spectral Analysis m/z=470.2 (M+H).sup.+
[1878] Elemental analysis:
[1879] C.sub.25H.sub.31N.sub.3O.sub.4S, 1HCl, 1.5H.sub.2O
[1880] Theory: % C, 56.33; % H, 6.62; % N, 7.88.
[1881] Found: % C, 56.06; % H, 6.50; % N, 8.18.
Example 4B
[1882] 4B was obtained according to a procedure similar to the one
described for 4A, with the following exception:
Step 4.3: 3.4b was replaced by 3.4c.
[1883] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.88 (brs, 1H),
7.67 (dd, 1H), 7.46 (m, 4H), 7.39 (d, 1H), 7.23 (d, 1H), 6.10 (s,
1H), 3.52-3.15 (m, 9H), 2.71 (m, 2H), 2.08 (m, 4H), 1.42 (m, 6H),
0.94 (t, 3H)
[1884] Mass Spectral Analysis m/z=484.3 (M+H).sup.+
[1885] Elemental analysis:
[1886] C.sub.26H.sub.33N.sub.3O.sub.4S, 1HCl, 1.25H.sub.2O
[1887] Theory: % C, 57.55; % H, 6.78; % N, 7.74.
[1888] Found: % C, 57.61; % H, 6.75; % N, 7.60.
Example 4C
[1889] 4C was obtained according to a procedure similar to the one
described for 4A, with the following exception:
Step 4.3: 3.4b was replaced by 3.4d.
[1890] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.85 (m, 2H),
7.67 (dd, 1H), 7.51 (t, 1H), 7.45 (m, 3H), 7.39 (d, 1H), 7.23 (d,
1H), 6.10 (s, 1H), 3.45 (m, 2H), 3.24 (m, 7H), 2.63 (m, 2H), 2.08
(m, 4H), 1.34 (m, 2H), 1.12 (m, 6H), 0.77 (t, 3H)
[1891] Mass Spectral Analysis m/z=498.3 (M+H).sup.+
[1892] Elemental analysis:
[1893] C.sub.27H.sub.35N.sub.3O.sub.4S, 1HCl, 1H.sub.2O
[1894] Theory: % C, 58.74; % H, 6.94; % N, 7.61.
[1895] Found: % C, 58.82; % H, 6.78; % N, 7.56.
Example 4D
[1896] 4D was obtained according to a procedure similar to the one
described for 4A, with the following exception:
Step 4.3: 3.4b was replaced by 3.4g.
[1897] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.90 (m, 2H),
7.68 (m, 2H), 7.45 (m, 3H), 7.40 (d, 1H), 7.22 (d, 1H), 6.09 (s,
1H), 3.45 (m, 2H), 3.24 (m, 7H), 2.59 (t, 2H), 2.07 (m, 4H), 1.12
(m, 6H), 0.75 (m, 1H), 0.32 (m, 2H), 0.04 (m, 2H)
[1898] Mass Spectral Analysis m/z=510.3 (M+H).sup.+
[1899] Elemental analysis:
[1900] C.sub.28H.sub.33N.sub.3O.sub.4S, 1HCl, 1H.sub.2O
[1901] Theory: % C, 59.61; % H, 6.79; % N, 7.45.
[1902] Found: % C, 59.55; % H, 6.75; % N, 7.40.
Example 4E
[1903] 4E was obtained according to a procedure similar to the one
described for 4A, with the following exception:
Step 4.3: 3.4b was replaced by 3.4h.
[1904] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.79 (m, 2H),
7.69 (dd, 1H), 7.54 (d, 1H), 7.44 (m, 4H), 7.22 (d, 1H), 6.10 (s,
1H), 3.51-3.09 (m, 10H), 2.07 (m, 4H), 1.12 (m, 6H), 0.92 (d,
6H)
[1905] Mass Spectral Analysis m/z=498.3 (M+H).sup.+
[1906] Elemental analysis:
[1907] C.sub.27H.sub.35N.sub.3O.sub.4S, 1HCl, 1.4H.sub.2O
[1908] Theory: % C, 57.98; % H, 6.99; % N, 7.51.
[1909] Found: % C, 57.99; % H, 7.04; % N, 7.38.
Example 4F
[1910] 4F was obtained according to a procedure similar to the one
described for 4A, with the following exception:
Step 4.3: 3.4b was replaced by 3.4j.
[1911] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.11 (m, 2H),
7.64 (dd, 1H), 7.46 (m, 4H), 7.29 (d, 1H), 7.24 (d, 1H), 6.13 (s,
1H), 3.45 (m, 2H), 3.23 (m, 6H), 2.56 (s, 6H), 2.11 (m, 4H), 1.12
(m, 6H)
[1912] Mass Spectral Analysis m/z=484.1 (M+H).sup.+
[1913] Elemental analysis:
[1914] C.sub.26H.sub.33N.sub.3O.sub.4S, 1HCl, 2.75H.sub.2O
[1915] Theory: % C, 54.82; % H, 6.99; % N, 7.38.
[1916] Found: % C, 54.66; % H, 6.89; % N, 7.30.
Example 4G
[1917] 4G was obtained according to a procedure similar to the one
described for 4A, with the following exception:
Step 4.3: 3.4b was replaced by 4.5.
[1918] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.85 (m, 2H),
7.83 (d, 1H), 7.69 (dd, 1H), 7.45 (m, 3H), 7.41 (d, 1H), 7.25 (d,
1H), 6.11 (s, 1H), 3.45 (m, 2H), 3.25 (m, 7H), 2.09 (m 5H), 1.12
(m, 6H), 0.45 (m, 2H), 0.34 (m, 2H)
[1919] Mass Spectral Analysis m/z=496.2 (M+H).sup.+
[1920] Elemental analysis:
[1921] C.sub.27H.sub.33N.sub.3O.sub.4S, 1HCl, 0.75H.sub.2O
[1922] Theory: % C, 59.44; % H, 6.56; % N, 7.70.
[1923] Found: % C, 59.37; % H, 6.46; % N, 7.60.
Example 4H
Preparation of 4H
[1924] To a solution of 4.4 (1.5 g, 2.82 mmol) in acetonitrile (20
mL) was added a concentrated aqueous solution of ammonium hydroxide
(28-35%, 20 mL). The reaction mixture was heated under reflux for
10 h. Brine (100 mL) was added and the aqueous phase was adjusted
to pH=10 with a 1M aqueous solution of sodium hydroxide. Chloroform
(150 mL) was added and the two phases were separated. The aqueous
phase was extracted with chloroform (3.times.50 mL). The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: dichloromethane/methanol mixtures
of increasing polarity). The desired fractions were combined and
concentrated under reduced pressure. To a cold (0.degree. C.)
solution of the resulting oil (0.32 g, 0.70 mmol, 1.0 eq) in
dichloromethane/methanol was added drop wise a 2.0M solution of
hydrogen chloride in diethyl ether (0.7 mL, 1.4 mmol, 2.0 eq). The
mixture was then stirred for 1 h at room temperature, concentrated
under reduced pressure, and dried under vacuum.
[1925] Yield: 80%
[1926] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.98 (m, 1.5H),
7.71 (dd, 1H), 7.45 (m, 5H), 7.27 (s, 2H), 7.22 (d, 1H), 6.09 (s,
1H), 3.46 (m, 2H), 3.23 (m, 6H), 2.07 (m, 4H), 1.12 (m, 6H)
[1927] Mass Spectral Analysis m/z=456.0 (M+H).sup.+
[1928] Elemental analysis:
[1929] C.sub.24H.sub.29N.sub.3O.sub.4S, 1HCl, 2H.sub.2O
[1930] Theory: % C, 54.59; % H, 6.49; % N, 7.96.
[1931] Found: % C, 54.50; % H, 6.49; % N, 7.82.
Example 4I
Preparation of 4.8
[1932] To a suspension of 4H (1.12 g, 2.45 mmol, 1.0 eq) in a
mixture of dichloromethane (50 mL) and methanol (5 mL) at 0.degree.
C. was added sequentially triethylamine (0.85 mL, 6.12 mmol, 2.5
eq), and di-tert-butyl dicarbonate 4.7 (0.80 g, 3.67 mmol, 1.5 eq)
portion wise. The reaction mixture was slowly warmed to room
temperature and stirred at room temperature for 10 h. The solvents
were removed under reduced pressure. The crude product was purified
by column chromatography (eluent: hexane/ethyl acetate mixtures of
increasing polarity).
[1933] Yield: 92%
[1934] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.75 (dd, 1H),
7.57 (d, 1H), 7.43 (m, 2H), 7.35 (m, 2H), 7.03 (d, 1H), 5.65 (s,
1H), 4.83 (s, 2H), 3.89 (m, 2H), 3.57 (m, 2H), 3.32 (m, 4H), 2.04
(m, 2H), 1.71 (m, 2H), 1.47 (s, 9H), 1.21 (m, 6H)
[1935] Mass Spectral Analysis m/z=556.3 (M+H).sup.+
Preparation of 4.10
[1936] To a solution of 4.8 (1.25 g, 2.25 mmol, 1.0 eq) in
dichloromethane (40 mL) was added triethylamine (0.94 mL, 6.75
mmol, 3.0 eq), and acetic anhydride (4.9) (0.64 mL, 6.75 mmol, 3.0
eq) drop wise. The mixture was stirred at room temperature for 10
h. Dichloromethane (100 mL) and water (100 mL) were added to the
reaction mixture and the two phases were separated. The aqueous
phase was extracted with dichloromethane (3.times.50 mL) and the
combined organic layers were dried over sodium sulfate, filtered,
and concentrated under reduced pressure. The crude product was
purified by column chromatography (eluent: hexane/ethyl acetate
mixtures of increasing polarity).
[1937] Yield: 70%
[1938] Mass Spectral Analysis m/z=598.3 (M+H).sup.+
Preparation of 41
[1939] To a solution of 4.10 (0.16 g, 0.27 mmol, 1.0 eq) in
dichloromethane (5 mL) was added iodotrimethylsilane (0.06 mL, 0.43
mmol, 1.6 eq) dropwise. The mixture was stirred at room temperature
for 30 min. The mixture was diluted in chloroform (100 mL) and
methanol (5 mL), washed with a 20% aqueous solution of sodium
thiosulfate (2.times.30 mL) and a 1M aqueous solution of sodium
carbonate (2.times.30 mL), dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: dichloromethane/methanol mixtures
of increasing polarity).
[1940] Yield: 60%
[1941] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.73 (dd, 1H),
7.51 (d, 1H), 7.45 (s, 4H), 7.17 (d, 1H), 6.01 (s, 1H), 3.45 (brs,
2H), 3.38-3.15 (m, 7H), 2.07 (m, 4H), 1.79 (s, 3H), 1.12 (m,
6H)
[1942] Mass Spectral Analysis m/z=498.3 (M+H).sup.+
Example 5A
Preparation of 5.2
[1943] To a solution of 4.4 (1.4 g, 2.45 mmol, 1.0 eq) in a mixture
tetrahydrofuran (5 mL) and dichloromethane (1 mL) at 0.degree. C.
was added a 1.0 M solution of hydrazine (5.1) in tetrahydrofuran
(24.5 mL, 24.5 mmol, 10.0 eq) in one portion. The reaction mixture
was stirred at 0.degree. C. for 30 min. Water (50 mL) and
chloroform (100 mL) were added and the two phases were separated.
The aqueous phase was extracted with chloroform (3.times.50 mL) and
the combined organic layers were dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography (eluent: hexane/ethyl
acetate mixtures of increasing polarity).
[1944] Yield: 70%
[1945] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.78 (dd, 1H),
7.59 (d, 1H), 7.46 (d, 2H), 7.35 (d, 2H), 7.10 (d, 1H), 5.64 (s,
1H), 4.42 (m, 1H), 3.91 (m, 1H), 3.69 (m, 1H), 3.57 (m, 2H), 3.35
(m, 4H), 2.23 (m, 2H), 1.80 (m, 2H), 1.22 (m, 6H)
[1946] Mass Spectral Analysis m/z=567.4 (M+H).sup.+
Preparation of 5.3
[1947] To a suspension of 5.2 (0.9 g, 1.59 mmol, 1.0 eq) in ethanol
(10 mL) was added sodium acetate (0.87 g, 10.8 mmol, 6.65 eq) and
iodomethane (2.8c) (0.54 mL, 8.85 mmol, 5.45 eq). The mixture was
heated under reflux for 10 h. Water (100 mL) and dichloromethane
(100 mL) were added and the two phases were separated. The aqueous
phase was extracted with dichloromethane (3.times.50 mL) and the
combined organic layers were dried over sodium sulfate, filtered,
and concentrated under reduced pressure. The crude product was
purified by column chromatography (eluent: hexane/ethyl acetate
mixtures of increasing polarity).
[1948] Yield: 74%
[1949] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.81 (dd, 1H),
7.64 (d, 1H), 7.46 (d, 2H), 7.35 (d, 2H), 7.11 (d, 1H), 5.64 (s,
1H), 4.42 (m, 1H), 3.91 (m, 1H), 3.69 (m, 1H), 3.57 (m, 2H), 3.35
(m, 3H), 3.00 (s, 3H), 2.23 (m, 2H), 1.80 (m, 2H), 1.22 (m, 6H)
[1950] Mass Spectral Analysis m/z=551.2 (M+H).sup.+
Preparation of 5A
[1951] To a solution of 5.3 (0.65 g, 1.18 mmol, 1.0 eq) in a
mixture of methanol (20 mL) and water (5 mL) at 0.degree. C. was
added potassium carbonate (0.98 g, 7.08 mmol, 6.0 eq) portion wise.
The mixture was warmed up to and stirred at room temperature for 10
h. Brine (50 mL) and chloroform (50 mL) were added and the two
phases were separated. The aqueous phase was extracted with
chloroform (3.times.50 mL). The combined organic layers were dried
over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatography
(eluent: dichloromethane/methanol mixtures of increasing polarity).
The desired fractions were combined and concentrated under reduced
pressure. To a cold (0.degree. C.) solution of the resulting oil in
anhydrous dichloromethane was added dropwise a 2.0M solution of
hydrogen chloride in diethyl ether (1.18 mL, 2.36 mmol, 2.0 eq).
The mixture was then stirred at room temperature for 1 h,
concentrated under reduced pressure, and dried under vacuum.
[1952] Yield: 88%
[1953] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.07 (m, 2H),
7.83 (dd, 1H), 7.47 (m, 5H), 7.30 (d, 1H), 6.12 (s, 1H), 3.63-3.10
(m, 1H), 2.10 (m, 4H), 1.12 (m, 6H)
[1954] Mass Spectral Analysis m/z=455.2 (M+H).sup.+
[1955] Elemental analysis:
[1956] C.sub.25H.sub.30N.sub.2O.sub.4S, 1HCl, 1.33H.sub.2O
[1957] Theory: % C, 58.30; % H, 6.59; % N, 5.44.
[1958] Found: % C, 58.35; % H, 6.56; % N, 5.37.
Example 6A
Preparation of 6.2
[1959] To a cold (0.degree. C.) solution of 4.2 (0.23 g, 0.48 mmol,
1.0 eq) in dry acetonitrile (3 mL) under nitrogen was added
nitronium tetrafluoroborate complex (6.1) (78.5 mg, 0.576 mmol, 1.2
eq) in one portion with rapid stirring. The reaction mixture was
kept at 0.degree. C. for 1 h and then quenched with ice/water (1:1)
(15 mL). Dichloromethane (50 mL) was added and the two phases were
separated. The aqueous phase was extracted with dichloromethane
(3.times.30 mL) and the combined organic layers were dried over
sodium sulfate, filtered, and concentrated under reduced pressure.
The crude product was purified by column chromatography (eluent:
hexane/ethyl acetate mixtures of increasing polarity).
[1960] Yield: 38%
[1961] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.14 (dd, 1H),
7.97 (d, 1H), 7.48 (m, 2H), 7.36 (m, 2H), 7.06 (d, 1H), 5.66 (s,
1H), 4.43 (m, 1H), 3.92 (m, 1H), 3.70 (m, 1H), 3.58 (m, 2H), 3.36
(m, 3H), 2.23 (m, 2H), 1.82 (m, 2H), 1.23 (m, 6H)
[1962] Mass Spectral Analysis m/z=518.3 (M+H).sup.+
Preparation of 6A
[1963] To a solution of 6.2 (0.2 g, 0.386 mmol, 1.0 eq) in a
mixture of methanol (15 mL) and water (5 mL) at 0.degree. C. was
added potassium carbonate (0.32 g, 2.32 mmol, 6.0 eq) portionwise.
The mixture was warmed up to room temperature and stirred at room
temperature for 10 h. Brine (50 mL) and chloroform (50 mL) were
added and the two phases were separated. The aqueous phase was
extracted with chloroform (3.times.30 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The crude product was purified by
preparative liquid chromatography (mobile phase:
acetonitrile/water/trifluoroacetic acid). The desired fractions
were combined and concentrated under reduced pressure. The product
was dissolved in chloroform (100 mL), washed with a 1M aqueous
solution of sodium carbonate (2.times.30 mL), dried over sodium
sulfate, filtered, and concentrated under reduced pressure. To a
cold (0.degree. C.) solution of the resulting oil in anhydrous
dichloromethane was added dropwise a 1.0M solution of hydrogen
chloride in diethyl ether (0.8 mL, 0.8 mmol, 2.0 eq). The mixture
was then stirred for 1 h at room temperature, concentrated under
reduced pressure, and dried under vacuum.
[1964] Yield: 50%
[1965] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.01 (m, 2H),
8.19 (dd, 1H), 7.79 (d, 1H), 7.49 (m, 4H), 7.29 (d, 1H), 6.19 (s,
1H), 3.56-3.14 (m, 8H), 2.11 (m, 4H), 1.13 (m, 6H)
[1966] Mass Spectral Analysis m/z=422.3 (M+H).sup.+
Example 6B
Preparation of 6.4
[1967] To a cold (0.degree. C.) solution of 6.2 (1.92 g, 3.71 mmol,
1.0 eq) in ethanol (50 mL) was added tin (II) chloride dihydrate
(6.3) (2.51 g, 11.13 mmol, 3.0 eq) in one portion. The reaction
mixture was heated under reflux for 10 h and then concentrated
under reduced pressure to give the crude product, which was used
for the next step without purification.
[1968] Mass Spectral Analysis m/z=488.2 (M+H).sup.+
Preparation of 6B
[1969] To a suspension of 6.4 (1.3 g, crude, as of 0.91 mmol, 1.0
eq) in a mixture of methanol (30 mL) and water (10 mL) at 0.degree.
C. was added potassium carbonate (0.75 g, 5.46 mmol, 6.0 eq)
portion wise. The reaction mixture was warmed up to room
temperature and stirred at room temperature for 10 h. Brine (50 mL)
and chloroform (50 mL) were added and the two phases were
separated. The aqueous phase was extracted with chloroform
(3.times.30 mL). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The
crude product was purified by preparative liquid chromatography
(mobile phase: acetonitrile/water/trifluoroacetic acid). The
desired fractions were combined, concentrated under reduced
pressure, and dried under vacuum.
[1970] Yield: 27% over two steps
[1971] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.98 (brs,
2.5H), 9.11 (m, 2H), 7.44 (m, 4H), 7.23 (dd, 1H), 7.15 (d, 1H),
7.00 (d, 1H), 6.06 (s, 1H), 3.78-3.10 (m, 8H), 2.06 (m, 4H), 1.12
(m, 6H)
[1972] Mass Spectral Analysis m/z=392.2 (M+H).sup.+
Example 6C
Preparation of 6.6a
[1973] To a suspension of 6.4 (1.5 g, crude, as of 1.05 mmol, 1.0
eq) in dichloroethane (50 mL) at 0.degree. C. was added pyridine
(0.42 g, 5.25 mmol, 5 eq) followed by drop wise addition of
ethylsulfonyl chloride (6.5a) (0.30 mL, 3.15 mmol, 3.0 eq)
dropwise. The mixture was stirred at 0.degree. C. for another 2 h.
A 1M aqueous solution of hydrochloric acid (100 mL) and chloroform
(100 mL) were added and the two phases were separated. The aqueous
phase was extracted with chloroform (3.times.50 mL). The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: hexane/ethyl acetate mixtures of
increasing polarity).
[1974] Yield: 90%
[1975] Mass Spectral Analysis m/z=580.3 (M+H).sup.+
Preparation of 6C
[1976] To a solution of 6.6a (0.55 g, 0.9 mmol, 1.0 eq) in a
mixture of methanol (20 mL) and water (5 mL) at 0.degree. C. was
added potassium carbonate (0.78 g, 5.4 mmol, 6.0 eq) portionwise.
The mixture was warmed up to room temperature and stirred at room
temperature for 10 h. Brine (100 mL) and chloroform (100 mL) were
added and the two phases were separated. The aqueous phase was
extracted with chloroform (3.times.50 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The crude product was purified by column
chromatography (eluent: dichloromethane/methanol mixture of
increasing polarity). The desired fractions were combined and
concentrated under reduced pressure. To a cold (0.degree. C.)
solution of the resulting oil in anhydrous dichloromethane was
added drop wise a 1.0M solution of hydrogen chloride in diethyl
ether (1.8 mL, 1.8 mmol, 2.0 eq). The mixture was then stirred for
1 h at room temperature, concentrated under reduced pressure, and
dried under vacuum.
[1977] Yield: 80%
[1978] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.49 (s, 1H),
8.91 (m, 2H), 7.43 (m, 4H), 7.11 (dd, 1H), 7.02 (d, 1H), 6.93 (d,
1H), 6.00 (s, 1H), 3.45 (brs, 2H), 3.21 (m, 6H), 2.97 (q, 2H), 2.03
(m, 4H), 1.20-1.00 (m, 9H)
[1979] Mass Spectral Analysis m/z=484.2 (M+H).sup.+
[1980] Elemental analysis:
[1981] C.sub.26H.sub.33N.sub.3O.sub.4S, 1HCl, 1.25H.sub.2O
[1982] Theory: % C, 57.55; % H, 6.78; % N, 7.74.
[1983] Found: % C, 57.52; % H, 6.67; % N, 7.73.
Example 6D
[1984] 6D was obtained according to a procedure similar to the one
described for 6C, with the following exception:
Step 6.5: 6.5a was replaced by 6.5b.
[1985] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.48 (s, 1H),
8.66 (brm, 1H), 7.43 (s, 4H), 7.12 (dd, 1H), 7.01 (d, 1H), 6.95 (d,
1H), 6.00 (s, 1H), 3.46 (brs, 4H), 3.23 (brm, 4H), 3.12 (m, 1H),
2.06 (m, 2H), 1.95 (m, 2H), 1.20 (d, 6H), 1.12 (brd, 6H)
[1986] Mass Spectral Analysis m/z=498.2 (M+H).sup.+
Example 6E
Preparation of 6.8
[1987] To a suspension of 6.4 (1.0 g, crude, as of 0.58 mmol, 1.0
eq) in dichloroethane (30 mL) at 0.degree. C. was added pyridine
(0.23 mL, 2.9 mmol, 5.0 eq) followed by a drop wise addition of
acetyl chloride (6.7) (0.16 mL, 2.32 mmol, 4.0 eq). The reaction
mixture was slowly warmed up to room temperature and stirred at
room temperature for 10 h. A 1M aqueous solution of hydrochloric
acid (50 mL) and chloroform (50 mL) were added and the two phases
were separated. The aqueous phase was extracted with chloroform
(3.times.50 mL). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography (eluent:
hexane/ethyl acetate mixture of increasing polarity).
[1988] Yield: 88%
[1989] Mass Spectral Analysis m/z=530.2 (M+H).sup.+
Preparation of 6E
[1990] To a solution of 6.8 (0.27 g, 0.5 mmol, 1.0 eq) in a mixture
of methanol (20 mL) and water (5 mL) at 0.degree. C. was added
potassium carbonate (0.42 g, 3.0 mmol, 6.0 eq) portion wise. The
reaction mixture was warmed up to room temperature and stirred at
room temperature for 10 h. Brine (100 mL) and chloroform (100 mL)
were added and the two phases were separated. The aqueous phase was
extracted with chloroform (3.times.30 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The crude product was first purified by
column chromatography (eluent: dichloromethane/methanol mixture of
increasing polarity) and then repurified by preparative liquid
chromatography (mobile phase: acetonitrile/water/trifluoroacetic
acid). The desired fractions were combined and concentrated under
reduced pressure. The product was dissolved in chloroform (100 mL)
and washed with a 1M solution of sodium carbonate (2.times.30 mL),
dried over sodium sulfate, filtered, and concentrated under reduced
pressure. To a cold (0.degree. C.) solution of the resulting oil in
anhydrous dichloromethane was added dropwise 1.0M hydrogen chloride
in diethyl ether (1.0 mL, 1.0 mmol, 2 eq). The mixture was then
stirred for 1 h at room temperature, concentrated under reduced
pressure, and dried under reduced pressure.
[1991] Yield: 73%
[1992] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.34 (s, 1H),
8.80 (brs, 2H), 7.68 (d, 1H), 7.42 (s, 4H), 6.90 (t, 1H), 6.77 (d,
1H), 5.95 (s, 1H), 3.45 (brs, 2H), 3.25 (m, 6H), 2.15 (s, 3H), 2.04
(m, 4H), 1.12 (m, 6H)
[1993] Mass Spectral Analysis m/z=434.2 (M+H).sup.+
[1994] Elemental analysis:
[1995] C.sub.26H.sub.31N.sub.3O.sub.3, 1HCl, 1.7H.sub.2O
[1996] Theory: % C, 62.38; % H, 7.13; % N, 8.39.
[1997] Found: % C, 62.26; % H, 6.81; % N, 8.29.
Example 7A
Preparation of 7.2
[1998] To a solution of 3.1a (3 g, 4.80 mmol, 1.0 eq), sodium
tert-butoxide (0.55 g, 5.67 mmol, 1.18 eq),
tris(dibenzylideneacetone)dipalladium(0) (0.22 g, 0.24 mmol, 0.05
eq) and 1,1'-bis(diphenylphosphino)ferrocene (dppf) (0.39 g, 0.70
mmol, 0.145 eq) in anhydrous toluene (48 mL) was added 7.1 (0.95
mL, 5.67 mmol, 1.18 eq) at room temperature. The solution was
stirred at 80.degree. C. overnight and then cooled to room
temperature. The mixture was diluted with ethyl acetate and vacuum
filtered through a plug of celite. The filtrate was washed with
brine, dried over sodium sulfate, filtered and concentrated under
reduced pressure. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[1999] Yield: 33%
[2000] Mass Spectral Analysis m/z=656.6 (M+H).sup.+
Preparation of 7.3
[2001] To a solution of 7.2 (1.00 g, 1.52 mmol, 1.0 eq) in
anhydrous methanol (5 mL) at room temperature under nitrogen was
added hydroxylamine hydrochloride (0.21 g, 2.97 mmol, 1.95 eq) and
sodium acetate (0.64 g, 7.78 mmol, 5.1 eq). The mixture was stirred
overnight at room temperature. The mixture was then diluted with
ethyl acetate, washed with a saturated aqueous solution of sodium
bicarbonate and brine, dried over sodium sulfate and filtered. The
organics were concentrated under reduced pressure and the crude
product was purified by column chromatography (eluent: hexane/ethyl
acetate mixtures of increasing polarity).
[2002] Yield: 99%
[2003] Mass Spectral Analysis m/z=492.5 (M+H).sup.+
Preparation of 7.5
[2004] To a solution of 7.3 (0.75 g, 1.53 mmol, 1.0 eq) and
triethylamine (1.06 mL, 7.63 mmol, 5.0 eq) in dichloromethane (10
mL) at 0.degree. C. under nitrogen was added drop wise 7.4 (0.35
mL, 4.58 mmol, 3.0 eq). The mixture was stirred overnight at room
temperature. An aqueous solution of sodium bicarbonate was added
and the mixture was stirred for 20 min. The phases were separated
and the organic phase was washed with an aqueous solution of sodium
bicarbonate, brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude product was used for
the next step without further purification.
[2005] Yield: 83%
[2006] Mass Spectral Analysis m/z=648.5 (M+H).sup.+
Preparation of 7.6
[2007] To a solution of 7.5 (0.82 g, 1.27 mmol, 1.0 eq) in
tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1N aqueous
solution of sodium hydroxide (5 mL, 5 mmol, 4.0 eq). The mixture
was stirred at room temperature for 3 h under nitrogen. The mixture
was then neutralized with a 1N aqueous solution of hydrochloric
acid (50 mL). The mixture was extracted with ethyl acetate and the
organic layer was further washed with brine, dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
crude product was purified by column chromatography (eluent:
hexane/ethyl acetate mixtures of increasing polarity).
[2008] Yield: 40%
[2009] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.35 (m, 1H),
7.41 (s, 4H), 7.09 (m, 1H), 6.97 (d, 1H), 6.91 (d, 1H), 5.92 (s,
1H), 3.72 (m, 2H), 3.44 (m, 2H), 3.23 (m, 4H), 2.87 (s, 3H), 1.86
(m, 2H), 1.71 (m, 2H), 1.42 (s, 9H), 1.11 (m, 6H)
[2010] Mass Spectral Analysis m/z=570.4 (M+H).sup.+
Preparation of 7A
[2011] A 2.0M solution of hydrochloric acid in diethyl ether (1.4
mL, 2.78 mmol, 5.5 eq) was added drop wise to a cooled (0.degree.
C.) solution of 7.6 (0.29 g, 0.51 mmol, 1.0 eq) in anhydrous
dichloromethane (5 mL). The mixture was warmed to room temperature
and stirring was continued for an additional 10 h at room
temperature. Diethyl ether (100 mL) was added to the solution and
the resulting precipitate was collected by filtration and washed
with diethyl ether. The crude product was purified by column
chromatography (eluent: dichloromethane/methanol mixtures of
increasing polarity).
[2012] Yield: 25%
[2013] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.42 (s, 1H),
8.85 (m, 2H), 7.43 (m, 4H), 7.12 (m, 1H), 7.05 (m, 1H), 6.93 (m,
1H), 6.00 (s, 1H), 3.45 (m, 2H), 3.37 (m, 2H), 3.24 (m, 4H), 2.88
(s, 3H), 2.07 (m, 2H), 1.98 (m, 2H), 1.11 (m, 6H)
[2014] Mass Spectral Analysis m/z=470.4 (M+H).sup.+
[2015] Elemental analysis:
[2016] C.sub.25H.sub.31N.sub.3O.sub.4S, 1HCl, 2H.sub.2O
[2017] Theory: % C, 55.39; % H, 6.69; % N, 7.75.
[2018] Found: % C, 55.03; % H, 6.33; % N, 7.36.
Example 7B
Preparation of 7.7
[2019] To a solution of 7.6 (0.5 g, 0.88 mmol, 1.0 eq) in dry
tetrahydrofuran (20 mL) at 0.degree. C. was added sodium hydride
(60% dispersion in mineral oil, 70 mg, 1.76 mmol, 2.0 eq) in one
portion. The reaction mixture was kept at 0.degree. C. for 1 h and
methyliodide (2.8c) (0.08 mL, 1.1 mmol, 1.3 eq) was added drop
wise. The mixture was kept at 0.degree. C. for another 30 min,
warmed up to room temperature, and then heated at 80.degree. C. for
10 h. Water (50 mL) and chloroform (100 mL) were added and the two
phases were separated. The aqueous phase was extracted with
chloroform (3.times.50 mL). The combined organic layers were dried
over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity).
[2020] Yield: 83%
[2021] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.43 (m, 2H), 7.36
(m, 2H), 7.19 (dd, 1H), 7.01 (d, 1H), 6.95 (d, 1H), 5.61 (s, 1H),
3.87 (brs, 2H), 3.57 (brs, 2H), 3.32 (m, 4H), 3.21 (s, 3H), 2.81 (s
3H), 2.05 (m, 2H), 1.68 (m, 2H), 1.48 (s, 9H), 1.20 (m, 6H)
[2022] Mass Spectral Analysis m/z=584.3 (M+H).sup.+
Preparation of 7B
[2023] To a cold (0.degree. C.) solution of 7.7 (0.43 g, 0.73 mmol,
1.0 eq) in anhydrous dichloromethane (20 mL) was added drop wise a
1.0 M solution of hydrogen chloride in diethyl ether (4.38 mL, 4.38
mmol, 6.0 eq). The reaction mixture was stirred at room temperature
for 10 h and then concentrated under reduced pressure. The crude
product was purified by preparative liquid chromatography (mobile
phase: acetonitrile/water/trifluoroacetic acid). The desired
fractions were combined and concentrated under reduced pressure.
The product was dissolved in chloroform (100 mL) and washed with a
1M solution of sodium carbonate (2.times.30 mL), dried over sodium
sulfate, filtered, and concentrated under reduced pressure. To a
cold (0.degree. C.) solution of the resulting oil in anhydrous
dichloromethane was added dropwise 1.0M hydrogen chloride in
diethyl ether (1.46 mL, 1.46 mmol, 2.0 eq). The mixture was then
stirred for 1 h at room temperature, concentrated under reduced
pressure, and dried under vacuum.
[2024] Yield: 60%
[2025] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.79 (m, 2H),
7.44 (m, 4H), 7.34 (dd, 1H), 7.10 (d, 1H), 7.00 (d, 1H), 6.03 (s,
1H), 3.23 (m, 8H), 3.14 (s, 3H), 2.89 (s, 3H), 2.04 (m, 4H), 1.11
(m, 6H)
[2026] Mass Spectral Analysis m/z=484.2 (M+H).sup.+
[2027] Elemental analysis:
[2028] C.sub.26H.sub.33N.sub.3O.sub.4S, 1HCl, 1.3H.sub.2O
[2029] Theory: % C, 57.46; % H, 6.79; % N, 7.73.
[2030] Found: % C, 57.46; % H, 6.86; % N, 7.80.
Example 7C
Preparation of 7.8
[2031] To a suspension of 6.4 (2 g, crude, as of 1.4 mmol, 1.0 eq)
in dichloromethane (50 mL) at 0.degree. C. was added triethylamine
(0.98 mL, 7.0 mmol, 5 eq) followed by drop wise addition of
methylsulfonyl chloride (7.4) (0.33 mL, 4.2 mmol, 3.0 eq). The
reaction mixture was stirred at 0.degree. C. for 1 h. A 1M aqueous
solution of hydrochloric acid (100 mL) and chloroform (100 mL) were
added and the two phases were separated. The aqueous phase was
extracted with chloroform (3.times.50 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated
under reduced pressure to give the crude product, which was used
for the next step without purification.
[2032] Mass Spectral Analysis m/z=644.2 (M+H).sup.+
Preparation of the Mixture of 7A & 7C
[2033] To a suspension of 7.8 (1.57 g, crude, as of 1.4 mmol, 1.0
eq) in a mixture of methanol (20 mL), tetrahydrofuran (20 mL) and
water (20 mL) was added lithium hydroxide hydrate (0.98 mL, 7.0
mmol, 5.0 eq). The reaction mixture was stirred at room temperature
for 10 h and then concentrated under reduced pressure to give the
crude product as a mixture of 7A and 7C, which was carried over for
the next step without purification.
[2034] Mass Spectral Analysis m/z=470.2 (M+H).sup.+ (7A)
[2035] Mass Spectral Analysis m/z=484.2 (M+H).sup.+ (7C)
Preparation of 7C
[2036] To a suspension of the mixture of 7A and 7C (2.2 g, crude,
as of 1.4 mmol, 1.0 eq) in dry dichloroethane (50 mL) at 0.degree.
C. was added pyridine (0.34 mL, 4.2 mmol, 3 eq) followed by
di-tert-butyl dicarbonate (4.7) (0.46 g, 2.1 mmol, 1.5 eq) portion
wise. The reaction mixture was slowly warmed up to room temperature
and stirred at room temperature for 10 h. Water (50 mL) and
chloroform (100 mL) were added. The two phases were separated and
the aqueous phase was further extracted with chloroform (3.times.50
mL). The combined organic layers were dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography (eluent: hexane/ethyl
acetate mixtures of increasing polarity to obtain 7.6 as pure
compound; eluent: dichloromethane/methanol mixture of increasing
polarity to obtain crude 7C).
[2037] Yield: 62% for 7.6 over three steps
[2038] The crude 7C (100 mg) was further purified by preparative
liquid chromatography (mobile phase:
acetonitrile/water/trifluoroacetic acid). The desired fractions
were combined and concentrated under reduced pressure. The product
was dissolved in chloroform (100 mL) and washed with a 1M aqueous
solution of sodium carbonate (2.times.30 mL), dried over sodium
sulfate, filtered, and concentrated under reduced pressure. To a
cold (0.degree. C.) solution of the resulting oil in anhydrous
dichloromethane was added drop wise a 1.0M solution of hydrogen
chloride in diethyl ether (0.41 mL, 0.41 mmol, 2.0 eq). The mixture
was then stirred for 1 h at room temperature, concentrated under
reduced pressure, and dried under vacuum.
[2039] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.47 (m, 1H),
9.435 & 9.422 (2s, 1H), 7.51-6.92 (m, 7H), 6.31 & 5.90 (2s,
1H,), 3.50-3.17 (m, 8H), 2.88 & 2.87 (2s, 3H,), 2.82 (d, 3H),
2.12 (m, 4H), 1.12 (m, 6H)
[2040] Mass Spectral Analysis m/z=484.2 (M+H).sup.+
[2041] Elemental analysis:
[2042] C.sub.26H.sub.33N.sub.3O.sub.4S, 1HCl, 0.9H.sub.2O
[2043] Theory: % C, 58.23; % H, 6.73; % N, 7.84.
[2044] Found: % C, 58.02; % H, 6.68; % N, 8.20.
Example 8A
[2045] 8A was obtained according to a procedure similar to the one
described for 2A, with the following exception:
Step 2.1: 2.1 was replaced by 8.1 (see also step 8.1).
[2046] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.16 (s, 1H),
8.92 (brs, 1H), 8.73 (brs, 1H), 7.40 (s, 4H), 6.78 (m, 2H), 6.43
(dd, 1H), 5.86 (s, 1H), 3.43 (brm, 4H), 3.20 (brm, 4H), 2.09 (m,
2H), 1.93 (m, 2H), 1.11 (brd, 6H)
[2047] Mass Spectral Analysis m/z=393.4 (M+H).sup.+
[2048] Elemental analysis:
[2049] C.sub.24H.sub.28N.sub.2O.sub.3, 1HCl, 0.33H.sub.2O
[2050] Theory: % C, 66.27; % H, 6.87; % N, 6.44.
[2051] Found: % C, 66.24; % H, 6.77; % N, 6.44.
Example 8B
[2052] 8B was obtained according to a procedure similar to the one
described for 2A, with the following exceptions:
Step 2.1: 2.1 was replaced by 8.1 (see also step 8.1). Step 2.4:
1.6 was replaced by 1.7 (see also step 8.4).
[2053] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.12 (brm, 1H),
8.99 (brm, 1H), 8.57 (d, 1H), 7.88 (dd, 1H), 7.59 (d, 1H), 6.84 (m,
1H), 6.78 (t, 1H), 6.40 (dd, 1H), 6.00 (s, 1H), 3.47 (q, 2H), 3.40
(m, 2H), 3.29 (q, 2H), 3.19 (m, 2H), 2.10 (m, 2H), 1.97 (m, 2H),
1.17 (t, 3H), 1.10 (t, 3H)
[2054] Mass Spectral Analysis m/z=394.2 (M+H).sup.+
[2055] Elemental analysis:
[2056] C.sub.24H.sub.27N.sub.3O.sub.3, 2HCl, 0.67H.sub.2O
[2057] Theory: % C, 57.74; % H, 6.39; % N, 8.78; % Cl, 14.82.
[2058] Found: % C, 57.70; % H, 6.28; % N, 8.73; % Cl, 14.47.
Example 8C
[2059] 8C was obtained according to a procedure similar to the one
described for 2C, with the following exception:
Step 2.1: 2.1 was replaced by 8.1 (see also step 8.1).
[2060] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.88 (brm, 2H),
7.42 (s, 4H), 7.00 (d, 1H), 6.86 (t, 1H), 6.58 (d, 1H), 5.97 (s,
1H), 3.90 (d, 2H), 3.44 (m, 2H), 3.23 (brm, 6H), 2.09 (m, 2H), 1.98
(m, 2H), 1.26 (m, 1H), 1.12 (brd, 6H), 0.59 (m, 2H), 0.37 (m,
2H)
[2061] Mass Spectral Analysis m/z=447.3 (M+H).sup.+
[2062] Elemental analysis:
[2063] C.sub.28H.sub.34N.sub.2O.sub.3, 1HCl, 1.5H.sub.2O
[2064] Theory: % C, 65.93; % H, 7.51; % N, 5.49.
[2065] Found: % C, 65.64; % H, 7.29; % N, 5.41.
Example 8D
[2066] 8D was obtained according to a procedure similar to the one
described for 2C, with the following exceptions:
Step 2.1: 2.1 was replaced by 8.1 (see also step 8.1). Step 2.7:
2.8a was replaced by 2.8c (method 2A was used) (see also step
8.7).
[2067] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.78 (brs, 2H),
7.41 (s, 4H), 7.04 (d, 1H), 6.90 (t, 1H), 6.58 (d, 1H), 5.97 (s,
1H), 3.83 (s, 3H), 3.44 (brs, 2H), 3.20 (brm, 6H), 2.08 (m, 2H),
1.97 (m, 2H), 1.12 (brd, 6H)
[2068] Mass Spectral Analysis m/z=407.3 (M+H).sup.+
[2069] Elemental analysis:
[2070] C.sub.25H.sub.30N.sub.2O.sub.3, 1HCl, 1H.sub.2O
[2071] Theory: % C, 65.14; % H, 7.22; % N, 6.08.
[2072] Found: % C, 65.22; % H, 6.85; % N, 6.02.
Example 8E
[2073] 8E was obtained according to a procedure similar to the one
described for 2C, with the following exceptions:
Step 2.1: 2.1 was replaced by 8.1 (see also step 8.1). Step 2.4:
1.6 was replaced by 1.7 (see also step 8.4).
[2074] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.94 (brm, 2H),
8.59 (d, 1H), 7.88 (dd, 1H), 7.60 (d, 1H), 7.03 (d, 1H), 6.88 (t,
1H), 6.56 (d, 1H), 6.11 (s, 1H), 3.91 (d, 2H), 3.47 (q, 2H0, 3.29
(m, 4H), 3.17 (m, 2H), 2.10 (m, 2H), 2.01 (m, 2H), 1.26 (m, 1H),
1.17 (t, 3H), 1.11 (t, 3H), 0.59 (m, 2H), 0.37 (m, 2H)
[2075] Mass Spectral Analysis m/z=448.3 (M+H).sup.+
[2076] Elemental analysis:
[2077] C.sub.27H.sub.33N.sub.3O.sub.3, 1.2HCl, 0.8H.sub.2O
[2078] Theory: % C, 64.12, % H, 7.14; % N, 8.31; % Cl, 8.41.
[2079] Found: % C, 64.09; % H, 7.20; % N, 8.18; % Cl, 8.15.
Example 8F
[2080] 8F was obtained according to a procedure similar to the one
described for 2C, with the following exceptions:
Step 2.1: 2.1 was replaced by 8.1 (see also step 8.1). Step 2.4:
1.6 was replaced by 1.7 (see also step 8.4). Step 2.7: 2.8a was
replaced by 2.8c (see also step 8.7).
[2081] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.96 (brm, 2H),
8.59 (d, 1H), 7.88 (dd, 1H), 7.60 (d, 1H), 7.06 (d, 1H), 6.92 (t,
1H), 6.56 (d, 1H), 6.12 (s, 1H), 3.84 (S, 3H), 3.47 (q, 2H), 3.28
(m, 4H), 3.14 (m, 2H), 2.09 (m, 2H), 2.02 (m, 2H), 1.17 (t, 3H),
1.11 (t, 3H)
[2082] Mass Spectral Analysis m/z=408.4 (M+H).sup.+
[2083] Elemental analysis:
[2084] C.sub.24H.sub.29N.sub.3O.sub.3, 2HCl, 1.5H.sub.2O
[2085] Theory: % C, 56.81; % H, 6.75; % N, 8.28; % Cl, 13.97.
[2086] Found: % C, 56.80; % H, 6.48; % N, 8.24; % Cl, 13.89.
Example 9A
[2087] 9A was obtained according to a procedure similar to the one
described for 2C, with the following exception:
Step 2.1: 2.1 was replaced by 9.1 (see also step 9.1).
[2088] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.68 (brd, 2H),
7.41 (d, 2H), 7.35 (d, 2H), 6.92 (d, 1H), 6.43 (s, 1H), 6.37 (d,
1H), 5.44 (s, 1H), 3.80 (d, 2H), 3.56 (brs, 2H), 3.40 (brs, 4H),
3.30 (brs, 2H), 2.30 (m, 2H), 2.19 (m, 2H), 1.27 (m, 4H), 1.17
(brs, 3H), 0.66 (m, 2H), 0.36 (m, 2H)
[2089] Mass Spectral Analysis m/z=447.3 (M+H).sup.+
[2090] Elemental analysis:
[2091] C.sub.28H.sub.34N.sub.2O.sub.3, 1.0HCl, 1.3H.sub.2O
[2092] Theory: % C, 66.40; % H, 7.48; % N, 5.53.
[2093] Found: % C, 66.28; % H, 7.48; % N, 5.48.
Example 9B
Preparation of 9.5
[2094] 9.5 was obtained according to a procedure similar to the one
described for 2.7a except 2.1 was replaced by 9.1 in step 2.1 (see
also step 9.1).
Preparation of 9.8
[2095] To a solution of 9.5 (1.00 g, 2.02 mmol, 1.0 eq) in
dimethylformamide (10 mL) was added sequentially cesium carbonate
(3.30 g, 10.1 mmol, 5.0 eq) and methyl chlorodifluoroacetate (9.7)
(1.47 g, 10.1 mmol, 5.0 eq.). The reaction mixture was heated at
90.degree. C. for 48 h, poured into water (100 mL) and extracted
with ethyl acetate. The organic extracts were washed with a 1N
aqueous solution of sodium hydroxide and brine, dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography (eluent:
hexane:ethyl acetate mixtures of increasing polarity).
[2096] Yield: 79%
[2097] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41 (d, 2H), 7.36
(d, 2H), 6.98 (d, 1H), 6.73 (d, 1H), 6.61 (dd, 1H), 6.52 (ts, 1H,
J=73.8 Hz), 5.54 (s, 1H), 3.86 (brs, 2H), 3.57 (brm, 2H), 3.32
(brm, 4H), 2.03 (d, 2H), 1.68 (m, 2H), 1.47 (s, 9H) 1.20 (brd,
6H)
[2098] Mass Spectral Analysis m/z=543.4 (M+H).sup.+
Preparation of 9B
[2099] To a solution of 9.8 (860 mg, 1.58 mmol, 1.0 eq) in
anhydrous methanol (15 mL) was added drop wise a 4.0M solution of
hydrochloric acid in dioxane (4.0 mL, 15.8 mmol, 10.0 eq). The
mixture was stirred at ambient temperature for 16 h and the solvent
was evaporated under vacuum. The crude oil was purified by reverse
phase HPLC chromatography (eluent: acetonitrile/water (0.1%
trifluoroacetic acid) mixtures of decreasing polarity). The solvent
was evaporated under vacuum and a 1N solution of HCl in diethyl
ether (25 mL) was added. The resulting solid was filtered and
washed with diethyl ether.
[2100] Yield: 23%
[2101] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.42 (d, 2H), 7.35
(d, 2H), 7.02 (d, 1H), 6.75 (m, 1H), 6.66 (dd, 1H), 6.54 (ts, 1H,
J=73.4 Hz), 5.59 (s, 1H), 3.57 (brs, 2H), 3.41 (brd, 4H), 3.31
(brs, 2H), 2.26 (m, 4H), 1.21 (brd, 6H)
[2102] Mass Spectral Analysis m/z=443.4 (M+H).sup.+
[2103] Elemental analysis:
[2104] C.sub.28H.sub.34N.sub.2O.sub.3, 1.0HCl, 1.2H.sub.2O
[2105] Theory: % C, 59.99; % H, 6.32; % N, 5.60.
[2106] Found: % C, 60.01; % H, 6.25; % N, 5.54.
Example 10A
[2107] 10A was obtained from 9.5 according to a procedure similar
to the one described for 3A, with the following exception:
Step 3.1: 2.7a was replaced by 9.5 (see also step 10.1).
[2108] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.80 (brs, 1H),
7.60 (s, 1H), 7.58 (d, 1H), 7.42 (d, 2H), 7.36 (d, 2H), 7.09 (d,
1H), 5.75 (s, 1H), 3.91 (s, 3H), 3.61 (brs, 2H), 3.40 (m, 4H), 3.30
(brs, 2H), 2.27 (m, 4H), 1.20 (brd, 6H)
[2109] Mass Spectral Analysis m/z=435.3 (M+H).sup.+
[2110] Elemental analysis:
[2111] C.sub.26H.sub.30N.sub.2O.sub.4, 1HCl, 1.1H.sub.2O
[2112] Theory: % C, 63.63; % H, 6.82; % N, 5.71.
[2113] Found: % C, 63.64; % H, 6.75; % N, 5.72.
Example 10B
[2114] 10B was obtained according to a procedure similar to the one
described for 3B, with the following exception:
Step 3.1: 2.7a was replaced by 9.5 (see also step 10.1).
[2115] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.10 (brs, 1H),
9.10 (brm, 2H), 7.57 (d, 1H), 7.52 (dd, 1H), 7.44 (s, 4H), 7.12 (d,
1H), 6.09 (s, 1H), 3.45 (brs, 2H), 3.35 (brm, 2H), 3.23 (brm, 4H),
2.08 (m, 4H), 1.10 (brd, 6H)
[2116] Mass Spectral Analysis m/z=421.3 (M+H).sup.+
Example 10C
[2117] 10C was obtained according to a procedure similar to the one
described for 3E, with the following exceptions:
Step 3.5: 3.3a was replaced by 10.3 and 3.4b was replaced by 3.4a
(see also step 10.5).
[2118] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.50 (brd, 2H),
7.64 (brm, 2H), 7.32 (brm, 5H), 7.00 (brs, 2H), 5.68 (s, 1H), 3.50
(brm, 4H), 3.27 (brm, 4H), 2.62 (brs, 2H), 2.19 (brs, 2H), 1.17
(brd, 6H)
[2119] Mass Spectral Analysis m/z=420.3 (M+H).sup.+
Example 10D
Preparation of 10.2
[2120] Compound 10.2 was obtained according to a procedure similar
to the one described for 3.2a except 2.7a was replaced by 9.5 in
step 3.1 (see also step 10.1).
Preparation of 10.4
[2121] To a solution of a 2N solution of methylamine (3.4b) in
methanol (10.0 mL, 20.0 mmol, 1.0 eq) was added portionwise at room
temperature 10.2 (1.00 g, 1.86 mmol) in a sealed tube. The mixture
was heated at 60.degree. C. for 20 h to form a homogeneous
solution. The mixture was poured into water (25 mL), extracted with
methylene chloride, washed with brine, dried over sodium sulfate,
filtered and evaporated solvent to an off-white solid. The crude
product was purified by column chromatography (eluent: hexane/ethyl
acetate mixtures of increasing polarity).
[2122] Yield: 80%
[2123] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.53 (s, 1H), 7.47
(s, 1H), 7.45 (d, 2H), 7.23 (d, 1H), 7.04 (d, 1H), 6.20 (brs, 1H),
5.64 (s, 1H), 3.88 (brs, 2H), 3.57 (brm, 2H), 3.33 (brm, 4H), 3.00
(d, 3H), 2.03 (d, 2H), 1.68 (brm, 2H), 1.45 (s, 9H) 1.21 (brd,
6H)
[2124] Mass Spectral Analysis m/z=534.4 (M+H).sup.+
Preparation of 10D
[2125] To a solution of 10.4a (790 mg, 1.48 mmol, 1.0 eq) in
anhydrous methanol (20 mL) was added drop wise a 4M solution of
hydrochloric acid in dioxane (3.7 mL, 14.8 mmol, 10.0 eq). The
mixture was stirred at ambient temperature for 16 h and the solvent
evaporated under vacuum to a white solid. The white solid was
triturated in diethyl ether (50 mL). The resulting solid was
collected by filtration and washed with diethyl ether.
[2126] Yield: 85%
[2127] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.43 (m, 3H), 7.34
(m, 3H), 7.05 (d, 1H), 6.90 (brd, 1H), 5.69, (s, 1H), 3.57 (brm,
2H), 3.35 (brm, 6H), 3.00 (d, 3H), 2.20 (brs, 4H), 1.19 (brd,
6H)
[2128] Mass Spectral Analysis m/z=434.3 (M+H).sup.+
[2129] Elemental analysis:
[2130] C.sub.26H.sub.31N.sub.3O.sub.3, 1.0HCl, 1.5H.sub.2O
[2131] Theory: % C, 62.83; % H, 7.10; % N, 8.45.
[2132] Found: % C, 62.74; % H, 6.95; % N, 8.29.
Example 10E
[2133] 10E was obtained according to a procedure similar to the one
described for 3E, with the following exceptions:
Step 3.5: 3.3a was replaced by 10.3 and 3.4b was replaced by 3.4c
(see also step 10.5) (method 10A was used).
[2134] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.68 (brs, 2H),
7.43 (m, 3H), 7.34 (m, 3H), 7.06 (d, 1H), 6.61 (brs, 1H), 5.68 (s,
1H), 3.57 (brs, 2H), 3.50 (brm, 2H), 3.40 (brs, 2H), 3.32 (brs,
2H), 2.25 (brs, 4H), 1.28 (brm, 6H), 1.15 (brs, 3H)
[2135] Mass Spectral Analysis m/z=448.3 (M+H).sup.+
Example 10F
[2136] 10F was obtained according to a procedure similar to the one
described for 3E, with the following exceptions:
Step 3.5: 3.3a was replaced by 10.3 and 3.4b was replaced by 3.4j
(see also step 10.5) and TBTU was replaced by HATU (method 10B was
used).
[2137] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.77 (brm, 2H),
7.42 (d, 2H), 7.36 (d, 2H), 7.08 (d, 1H), 7.03 (s, 1H), 6.97 (d,
1H), 5.66 (s, 1H), 3.59 (brs, 2H), 3.40 (brs, 4H), 3.32 (brs, 2H),
3.12 (s, 3H), 3.04 (s, 3H), 2.28 (m, 4H), 1.20 (brd, 6H)
[2138] Mass Spectral Analysis m/z=448.3 (M+H).sup.+
[2139] Elemental analysis:
[2140] C.sub.27H.sub.33N.sub.3O.sub.3, 1HCl, 1.7H.sub.2O
[2141] Theory: % C, 63.01; % H, 7.32; % N, 8.16.
[2142] Found: % C, 63.06; % H, 7.18; % N, 8.09.
Example 10G
[2143] 10G was obtained according to a procedure similar to the one
described for 3E, with the following exceptions:
Step 3.5: 3.3a was replaced by 10.3 and 3.4b was replaced by 1.12
(see also step 10.5) (method 10A was used).
[2144] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.73 (brs, 2H),
7.43 (d, 2H), 7.36 (d, 2H), 7.07 (d, 1H), 6.98 (s, 1H), 6.92 (d,
1H), 5.67 (s, 1H), 3.56 (brs, 4H), 3.40 (brs, 4H), 3.31 (brs, 4H),
2.26 (brs, 4H), 1.22 (brd, 12H)
[2145] Mass Spectral Analysis m/z=476.2 (M+H).sup.+
[2146] Elemental analysis:
[2147] C.sub.29H.sub.37N.sub.3O.sub.3, 1HCl, 1.7H.sub.2O
[2148] Theory: % C, 64.18; % H, 7.69; % N, 7.74.
[2149] Found: % C, 64.08; % H, 7.45; % N, 7.60.
Example 10H
[2150] 10H was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.3a was replaced by 10.3 and 3.4b was replaced by 3.4k
(see also step 10.5) (method 10A was used).
[2151] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.77 (brs, 2H),
7.43 (d, 2H), 7.37 (d, 2H), 7.12 (s, 1H), 7.09 (s, 2H), 5.68 (s,
1H), 3.64 (m, 2H), 3.60 (brm, 2H), 3.47 (m, 2H), 3.40 (brm, 4H),
3.30 (brs, 2H), 2.30 (brs, 4H), 2.00 (m, 2H), 1.93 (m, 2H), 1.24
(brd, 6H)
[2152] Mass Spectral Analysis m/z=474.3 (M+H).sup.+
[2153] Elemental analysis:
[2154] C.sub.29H.sub.35N.sub.3O.sub.3, 1HCl, 0.7H.sub.2O
[2155] Theory: % C, 66.64; % H, 7.21; % N, 8.04.
[2156] Found: % C, 66.56; % H, 7.07; % N, 7.91.
Example 10I
[2157] 10I was obtained according to a procedure similar to the one
described for 3E, with the following exception:
Step 3.5: 3.3a was replaced by 10.3 and 3.4b was replaced by 3.4c
(see also step 10.5) (method 10A was used).
[2158] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.70 (brs, 2H),
7.44 (d, 2H), 7.35 (d, 2H), 7.09 (d, 1H), 7.02 (s, 1H), 6.96 (dd,
1H), 5.68 (s, 1H), 3.73 (brm, 6H), 3.58 (brs, 4H), 3.41 (brim, 4H),
3.31 (brs, 2H), 2.28 (m, 4H), 1.21 (m, 6H)
[2159] Mass Spectral Analysis m/z=490.2 (M+H).sup.+
Example 10J
Preparation of 10.5
[2160] To a slurry of LiBH.sub.4 (82.0 mg, 3.75 mmol, 2.0 eq.) in
tetrahydrofuran (20 mL) cooled to 0.degree. C. under a nitrogen
atmosphere was added drop wise a solution of 10.2 (1.00 g, 1.87
mmol, 1.0 eq) in tetrahydrofuran (10 mL). The reaction mixture was
warmed to room temperature and stirred for 16 h at room
temperature. The reaction mixture was quenched with water (0.54 mL,
8 eq.), extracted with ethyl acetate, washed with brine, dried over
sodium sulfate and filtered. The solvent was removed under vacuum
and the crude product was purified by column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity).
[2161] Yield: 49%
[2162] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.40 (d, 2H), 7.36
(d, 2H), 6.98 (m, 2H), 6.85 (d, 1H), 5.56 (s, 1H), 4.65 (s, 2H),
3.87 (brs, 2H), 3.57 (brs, 2H), 3.32 (brm, 4H), 2.05 (d, 2H), 1.91
(brt, 1H), 1.66 (m, 2H), 1.48 (s, 9H) 1.21 (brd, 6H)
[2163] Mass Spectral Analysis m/z=507.3 (M+H).sup.+
Preparation of 10J
[2164] To a solution of 10.5 (460 mg, 0.91 mmol, 1.0 eq) in
anhydrous methanol (30 mL) was added drop wise a 4M solution of
hydrochloric acid in dioxane (2.3 mL, 9.1 mmol, 10.0 eq). The
mixture was stirred at room temperature for 16 h and the solvent
was evaporated under vacuum. The residue was triturated in ethyl
ether (50 mL); the solid was collected by filtration and washed
with diethyl ether. The crude product was purified by column
chromatography (eluent: methylene chloride/methanol mixtures of
increasing polarity).
[2165] Yield: 46%
[2166] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.62 (brs, 2H),
7.38 (brd, 4H), 7.00 (m, 2H), 6.90 (brd, 1H), 5.60, (brs, 1H), 4.66
(brs, 2H), 3.58 (brm, 2H), 3.40 (brm, 4H), 3.31 (brm, 2H), 2.50
(brs, 1H), 2.25 (brs, 4H), 1.21 (brd, 6H)
[2167] Mass Spectral Analysis m/z=407.4 (M+H).sup.+
[2168] Elemental analysis:
[2169] C.sub.26H.sub.31N.sub.3O.sub.3, 1HCl, 0.7H.sub.2O
[2170] Theory: % C, 65.91; % H, 7.17; % N, 6.15.
[2171] Found: % C, 65.93; % H, 6.99; % N, 6.08.
Example 11A
Preparation of 11.2
[2172] 2',6'-hydroxyacetophenone (11.1) (200.0 g, 1.31 mol, 1.0 eq)
was added portion wise at room temperature to pyrrolidine (220 mL,
2.0 eq) followed by portion wise addition of 1-Boc-4-piperidone
(1.2) (262.0 g, 1.31 mo, 1.0 eq). Anhydrous methanol (100 mL) was
then added and the red slurry heated to reflux to dissolve all
solids. On dissolution the reaction was cooled to room temperature
overnight with stirring to form a solid mass. This solid mass was
dissolved in ethyl acetate, washed with a 1N aqueous solution of
hydrochloric acid, a 1N aqueous solution of sodium hydroxide and
brine, dried over sodium sulfate and filtered. The solvent was
evaporated under vacuum. A mixture of hexane and diethyl ether
(80:20) (400 mL) was added to the mixture and the resulting
precipitate was collected by filtration, washed with hexane and
used for the next step without further purification.
[2173] Yield: 74%.
[2174] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.61 (s, 1H),
7.37 (t, 1H), 6.49 (d, 1H), 6.44 (d, 1H), 3.89 (brs, 2H), 3.20
(brm, 2H), 2.73 (s, 2H), 2.02 (d, 2H), 1.64 (m, 2H), 1.46 (s,
9H)
[2175] Mass Spectral Analysis m/z=334.0 (M+H).sup.+
Preparation of 11.4
[2176] To a solution of 11.2 (140.0 g, 0.420 mol, 1.0 eq) in
dichloromethane (700 mL) at ambient temperature under nitrogen was
added drop wise diisopropylethylamine (294.0 mL, 1.68 mol, 4.0 eq).
To this solution was added drop wise chloro(methoxy)methane (11.3)
(100.0 g, 1.26 mol, 3.0 eq). The mixture was heated to reflux for
16 h, cooled to room temperature and the solvent was removed under
vacuum to afford a brown oil. This oil was dissolved in ethyl
acetate (700 mL) and washed with a 1N aqueous solution of
hydrochloric acid, an aqueous saturated solution of sodium
bicarbonate and brine. The organic extracts were dried over sodium
sulfate, filtered and the solvent was removed under vacuum to
afford a brown oil. Diethyl ether (400 mL) was added and the
resulting white precipitate was filtered and used for the next step
without further purification.
[2177] Yield: 83%
[2178] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.36 (t, 1H), 6.74
(d, 1H), 6.65 (d, 1H), 5.27 (s, 2H), 3.86 (brs, 2H), 3.52 (s, 3H),
3.22 (m, 2H), 2.69 (s, 2H), 2.02 (d, 2H), 1.60 (m, 2H), 1.46 (s,
9H)
[2179] Mass Spectral Analysis m/z=378.2 (M+H).sup.+
Preparation of 11.5
[2180] To a solution of 11.4 (131.2 g, 0.348 mol) in
tetrahydrofuran (600 mL) at -78.degree. C. under nitrogen
atmosphere was added drop wise a 1.0M solution of LiHMDS in
tetrahydrofuran (420.0 mL, 1.2 eq). The mixture was stirred for 1 h
at -78.degree. C. A solution of 1.4 (149.4 g, 0.418 mol, 1.2 eq) in
tetrahydrofuran (200 mL) was added drop wise. The mixture was
warmed slowly to room temperature and stirring was continued for a
further 12 h at room temperature. The mixture was then poured into
ice water and the two phases were separated. The organic phase was
washed with a 1N aqueous solution of hydrochloric acid, a 1N
aqueous solution of sodium hydroxide and brine, dried over sodium
sulfate and filtered. The solvent was removed under vacuum and the
tan oily residue was used for the next step without further
purification.
[2181] Yield: 100%
[2182] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.98 (t, 1H), 6.62
(d, 1H), 6.39 (d, 1H), 5.24 (s, 1H), 5.03 (s, 2H), 3.62 (brs, 2H),
3.30 (s, 3H), 3.07 (m, 2H), 1.84 (d, 2H), 1.46 (m, 2H), 1.26 (s,
9H)
[2183] Mass Spectral Analysis m/z=510.0 (M+H).sup.+
Preparation of 11.6a
[2184] To a solution of 11.5 (100 g, 196 mmol, 1.0 eq) in
dimethoxyethane (DME) (600 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (294 mL, 588 mmol, 3.0 eq), lithium
chloride (25.0 g, 588 mmol, 3.0 eq),
4-(N,N-diethylaminocarbonyl)phenylboronic acid) (1.6) (36.9 g, 166
mmol, 1.1 eq) and tetrakis(triphenylphosphine)palladium(0) (4.54 g,
3.92 mmol, 0.02 eq). The mixture was refluxed for 10 h under
nitrogen. The mixture was then cooled to room temperature, filtered
through a celite pad and the filtercake was washed with DME (100
mL) and water (750 mL). The aqueous mixture was extracted with
ethyl acetate. The organic layer was further washed with brine and
dried over sodium sulfate. The crude product was purified by
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[2185] Yield: 62%
[2186] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.21 (d, 2H), 7.17
(d, 2H), 7.05 (t, 1H), 6.60 (m, 2H), 5.45 (s, 1H), 4.58 (s, 2H),
3.71 (brs, 2H), 3.45 (brm, 2H), 3.22 (brm, 4H), 3.06 (s, 3H), 1.90
(d, 2H), 1.56 (m, 2H), 1.38 (s, 9H), 1.09 (brd, 6H)
[2187] Mass Spectral Analysis m/z=537.4 (M+H).sup.+
Preparation of 11A
[2188] To a solution of 11.6a (25.0 g, 46.6 mmol, 1.0 eq) in
anhydrous methanol (250 mL) was added drop wise a 4M solution of
hydrochloric acid in dioxane (58.2 mL, 233 mmol, 5.0 eq). The
mixture was stirred at room temperature for 16 h and the solvent
was evaporated under vacuum to afford a brown oil. Methanol (20 mL)
followed by diethyl ether (300 mL) was added to the brown oil and
the resulting precipitate was collected by filtration and washed
with diethyl ether. The solid was used for the next step without
further purification.
[2189] Yield: 100%
[2190] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.55 (s, 1H),
9.07 (brs, 2H), 7.27 (m, 4H), 7.06 (t, 1H), 6.52 (d, 1H), 6.47 (d,
1H), 5.76 (s, 1H), 3.42 (brm, 2H), 3.35 (s, 4H), 3.19, (brm, 6H),
2.03 (m, 4H), 1.11 (brm, 6H)
[2191] Mass Spectral Analysis m/z=393.0 (M+H).sup.+
[2192] Elemental analysis:
[2193] C.sub.24H.sub.28N.sub.2O.sub.3, 1HCl, 0.67H.sub.2O
[2194] Theory: % C, 65.37; % H, 6.93; % N, 6.35.
[2195] Found: % C, 65.41; % H, 6.98; % N, 6.31.
Example 11B
[2196] 11B was obtained according to a procedure similar to the one
described for 11A, with the following exception:
Step 11.4: 1.6 was replaced by 1.7.
[2197] .sup.1H NMR (400 MHz, DMSO d.sub.6) 9.67 (brs, 1H), 9.23
(brd, 2H), 8.50 (s, 1H), 7.79 (d, 1H), 7.52 (d, 1H), 7.09 (t, 1H),
6.57 (d, 1H), 6.50 (d, 1H), 5.93 (s, 1H), 3.43 (q, 2H), 3.26 (q,
2H), 3.21 (m, 2H), 3.14 (m, 2H), 2.05 (m, 4H), 1.18 (t, 3H), 1.11
(t, 3H)
[2198] Mass Spectral Analysis m/z=394.3 (M+H).sup.+
[2199] Elemental analysis:
[2200] C.sub.23H.sub.27N.sub.3O.sub.3, 2HCl, 1.5H.sub.2O
[2201] Theory: % C, 55.99; % H, 6.54; % N, 8.52.
[2202] Found: % C, 56.11; % H, 6.54; % N, 8.53.
Example 11C
Preparation of 11.7a
[2203] To a slurry of 11A (10.0 g, 23.3 mmol, 1.0 eq) in
tetrahydrofuran (200 mL) under a nitrogen atmosphere was added
triethylamine (9.75 mL, 69.9 mmol, 3.0 eq). The reaction mixture
was cooled to 0.degree. C. A solution of di-tert-butyl dicarbonate
(4.7) (4.58 g, 21.0 mmol, 0.9 eq) in tetrahydrofuran (50 mL) was
added drop wise to the reaction mixture which was stirred for 3 h
at room temperature. The solvent was evaporated under vacuum and
the residue was dissolved in ethyl acetate (500 mL), washed with
water and brine, and dried over sodium sulfate and filtered. The
solvent was evaporated under vacuum. The residue was sonicated and
triturated in a mixture ethyl acetate/methanol 95:5 (75 mL). The
solid was collected by filtration and washed with ethyl
acetate.
[2204] Yield: 100%
[2205] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.49 (s, 1H),
7.31 (s, 4H), 7.08 (t, 1H), 6.54 (d, 1H), 6.47 (d, 1H), 5.77 (s,
1H), 3.70 (m, 2H), 3.48 (brm, 2H), 3.30 (brm, 4H), 1.87 (d, 2H),
1.74 (m, 2H), 1.47 (s, 9H) 1.16 (brs, 6H)
[2206] Mass Spectral Analysis m/z=493.4 (M+H).sup.+
Preparation of 11.9a
[2207] To a solution of 11.7a (1.00 g, 2.02 mmol, 1.0 eq) in
dichloromethane (4 mL) under a nitrogen atmosphere was added
sequentially cyclopropylmethanol (2.8e) (189 mg, 2.63 mmol, 1.3 eq)
and triphenylphosphine (690 mg, 2.63 mmol, 1.3 eq). The reaction
mixture was stirred for 5 min at room temperature and a solution of
diethylazodicarboxylate (460 mg, 2.63 mmol, 1.3 eq) was added drop
wise. The reaction was stirred an additional 30 min at room
temperature and the solvent was evaporated under vacuum. The crude
product was purified by chromatography (eluent: hexane/ethyl
acetate mixtures of increasing polarity).
[2208] Yield: 42%
[2209] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.31 (d, 2H), 7.27
(d, 2H), 7.13 (t, 1H), 6.64 (d, 1H), 6.42 (d, 1H), 5.50 (s, 1H),
3.78 (brd, 2H), 3.54 (brm, 2H), 3.49 (d, 2H), 3.35 (brt, 4H), 2.02
(d, 2H), 1.69 (m, 2H), 1.47 (s, 9H) 1.26 (brd, 6H), 0.53 (m, 1H),
0.29 (m, 2H), -0.07 (m, 2H)
[2210] Mass Spectral Analysis m/z=547.5 (M+H).sup.+
Preparation of 11C
[2211] To a solution of 11.9a (460 mg, 0.84 mmol, 1.0 eq) in
anhydrous methanol (15 mL) was added dropwise a 4M solution of
hydrochloric acid in dioxane (2.0 mL, 8.4 mmol, 10.0 eq). The
mixture was stirred at room temperature for 16 h and the solvent
was evaporated under vacuum. The residue was triturated in diethyl
ether (50 mL). The resulting solid was collected by filtration and
washed with diethyl ether.
[2212] Yield: 97%
[2213] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.67 (brs, 2H),
7.32 (d, 2H), 7.26 (d, 2H), 7.16 (t, 1H), 6.64 (d, 1H), 6.46 (d,
1H), 5.50 (s, 1H), 3.54 (brm, 2H), 3.49 (d, 2H), 3.36 (brm, 6H),
2.28 (d, 2H), 2.18 (m, 2H), 1.19 (brd, 6H), 0.53 (m, 1H), 0.30 (m,
2H), -0.07 (m, 2H)
[2214] Mass Spectral Analysis m/z=447.4 (M+H).sup.+
[2215] Elemental analysis:
[2216] C.sub.28H.sub.34N.sub.2O.sub.3, 1.0HCl, 0.7H.sub.2O
[2217] Theory: % C, 67.73; % H, 7.41; % N, 5.64.
[2218] Found: % C, 67.73; % H, 7.24; % N, 5.59.
Example 11D
[2219] 11D was obtained according to a procedure similar to the one
described for 11C, with the following exceptions:
Step 11.4: 1.6 was replaced by 1.7.
[2220] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.67 (brs, 1H),
8.44 (m, 1H), 7.61 (dd, 1H), 7.55 (d, 1H), 7.19 (t, 1H), 6.64 (d,
1H), 6.43 (d, 1H), 5.55 (s, 1H), 3.56 (q, 2H), 3.50 (d, 2H), 3.46
(q, 2H), 3.38 (m, 4H), 2.29 (m, 2H), 2.21 (m, 2H), 1.28 (t, 3H),
1.17 (t, 3H), 0.54 (m, 1H), 0.33 (m, 2H), -0.05 (m, 2H)
[2221] Mass Spectral Analysis m/z=448.4 (M+H).sup.+
Example 11E
Preparation of 11.9b
[2222] To a solution of 11.7a (1.00 g, 2.02 mmol, 1.0 eq) in
acetone (20 mL) was added sequentially potassium carbonate (1.70 g,
12.1 mmol, 6.0 eq) and bromocyclobutane (11.8) (1.66 g, 12.1 mmol,
6.0 eq). The reaction mixture was refluxed for 90 h, poured into
water (100 mL) and extracted with ethyl acetate. The organic
extracts were washed with a 1N aqueous solution of sodium hydroxide
and brine, dried over sodium sulfate and filtered. The solvent was
evaporated and the crude product was first purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity) and then repurified by reverse phase HPLC chromatography
(eluent: acetonitrile/water (0.1% trifluoroacetic acid) mixtures of
decreasing polarity).
[2223] Yield: 18%
[2224] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.31 (d, 2H), 7.27
(d, 2H), 7.11 (t, 1H), 6.64 (d, 1H), 6.26 (d, 1H), 4.36 (m, 1H),
5.50 (s, 1H), 3.79 (brd, 2H), 3.54 (brm, 2H), 3.48 (d, 2H), 3.34
(brm, 4H), 2.12 (m, 2H), 2.02 (d, 2H), 1.67 (m, 2H), 1.55 (m, 2H),
1.47 (s, 9H) 1.19 (brd, 6H)
[2225] Mass Spectral Analysis m/z=547.5 (M+H).sup.+
Preparation of 11E
[2226] To a solution of 11.9b (200 mg, 0.37 mmol, 1.0 eq) in
anhydrous methanol (25 mL) was added drop wise a 2M solution of
hydrochloric acid in diethyl ether (0.73 mL, 1.44 mmol, 4.0 eq).
The mixture was stirred at room temperature for 16 h and the
solvent was evaporated under vacuum. The residue was triturated in
diethyl ether (50 mL). The solid was collected by filtration and
washed with diethyl ether.
[2227] Yield: 96%
[2228] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.14 (brs, 2H),
7.29 (d, 2H), 7.24 (d, 2H), 7.19 (t, 1H), 6.68 (d, 1H), 6.42 (d,
1H), 5.79 (s, 1H), 4.43 (m, 1H), 3.40 (brm, 4H), 3.35 (brs, 4H),
3.17 (brm, 4H), 2.10 (m, 2H), 2.03 (m, 2H), 1.45 (m, 2H), 1.11 (m,
6H)
[2229] Mass Spectral Analysis m/z=447.3 (M+H).sup.+
Example 11F
[2230] 11F was obtained according to a procedure similar to the one
described for 11C, with the following exceptions:
Step 11.4: 1.6 was replaced by 1.7. Step 11.7: 2.8e was replaced by
11.10.
[2231] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.71 (brd, 2H),
8.40 (s, 1H), 7.56 (m, 2H), 7.18 (t, 1H), 6.62 (d, 1H), 6.48 (d,
1H), 5.50 (s, 1H), 4.50 (m, 1H), 3.58 (m, 2H), 3.48 (m, 2H), 3.38
(brs, 4H), 2.30 (d, 2H), 2.22 (brs, 2H), 1.64 (m, 2H), 1.36 (m,
2H), 1.30 (m, 5H), 1.19 (m, 5H)
[2232] Mass Spectral Analysis m/z=462.4 (M+H).sup.+
Example 12A
Preparation of 12.1
[2233] To a solution of compound 11.2 (3.33 g, 10 mmol) in
anhydrous methylene chloride (100 mL) was added sequentially
triethylamine (3.48 mL, 25 mmol, 2.5 eq), 4-dimethylaminopyridine
(122 mg, 1 mmol, 0.1 eq) and N-phenyltrifluoromethanesulfonimide
(1.4) (4.48 g, 12.5 mmol, 1.25 eq). The reaction mixture was
stirred at room temperature for 24 h, washed with a saturated
aqueous solution of sodium bicarbonate, dried over sodium sulfate
and filtered. The solvent was evaporated under vacuum and the
residue was purified by column chromatography (eluent: hexane/ethyl
acetate, 3:1).
[2234] Yield: 92.5%
[2235] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.52 (t, 1H),
7.09 (d, 1H), 6.88 (d, 1H), 3.90 (m, 2H), 3.21 (m, 2H), 2.80 (s,
2H), 2.03 (m, 2H), 1.63 (m, 2H), 1.48 (s, 9H)
Preparation of 12.3
[2236] To a solution of 12.1 (5.4 g, 11.6 mmol) in tetrahydrofuran
(100 mL) at room temperature was added
tetrakis(triphenylphosphine)palladium(0) (670 mg, 0.58 mmol, 0.05
eq) followed by drop wise addition of a 2.0 M solution of
methylzinc chloride (12.2a) in tetrahydrofuran (10 mL, 20 mmol,
1.72 eq). The mixture was stirred at room temperature for 2 days.
The reaction mixture was then quenched with a saturated aqueous
solution of ammonium chloride and extracted with ethyl acetate. The
organic layer was washed with brine and dried over sodium sulfate.
The solvent was evaporated under vacuum and the crude product was
purified by column chromatography (eluent: hexane/ethyl acetate,
4:1).
[2237] Yield: 80.6%
[2238] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30 (t, 1H), 6.86
(d, 1H), 6.80 (d, 1H), 3.88 (m, 2H), 2.70 (s, 2H), 2.60 (s, 3H),
2.00 (m, 2H), 1.60 (m, 2H), 1.45 (s, 9H)
Preparation of 12.4
[2239] To a solution of 12.3 (2.8 g, 8.46 mmol) in anhydrous
tetrahydrofuran (80 mL) at -78.degree. C. under nitrogen was added
drop wise a 1.0 M solution of LiHMDS in tetrahydrofuran (11 mL, 11
mmol, 1.1 eq). The reaction mixture was stirred for 45 min at
-78.degree. C. A solution of N-phenyltrifluoromethanesulfonimide
(1.4) (3.95 g, 11 mmol, 1.1 eq) in tetrahydrofuran (15 mL) was
added drop wise to the reaction mixture. The mixture was warmed
slowly to room temperature and stirring was continued for a further
3 h at room temperature. The mixture was then poured into ice water
and extracted with a mixture of hexane and diethyl ether (1:1). The
organic layer was washed with water and brine, and dried over
sodium sulfate and filtered. The organics were concentrated under
vacuum and the crude product was purified by column chromatography
(eluent: hexane/ethyl acetate, 6:1).
[2240] Yield: 61.3%
[2241] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.11 (t, 1H), 6.80
(m, 2H), 3.82 (m, 2H), 3.29 (m, 2H), 2.50 (s, 3H), 2.03 (m, 2H),
1.68 (m, 2H), 1.48 (s, 9H)
Preparation of 12.5
[2242] To a solution of 12.4 (848 mg, 1.83 mmol) in dimethoxyethane
(DME) (16 mL) was added sequentially a 2 N aqueous solution of
sodium carbonate (3.1 mL, 6.2 mmol, 3.4 eq), lithium chloride (259
mg, 6.1 mmol, 3.3 eq), 4-(N,N-diethylaminocarbonyl)phenylboronic
acid (1.6) (486 mg, 2.2 mmol, 1.2 eq) and
tetrakis(triphenylphosphine)palladium(0) (64 mg, 0.055 mmol, 0.03
eq). The mixture was refluxed overnight under nitrogen. The mixture
was then cooled to room temperature and water (20 mL) was added.
The mixture was extracted with ethyl acetate. The organic layer was
further washed with brine, dried over sodium sulfate, filtered and
concentrated under vacuum. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate, 1:1).
[2243] Yield: 96.9%
[2244] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.36 (d, 2H), 7.26
(d, 2H), 7.10 (t, 1H), 6.86 (d, 1H), 6.70 (d, 1H), 5.60 (s, 1H),
3.80 (m, 2H), 3.55 (m, 2H), 3.30 (m, 4H), 2.00 (m, 2H), 1.74 (s,
3H), 1.65 (m, 2H), 1.49 (s, 9H), 1.20 (m, 6H)
Preparation of 12A
[2245] To a solution of 12.5 (860 mg, 1.76 mmol) in methylene
chloride (10 mL) was added a 2.0 M solution of anhydrous
hydrochloric acid in diethyl ether (30 mL). The mixture was stirred
at room temperature for 24 h and diethyl ether was added. The
resulting precipitate was collected by filtration and washed with
diethyl ether.
[2246] Yield: 97.8%
[2247] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.99 (m, 2H),
7.38 (d, 2H), 7.29 (d, 2H), 7.18 (t, 1H), 6.93 (d, 1H), 6.80 (d,
1H), 5.95 (s, 1H), 3.45 (m, 2H), 3.20 (m, 6H), 2.00 (m, 4H), 1.70
(s, 3H), 1.10 (m, 6H)
[2248] Mass Spectral Analysis m/z=391.4 (M+H).sup.+
[2249] Elemental analysis:
[2250] C.sub.24H.sub.28N.sub.2O.sub.2, 1HCl, 1/2H.sub.2O
[2251] Theory: % C, 68.87; % H, 7.40; % N, 6.43.
[2252] Found: % C, 68.99; % H, 7.33; % N, 6.39.
Example 12B
Preparation of 12.6
[2253] To a solution of 12.1 (14.4 g, 31 mmol) in
N,N-dimethylformamide was added sequentially methanol (50 mL),
triethylamine (7 mL, 50 mmol, 1.6 eq),
1,3-bis(diphenylphosphino)propane (dppp) (1.04 g, 2.5 mmol, 0.08
eq) and palladium (II) acetate (565 mg, 2.5 mmol, 0.08 eq). The
carbon monoxide was then bubbled through the reaction solution
while the mixture was heated to 65-70.degree. C. for 3.5 h. The
reaction mixture was cooled to room temperature, diluted with
diethyl ether and washed with water and brine. The organic layer
was dried over sodium sulfate, filtered and concentrated under
vacuum. The crude product was purified by column chromatography
(eluent: hexane/ethyl acetate, 4:1).
[2254] Yield: 87.9%
[2255] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.50 (t, 1H), 7.10
(d, 1H), 6.99 (d, 1H), 3.94 (s, 3H), 3.90 (m, 2H), 3.21 (m, 2H),
2.73 (s, 2H), 2.05 (m, 2H), 1.63 (m, 2H), 1.48 (s, 9H)
Preparation of 12.11
[2256] To a solution of 12.6 (13.2 g, 35.2 mmol) in anhydrous
tetrahydrofuran (300 mL) at -78.degree. C. was added drop wise a
1.0 M solution of LiHMDS in tetrahydrofuran (42 mL, 42 mmol, 1.2
eq) under nitrogen. The reaction mixture was stirred for 45 min at
-78.degree. C. A solution of N-phenyltrifluoromethanesulfonimide
(1.4) (15.1 g, 42 mmol, 1.2 eq) in tetrahydrofuran (60 mL) was
added drop wise to the reaction mixture. The mixture was warmed
slowly to room temperature and stirred for 3 h. The mixture was
then poured into ice water and extracted with a mixture of hexane
and diethyl ether (1:1). The organic layer was washed with water
and brine, dried over sodium sulfate and filtered. The organics
were concentrated under vacuum and the crude product was purified
by column chromatography (eluent: hexane/ethyl acetate, 4:1).
[2257] Yield: 90.2%
[2258] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.32 (d, 1H), 7.26
(t, 1H), 7.10 (d, 1H), 5.70 (s, 1H), 3.90 (s, 3H), 3.83 (m, 2H),
3.30 (m, 2H), 2.10 (m, 2H), 1.77 (m, 2H), 1.48 (s, 9H)
Preparation of 12.12
[2259] To a solution of 12.11 (16 g, 31.6 mmol) in dimethoxyethane
(DME) (260 mL) was added sequentially a 2 N aqueous solution of
sodium carbonate (53 mL, 106 mmol, 3.4 eq), lithium chloride (4.5
mg, 106 mmol, 3.4 eq.), 4-(N,N-diethylaminocarbonyl)phenylboronic
acid (1.6) (8.4 g, 38 mmol, 1.2 eq) and
tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.95 mmol, 0.03
eq). The mixture was refluxed overnight under nitrogen and then
cooled to room temperature. Water (300 mL) was added to the mixture
and the crude product was extracted with ethyl acetate. The organic
layer was further washed with brine, dried over sodium sulfate and
filtered. The organics were concentrated under vacuum and the crude
product was purified by column chromatography (eluent: hexane/ethyl
acetate, 1:1).
[2260] Yield: 98.5%
[2261] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.33 (d, 2H), 7.25
(m, 4H), 7.15 (d, 1H), 5.72 (s, 1H), 3.85 (m, 2H), 3.53 (m, 2H),
3.32 (m, 4H), 3.10 (s, 3H), 2.06 (m, 2H), 1.76 (m, 2H), 1.50 (s,
9H), 1.20 (m, 6H)
Preparation of 12.13
[2262] To a suspension of potassium tert-butoxide (9 g, 80 mmol,
8.0 eq) in diethyl ether (200 mL) was added drop wise water (0.72
mL, 40 mmol, 4.0 eq) at 0.degree. C. The slurry was stirred for 30
min. To this mixture was added 12.12 (5.34 g, 10 mmol). The
ice-bath was removed and the reaction mixture was stirred at room
temperature overnight and quenched by addition of ice water. The
aqueous layer was separated, acidified to pH 2-3 with a 1N aqueous
solution of hydrochloric acid and extracted with methylene
chloride. The organic layers were combined, dried over sodium
sulfate and concentrated under vacuum. The crude product was used
for the next step without further purification.
[2263] Yield: 86.9%
[2264] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 12.55 (brs, 1H),
7.23 (m, 7H), 5.98 (s, 1H), 3.68 (m, 2H), 3.42-3.20 (m, 6H), 1.80
(m, 4H), 1.42 (s, 9H), 1.10 (m, 6H)
Preparation of 12B
[2265] To a solution of 12.13 (300 mg, 0.58 mmol) in methylene
chloride (4 mL) was added a 2.0 M solution of anhydrous
hydrochloric acid in diethyl ether (15 mL). The mixture was stirred
at room temperature for 24 h and diluted with diethyl ether. The
resulting precipitate was collected by filtration and washed with
diethyl ether.
[2266] Yield: 95%
[2267] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 12.61 (brs, 1H),
8.69 (m, 6H), 7.38-7.25 (m, 7H), 6.06 (s, 1H), 3.41 (m, 2H), 3.25
(m, 6H), 2.06 (m, 4H), 1.11 (m, 6H)
[2268] Mass Spectral Analysis m/z=421.3 (M+H).sup.+
Example 12C
Preparation of 12.14a
[2269] To a solution of 12.13 (780 mg, 1.5 mmol) in acetonitrile
(50 mL) was added sequentially diisopropylethylamine (1.75 mL, 10
mmol, 6.7 eq), a 0.5 M solution of ammonia (12.15) in dioxane (30
mL, 15 mmol, 10 eq) and TBTU (580 mg, 1.8 mmol, 1.2 eq). The
reaction mixture was stirred at room temperature for 3 days and
then concentrated under vacuum. The residue was dissolved in ethyl
acetate and washed with a saturated aqueous solution of sodium
bicarbonate. The organic layer was dried over sodium sulfate,
filtered and concentrated under vacuum. The crude product was
purified by column chromatography (eluent: hexane/acetone,
1:1).
[2270] Yield: 60.4%
[2271] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.51 (s, 1H),
7.29 (t, 1H), 7.22 (s, 4H), 7.10 (d, 1H), 7.05 (d, 1H), 6.97 (s,
1H), 5.90 (s, 1H), 3.63 (m, 2H), 3.41 (m, 2H), 3.32 (m, 2H), 3.20
(m, 2H), 1.80 (m, 4H), 1.42 (s, 9H), 1.10 (m, 6H)
Preparation of 12C
[2272] To a solution of 12.14a (420 mg, 0.81 mmol) in methylene
chloride (6 mL) was added a 2.0 M solution of anhydrous
hydrochloric acid in diethyl ether (20 mL). The mixture was stirred
at room temperature for 2 days and diluted with diethyl ether. The
resulting precipitate was collected by filtration and washed with
diethyl ether.
[2273] Yield: 87.5%
[2274] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.21 (m, 2H),
7.54 (s, 1H), 7.32-7.10 (m, 7H), 6.88 (s, 1H), 5.98 (s, 1H), 3.42
(m, 2H), 3.20 (m, 6H), 2.10 (m, 4H), 1.10 (m, 6H)
[2275] Mass Spectral Analysis m/z=420.3 (M+H).sup.+
Example 12D
[2276] 12D was obtained according to a procedure similar to the one
described for 12C, with the following exception:
Step 12.16: 12.15 was replaced by 3.4b.
[2277] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.19 (m, 2H),
7.83 (m, 1H), 7.30-7.20 (m, 6H), 7.00 (d, 1H), 5.96 (s, 1H), 3.41
(m, 2H), 3.20 (m, 6H), 2.11 (m, 4H), 2.06 (d, 3H), 1.10 (m, 6H)
[2278] Mass Spectral Analysis m/z=434.3 (M+H).sup.+
Example 12E
[2279] 12E was obtained according to a procedure similar to the one
described for 12C, with the following exception:
Step 12.16: 12.15 was replaced by 3.4c.
[2280] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.18 (m, 2H),
7.90 (t, 1H), 7.30-7.20 (m, 6H), 7.00 (d, 1H), 5.96 (s, 1H), 3.40
(m, 2H), 3.20 (m, 6H), 2.50 (m, 2H), 2.10 (m, 4H), 1.10 (m, 6H),
0.78 (t, 3H)
[2281] Mass Spectral Analysis m/z=448.4 (M+H).sup.+
[2282] Elemental analysis:
[2283] C.sub.27H.sub.33N.sub.3O.sub.3, 5/4H.sub.2O
[2284] Theory: % C, 68.99; % H, 7.61; % N, 8.94.
[2285] Found: % C, 69.27; % H, 7.43; % N, 8.93.
Example 12F
[2286] 12 F was obtained according to a procedure similar to the
one described for 12C, with the following exception:
Step 12.16: 12.15 was replaced by 3.4d.
[2287] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.98 (m, 2H),
7.91 (t, 1H), 7.31 (m, 1H), 7.20 (m, 5H), 7.00 (m, 1H), 5.96 (s,
1H), 3.45 (m, 4H), 3.20 (m, 6H), 2.40 (m, 2H), 2.08 (m, 4H), 1.10
(m, 6H), 0.70 (t, 3H)
[2288] Mass Spectral Analysis m/z=462.4 (M+H).sup.+
[2289] Elemental analysis:
[2290] C.sub.28H.sub.35N.sub.3O.sub.3, 1HCl, 7/3H.sub.2O
[2291] Theory: % C, 62.27; % H, 7.59; % N, 7.78.
[2292] Found: % C, 62.37; % H, 7.23; % N, 7.74.
Example 12G
Preparation of 12.7
[2293] To a solution of 12.6 (2.25 g, 6 mmol) in a mixed solvent of
methanol (40 mL), tetrahydrofuran (40 mL) and water (40 mL) was
added lithium hydroxide (1.52 g, 36.2 mmol, 6-0 eq) in one portion.
The reaction mixture was stirred at room temperature overnight. The
mixture was concentrated under vacuum and extracted with diethyl
ether. The aqueous phase was acidified to pH 2-3 using a 1 N
aqueous solution of hydrochloric acid. The acidified solution was
extracted with methylene chloride. The organics were combined,
dried over sodium sulfate, filtered and concentrated under vacuum.
The crude product was used in the next step without further
purification.
[2294] Yield: 100%
[2295] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 12.93 (brs, 1H),
7.59 (t, 1H), 7.15 (d, 1H), 6.97 (d, 1H), 3.71 (m, 2H), 3.12 (m,
2H), 1.90 (m, 2H), 1.65 (m, 2H), 1.40 (s, 9H)
Preparation of 12.8
[2296] To a solution of 12.7 (1.63 g, 4.5 mmol) in acetonitrile
(100 mL) was added sequentially diisopropylethylamine (5.23, 30
mmol, 6.7 eq), dimethylamine (3.4j) hydrochloride (1.14 g, 14 mmol,
3.0 eq) and TBTU (1.74 g, 5.4 mmol, 1.2 eq). The reaction mixture
was stirred at room temperature for 3 days and then concentrated
under vacuum. The residue was dissolved in ethyl acetate and washed
with a saturated aqueous solution of sodium bicarbonate. The
organic layer was dried over sodium sulfate, filtered and
concentrated under vacuum. The crude product was purified by column
chromatography (eluent: hexane/acetone, 2:1).
[2297] Yield: 60%
[2298] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.50 (t, 1H),
7.00 (d, 1H), 6.85 (d, 1H), 3.89 (m, 2H), 3.22 (m, 2H), 3.14 (s,
3H), 2.74 (s, 3H), 2.03 (m, 2H), 1.62 (m, 2H), 1.48 (s, 6H)
Preparation of 12.9
[2299] To a solution of 12.8 (950 mg, 2.45 mmol) in anhydrous
tetrahydrofuran (20 mL) at -78.degree. C. under nitrogen was added
drop wise a 1.0 M solution of LiHMDS in tetrahydrofuran (3.2 mL,
3.2 mmol, 1.3 eq). The reaction mixture was stirred for 45 min at
-78.degree. C. A solution of N-phenyltrifluoromethanesulfonimide
(1.4) (1.15 g, 3.2 mmol, 1.3 eq) in tetrahydrofuran (8 mL) was
added drop wise to the reaction mixture. The mixture was warmed
slowly to room temperature and stirring was continued for an
additional 2.5 h at room temperature. The mixture was then poured
into ice water and extracted with a mixture of hexane and diethyl
ether (1:1). The organic layer was washed with water and brine, and
dried over sodium sulfate and filtered. The organic extracts were
concentrated under vacuum and the crude product was purified by
column chromatography (eluent: methylene chloride/ethyl acetate,
3:1).
[2300] Yield: 78.6%
[2301] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.28 (t, 1H), 6.96
(d, 1H), 6.83 (d, 1H), 5.65 (s, 1H), 3.80 (m, 2H), 3.38 (m, 1H),
3.20 (m, 1H), 3.10 (s, 3H), 2.92 (s, 3H), 2.09 (m, 2H), 1.70 (m,
2H), 1.48 (s, 9H)
Preparation of 12.10
[2302] To a solution of 12.9 (950 mg, 1.83 mmol) in dimethoxyethane
(DME) (16 mL) was added sequentially a 2N aqueous solution of
sodium carbonate (3.1 mL, 6.2 mmol, 3.4 eq), lithium chloride (259
mg, 6.1 mmol, 3.3 eq.), 4-(N,N-diethylaminocarbonyl)phenylboronic
acid (1.6) (486 mg, 2.2 mmol, 1.2 eq) and
tetrakis(triphenylphosphine)palladium(0) (64 mg, 0.055 mmol, 0.03
eq). The mixture was refluxed overnight under nitrogen and then
cooled to room temperature. To this mixture was added water (20 mL)
and the crude product was extracted with ethyl acetate. The organic
layer was washed with brine, dried over sodium sulfate and
filtered. The organics were concentrated under vacuum and the crude
product was purified by column chromatography (eluent:
hexane/acetone, 2:1).
[2303] Yield: 88%
[2304] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.35 (d, 2H), 7.25
(m, 3H), 7.05 (d, 1H), 6.91 (d, 1H), 5.62 (s, 1H), 3.86 (m, 2H),
3.55 (m, 2H), 3.30 (m, 4H), 2.69 (s, 3H), 2.30 (s, 3H), 2.10 (m,
1H), 1.98 (m, 1H), 1.70 (m, 2H), 1.49 (s, 6H), 1.20 (m, 6H)
Preparation of 12G
[2305] To a solution of 12.10 (840 mg, 1.54 mmol) in methylene
chloride (10 mL) was added a 2.0 M solution of anhydrous
hydrochloric acid in diethyl ether (30 mL). The mixture was stirred
at room temperature for 2 days and diluted with diethyl ether. The
resulting precipitate was collected by filtration and washed with
diethyl ether.
[2306] Yield: 100%
[2307] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.28 (m, 2H),
7.35-7.19 (m, 6H), 6.90 (d, 1H), 5.96 (s, 1H), 3.43 (m, 2H), 3.22
(m, 6H), 2.66 (s, 3H), 2.18 (s, 3H), 2.18 (s, 3H), 2.09 (m, 4H),
1.11 (m, 6H)
[2308] Mass Spectral Analysis m/z=448.4 (M+H).sup.+
Example 12H
[2309] 12H was obtained according to a procedure similar to the one
described for 12A, with the following exception:
Step 12.4: 1.6 was replaced by 1.7.
[2310] .sup.1H NMR (400 MHz, DMSO d.sub.6) 9.20 (m, 2H), 8.48 (s,
1H), 7.73 (d, 1H), 7.58 (d, 1H), 7.20 (t, 1H), 6.98 (d, 1H), 6.82
(d, 1H), 6.10 (s, 1H), 3.42-3.12 (m, 8H), 2.02 (m, 4H), 1.70 (s,
3H), 1.18 (t, 3H), 1.10 (t, 3H)
[2311] Mass Spectral Analysis m/z=392.4 (M+H).sup.+
[2312] Elemental analysis:
[2313] C.sub.24H.sub.29N.sub.3O.sub.3, 7/5HCl, 7/5H.sub.2O
[2314] Theory: % C, 61.60; % H, 7.15; % N, 8.98; % Cl, 10.61.
[2315] Found: % C, 61.70; % H, 6.78; % N, 8.86; % Cl, 10.73.
Example 12I
[2316] 12I was obtained according to a procedure similar to the one
described for 12A, with the following exception:
Step 12.2: 12.2a was replaced by 12.2b.
[2317] .sup.1H NMR (400 MHz, DMSO d.sub.6) 8.89 (brs, 2H), 7.12 (d,
2H), 7.04 (d, 2H), 6.95 (t, 1H), 6.71 (d, 1H), 6.58 (d, 1H), 5.66
(s, 1H), 3.20 (brs, 2H), 2.92 (brm, 6H), 1.75 (brm, 6H), 0.86 (brm,
8H), 0.22 (t, 3H)
[2318] Mass Spectral Analysis m/z=419.4 (M+H).sup.+
[2319] Elemental analysis:
[2320] C.sub.27H.sub.34N.sub.2O.sub.2, 1HCl, 1H.sub.2O
[2321] Theory: % C, 68.55; % H, 7.88; % N, 5.92.
[2322] Found: % C, 68.42; % H, 7.73; % N, 5.92.
Example 12J
[2323] 12J was obtained according to a procedure similar to the one
described for 12A, with the following exception:
Step 12.2: 12.2a was replaced by 12.2c.
[2324] .sup.1H NMR (400 MHz, DMSO d.sub.6) 9.12 (brs, 1.5H), 7.54
(d, 2H), 7.47 (d, 2H), 7.38 (t, 1H), 7.13 (d, 1H), 7.02 (d, 1H),
6.09 (s, 1H), 3.62 (brs, 2H), 3.36 (brm, 5H), 2.18 (brm, 6H), 1.30
(brm, 8H), 1.00 (m, 2H), 0.81 (t, 3H)
[2325] Mass Spectral Analysis m/z=433.4 (M+H).sup.+
[2326] Elemental analysis:
[2327] C.sub.28H.sub.36N.sub.2O.sub.2, 1HCl, 2H.sub.2O
[2328] Theory: % C, 66.58; % H, 8.18; % N, 5.55.
[2329] Found: % C, 66.82; % H, 7.88; % N, 5.59.
Example 12K
[2330] 12K was obtained according to a procedure similar to the one
described for 12A, with the following exceptions:
Step 12.2: 12.2a was replaced by 12.2b. Step 12.4: 1.6 was replaced
by 1.7 and Method 12A was used.
[2331] .sup.1H NMR (400 MHz, DMSO d.sub.6) 9.73 (brs, 1H), 9.61
(brs, 1H), 8.47 (s, 1H), 7.65 (m, 2H), 7.20 (m, 1H), 6.90 (d, 1H),
6.82 (d, 1H), 5.66 (s, 1H), 3.59 (q, 2H), 3.41 (brm, 6H), 2.24
(brs, 4H), 2.01 (brm, 2H), 1.25 (brm, 8H), 0.54 (t, 3H)
[2332] Mass Spectral Analysis m/z=420.4 (M+H).sup.+
Example 12L
[2333] 12L was obtained according to a procedure similar to the one
described for 12A, with the following exceptions:
Step 12.2: 12.2a was replaced by 12.2c. Step 12.4: 1.6 was replaced
by 1.7 and Method 12A was used.
[2334] .sup.1H NMR (400 MHz, DMSO d.sub.6) 8.86 (brd, 1.5H), 8.43
(d, 1H), 7.66 (dd, 1H), 7.48 (d, 1H), 7.16 (t, 1H), 6.91 (d, 1H),
6.79 (d, 1H), 5.98 (s, 1H), 3.40 (q, 2H), 3.12 (brm, 5H), 1.94
(brm, 6H), 1.10 (m, 5H), 1.01 (t, 3H), 0.76 (m, 2H), 0.56 (t,
3H)
[2335] Mass Spectral Analysis m/z=434.3 (M+H).sup.+
Example 13A
Preparation of 13.2
[2336] To a solution of 1.5a (7.80 g, 17.35 mmol, 1.0 eq) in
dimethoxyethane (75 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (26.03 mL, 52.06 mmol, 3.0 eq),
lithium chloride (2.21 g, 52.06 mmol, 3.0 eq), 13.1 (3.44 g, 19.09
mmol, 1.1 eq) and tetrakis(triphenylphosphine)palladium(0) (0.40 g,
0.35 mmol, 0.02 eq). The mixture was refluxed overnight under
nitrogen. The mixture was then cooled to room temperature and water
(250 mL) was added. The mixture was extracted with ethyl acetate.
The organic layer was further washed with brine and dried over
sodium sulfate. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[2337] Yield: 64%
[2338] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.02 (d, 2H),
7.49 (d, 2H), 7.23 (m, 1H), 6.99 (d, 1H), 6.92 (m, 2H), 5.92 (s,
1H), 3.88 (s, 3H), 3.70 (m, 2H), 3.27 (m, 2H), 1.89 (m, 2H), 1.71
(m, 2H), 1.42 (s, 9H)
[2339] Mass Spectral Analysis m/z=436.0 (M+H).sup.+
Preparation of 13.3
[2340] A solution of 13.2 (4.71 g, 10.81 mmol, 1.0 eq) in
tetrahydrofuran (30 mL) at 0.degree. C. under nitrogen was added
drop wise to a solution of lithium hydroxide monohydrate (0.54 g,
12.98 mmol, 1.2 eq) in water (30 mL). The mixture was stirred
overnight at room temperature. The mixture was then concentrated
under reduced pressure and redissolved in water. The mixture was
then acidified to pH 2 using concentrated hydrochloric acid. The
resulting precipitate was collected by filtration and the crude
product was used for the next step without further
purification.
[2341] Yield: 98%
[2342] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 13.03 (br s,
1H), 8.01 (d, 2H), 7.47 (d, 2H), 7.23 (m, 1H), 6.98 (d, 1H), 6.92
(m, 2H), 5.91 (s, 1H), 3.70 (m, 2H), 3.28 (m, 2H), 1.86 (m, 2H),
1.72 (m, 2H), 1.42 (s, 9H)
[2343] Mass Spectral Analysis m/z=420.1 (M-H).sup.-
Preparation of 13A
[2344] Trifluoroacetic acid (0.15 mL, 1.96 mmol, 5.5 eq) was added
drop wise to a cold (0.degree. C.) solution of 13.3 (0.15 g, 0.36
mmol, 1.0 eq) in anhydrous dichloromethane (5 mL). The mixture was
warmed to room temperature and stirred overnight at room
temperature. The mixture was then concentrated under reduced
pressure. The crude product was triturated with diethyl ether. The
resulting precipitate was collected by filtration.
[2345] Yield: 87%
[2346] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 13.05 (brs, 1H),
8.67 (m, 2H), 8.02 (d, 2H), 7.49 (d, 2H), 7.27 (m, 1H), 7.05 (d,
1H), 6.96 (m, 2H), 5.98 (s, 1H), 3.26 (m, 4H), 2.08 (m, 2H), 1.97
(m, 2H)
[2347] Mass Spectral Analysis m/z=322.1 (M+H).sup.+
[2348] Elemental analysis:
[2349] C.sub.20H.sub.19NO.sub.3, CF.sub.3CO.sub.2H, 0.2H.sub.2O
[2350] Theory: % C, 60.19; % H, 4.68; % N, 3.19.
[2351] Found: % C, 60.18; % H, 4.61; % N, 3.24.
Example 13B
Preparation of 13.5a
[2352] O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
tetrafluoroborate (150.8 mg, 0.47 mmol, 1.1 eq) was added to a
cooled (0.degree. C.) solution of 13.3 (180.0 mg, 0.43 mmol, 1.0
eq), 3.4a (50.3 mg, 0.94 mmol, 2.2 eq), and
N,N-diisopropylethylamine (0.25 mL, 0.94 mmol, 2.2 eq) in
acetonitrile (5 mL). The solution was stirred overnight at room
temperature and then concentrated under reduced pressure. Ethyl
acetate (10 mL) and a saturated aqueous solution of sodium
bicarbonate (10 mL) were added to the crude product and the mixture
was stirred for 20 min at room temperature. The phases were
separated and the organic phase was washed with a saturated aqueous
solution of sodium bicarbonate, brine, dried over sodium sulfate
and filtered. The organics were concentrated under reduced pressure
and the crude product was purified by column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity).
[2353] Yield: 10%
[2354] Mass Spectral Analysis m/z=421.2 (M+H).sup.+
Preparation of 13B
[2355] A 2.0M solution of hydrochloric acid in diethyl ether (0.12
mL, 0.24 mmol, 5.5 eq) was added drop wise to a cooled (0.degree.
C.) solution of 13.5a (18 mg, 0.04 mmol, 1.0 eq) in anhydrous
methanol (5 mL). The mixture was stirred overnight at room
temperature and then concentrated under reduced pressure. The crude
product was triturated with ethyl acetate. The resulting
precipitate was collected by filtration.
[2356] Yield: 70%
[2357] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.99 (m, 2H),
8.06 (m, 1H), 7.95 (m, 2H), 7.46 (m, 3H), 7.27 (m, 1H), 7.06 (m,
1H), 6.96 (m, 2H), 5.95 (s, 1H), 3.24 (m, 4H), 2.08 (m, 4H)
[2358] Mass Spectral Analysis m/z=321.1 (M+H).sup.+
Example 13C
[2359] 13C was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 3.4b.
[2360] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.05 (m, 2H),
8.55 (m, 1H), 7.92 (m, 2H), 7.41 (m, 2H), 7.26 (m, 1H), 7.06 (m,
1H), 6.95 (m, 2H), 5.95 (s, 1H), 3.20 (m, 4H), 2.81 (m, 3H), 2.08
(m, 4H)
[2361] Mass Spectral Analysis m/z=335.2 (M+H).sup.+
Example 13D
[2362] 13D was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 3.4c.
[2363] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.50 (m, 1H),
7.90 (d, 2H), 7.40 (d, 2H), 7.20 (m, 1H), 6.90 (m, 3H), 5.85 (s,
1H), 3.30 (m, 2H), 2.90 (m, 2H), 2.70 (m, 2H), 1.85-1.70 (m, 4H),
1.10 (t, 3H)
[2364] Mass Spectral Analysis m/z=349.2 (M+H).sup.+
[2365] Elemental analysis:
[2366] C.sub.22H.sub.24N.sub.2O.sub.2, 0.25 (CH.sub.3).sub.2CO,
0.25H.sub.2O
[2367] Theory: % C, 70.89; % H, 7.32; % N, 7.27.
[2368] Found: % C, 71.13; % H, 7.04; % N, 7.07.
Example 13E
[2369] 13E was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 3.4e.
[2370] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.75 (brs, 1H),
9.31 (brs, 1H), 7.81 (d, 2H), 7.39 (d, 2H), 7.21 (m, 1H), 6.98 (m,
2H), 6.90 (m, 1H), 6.25 (m, 1H), 5.56 (s, 1H), 3.46 (m, 2H), 3.33
(m, 4H), 2.30 (m, 2H), 2.12 (m, 2H), 1.94 (m, 1H), 1.04 (d, 6H)
[2371] Mass Spectral Analysis m/z=377.2 (M+H).sup.+
Example 13F
[2372] 13F was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 3.4j.
[2373] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.08 (m, 2H),
7.42 (m, 4H), 7.24 (m, 1H), 7.00 (m, 3H), 5.91 (s, 1H), 3.25 (m,
4H), 2.96 (m, 6H), 2.07 (m, 4H)
[2374] Mass Spectral Analysis m/z=349.1 (M+H).sup.+
Example 13G
[2375] 13G was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 3.4k.
[2376] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.91 (m, 2H),
7.58 (d, 2H), 7.41 (d, 2H), 7.25 (m, 1H), 7.00 (m, 3H), 5.92 (s,
1H), 3.49 (m, 2H), 3.41 (m, 2H), 3.24 (m, 4H), 2.09 (m, 2H), 2.00
(m, 2H), 1.84 (m, 4H)
[2377] Mass Spectral Analysis m/z=375.1 (M+H).sup.+
Example 13H
[2378] 13H was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 3.4o.
[2379] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.98 (m, 2H),
7.39 (dd, 4H), 7.24 (m, 1H), 6.95 (m, 3H), 5.91 (s, 1H), 3.66 (brs,
2H), 3.22 (m, 4H), 2.10 (m, 4H), 1.30 (m, 12H)
[2380] Mass Spectral Analysis m/z=405.3 (M+H).sup.+
[2381] Elemental analysis:
[2382] C.sub.26H.sub.32N.sub.2O.sub.2, 1HCl, 0.5H.sub.2O
[2383] Theory: % C, 69.39; % H, 7.62; % N, 6.22.
[2384] Found: % C, 69.31; % H, 7.64; % N, 6.19.
Example 13I
[2385] 13I was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 3.4p.
[2386] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.91 (m, 2H),
7.46 (m, 4H), 7.26 (m, 1H), 7.01 (m, 3H), 5.94 (s, 1H), 3.61 (m,
6H), 3.35 (m, 2H), 3.21 (m, 4H), 2.09 (m, 2H), 1.98 (m, 2H)
[2387] Mass Spectral Analysis m/z=391.1 (M+H).sup.+
Example 13J
[2388] 13J was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 3.4q.
[2389] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.90 (m, 2H),
7.44 (m, 4H), 7.26 (m, 1H), 7.00 (m, 3H), 5.91 (s, 1H), 3.59 (m,
2H), 3.21 (m, 6H), 2.09 (m, 2H), 1.99 (m, 2H), 1.55 (m, 6H)
[2390] Mass Spectral Analysis m/z=389.1 (M+H).sup.+
Example 13K
[2391] 13K was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 13.4a.
[2392] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.75 (m, 2H),
7.49 (m, 2H), 7.41 (m, 2H), 7.26 (m, 1H), 7.05 (m, 1H), 6.97 (m,
2H), 5.95 (s, 1H), 4.00 (brm, 4H), 3.23 (m, 4H), 2.10 (m, 2H), 1.97
(m, 2H), 1.64 (m, 2H), 1.15 (brm, 6H)
[2393] Mass Spectral Analysis m/z=403.3 (M+H).sup.+
[2394] Elemental analysis:
[2395] C.sub.26H.sub.30N.sub.2O.sub.2, 1HCl, 0.3H.sub.2O
[2396] Theory: % C, 70.27; % H, 7.17; % N, 6.30.
[2397] Found: % C, 70.02; % H, 7.04; % N, 6.27.
Example 13L
[2398] 13L was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 13.4b.
[2399] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.90 (m, 2H),
7.70 (d, 2H), 7.50 (d, 2H), 7.40 (m, 1H), 7.30 (m, 4H), 7.00 (m,
3H), 5.95 (s, 1H), 4.90 (s, 2H), 4.80 (s, 2H), 3.30 (brm, 4H), 2.05
(m, 4H)
[2400] Mass Spectral Analysis m/z=423.1 (M+H).sup.+
[2401] Elemental analysis:
[2402] C.sub.28H.sub.26N.sub.2O.sub.2, 1HCl, 1H.sub.2O
[2403] Theory: % C, 70.50; % H, 6.13; % N, 5.87.
[2404] Found: % C, 70.58; % H, 5.95; % N, 5.89.
Example 13M
[2405] 13M was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 13.4c.
[2406] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.00 (m, 1H),
7.40 (m, 4H), 7.25 (m, 1H), 7.00 (m, 3H), 5.90 (s, 1H), 3.55-3.05
(m, 8H), 2.05 (m, 4H), 1.60 (m, 2H), 1.10 (m, 1H), 0.90 (m, 2H),
0.65 (m, 1H), 0.40 (m, 2H), 0.15 (m, 1H), 0.10 (m, 1H)
[2407] Mass Spectral Analysis m/z=417.2 (M+H).sup.+
[2408] Elemental analysis:
[2409] C.sub.27H.sub.32N.sub.2O.sub.2, 1HCl, 0.4H.sub.2O
[2410] Theory: % C, 70.46; % H, 7.40; % N, 6.09.
[2411] Found: % C, 70.54; % H, 7.30; % N, 6.15.
Example 13N
[2412] 13N was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 13.4d.
[2413] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.88 (m, 2H),
7.40 (brm, 10H), 7.00 (m, 3H), 5.94 (s, 1H), 4.70 (m, 1H), 4.52 (m,
1H), 3.21 (m, 4H), 2.88 (m, 3H), 2.02 (m, 4H)
[2414] Mass Spectral Analysis m/z=425.2 (M+H).sup.+
[2415] Elemental analysis:
[2416] C.sub.28H.sub.28N.sub.2O.sub.2, 1HCl, 0.6H.sub.2O
[2417] Theory: % C, 71.28; % H, 6.45; % N, 5.94.
[2418] Found: % C, 71.13; % H, 6.51; % N, 5.97.
Example 13O
[2419] 13O was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 13.4e.
[2420] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.65 (m, 2H),
7.45 (m, 4H), 7.26 (m, 1H), 7.00 (m, 3H), 5.95 (s, 1H), 4.36 (m,
2H), 4.11 (m, 2H), 3.88 (m, 2H), 3.60 (m, 2H), 3.00 (m, 2H), 2.65
(m, 1H), 2.09 (m, 2H), 1.99 (m, 4H), 1.52 (m, 2H), 1.19 (m, 3H)
[2421] Mass Spectral Analysis m/z=461.2 (M+H).sup.+
Example 13P
[2422] 13P was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 13.4f.
[2423] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.60 (m, 2H),
7.47 (m, 4H), 7.25 (m, 1H), 7.00 (m, 3H), 5.95 (s, 1H), 4.18 (m,
2H), 3.80 (brs, 4H), 3.24 (m, 2H), 3.00 (s, 3H), 2.10 (m, 2H), 1.94
(m, 2H), 1.20 (m, 3H)
[2424] Mass Spectral Analysis m/z=421.2 (M+H).sup.+
Example 13Q
[2425] 13Q was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 13.4g.
[2426] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.32 (brs, 1H),
8.80 (m, 2H), 7.54 (m, 2H), 7.46 (m, 2H), 7.27 (m, 1H), 7.00 (m,
3H), 5.92 (s, 1H), 4.54 (brs, 2H), 3.84 (brs, 2H), 3.45 (m, 2H),
3.24 (m, 4H), 3.12 (m, 2H), 2.83 (s, 3H), 2.10 (m, 2H), 1.97 (m,
2H)
[2427] Mass Spectral Analysis m/z=404.3 (M+H).sup.+
Example 13R
[2428] 13R was obtained according to a procedure similar to the one
described for 13B, with the following exception:
Step 13.6: 3.4a was replaced by 13.4h.
[2429] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.55 (m, 1H),
8.95 (m, 1H), 7.55 (m, 5H), 7.30 (brm, 10H), 7.04 (m, 1H), 6.95 (m,
2H), 5.93 (s, 1H), 4.62 (s, 2H), 4.46 (s, 2H), 3.20 (m, 4H), 2.02
(m, 4H)
[2430] Mass Spectral Analysis m/z=501.2 (M+H).sup.+
Example 13S
Preparation of 13S
[2431] A 2N aqueous solution of sodium hydroxide (1.0 mL, 2 mmol,
9.2 eq) was added to a solution of 130 (0.10 g, 0.22 mmol, 1.0 eq)
in tetrahydrofuran (5 mL) and anhydrous absolute ethanol (1 mL).
The mixture was stirred for 10 h at room temperature and acidified
to pH 6 using a 2N aqueous solution of hydrochloric acid. The
mixture was concentrated under reduced pressure. The crude product
was dissolved in dichloromethane. The mixture was filtered and the
filtrate was concentrated under reduced pressure.
[2432] Yield: 60%
[2433] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.43 (m, 4H),
7.25 (m, 1H), 7.01 (m, 2H), 6.94 (m, 1H), 5.93 (s, 1H), 4.33 (br s,
2H), 3.65-2.90 (m, 9H), 1.91 (m, 6H), 1.52 (m, 2H)
[2434] Mass Spectral Analysis m/z=433.1 (M+H).sup.+
Example 14A
Preparation of 14.2
[2435] To a solution of 1.5a (5.00 g, 11.12 mmol, 1.0 eq) in
dimethoxyethane (17 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (16.69 mL, 33.37 mmol, 3.0 eq),
lithium chloride (1.41 g, 33.37 mmol, 3.0 eq), 14.1 (1.80 g, 12.24
mmol, 1.1 eq) and tetrakis(triphenylphosphine)palladium(0) (0.26 g,
0.22 mmol, 0.02 eq). The mixture was refluxed for 10 h under
nitrogen. The mixture was then cooled to room temperature and a 1N
aqueous solution of sodium hydroxide was added. The mixture was
extracted with dichloromethane. The organic layer was further
washed with brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude product was
triturated with diethyl ether. The resulting solid was collected bu
filtration.
[2436] Yield: 78%
[2437] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.90 (d, 2H),
7.50 (d, 2H), 7.20 (m, 1H), 7.00 (m, 1H), 6.90 (m, 2H), 5.95 (s,
1H), 3.70 (m, 2H), 3.25 (m, 2H), 1.85 (m, 2H), 1.70 (m, 2H), 1.40
(s, 9H)
[2438] Mass Spectral Analysis m/z=403.1 (M+H).sup.+
Preparation of 14.4
[2439] A mixture of 14.2 (3.49 g, 8.67 mmol, 1.0 eq), 14.3 (1.13 g,
17.34 mmol, 2.0 eq) and zinc bromide (0.98 g, 4.34 mmol, 0.5 eq) in
isopropanol (70 mL) and water (50 mL) was refluxed for 3 days. The
reaction mixture was then cooled to 0.degree. C. and acidified to
pH 1 using a 3N aqueous solution of hydrochloric acid. The mixture
was extracted with ethyl acetate. The organic phase was washed with
brine, dried over sodium sulfate, filtered and concentrated under
reduced pressure. Diethyl ether (30 mL) was added. The resulting
precipitate was collected by filtration and washed with diethyl
ether. The crude compound was used for the next step without
further purification.
[2440] Yield: 89%
[2441] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.10 (d, 2H),
7.55 (d, 2H), 7.20 (m, 1H), 7.00 (m, 2H), 6.90 (m, 1H), 5.90 (s,
1H), 3.70 (m, 2H), 3.30 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1.40
(s, 9H)
[2442] Mass Spectral Analysis m/z=446.0 (M+H).sup.+
Preparation of 14A
[2443] A 2.0M solution of hydrochloric acid in diethyl ether (21.3
mL, 42.58 mmol, 5.5 eq) was added drop wise to a cooled (0.degree.
C.) solution of 14.4 (3.71 g, 7.74 mmol, 1.0 eq) in anhydrous
dichloromethane (25 mL). The mixture was warmed to room temperature
and stirring was continued for an additional 10 h at room
temperature. Diethyl ether (100 mL) was added to the solution. The
resulting precipitate was collected by filtration and washed with
diethyl ether. The crude product was purified by column
chromatography (eluent: dichloromethane/methanol mixtures of
increasing polarity).
[2444] Yield: 20%
[2445] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.08 (brs, 2H),
8.16 (d, 2H), 7.61 (d, 2H), 7.28 (m, 1H), 7.02 (m, 3H), 6.02 (s,
1H), 3.59 (brs, 1H), 3.24 (m, 4H), 2.06 (m, 4H)
[2446] Mass Spectral Analysis m/z=346.1 (M+H).sup.+
[2447] Elemental analysis:
[2448] C.sub.20H.sub.19N.sub.5O, 1HCl, 0.5H.sub.2O
[2449] Theory: % C, 61.46; % H, 5.42; % N, 17.92.
[2450] Found: % C, 61.52; % H, 5.23; % N, 17.63.
Example 14B
Preparation of 14.5 and 14.6
[2451] Methyl iodide (2.8c) (0.35 mL, 0.0056 mol, 5.0 eq) was added
drop wise to a solution of 14.4 (0.500 g, 0.0011 mol, 1.0 eq) and
triethylamine (0.80 mL, 0.0056 mol, 5.0 eq) in anhydrous
dimethylformamide (5 mL) and the mixture was stirred at room
temperature for 3 days. The mixture was poured into water (50 mL)
and extracted with ethyl acetate. The organic phase was washed with
brine, dried over sodium sulfate, filtered and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[2452] Yield 14.5 (major regioisomer): 65%
[2453] Mass Spectral Analysis m/z=460.1 (M+H).sup.+
[2454] Yield 14.6 (minor regioisomer): 17%
[2455] Mass Spectral Analysis m/z=460.2 (M+H).sup.+
Preparation of 14B
[2456] A 2.0M anhydrous solution of hydrochloric acid in diethyl
ether (10 mL) was added drop wise to a cold (0.degree. C.) solution
of 14.5 (0.330 g, 0.00071 mol, 1.0 eq) in anhydrous dichloromethane
(10 mL). The mixture was warmed to room temperature and stirring
was continued for an additional 16 h at room temperature. The
mixture was concentrated under reduced pressure and diethyl ether
was added to the residue. The resulting precipitate was collected
by filtration and washed with diethyl ether.
[2457] Yield: 90%
[2458] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.80 (m, 1H),
8.10 (d, 2H), 7.55 (d, 2H), 7.25 (t, 1H), 6.90-7.10 (m, 3H), 6.00
(s, 1H), 4.45 (s, 3H), 3.15-3.40 (m, 4H), 1.95-2.15 (m, 4H)
[2459] Mass Spectral Analysis m/z=360.1 (M+H).sup.+
Example 14C
Preparation of 14C
[2460] A 2.0M anhydrous solution of hydrochloric acid in diethyl
ether (5 mL) was added drop wise to a cold (0.degree. C.) solution
of 14.6 (0.090 g, 0.00019 mol, 1.0 eq) in anhydrous dichloromethane
(10 mL). The mixture was warmed to room temperature and stirring
was continued for an additional 10 h at room temperature. The
mixture was concentrated under reduced pressure and diethyl ether
was added to the residue. The resulting precipitate was collected
by filtration and washed with diethyl ether.
[2461] Yield: 88%
[2462] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.80 (m, 1.5H),
7.90 (d, 2H), 7.60 (d, 2H), 7.25 (t, 1H), 6.90-7.10 (m, 3H), 6.00
(s, 1H), 4.20 (s, 3H), 3.20 (m, 4H), 1.95-2.15 (m, 4H)
[2463] Mass Spectral Analysis m/z=360.2 (M+H).sup.+
Example 15A
[2464] 15A was obtained according to a procedure similar to the one
described for 15C, with the following exception:
Step 15.1: 15.1c was replaced by 15.1a.
[2465] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.87 (brm, 1H),
8.16 (d, 2H), 7.59 (d, 2H), 7.29 (m, 1H), 7.06 (m, 2H), 6.97 (m,
1H), 6.02 (s, 1H), 5.96 (s, 2H), 3.77 (s, 3H), 3.23 (brm, 4H), 2.11
(brm, 2H), 2.00 (brm, 2H)
[2466] Mass Spectral Analysis m/z=418.1 (M+H).sup.+
Example 15B
[2467] 15B was obtained according to a procedure similar to the one
described for 15C, with the following exception:
Step 15.1: 15.1c was replaced by 15.1b.
[2468] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.75 (m, 1H),
8.15 (d, 2H), 7.57 (d, 2H), 7.25 (t, 1H), 7.00 (m, 3H), 6.00 (s,
1H), 5.00 (t, 2H), 3.60 (s, 3H), 3.10-3.40 (m, 6H), 1.95-2.18 (m,
4H)
[2469] Mass Spectral Analysis m/z=432.2 (M+H).sup.+
Example 15C
Preparation of 15.2a and 15.3a
[2470] Ethyl bromobutyrate (15.1c) (0.40 mL, 0.0028 mol, 2.5 eq)
was added drop wise to a solution of 14.4 (0.500 g, 0.0011 mol, 1.0
eq) and triethylamine (0.40 mL, 0.0028 mol, 2.5 eq) in anhydrous
N,N-dimethylformamide and the mixture was stirred at room
temperature for 3 days. The mixture was poured into water (50 mL)
and extracted with ethyl acetate. The organic phase was washed with
brine, dried over sodium sulfate, filtered and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[2471] Yield 15.2a (major regioisomer): 82%.
[2472] (15.2a) .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.10 (d,
2H), 7.50 (d, 2H), 7.20 (m, 1H), 7.00 (m, 2H), 6.90 (m, 1H), 5.90
(s, 1H), 4.70 (t, 2H), 4.00 (q, 2H), 3.70 (m, 2H), 3.30 (m, 2H),
2.40 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1.40 (s,
9H), 1.15 (t, 3H)
[2473] Mass Spectral Analysis m/z=560.2 (M+H).sup.+
[2474] Yield 15.3a (minor regioisomer): 6%.
[2475] (15.3a) .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.90 (d,
2H), 7.60 (d, 2H), 7.20 (m, 1H), 7.00 (m, 2H), 6.90 (m, 1H), 5.95
(s, 1H), 4.55 (t, 2H), 4.00 (q, 2H), 3.70 (m, 2H), 3.30 (m, 2H),
2.40 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1.40 (s,
9H), 1.10 (t, 3H)
[2476] Mass Spectral Analysis m/z=560.2 (M+H).sup.+
Preparation of 15C
[2477] A 2.0M anhydrous solution of hydrochloric acid in diethyl
ether (10 mL) was added drop wise to a cold (0.degree. C.) solution
of 15.2a (0.520 g, 0.00092 mol, 1.0 eq) in anhydrous
dichloromethane (10 mL). The mixture was warmed to room temperature
and stirring was continued for an additional 10 h at room
temperature. An additional amount of a 2.0M anhydrous solution of
hydrochloric acid in diethyl ether (10 mL) was added to the
mixture, which was stirred for an additional 6 h at room
temperature. The mixture was concentrated under reduced pressure
and diethyl ether was added. The resulting precipitate was
collected by filtration and washed with diethyl ether.
[2478] Yield: 70%
[2479] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.80 (m, 1H),
8.15 (d, 2H), 7.60 (d, 2H), 7.25 (m, 1H), 7.00 (m, 3H), 6.00 (s,
1H), 4.80 (t, 2H), 4.00 (q, 2H), 3.35 (m, 2H), 3.20 (m, 2H), 2.40
(m, 2H), 2.20 (m, 2H), 2.10 (m, 2H), 1.95 (m, 2H), 1.15 (t, 3H)
[2480] Mass Spectral Analysis m/z=460.2 (M+H).sup.+
Example 15D
[2481] 15D was obtained according to a procedure similar to the one
described for 15C, with the following exception:
Step 15.1: 15.1c was replaced by 15.1d.
[2482] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.90 (brm,
1.5H), 8.14 (d, 2H), 7.57 (d, 2H), 7.28 (t, 1H), 7.04 (m, 2H), 6.96
(m, 1H), 6.00 (s, 1H), 4.78 (t, 2H), 4.04 (q, 2H), 3.22 (brm, 4H),
2.37 (t, 2H), 2.11 (brm, 2H), 2.01 (brm, 4H), 1.57 (m, 2H), 1.16
(t, 3H)
[2483] Mass Spectral Analysis m/z=474.2 (M+H).sup.+
Example 15E
[2484] 15E was obtained according to a procedure similar to the one
described for 15C, with the following exception:
Step 15.1: 15.1c was replaced by 15.1e.
[2485] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.88 (brm,
1.5H), 8.14 (d, 2H), 7.57 (d, 2H), 7.28 (t, 1H), 7.05 (m, 2H), 6.96
(m, 1H), 6.00 (s, 1H), 4.76 (t, 2H), 4.02 (q, 2H), 3.22 (brm, 4H),
2.29 (t, 2H), 2.10 (brm, 2H), 2.00 (brm, 4H), 1.57 (m, 2H), 1.30
(m, 2H), 1.14 (t, 3H)
[2486] Mass Spectral Analysis m/z=488.2 (M+H).sup.+
Example 15F
[2487] 15F was obtained according to a procedure similar to the one
described for 15H, with the following exception:
Step 15.1: 15.1c was replaced by 15.1a.
[2488] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.86 (brm, 1H),
7.84 (d, 2H), 7.62 (d, 2H), 7.29 (m, 1H), 7.07 (d, 1H), 6.99 (m,
2H), 6.03 (s, 1H), 5.71 (s, 2H), 3.70 (s, 3H), 3.23 (m, 4H), 2.11
(brm, 2H), 2.00 (brm, 2H)
[2489] Mass Spectral Analysis m/z=418.2 (M+H).sup.+
Example 15G
[2490] 15G was obtained according to a procedure similar to the one
described for 15H, with the following exception:
Step 15.1: 15.1c was replaced by 15.1b.
[2491] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.78 (brm, 1H),
7.91 (d, 2H), 7.64 (d, 2H), 7.29 (m, 1H), 7.05 (m, 2H), 6.98 (m,
1H), 6.04 (s, 1H), 4.71 (t, 2H), 3.56 (s, 3H), 3.23 (m, 4H), 3.11
(t, 2H), 2.12 (brm, 2H), 2.00 (brm, 2H)
[2492] Mass Spectral Analysis m/z=432.1 (M+H).sup.+
Example 15H
Preparation of 15H
[2493] A 2.0M anhydrous solution of hydrochloric acid in diethyl
ether (10 mL) was added drop wise to a cold (0.degree. C.) solution
of 15.3a (0.030 g, 0.000053 mol, 1.0 eq) in anhydrous
dichloromethane (10 mL). The mixture was warmed to room temperature
and stirring was continued for an additional 10 h at room
temperature. An additional amount of a 2.0M anhydrous solution of
hydrochloric acid in diethyl ether (10 mL) was added to the
mixture, which was stirred for an additional 6 h at room
temperature. The mixture was concentrated under reduced pressure
and diethyl ether was added. The resulting precipitate was
collected by filtration and washed with diethyl ether.
[2494] Yield: 57%
[2495] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.00 (m, 1.5H),
7.90 (d, 2H), 7.62 (d, 2H), 7.30 (m, 1H), 7.05 (m, 2H), 6.95 (m,
1H), 6.00 (s, 1H), 4.60 (t, 2H), 4.00 (q, 2H), 3.25 (m, 4H), 2.40
(m, 2H), 2.10 (m, 6H), 1.15 (t, 3H)
[2496] Mass Spectral Analysis m/z=460.2 (M+H).sup.+
Example 15I
[2497] 15I was obtained according to a procedure similar to the one
described for 15H, with the following exception:
Step 15.1: 15.1c was replaced by 15.1d.
[2498] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.96 (brm,
1.5H), 7.89 (d, 2H), 7.63 (d, 2H), 7.29 (t, 1H), 7.06 (m, 2H), 6.97
(m, 1H), 6.03 (s, 1H), 4.55 (t, 2H), 4.01 (q, 2H), 3.22 (brm, 4H),
2.29 (t, 2H), 2.12 (brm, 2H), 2.02 (brm, 2H), 1.85 (m, 2H), 1.49
(m, 2H), 1.13 (t, 3H)
[2499] Mass Spectral Analysis m/z=474.3 (M+H).sup.+
Example 15J
[2500] 15J was obtained according to a procedure similar to the one
described for 15H, with the following exception:
Step 15.1: 15.1c was replaced by 15.1e.
[2501] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.93 (brm, 1H),
7.87 (d, 2H), 7.62 (d, 2H), 7.29 (t, 1H), 7.05 (m, 2H), 6.97 (m,
1H), 6.03 (s, 1H), 4.52 (t, 2H), 4.01 (q, 2H), 3.23 (brm, 4H), 2.22
(t, 2H), 2.11 (brm, 2H), 2.02 (brm, 2H), 1.83 (m, 2H), 1.47 (m,
2H), 1.23 (m, 2H), 1.14 (t, 3H)
[2502] Mass Spectral Analysis m/z=488.3 (M+H).sup.+
Example 15K
[2503] 15K was obtained according to a procedure similar to the one
described for 15L, with the following exception:
Step 15.6: 15C was replaced by 15A.
[2504] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.18 (d, 2H),
7.60 (d, 2H), 7.29 (t, 1H), 7.06 (t, 2H), 6.97 (m, 1H), 6.02 (s,
1H), 5.80 (s, 2H), 3.27 (brm, 4H), 2.13 (brm, 2H), 2.00 (brm,
2H)
[2505] Mass Spectral Analysis m/z=404.1 (M+H).sup.+
Example 15L
Preparation of 15L
[2506] A 2N aqueous solution of sodium hydroxide (1.8 mL, 0.0036
mol, 5.5 eq) was added to a solution of 15C (0.300 g, 0.00060 mol,
1.0 eq) in tetrahydrofuran (10 mL) and absolute ethanol (1 mL). The
mixture was stirred for 10 h at room temperature and acidified to
pH 6 using a 2N aqueous solution of hydrochloric acid. The mixture
was concentrated under reduced pressure and diethyl ether was
added. The mixture was then stirred for 1 h at room temperature.
The resulting precipitate was collected by filtration and washed
several times with water and diethyl ether.
[2507] Yield: 98%
[2508] .sup.1H NMR (400 MHz, DMSO d.sub.6+CF.sub.3CO.sub.2D)
.delta. 8.80 (m, 1H), 8.20 (m, 2H), 7.70 (m, 2H), 7.30 (m, 1H),
7.00 (m, 3H), 6.00 (s, 1H), 4.80 (m, 2H), 3.30 (m, 4H), 2.60-1.95
(m, 8H)
[2509] Mass Spectral Analysis m/z=432.1 (M+H).sup.+
Example 15M
[2510] 15M was obtained according to a procedure similar to the one
described for 15L, with the following exception:
Step 15.6: 15C was replaced by 15D.
[2511] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.76 (brm 1H),
8.16 (d, 2H), 7.58 (d, 2H), 7.29 (t, 1H), 7.06 (t, 2H), 6.97 (m,
1H), 6.00 (s, 1H), 4.78 (t, 2H), 3.24 (m, 4H), 2.31 (t, 2H), 2.13
(brm, 2H), 2.01 (brm, 4H), 1.56 (m, 2H)
[2512] Mass Spectral Analysis m/z=446.2 (M+H).sup.+
Example 15N
[2513] 15N was obtained according to a procedure similar to the one
described for 15L, with the following exception:
Step 15.6: 15C was replaced by 15E.
[2514] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.62 (brm,
1.5H), 8.15 (d, 2H), 7.57 (d, 2H), 7.28 (m, 1H), 7.05 (m, 2H), 6.97
(m, 1H), 6.00 (s, 1H), 4.76 (t, 2H), 3.25 (brm, 4H), 2.21 (t, 2H),
2.11 (brm, 2H), 1.98 (brm, 4H), 1.55 (m, 2H), 1.31 (m, 2H)
[2515] Mass Spectral Analysis m/z=460.2 (M+H).sup.+
Example 16A
[2516] 16A was obtained according to a procedure similar to the one
described for 14A, with the following exception:
Step 14.1: 14.1 was replaced by 16.1 (see also step 16.1).
[2517] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.00 (brs, 2H),
8.12 (t, 2H), 7.70 (t, 1H), 7.60 (t, 1H), 7.25 (t, 1H), 7.00 (m,
3H), 6.00 (s, 1H), 3.30 (m, 4H), 2.05 (m, 4H)
[2518] Mass Spectral Analysis m/z=346.1 (M+H).sup.+
Example 16B
[2519] 16B was obtained according to a procedure similar to the one
described for 14B, with the following exception:
Step 14.1: 14.1 was replaced by 16.1 (see also step 16.1).
[2520] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.66 (brm, 2H),
8.11 (m, 1H), 8.01 (m, 1H), 7.66 (t, 1H), 7.54 (m, 1H), 7.28 (m,
1H), 7.06 (d, 1H), 6.97 (m, 2H), 6.00 (s, 1H), 4.43 (s, 3H), 3.23
(brm, 4H), 2.12 (brm, 2H), 2.00 (brm, 2H)
[2521] Mass Spectral Analysis m/z=360.1 (M+H).sup.+
Example 16C
[2522] 16C was obtained according to a procedure similar to the one
described for 14C, with the following exception:
Step 14.1: 14.1 was replaced by 16.1 (see also step 16.1).
[2523] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.73 (brm, 2H),
7.91 (m, 1H), 7.83 (t, 1H), 7.72 (t, 1H), 7.03 (m, 1H), 7.28 (m,
1H), 7.05 (m, 2H), 6.96 (m, 1H), 6.02 (s, 1H), 4.20 (s, 3H), 3.23
(brm, 4H), 2.11 (brm, 2H), 1.99 (brm, 2H)
[2524] Mass Spectral Analysis m/z=360.1 (M+H).sup.+
Example 17A
[2525] 17A was obtained according to a procedure similar to the one
described for 15A, with the following exception:
Step 15.1: 14.4 was replaced by 16.3 (see also step 17.1).
[2526] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.93 (brs,
1.5H), 8.13 (m, 1H), 8.03 (t, 1H), 7.68 (t, 1H), 7.56 (m, 1H), 7.28
(m, 1H), 7.07 (m, 1H), 6.97 (m, 2H), 6.01 (s, 1H), 5.94 (s, 2H),
3.75 (s, 3H), 3.22 (brm, 4H), 2.12 (brm, 2H), 2.02 (brm, 2H)
[2527] Mass Spectral Analysis m/z=418.1 (M+H).sup.+
Example 17B
[2528] 17B was obtained according to a procedure similar to the one
described for 15C, with the following exception:
Step 15.1: 14.4 was replaced by 16.3 (see also step 17.1).
[2529] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.07 (brs, 2H),
8.11 (m, 1H), 8.01 (t, 1H), 7.66 (t, 1H), 7.54 (m, 1H), 7.28 (m,
1H), 7.07 (dd, 1H), 6.96 (m, 2H), 5.99 (s, 1H), 4.79 (t, 2H), 4.03
(q, 2H), 3.22 (brm, 4H), 2.42 (t, 2H), 2.21 (m, 2H), 2.09 (brm,
4H), 1.16 (t, 3H)
[2530] Mass Spectral Analysis m/z=460.2 (M+H).sup.+
Example 17C
[2531] 17C was obtained according to a procedure similar to the one
described for 15F, with the following exceptions:
Step 15.1: 14.4 was replaced by 16.3 (see also step 17.1).
[2532] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.95 (brs, 2H),
7.80 (m, 1H), 7.69 (m, 3H), 7.28 (m, 1H), 7.06 (d, 1H), 6.97 (m,
2H), 5.99 (s, 1H), 5.70 (s, 2H), 3.64 (s, 3H), 3.23 (brm, 4H), 2.10
(brm, 2H), 2.01 (brm, 2H)
[2533] Mass Spectral Analysis m/z=418.1 (M+H).sup.+
Example 17D
[2534] 17D was obtained according to a procedure similar to the one
described for 15C, with the following exceptions:
Step 15.1: 14.4 was replaced by 16.3 (see also step 17.1).
[2535] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.37 (dt, 1H),
8.30 (t, 1H), 7.81 (t, 1H), 7.71 (dt, 1H), 7.44 (m, 1H), 7.22 (m,
2H), 7.10 (m, 1H), 5.98 (s, 1H), 5.47 (t, 2H), 4.22 (brs, 2H), 4.15
(t, 2H), 4.02-3.46 (brm, 10H), 2.48 (brm, 2H), 2.22 (brm, 2H)
[2536] Mass Spectral Analysis m/z=459.2 (M+H).sup.+
Example 17E
[2537] 17E was obtained according to a procedure similar to the one
described for 15K, with the following exceptions:
Step 15.1: 14.4 was replaced by 16.3 (see also step 17.1).
[2538] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.87 (brm, 2H),
8.13 (dt, 1H), 8.03 (t, 1H), 7.68 (t, 1H), 7.56 (m, 1H), 7.28 (m,
1H), 7.07 (d, 1H), 6.98 (m, 2H), 6.01 (s, 1H), 5.77 (s, 2H), 3.24
(brm, 4H), 2.12 (brm, 2H), 2.02 (brm, 2H)
[2539] Mass Spectral Analysis m/z=404.1 (M+H).sup.+
Example 17F
[2540] 17F was obtained according to a procedure similar to the one
described for 15L, with the following exception:
Step 15.1: 14.4 was replaced by 16.3 (see also step 17.1).
[2541] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.11 (dt, 1H),
8.01 (m, 1H), 7.66 (t, 1H), 7.54 (dt, 1H), 7.28 (m, 1H), 7.07 (d,
1H), 6.97 (m, 2H), 5.99 (s, 1H), 4.78 (t, 2H), 3.21 (brm, 4H), 2.34
(t, 2H), 2.18 (m, 2H), 2.10 (brm, 4H)
[2542] Mass Spectral Analysis m/z=432.1 (M+H).sup.+
Example 18A
Preparation of 18.2
[2543] A mixture of 13.5a (0.300 g, 0.00071 mole, 1.0 eq), and the
Lawesson's reagent (18.1) (0.288 g, 0.00071 mole, 1 eq) in toluene
(10 mL) was refluxed for 6 h. The mixture was cooled to room
temperature, poured onto a saturated aqueous solution of sodium
bicarbonate (50 mL) and extracted with ethyl acetate. The organic
phase was washed with brine, dried over sodium sulfate, filtered
and concentrated under reduced pressure. Diethyl ether was added to
the mixture, which was stirred at room temperature for 1 h. The
resulting precipitate was collected by filtration, washed with
diethyl ether and used for the next step without further
purification.
[2544] Yield: 64%
[2545] Mass Spectral Analysis m/z=434.93 (M-H).sup.-
Preparation of 18.4a
[2546] A mixture of 18.2 (1 g, 0.0022 mole, 1.0 eq) and
1-bromopinacolone (18.3a) (0.30 mL, 0.0022 mole, 1.0 eq) in
N,N-dimethylformamide (5 mL) was stirred at room temperature for 48
h. The mixture was poured into a saturated aqueous solution of
sodium bicarbonate and extracted with ethyl acetate. The organic
phase was washed with brine, dried over sodium sulfate, filtered
and concentrated under reduced pressure. The crude product was
purified by flash column chromatography (eluent: hexane/ethyl
acetate mixtures of increasing polarity).
[2547] Yield: 55%
[2548] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.00 (d, 2H),
7.45 (d, 2H), 7.35 (s, 1H), 7.20 (t, 1H), 7.00 (d, 2H), 6.90 (t,
1H), 5.90 (s, 1H), 3.70 (m, 2H), 3.30 (m, 2H), 1.90 (m, 2H), 1.70
(m, 2H), 1.30 (s, 9H), 1.35 (s, 9H)
[2549] Mass Spectral Analysis m/z=517.2 (M+H).sup.+
Preparation of 18A
[2550] To a cold (0.degree. C.) solution of 18.4a (0.600 g, 0.0011
mole, 1.0 eq) in anhydrous dichloromethane (20 mL) was added drop
wise a 2.0M solution of anhydrous hydrochloric acid in diethyl
ether (5.8 mL, 0.0011 mole, 10.0 eq). The mixture was warmed slowly
to room temperature and stirring was continued for 12 h. The
mixture was concentrated under reduced pressure. Diethyl ether was
then added to the mixture, which was stirred for 1 h at room
temperature. The precipitate was collected by filtration, washed
with diethyl ether and dried under vacuum.
[2551] Yield: 80%
[2552] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.00 (s, 2H),
8.00 (d, 2H), 7.50 (d, 2H), 7.40 (s, 1H), 7.25 (t, 1H), 7.00 (m,
3H), 6.00 (s, 1H), 3.20 (m, 4H), 2.00 (m, 4H), 1.30 (s, 9H)
[2553] Mass Spectral Analysis m/z=417.3 (M+H).sup.+
Example 18B
[2554] 18B was obtained according to a procedure similar to the one
described for 18A, with the following exception:
Step 18.3: 18.3a was replaced by 18.3b.
[2555] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.93 (brs, 2H),
8.24 (s, 1H), 8.10 (m, 4H), 7.52 (m, 4H), 7.40 (m, 1H), 7.29 (m,
1H), 7.06 (t, 2H), 6.97 (m, 1H), 6.00 (s, 1H), 3.22 (brm, 4H), 2.07
(brm, 4H)
[2556] Mass Spectral Analysis m/z=437.1 (M+H).sup.+
Example 18C
Preparation of 18.6
[2557] A mixture of 14.2 (1 g, 0.00248 mole, 1.0 eq), hydroxylamine
hydrochloride (18.5) (0.260 g, 0.0037 mole, 1.5 eq.) and
triethylamine (0.70 mL, 0.0049 mole, 2.0 eq) in absolute ethanol
(15 mL) was refluxed for 6 h. The mixture was cooled to room
temperature and poured onto water. The resulting precipitate was
collected by filtration, washed with water, dried under high vacuum
and used for the next step without further purification.
[2558] Yield: 75%
[2559] Mass Spectral Analysis m/z=436.2 (M+H).sup.+
Preparation of 18.7
[2560] Acetyl chloride (6.7) (0.07 mL, 0.00097 mol, 2.0 eq) was
added drop wise to a refluxing solution of 18.6 (0.212 g, 0.00048
mole, 1.0 eq) in pyridine (2 mL). The mixture was heated to reflux
for 3 h. The mixture was cooled to room temperature, poured onto a
saturated aqueous solution of sodium bicarbonate and extracted with
ethyl acetate. The organic phase was washed with a 1N aqueous
solution of hydrochloric acid and brine, dried over sodium sulfate
and filtered. The organics were concentrated under reduced pressure
and the crude product was purified by flash column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity).
[2561] Yield: 35%
[2562] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.10 (d, 2H), 7.45
(d, 2H), 7.20 (m, 1H), 7.00 (m, 1H), 6.95 (m, 1H), 6.85 (m, 1H),
5.60 (s, 1H), 3.90 (m, 2H), 3.35 (m, 2H), 2.65 (s, 3H), 2.05 (d,
2H), 1.70 (m, 2H), 1.55 (s, 4H), 1.40 (s, 5H)
[2563] Mass Spectral Analysis m/z=460.1 (M+H).sup.+
Preparation of 18C
[2564] To a cold (0.degree. C.) solution of 18.7 (0.300 g, 0.00065
mole, 1.0 eq) in anhydrous dichloromethane (20 mL) was added drop
wise a 2.0M solution of anhydrous hydrochloric acid in diethyl
ether (3.2 mL, 0.0065 mole, 10.0 eq). The mixture was warmed slowly
to room temperature and stirring was continued for 12 h. The
mixture was concentrated under reduced pressure. Diethyl ether was
then added to the mixture, which was stirred for 1 h at room
temperature. The precipitate was collected by filtration, washed
with diethyl ether and dried under vacuum.
[2565] Yield: 60%
[2566] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.00 (m, 2H),
8.10 (m, 2H), 7.60 (m, 2H), 7.30 (m, 1H), 7.05 (m, 3H), 6.00 (s,
1H), 3.30 (m, 4H), 2.45-2.80 (m, 3H), 2.10 (m, 4H)
[2567] Mass Spectral Analysis m/z=360.3 (M+H).sup.+
Example 19A
Preparation of 19.2
[2568] To a solution of 19.1 (29.75 g, 127.5 mmol, 1.2 eq) in dry
methanol (200 mL) was added pyrrolidine (17.6 mL, 212.6 mmol, 2.0
eq) followed by 2'-hydroxyacetophenone (1.1a) (12.8 mL, 106.3 mmol,
1.0 eq). The mixture was heated under reflux for 10 h. The
volatiles were removed under reduced pressure and the residue was
dissolved in ethyl acetate (500 mL), washed with a 1M aqueous
solution of hydrochloric acid (3.times.200 mL), a 1M aqueous
solution of sodium hydroxide (3.times.200 mL) and brine. The
organics were dried over sodium sulfate, filtered and concentrated
under reduced pressure to give the crude product, which was used in
the next step without further purification.
[2569] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.86 (dd, 1H),
7.50 (m, 1H), 7.42-7.29 (m, 5H), 7.00 (m, 2H), 5.14 (s, 2H), 3.97
(brs, 2H), 3.29 (brs, 2H), 2.71 (s, 2H), 2.04 (m, 2H), 1.61 (m,
2H)
[2570] Mass Spectral Analysis m/z=352.1 (M+H).sup.+
Preparation of 19.3
[2571] Under nitrogen, to an oven-dried two-necked 1 L flask
charged with a solution of 19.2 (45.4 g, as of 106.3 mmol, 1.0 eq)
in dry tetrahydrofuran (350 mL) at -78.degree. C. was added a
solution of 1.0M solution of lithium bis(trimethylsilyl)amide in
tetrahydrofuran (127.6 mL, 127.6 mmol, 1.2 eq) over a 45 min time
period. The reaction mixture was kept at -78.degree. C. for 1 h and
a solution of N-phenylbis(trifluoromethanesulfonamide) (1.4) (45.57
g, 127.6 mmol, 1.2 eq) in tetrahydrofuran (150 mL) was added over a
45 min time period. The reaction mixture was kept at -78.degree. C.
for 1 h, then slowly warmed up to room temperature and stirred for
an additional 10 h at room temperature. Ice water (300 mL) was
added to quench the reaction and the product was extracted with
diethyl ether (500 mL). The organic phase was then washed with a 1M
aqueous solution of hydrochloric acid (3.times.150 mL), a 1M
aqueous solution of sodium hydroxide (3.times.150 mL), and brine,
dried over sodium sulfate and filtered. The organics were
concentrated under reduced pressure to give the crude product,
which was used for the next step without further purification.
[2572] Mass Spectral Analysis m/z=484.0 (M+H).sup.+
Preparation of 19.4
[2573] To a solution of 1.14 (53.58 g, 212.6 mmol, 2.0 eq) in
N,N-dimethylformamide (200 mL) at 0.degree. C. was added potassium
acetate (31.3 g, 318.9 mmol, 3.0 eq),
1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride complex
with dichloromethane (2.33 g, 3.19 mmol, 0.03 eq). The reaction
mixture was heated to 80.degree. C. at which point a solution of
19.3 (60 g, crude, as of 106.3 mmol, 1.0 eq) in
N,N-dimethylformamide (100 mL) was added to the reaction mixture
over a 30 min time period. The reaction mixture was then stirred at
80.degree. C. for 10 h. Diethyl ether (500 mL) and water (300 mL)
were added and the two phases were separated. The organic phase was
washed with a 1M aqueous solution of hydrochloric acid (2.times.150
mL) and brine, dried over sodium sulfate and filtered. The organics
were concentrated under reduced pressure and the crude product was
purified by column chromatography (eluent: hexane/ethyl acetate
mixtures of increasing polarity).
[2574] Yield: 75% over three steps
[2575] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.71 (dd, 1H),
7.43-7.28 (m, 5H), 7.11 (m, 1H), 6.90 (m, 1H), 6.82 (dd, 1H), 6.27
(s, 1H), 5.14 (s, 2H), 3.94 (brs, 2H), 3.34 (brs, 2H), 1.96 (m,
2H), 1.61 (m, 2H), 1.33 (s, 12H)
[2576] Mass Spectral Analysis m/z=462.2 (M+H).sup.+
Preparation of 19.6
[2577] To a solution of tert-butyl 4-bromophenylcarbamate (19.5)
(20.7 g, 76 mmol, 1.04 eq) in dimethoxyethane (200 mL) was added
sequentially a 2M aqueous solution of sodium carbonate (109.5 mL,
210 mmol, 3.0 eq), lithium chloride (9.28 g, 210 mmol, 3.0 eq),
tetrakis(triphenylphosphine)palladium(0) (1.69 g, 1.46 mmol, 0.02
eq), and 19.4 (33.7 g, 73 mmol, 1.0 eq) under nitrogen. The
reaction mixture was heated under reflux for 10 h. Water (500 mL)
and diethyl ether (300 mL) were added and the two phases were
separated. The organic phase was washed with brine, dried over
sodium sulfate, filtered, and concentrated under reduced pressure.
The resulting foamy solids were soaked with hexane and the fine
powders were collected by filtration.
[2578] Yield: 91%
[2579] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.43-7.30 (m, 7H),
7.28-7.23 (m, 2H), 7.17 (m, 1H), 7.02 (m, 1H), 6.92 (m, 1H), 6.85
(m, 1H), 6.53 (s, 1H), 5.50 (s, 1H), 5.15 (s, 2H), 3.96 (brs, 2H),
3.40 (brs, 2H), 2.06 (m, 2H), 1.67 (m, 2H), 1.53 (s, 9H)
[2580] Mass Spectral Analysis m/z=527.4 (M+H).sup.+
Preparation of 19.7
[2581] To a cold (0.degree. C.) solution of 19.6 (35.5 g, 67 mmol,
1.0 eq) in anhydrous dichloromethane (150 mL) was slowly added a
2.0M solution of hydrogen chloride in diethyl ether (167.5 mL, 335
mmol, 5.0 eq). The reaction mixture was stirred at room temperature
for 10 h and then concentrated under reduced pressure. The
resulting foamy solids were soaked in diethyl ether and the fine
powders were collected by filtration. This crude product was used
for the next steps without further purification.
[2582] Mass Spectral Analysis m/z=427.3 (M+H).sup.+
Preparation of 19.9a
[2583] To a suspension of 19.7 (1.28 g, crude, as of 3 mmol, 1.0
eq) in dry dichloromethane (80 mL) at 0.degree. C. was slowly added
triethylamine (2.1 mL, 15 mmol, 5.0 eq) followed by drop wise
addition of isobutyryl chloride (19.8a) (0.48 mL, 4.5 mmol, 1.5
eq). The mixture was slowly warmed to room temperature and stirred
for 10 h at room temperature. Dichloromethane (100 mL) was added
and the mixture was washed with a 1N aqueous solution of
hydrochloric acid (3.times.50 mL), a saturated aqueous solution of
sodium bicarbonate (2.times.50 mL) and brine, dried over sodium
sulfate and filtered. The crude product was concentrated under
reduced pressure and purified by column chromatography (eluent:
hexane/ethyl acetate mixtures of increasing polarity).
[2584] Yield: 81% over two steps
[2585] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.57 (d, 2H),
7.40-7.27 (m, 8H), 7.17 (m, 1H), 7.01 (d, 1H), 6.93 (d, 1H), 6.85
(m, 1H), 5.50 (s, 1H), 5.15 (s, 2H), 3.96 (brs, 2H), 3.41 (brs,
2H), 2.53 (m, 1H), 2.06 (m, 2H), 1.67 (m, 2H), 1.28 (d, 6H)
[2586] Mass Spectral Analysis m/z=467.3 (M+H).sup.+
Preparation of 19A
[2587] To a stirred solution of 19.9a (1.2 g, 2.44 mmol, 1.0 eq) in
dry dichloromethane (20 mL) was added iodotrimethylsilane (0.66 mL,
4.89 mmol, 2.0 eq) drop wise. After stirring at room temperature
for 1 h, the mixture was concentrated to dryness under reduced
pressure. A 1N aqueous solution of hydrochloric acid (300 mL) and
diethyl ether (200 mL) were added to the residue. The resulting
solid was collected by filtration, washed with diethyl ether, and
dried under vacuum.
[2588] Yield: 92%
[2589] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.02 (s, 1H),
8.98 (brs, 2H), 7.70 (d, 2H), 7.36-7.22 (m, 3H), 7.02 (m, 2H), 6.94
(m, 1H), 5.82 (s, 1H), 3.21 (m, 4H), 2.63 (m, 1H), 2.03 (m, 4H),
1.11 (d, 6H)
[2590] Mass Spectral Analysis m/z=363.4 (M+H).sup.+
Example 19B
[2591] 19B was obtained according to a procedure similar to the one
described for 19A, with the following exception:
Step 19.6: 19.8a was replaced by 19.8b.
[2592] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.04 (s, 1H),
8.90 (m, 2H), 7.71 (m, 2H), 7.29 (m, 2H), 7.25 (m, 1H), 7.03 (m,
2H), 6.94 (m, 1H), 5.82 (s, 1H), 3.44-3.11 (m, 4H), 2.25 (m, 1H),
2.02 (m, 4H), 1.51 (m, 4H), 0.86 (t, 6H)
[2593] Mass Spectral Analysis m/z=391.4 (M+H).sup.+
Example 19C
Preparation of 19.10
[2594] To a solution of 19.7 (4.63 g, crude, as of 10 mmol, 1.0 eq)
in dry pyridine (10 mL) at 0.degree. C. was slowly added
isopropylsulfonyl chloride (6.5b) (1.68 mL, 15 mmol, 1.5 eq). The
reaction mixture was stirred at room temperature for 10 h. Pyridine
was removed under reduced pressure and the residue was dissolved in
ethyl acetate (200 mL). The solution was washed with a 1M aqueous
solution of hydrochloric acid (5.times.50 mL) and brine, dried over
sodium sulfate and filtered. The filtrate was concentrated under
reduced pressure and the crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[2595] Yield: 55% over two steps
[2596] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.43-7.16 (m,
10H), 6.99 (dd, 1H), 6.94 (dd, 1H), 6.86 (m, 1H), 6.60 (s, 1H),
5.51 (s, 1H), 5.15 (s, 2H), 3.96 (brs, 2H), 3.49-3.30 (m, 3H), 2.06
(m, 2H), 1.67 (m, 2H), 1.43 (d, 6H)
[2597] Mass Spectral Analysis m/z=533.3 (M+H).sup.+
Preparation of 19C
[2598] To a stirred solution of 19.9a (1.37 g, 2.57 mmol, 1.0 eq)
in dry dichloromethane (20 mL) was added iodotrimethylsilane (0.70
mL, 5.14 mmol, 2.0 eq) dropwise. The mixture was stirred at room
temperature for 1 h and then concentrated under reduced pressure.
To the residue was added a 1M aqueous solution of hydrochloric acid
(300 mL) and diethyl ether (200 mL). The resulting solid was
collected by filtration and washed with diethyl ether. The crude
compound was further purified by preparative liquid chromatography
(mobile phase: acetonitrile/water/trifluoroacetic acid). The
desired fractions were combined, concentrated under reduced
pressure, and dried under vacuum.
[2599] Yield: 66%
[2600] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.93 (brs, 1H),
8.67 (brs, 2H), 7.36-7.22 (m, 5H), 7.05-6.91 (m, 3H), 5.83 (s, 1H),
3.32-3.14 (m, 5H), 2.06 (m, 2H), 1.93 (m, 2H), 1.26 (d, 6H)
[2601] Mass Spectral Analysis m/z=399.3 (M+H).sup.+
Example 19D
Preparation of 19.12
[2602] To a solution of 19.7 (1.28 g, crude, as of 2.67 mmol, 1.0
eq) in dry pyridine (15 mL) at 0.degree. C. was slowly added ethyl
isocyanate (19.11) (0.33 mL, 4.15 mmol, 1.5 eq). The reaction
mixture was stirred at room temperature for 10 h. Pyridine was
removed under reduced pressure and the residue was partitioned
between water (100 mL) and dichlorometnane (200 mL). The organic
layer was washed with brine, dried over sodium sulfate, filtered,
and concentrated under reduced pressure. The crude product was
purified by column chromatography (eluent: hexane/ethyl acetate
mixtures of increasing polarity).
[2603] Yield: 78% over two steps
[2604] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.44-7.12 (m,
10H), 7.05-6.79 (m, 4H), 5.45 (s, 1H), 5.16 (m, 3H), 3.95 (brs,
2H), 3.50-3.26 (m, 4H), 2.04 (m, 2H), 1.65 (m, 2H), 1.16 (t,
3H)
[2605] Mass Spectral Analysis m/z=498.4 (M+H).sup.+
Preparation of 19D
[2606] To a stirred solution of 19.12 (1.03 g, 2.09 mmol, 1.0 eq)
in dry dichloromethane (20 mL) was added iodotrimethylsilane (0.57
mL, 4.18 mmol, 2.0 eq) drop wise. The reaction mixture was stirred
at room temperature for 1 h and then concentrated under reduced
pressure. The residue was suspended in methanol (50 mL) and stirred
for another 1 h at room temperature. The resulting solid was
collected by filtration and washed with methanol. The solid was
further washed with a 1M aqueous solution of sodium hydroxide
(3.times.10 mL) and water (2.times.10 mL), and then dried under
vacuum.
[2607] Yield: 60%
[2608] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.54 (s, 1H),
7.44 (d, 2H), 7.18 (m, 3H), 6.98 (m, 1H), 6.91 (m, 1H), 6.86 (m,
1H), 6.13 (t, 1H), 5.72 (s, 1H), 3.11 (m, 2H), 2.89 (m, 2H), 2.74
(m, 2H), 1.77 (m, 2H), 1.67 (m, 2H), 1.06 (t, 3H)
[2609] Mass Spectral Analysis m/z=364.4 (M+H).sup.+
Example 20A
Preparation of 20A
[2610] Triethylamine (0.37 mL, 2.66 mmol, 2.2 eq) was added to a
solution of 1A (0.50 g, 1.21 mmol, 1.0 eq) in anhydrous
tetrahydrofuran (4 mL). Anhydrous methanol (4 mL) was then added
followed by 20.1a (0.20 mL, 2.42 mmol, 2.0 eq). Sodium
cyanoborohydride (0.09 g, 1.45 mmol, 1.2 eq) was added to the
reaction mixture which was stirred for 30 min at room temperature
under nitrogen. The mixture was concentrated under reduced
pressure. Dichloromethane (30 mL) and water (10 mL) were added and
the suspension was stirred at room temperature for 10 min. The
phases were separated. The organic phase was further washed with
water and brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure. To a cold (0.degree. C.)
solution of the resulting oil in anhydrous dichloromethane was
added drop wise a 2.0M solution of anhydrous hydrochloric acid in
diethyl ether (5 mL). The mixture was then stirred for 1 h at room
temperature and concentrated under reduced pressure. Diethyl ether
was added. The resulting precipitate was collected by filtration
and washed with diethyl ether.
[2611] Yield: 65%
[2612] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.63 (brs,
0.25H), 10.50 (brs, 0.75H), 7.42 (m, 4H), 7.28 (m, 1H), 7.08 (d,
1H), 6.98 (m, 2H), 6.27 (s, 0.25H), 5.85 (s, 0.75H), 3.37 (brm,
8H), 2.82 (s, 3H), 2.11 (m, 4H), 1.12 (m, 6H)
[2613] Mass Spectral Analysis m/z=391.2 (M+H).sup.+
[2614] Elemental analysis:
[2615] C.sub.25H.sub.30N.sub.2O.sub.2, 1HCl, 0.9H.sub.2O
[2616] Theory: % C, 67.75; % H, 7.46; % N, 6.32.
[2617] Found: % C, 67.89; % H, 7.32; % N, 6.26.
Example 20B
[2618] 20B was obtained according to a procedure similar to the one
described for 20A, with the following exception:
Step 20.1: 1A was replaced by 11A.
[2619] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.42 (brs, 1H),
9.47 (s, 1H), 7.30 (m, 4H), 7.08 (t, 1H), 6.60 (d, 1H), 6.46 (d,
1H), 5.68 (s, 1H), 3.40 (m, 4H), 3.30 (s, 3H), 3.20 (m, 2H), 2.81
(s, 2H), 2.15 (m, 2H), 2.05 (m, 2H), 1.10 (m, 6H)
[2620] Mass Spectral Analysis m/z=407.3 (M+H).sup.+
[2621] Elemental analysis:
[2622] C.sub.25H.sub.30N.sub.2O.sub.3, 1HCl, 0.5H.sub.2O
[2623] Theory: % C, 66.43; % H, 7.14; % N, 6.20.
[2624] Found: % C, 66.53; % H, 7.06; % N, 6.24.
Example 20C
[2625] 20C was obtained according to a procedure similar to the one
described for 20A, with the following exception:
Step 20.1: 1A was replaced by 111B.
[2626] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.79 (brs, 1H),
9.74 (d, 1H), 8.41 (s, 1H), 7.69 (dd, 1H), 7.45 (d, 1H), 7.09 (t,
1H), 6.62 (d, 1H), 6.49 (d, 2H), 5.81 (s, 1H), 3.42 (m, 4H), 3.30
(m, 4H), 2.79 (d, 3H), 2.12 (m, 4H), 1.16 (m, 3H), 1.08 (m, 3H)
[2627] Mass Spectral Analysis m/z=408.3 (M+H).sup.+
Example 20D
[2628] 20D was obtained according to a procedure similar to the one
described for 20A, with the following exception:
Step 20.1: 1A was replaced by 3D.
[2629] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 11.00 (m,
0.25H), 10.85 (m, 0.75H), 7.80 (m, 2H), 7.54 (m, 1H), 7.40 (m, 4H),
7.22 (m, 1H), 7.10 (m, 0.75H), 7.02 (m, 0.25H), 6.32 (s, 0.25H),
5.91 (s, 0.75H), 3.33 (m, 10H), 2.80 (m, 2H), 2.20 (m, 3H), 1.11
(m, 6H)
[2630] Mass Spectral Analysis m/z=434.4 (M+H).sup.+
[2631] Elemental analysis:
[2632] C.sub.26H.sub.31N.sub.3O.sub.3, 1HCl, 1H.sub.2O
[2633] Theory: % C, 63.99; % H, 7.02; % N, 8.61.
[2634] Found: % C, 64.11; % H, 6.70; % N, 8.49.
Example 20E
[2635] 20E was obtained according to a procedure similar to the one
described for 20A, with the following exception:
Step 20.1: 1A was replaced by 3E.
[2636] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.84 (m, 1H),
8.31 (m, 1H), 7.78 (m, 1H), 7.52 (m, 1H), 7.42 (m, 3H), 7.10 (m,
1H), 5.90 (s, 1H), 3.46 (m, 2H), 3.31 (m, 10H), 2.82 (m, 2H), 2.72
(m, 2H), 2.12 (m, 3H), 1.16 (m, 6H)
[2637] Mass Spectral Analysis m/z=448.5 (M+H).sup.+
[2638] Elemental analysis:
[2639] C.sub.27H.sub.33N.sub.3O.sub.3, 1HCl, 1H.sub.2O
[2640] Theory: % C, 64.59; % H, 7.23; % N, 8.37.
[2641] Found: % C, 64.77; % H, 7.27; % N, 8.40.
Example 20F
[2642] 20F was obtained according to a procedure similar to the one
described for 20A, with the following exception:
Step 20.1: 1A was replaced by 3F.
[2643] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.80 (brs, 1H),
8.35 (m, 1H), 7.78 (m, 1H), 7.50 (m, 1H), 7.40 (m, 3H), 7.09 (m,
1H), 5.93 (s, 1H), 3.41 (m, 2H), 3.20 (m, 10H), 2.72 (m, 2H), 2.10
(m, 3H), 1.10 (m, 9H)
[2644] Mass Spectral Analysis m/z=462.5 (M+H).sup.+
[2645] Elemental analysis:
[2646] C.sub.28H.sub.35N.sub.3O.sub.3, 1HCl, 1H.sub.2O
[2647] Theory: % C, 65.17; % H, 7.42; % N, 8.14.
[2648] Found: % C, 65.28; % H, 7.37; % N, 8.21.
Example 20G
[2649] 20G was obtained according to a procedure similar to the one
described for 20A, with the following exception:
Step 20.1: 1A was replaced by 3V.
[2650] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.57 (s, 1H), 7.70
(m, 2H), 7.66 (d, 1H), 7.38 (s, 1H), 7.02 (d, 1H), 5.70 (s, 1H),
3.61 (m, 2H), 3.46 (m, 2H), 2.62 (m, 2H), 2.52 (m 2H), 2.12 (m,
2H), 2.78 (m, 2H), 1.30 (t, 3H), 1.23 (t, 3H)
[2651] Mass Spectral Analysis m/z=435.4 (M+H).sup.+
Example 20H
[2652] 20H was obtained according to a procedure similar to the one
described for 20L, with the following exception:
Step 20.1: 21A was replaced by 4H and 20.1d was replaced by
20.1a.
[2653] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.44-10.12 (m,
1H), 7.74 (dd, 0.7H), 7.67 (dd, 0.7H), 7.45 (m, 5H), 7.27 (m, 3H),
6.38 (s, 0.3H), 6.00 (s, 0.7H), 3.53-3.16 (m, 8H), 2.84 (m, 3H),
2.35-2.03 (m, 4H), 1.12 (brd, 6H)
[2654] Mass Spectral Analysis m/z=470.3 (M+H).sup.+
[2655] Elemental analysis:
[2656] C.sub.25H.sub.31N.sub.3O.sub.4S, 1HCl, 1H.sub.2O
[2657] Theory: % C, 57.30; % H, 6.54; % N, 8.02.
[2658] Found: % C, 57.46; % H, 6.44; % N, 7.96.
Example 20I
[2659] 20I was obtained according to a procedure similar to the one
described for 20L, with the following exception:
Step 20.1: 20.1d was replaced by 20.1a.
[2660] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.62 (brs, 1H),
7.41 (m, 4H), 7.24 (m, 1H), 6.97 (m, 2H), 6.93 (m, 1H), 5.92 &
5.86 (2s, 1H, rotamer), 3.55-2.92 (m, 8H), 2.80 & 2.77 (d, 3H),
2.56-1.76 (m, 6H), 1.12 (m, 6H)
[2661] Mass Spectral Analysis m/z=405.4 (M+H).sup.+
Example 20J
[2662] 20J was obtained according to a procedure similar to the one
described for 20L, with the following exception:
Step 20.1: 20.1d was replaced by 20.1b.
[2663] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.72 (m, 1H),
7.41 (m, 4H), 7.24 (m, 1H), 6.95 (m, 3H), 5.91 & 5.84 (2s, 1H,
rotamer), 3.56-2.94 (m, 10H), 2.57-1.77 (m, 6H), 1.27 (m, 3H), 1.12
(m, 6H)
[2664] Mass Spectral Analysis m/z=419.4 (M+H).sup.+
Example 20K
[2665] 20K was obtained according to a procedure similar to the one
described for 20L, with the following exception:
Step 20.1: 20.1d was replaced by 20.1c.
[2666] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.99 (m, 1H),
7.41 (m, 4H), 7.25 (m, 1H), 6.95 (m, 3H), 5.88 & 5.86 (2s, 1H
rotamer), 3.70-2.93 (m, 10H), 2.57-1.76 (m, 7H), 1.12 (m, 6H), 0.99
(m, 6H)
[2667] Mass Spectral Analysis m/z=447.5 (M+H).sup.+
Example 20L
Preparation of 20L
[2668] To a stirred solution of cyclopropanecarbaldehyde (20.1d)
(0.22 mL, 3.0 mmol, 2.0 eq) in dry dichloromethane (25 mL) was
added sequentially 21A (0.64 g, 1.5 mmol, 1.0 eq), acetic acid
(0.10 mL, 1.8 mmol, 1.2 eq), and sodium cyanoborohydride (0.14 g,
2.25 mmol, 1.5 eq). The reaction mixture was stirred at room
temperature for 10 h. Water (40 mL) was added and the aqueous layer
was basified to pH=10 with a 1M aqueous solution of sodium
hydroxide. The two phases were separated and the aqueous phase was
saturated with sodium chloride and extracted with dichloromethane
(3.times.50 mL). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography (eluent:
dichloromethane/methanol mixtures of increasing polarity). The
desired fractions were combined and concentrated under reduced
pressure. To a cold (0.degree. C.) solution of the resulting oil in
dichloromethane was added dropwise a 2.0M solution of hydrogen
chloride in diethyl ether (1.0 mL, 2.0 mmol, 2.0 eq). The mixture
was then stirred for 1 h at room temperature, concentrated under
reduced pressure, and dried under vacuum.
[2669] Yield: 65%
[2670] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.66 (brs, 1H),
7.41 (m, 4H), 7.25 (m, 1H), 7.03-6.89 (m, 3H), 5.91 & 5.86 (2s,
1H, rotomer), 3.80-2.95 (m, 10H), 2.44-1.78 (m, 6H), 1.12 (m, 7H),
0.64 (m, 2H), 0.42 (m, 2H)
[2671] Mass Spectral Analysis m/z=445.4 (M+H).sup.+
Example 20M
Preparation of 20M
[2672] Triethylamine (0.98 mL, 7.00 mmol, 3.3 eq) was added to a
solution of 1A (0.80 g, 2.12 mmol, 1.0 eq) in anhydrous
dichloromethane (5 mL). Compound 2.8a (0.68 mL, 7.00 mmol, 3.3 eq)
was then added to the reaction mixture, which was stirred overnight
at room temperature under nitrogen. The mixture was concentrated
under reduced pressure. The crude product was purified by column
chromatography (eluent: dichloromethane/methanol mixtures of
increasing polarity). To a solution of the purified product in
dichloromethane (5 mL) was added at 0.degree. C. a 2.0 M solution
of hydrochloric acid in diethyl ether (3.2 mL, 1.16 mmol, 5.5 eq).
Diethyl ether was added to the mixture. The resulting precipitate
was collected by filtration and washed with diethyl ether.
[2673] Yield: 46%
[2674] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.83 (m,
0.25H), 10.71 (m, 0.75H), 7.45 (m, 4H), 7.28 (m, 1H), 7.08 (m, 1H),
7.00 (m, 2H), 6.24 (s, 0.25H), 5.85 (s, 0.75H), 3.47 (m, 5H), 3.25
(m, 4H), 3.06 (m, 2H), 2.18 (m, 4H), 1.12 (m, 6H), 0.65 (m, 2H),
0.43 (m, 2H)
[2675] Mass Spectral Analysis m/z=431.0 (M+H).sup.+
Example 20N
[2676] 20N was obtained according to a procedure similar to the one
described for 20M, with the following exception:
Step 20.1: 2.8a was replaced by 20.2a.
[2677] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.10 (m, 1H),
7.43 (m, 4H), 7.28 (m, 1H), 7.09 (m, 1H), 6.98 (m, 2H), 6.28 (s,
0.25H), 5.85 (s, 0.75H), 3.35 (brm, 10H), 2.15 (m, 4H), 1.28 (m,
3H), 1.11 (m, 6H)
[2678] Mass Spectral Analysis m/z=405.0 (M+H).sup.+
Example 20O
[2679] 20O was obtained according to a procedure similar to the one
described for 20M, with the following exception:
Step 20.1: 2.8a was replaced by 20.2b.
[2680] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.18 (m, 1H),
7.45 (m, 4H), 7.29 (m, 1H), 7.09 (m, 1H), 6.98 (m, 2H), 6.25 (m,
0.25H), 5.84 (m, 0.75H), 3.41 (m, 4H), 3.21 (m, 4H), 3.09 (m, 2H),
2.16 (m, 4H), 1.75 (m, 2H), 1.11 (m, 6H), 0.91 (m, 3H)
[2681] Mass Spectral Analysis m/z=419.1 (M+H).sup.+
Example 20P
[2682] 20P was obtained according to a procedure similar to the one
described for 20M, with the following exception:
Step 20.1: 2.8a was replaced by 20.2c.
[2683] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.35 (m, 9H), 7.17
(m, 1H), 6.98 (dd, 1H), 6.94 (dd, 1H), 6.84 (m, 1H), 5.61 (s, 1H),
3.58 (brs, 4H), 3.32 (brs, 2H), 2.60 (brm, 4H), 2.08 (brm, 2H),
1.81 (brm, 2H), 1.20 (brd, 6H)
[2684] Mass Spectral Analysis m/z=467.3 (M+H).sup.+
Example 20Q
[2685] 20Q was obtained according to a procedure similar to the one
described for 20M, with the following exception:
Step 20.1: 2.8a was replaced by 20.2d.
[2686] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.95 (brs,
0.5H) 7.44 (m, 4H), 7.33 (m, 6H), 7.04 (d, 1H), 6.99 (m, 2H), 6.24
(s, 0.3H), 5.87 (s, 0.7H), 3.40 (brm, 10H), 3.12 (m, 2H), 2.18
(brm, 4H), 1.13 (brd, 6H)
[2687] Mass Spectral Analysis m/z=481.3 (M+H).sup.+
Example 20R
[2688] 20R was obtained according to a procedure similar to the one
described for 20M, with the following exception:
Step 20.1: 2.8a was replaced by 20.2e.
[2689] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.70 (brm,
0.50H), 7.43 (m, 4H), 7.28 (m, 6H), 7.08 (d, 1H), 6.97 (m, 2H),
6.36 (s, 0.3H), 5.83 (s, 0.7H), 3.44 (m, 4H), 3.18 (brm, 6H), 2.67
(t, 2H), 2.12 (brm, 6H), 1.12 (brd, 6H)
[2690] Mass Spectral Analysis m/z=495.3 (M+H).sup.+
Example 21A
Preparation of 21.2
[2691] To a stirred solution of N-boc 4-piperidone (1.2) (2.0 g, 10
mmol, 1.0 eq) in dry diethyl ether (15 mL) at -25.degree. C. was
simultaneously but independently added ethyl diazoacetate (21.1)
(1.35 mL, 13 mmol, 1.3 eq) and boron trifluoride diethyl ether
complex (1.33 mL, 10.5 mmol, 1.05 eq) under nitrogen atmosphere
over a 20 min time period. The reaction mixture was stirred for
another 1 h at -25.degree. C. A 1M aqueous solution of potassium
carbonate was added drop wise to the stirred reaction mixture until
gaseous evolution ceased. The two phases were separated and the
organic phase was dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The crude product was used for
the next step without further purification.
Preparation of 21.3
[2692] A mixture of the crude 21.2 (3 g, as of 10 mmol) in a 4M
aqueous hydrochloric acid solution (50 mL) was heated under reflux
for 6 h. Water was removed under reduced pressure and the resulting
solid was washed with diethyl ether and dried under vacuum.
[2693] Yield: 90% over two steps
[2694] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.41 (brs, 2H),
3.30 (m, 2H), 3.21 (m, 2H), 2.77 (m, 2H), 2.62 (m, 2H), 1.94 (m,
2H)
Preparation of 21.4
[2695] To a suspension of 21.3 (4.98 g, 33.3 mmol, 1.0 eq) in dry
dichloromethane (100 mL) at 0.degree. C. was slowly added
triethylamine (11 mL, 79.92 mmol, 2.4 eq) followed by a solution of
di-tert-butyl-dicarbonate (4.7) (8.72 g, 39.96 mmol, 1.2 eq) in
dichloromethane (30 mL) over a 20 min time period. The reaction
mixture was stirred at room temperature for 10 h and washed with a
1M aqueous solution of hydrochloric acid (3.times.100 mL), brine,
dried over sodium sulfate and filtered. The filtrate was
concentrated under reduced pressure and the crude product was used
for next step without further purification.
[2696] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.58 (m, 4H), 2.65
(m, 4H), 1.78 (m, 2H), 1.45 (s, 9H)
Preparation of 21.5
[2697] To a solution of 21.4 (2.56 g, 12 mmol, 1.0 eq) in dry
methanol (30 mL) was added pyrrolidine (2 mL, 24 mmol, 2.0 eq)
followed by 2'-hydroxyacetophenone (1.1a) (1.44 mL, 12 mmol, 1.0
eq). The mixture was heated under reflux for 10 h. The volatiles
were removed under reduced pressure and the residue was dissolved
in ethyl acetate (200 mL) and washed with a 1M aqueous solution of
hydrochloric acid (3.times.50 mL), a 1M aqueous solution of sodium
hydroxide (3.times.50 mL) and brine, dried over sodium sulfate and
filtered. The filtrate was concentrated under reduced pressure and
the crude product was purified by column chromatography (eluent:
hexane/ethyl acetate mixtures of increasing polarity).
[2698] Yield: 72% over two steps
[2699] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85 (dd, 1H),
7.49 (m, 1H), 6.99 (m, 2H), 3.78-3.49 (m, 2H), 3.32 (m, 2H),
2.83-2.63 (m, 2H), 2.19 (m, 2H), 2.00-1.55 (m, 4H), 1.47 (s,
9H)
[2700] Mass Spectral Analysis m/z=331.9 (M+H).sup.+
Preparation of 21.6
[2701] To an oven-dried two-neck 250 mL flask charged with a
solution of 21.5 (2.86 g, 8.6 mmol, 1.0 eq) in dry tetrahydrofuran
(40 mL) at -78.degree. C. under nitrogen was added a 1.0M solution
of lithium bis(trimethylsilyl)amide in tetrahydrofuran (10.3 mL,
10.3 mmol, 1.2 eq) over a 10 min time period. The mixture was kept
at -78.degree. C. for 1 h and a solution of
N-phenylbis(trifluoromethanesulfonamide) (1.4) (3.68 g, 10.3 mmol,
1.2 eq) in tetrahydrofuran (20 mL) was added to the mixture over a
10 min time period. The mixture was kept at -78.degree. C. for
another 1 h, then slowly warmed to room temperature and stirred for
an additional 10 h at room temperature. Ice water (50 mL) was added
to quench the reaction and the product was extracted with diethyl
ether (200 mL). The organic phase was then washed with a 1N aqueous
solution of hydrochloric acid (3.times.50 mL), a 1N aqueous
solution of sodium hydroxide (3.times.50 mL) and brine, dried over
sodium sulfate and filtered. The filtrate was concentrated under
reduced pressure and the crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[2702] Yield: 85%
[2703] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30-7.23 (m, 2H),
6.97 (m, 1H), 6.89 (m, 1H), 5.60 (s, 1H), 3.80-3.53 (m, 2H),
3.36-3.24 (m, 2H), 2.30-2.06 (m, 3H), 1.90-1.64 (m, 3H), 1.47 (s,
9H)
Preparation of 21.7
[2704] To a solution of 21.6 (3.38 g, 7.3 mmol, 1.0 eq) in
dimethoxyethane (50 mL) was added sequentially a 2M aqueous
solution of sodium carbonate (11 mL, 22 mmol, 3.0 eq), lithium
chloride (0.93 g, 22 mmol, 3.0 eq),
tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol, 0.02
eq), and 4-N,N-diethylphenylboronic acid (1.6) (1.77 g, 8.02 mmol,
1.1 eq) under a nitrogen atmosphere. The reaction mixture was
heated under reflux for 10 h and then cooled to room temperature.
Water (200 mL) and diethyl ether (300 mL) were added and the two
phases were separated. The organic phase was washed with brine,
dried over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity).
[2705] Yield: 81%
[2706] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (m, 4H), 7.18
(m, 1H), 6.99 (d, 1H), 6.92 (d, 1H), 6.85 (m, 1H), 5.60 (s, 1H),
3.86-3.50 (m, 4H), 3.42-3.24 (m, 4H), 2.27-1.68 (m, 6H), 1.48 (s,
9H), 1.21 (m, 6H)
[2707] Mass Spectral Analysis m/z=491.0 (M+H).sup.+
Preparation of 21A
[2708] To a cold (0.degree. C.) solution of 21.7 (1.15 g, 2.34
mmol, 1.0 eq) in anhydrous dichloromethane (20 mL) was added
dropwise a 4.0M solution of hydrogen chloride in dioxane (3.51 mL,
14.04 mmol, 6.0 eq). The mixture was stirred at room temperature
for 10 h and concentrated under reduced pressure. The resulting
foamy solids were soaked in diethyl ether. The resulting fine
powder was collected by filtration and washed with diethyl
ether.
[2709] Yield: 98%
[2710] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.76 (m, 2H), 7.41
(m, 2H), 7.36 (m, 2H), 7.20 (m, 1H), 7.00 (dd, 1H), 6.97 (dd, 1H),
6.88 (m, 1H), 5.63 (s, 1H), 3.68-3.23 (m, 8H), 2.50-2.23 (m, 4H),
2.02-1.82 (m, 2H), 1.35-1.07 (m, 6H)
[2711] Mass Spectral Analysis m/z=391.2 (M+H).sup.+
[2712] Elemental analysis:
[2713] C.sub.25H.sub.30N.sub.2O.sub.2, 1HCl
[2714] Theory: % C, 70.32; % H, 7.32; % N, 6.56.
[2715] Found: % C, 70.14; % H, 7.23; % N, 6.55.
Example 21B
Preparation of 21.7a & 21.7b
[2716] The racemic compound 21.7 (15 g) was resolved by chiral HPLC
to provide 21.7a (6.7 g) and 21.7b (6.0 g) as pure enantiomers.
Chiral separation conditions: [2717] Column: Chiralcel OJ,
4.6.times.250 mm [2718] Flow: 1.0 mL/min [2719] Temperature: room
temperature [2720] Detection: 335 nm [2721] Mobile Phase
Methanol
[2722] 21.7a: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.38 (m,
4H), 7.18 (m, 1H), 6.99 (dd, 1H), 6.92 (dd, 1H), 6.85 (m, 1H), 5.60
(s, 1H), 3.84-3.49 (m, 4H), 3.31 (m, 4H), 2.25-1.65 (m, 6H), 1.48
(s, 9H), 1.21 (m, 6H)
[2723] Mass Spectral Analysis m/z=491.3 (M+H).sup.+
[2724] [.quadrature.].sub.D.sup.25=-1.04 (c. 1.14 mg/mL, MeOH)
[2725] Chiral purity: ee=99%; t.sub.R=4.6 min
[2726] 21.7b: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (m,
4H), 7.18 (m, 1H), 6.99 (dd, 1H), 6.92 (dd, 1H), 6.85 (m, 1H), 5.60
(s, 1H), 3.85-3.48 (m, 4H), 3.31 (m, 4H), 2.25-1.66 (m, 6H), 1.48
(s, 9H), 1.21 (m, 6H)
[2727] Mass Spectral Analysis m/z=491.3 (M+H).sup.+
[2728] [.quadrature.].sub.D.sup.25=+1.07 (c. 1.16 mg/mL, MeOH)
[2729] Chiral purity: ee=99%; t.sub.R=5.2 min
Preparation of 21B
[2730] To a cold (0.degree. C.) solution of 21.7a (1.3 g, 2.65
mmol, 1.0 eq) in anhydrous dichloromethane (20 mL) was added drop
wise a 4.0M solution of hydrogen chloride in dioxane (3.31 mL,
13.25 mmol, 5.0 eq). The reaction mixture was stirred at room
temperature for 10 h and then concentrated under reduced pressure.
The foamy solids were soaked in diethyl ether and the resulting
fine powder was collected by filtration and washed with diethyl
ether.
[2731] Yield: 87%
[2732] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.97 (brs, 2H),
7.41 (m, 4H), 7.24 (m, 1H), 7.00-6.89 (m, 3H), 5.89 (s, 1H),
3.54-3.01 (m, 8H), 2.30-2.10 (m, 3H), 2.03-1.88 (m, 2H), 1.78 (m,
1H), 1.23-0.99 (m, 6H)
[2733] Mass Spectral Analysis m/z=391.3 (M+H).sup.+
[2734] Elemental analysis:
[2735] C.sub.25H.sub.30N.sub.2O.sub.2, 1HCl, 1/6H.sub.2O
[2736] Theory: % C, 69.83; % H, 7.35; % N, 6.51.
[2737] Found: % C, 69.84; % H, 7.27; % N, 6.46.
[2738] [.alpha.].sub.D.sup.25=+0.18 (c. 10.0 mg/mL, MeOH)
Example 21C
Preparation of 21C
[2739] To a cold (0.degree. C.) solution of 21.7b (1.3 g, 2.65
mmol, 1.0 eq) in anhydrous dichloromethane (20 mL) was added drop
wise a 4.0 M solution of hydrogen chloride in dioxane (3.31 mL,
13.25 mmol, 5.0 eq). The reaction mixture was stirred at room
temperature for 10 h and then concentrated under reduced pressure.
The foamy solids were soaked in diethyl ether and the resulting
fine powder was collected by filtration and washed with diethyl
ether.
[2740] Yield: 89%
[2741] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.00 (brs, 2H),
7.41 (m, 4H), 7.24 (m, 1H), 7.02-6.89 (m, 3H), 5.89 (s, 1H),
3.52-3.02 (m, 8H), 2.35-2.10 (m, 3H), 2.04-1.88 (m, 2H), 1.78 (m,
1H), 1.23-0.99 (m, 6H)
[2742] Mass Spectral Analysis m/z=391.3 (M+H).sup.+
[2743] Elemental analysis:
[2744] C.sub.25H.sub.30N.sub.2O.sub.2, 1HCl, 1/6H.sub.2O
[2745] Theory: % C, 69.83; % H, 7.35; % N, 6.51.
[2746] Found: % C, 69.84; % H, 7.32; % N, 6.47.
[2747] [.alpha.].sub.D.sup.25=-0.18 (c. 10.25 mg/mL, MeOH)
Example 21D
Preparation of 21D
[2748] To a stirred solution of 21B (0.47 g, 1.1 mmol, 1.0 eq) in
methanol (20 mL) was added palladium [90 mg, 10 wt. % (dry basis)
on activated carbon, 20% wt. eq]. The reaction mixture was stirred
under hydrogen atmosphere using a hydrogen balloon at room
temperature for 10 h. The palladium on activated carbon was
filtered off on a celite pad and the filtrate was concentrated
under reduced pressure. The crude product was purified by column
chromatography (eluent: dichloromethane/methanol/ammonium hydroxide
mixtures of increasing polarity). The desired fractions were
combined and concentrated under reduced pressure. To a cold
(0.degree. C.) solution of the resulting oil in dichloromethane was
added dropwise a 2.0M solution of hydrogen chloride in diethyl
ether (1.1 mL, 2.2 mmol, 2.0 eq). The mixture was then stirred for
1 h at room temperature, concentrated under reduced pressure, and
dried under vacuum.
[2749] Yield: 89%
[2750] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.88 (brs, 2H),
7.30 (m, 4H), 7.12 (m, 1H), 6.86 (m, 1H), 6.78 (m, 1H), 6.62 (m,
1H), 4.20 (m, 1H), 3.50-2.96 (m, 8H), 2.29-1.66 (m, 8H), 1.10 (brm,
6H)
[2751] Mass Spectral Analysis m/z=393.3 (M+H).sup.+
Example 21E
Preparation of 21E
[2752] To a stirred solution of 21C (0.49 g, 1.14 mmol, 1.0 eq) in
methanol (20 mL) was added palladium [98 mg, 10 wt. % (dry basis)
on activated carbon, 20% wt. eq]. The reaction mixture was stirred
under hydrogen using a hydrogen balloon at room temperature for 10
h. The palladium on activated carbon was filtered off on a celite
pad and the filtrate was concentrated under reduced pressure. The
crude product was purified by column chromatography (eluent:
dichloromethane/methanol/ammonium hydroxide mixtures of increasing
polarity). The desired fractions were combined and concentrated
under reduced pressure. To a cold (0.degree. C.) solution of the
resulting oil in dichloromethane was added dropwise a 2.0M solution
of hydrogen chloride in diethyl ether (1.14 mL, 2.28 mmol, 2.0 eq).
The mixture was then stirred for 1 h at room temperature,
concentrated under reduced pressure, and dried under vacuum.
[2753] Yield: 93%
[2754] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.80 (brs, 2H),
7.29 (m, 4H), 7.12 (m, 1H), 6.85 (m, 1H), 6.77 (m, 1H), 6.62 (m,
1H), 4.20 (m, 1H), 3.52-2.96 (m, 8H), 2.22-1.66 (m, 8H), 1.10 (brm,
6H)
[2755] Mass Spectral Analysis m/z=393.3 (M+H).sup.+
Example 21F
Preparation of 21.9
[2756] To a stirred solution of 21A (1.93 g, 4.52 mmol, 1.0 eq) in
dry dichloromethane (30 mL) at 0.degree. C. was added triethylamine
(1.51 mL, 10.85 mmol, 2.4 eq) followed by drop wise addition of
benzyl chloroformate (21.8) (0.76 mL, 5.42 mmol, 1.2 eq). The
reaction mixture was slowly warmed to room temperature and stirred
for 10 h at room temperature. The volatiles were removed under
reduced pressure and the residue was partitioned between diethyl
ether (200 mL) and water (100 mL). The organic layer was washed
with a 1N aqueous solution of hydrochloric acid (3.times.50 mL) and
brine, dried over sodium sulfate and filtered. The filtrate was
concentrated under reduced pressure to give the crude product,
which was used for the next step without further purification.
[2757] Mass Spectral Analysis m/z=525.0 (M+H).sup.+
Preparation of 21.10
[2758] To a solution of 21.9 (0.9 g, crude, as of 1.71 mmol, 1.0
eq) in dry dichloroethane (10 mL) was added sulfur trioxide
N,N-dimethylformamide complex (4.3) (315 mg, 2.06 mmol, 1.2 eq)
portion wise. The reaction mixture was heated at 75.degree. C. for
10 h and then cooled down to 0-10.degree. C. at which point oxalyl
chloride (0.2 mL, 2.22 mmol, 1.3 eq) was added drop wise. The
mixture was then stirred at 65.degree. C. for another 3 h and then
quenched with ice water (50 mL) at room temperature.
Dichloromethane (100 mL) was added and the two phases were
separated. The aqueous phase was extracted with dichloromethane
(3.times.50 mL) and the combined organic layers were dried over
sodium sulfate, filtered, and concentrated under reduced pressure
to give the crude product, which was used for next step without
further purification.
[2759] Mass Spectral Analysis m/z=622.9 (M+H).sup.+
Preparation of 21.11
[2760] To a solution of 21.10 (0.9 g, crude, as of 1.4 mmol, 1.0
eq) in dry dichloromethane (50 mL) at 0.degree. C. was slowly added
triethylamine (0.4 mL, 2.8 mmol, 2.0 eq) and a 2.0M solution of
ethylamine (3.4c) in tetrahydrofuran (7 mL, 14 mmol, 10.0 eq) drop
wise. The mixture was slowly warmed to room temperature and stirred
for 10 h at room temperature. Water (50 mL) and chloroform (50 mL)
were added and the two phases were separated. The aqueous phase was
extracted with chloroform (3.times.50 mL) and the combined organic
layers were dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[2761] Yield: 34% over three steps
[2762] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.68 (m, 1H), 7.50
(m, 1H), 7.43 (m, 2H), 7.40-7.30 (m, 7H), 6.98 (d, 1H), 5.66 &
5.44 (2s, 1H), 5.18 & 5.16 (2s, 2H), 4.21 (t, 1H), 3.89-3.23
(m, 8H), 2.97 (m, 2H), 2.32-1.66 (m, 6H), 1.35-1.05 (m, 9H)
[2763] Mass Spectral Analysis m/z=631.95 (M+H).sup.+
Preparation of 21F
[2764] To a solution of 21.11 (0.35 g, 0.55 mmol, 1.0 eq) in
dichloromethane (10 mL) was added iodotrimethylsilane (0.15 mL, 1.1
mmol, 2.0 eq) drop wise. The mixture was stirred at room
temperature for 2 h. The mixture was diluted with chloroform 9100
mL) and methanol (5 mL). The solution was washed with a 20% aqueous
solution of sodium thiosulfate (2.times.30 mL), with a 1M aqueous
solution of sodium carbonate (2.times.30 mL), dried over sodium
sulfate and filtered. The filtrate was concentrated under reduced
pressure and the crude product was purified by preparative liquid
chromatography (mobile phase: acetonitrile/water/trifluoroacetic
acid). The desired fractions were combined and concentrated under
reduced pressure. The product was dissolved in dichloromethane (50
mL); the organic phase was washed with a 1N aqueous solution of
sodium hydroxide (2.times.20 mL), dried over sodium sulfate,
filtered, and concentrated under reduced pressure. To a cold
(0.degree. C.) solution of the resulting oil in anhydrous
dichloromethane was added dropwise a 1.0M solution of hydrogen
chloride in diethyl ether (1.1 mL, 1.1 mmol, 2.0 eq). The mixture
was then stirred for 1 h at room temperature, concentrated under
reduced pressure, and dried under vacuum.
[2765] Yield: 56%
[2766] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.03 (brs, 2H),
7.65 (dd, 1H), 7.54-7.36 (m, 6H), 7.16 (d, 1H), 6.04 (s, 1H),
3.54-3.02 (m, 8H), 2.71 (m, 2H), 2.37-2.13 (m, 3H), 2.06-1.72 (m,
3H), 1.22-1.03 (m, 6H), 0.94 (t, 3H)
[2767] Mass Spectral Analysis m/z=498.5 (M+H).sup.+
[2768] Elemental analysis:
[2769] C.sub.27H.sub.35N.sub.3O.sub.4S, 1HCl, 0.33H.sub.2O
[2770] Theory: % C, 60.04; % H, 6.84; % N, 7.78.
[2771] Found: % C, 59.93; % H, 6.81; % N, 7.80.
Example 22A
Preparation of 22.1
[2772] To a suspension of 21B (4.06 g, 9.5 mmol, 1.0 eq) in
tetrahydrofuran (50 mL) at 0.degree. C. was added triethylamine
(3.3 mL, 23.75 mmol, 2.5 eq) followed by drop wise addition of
trifluoroacetic anhydride (4.1) (1.6 ml, 11.4 mmol, 1.2 eq). The
reaction mixture was slowly warmed to room temperature and stirred
for 10 h at room temperature. Ethyl acetate (200 mL) was added to
the reaction mixture and the organic layer was washed with a 1M
aqueous solution of hydrochloric acid (3.times.50 mL) and brine,
dried over sodium sulfate and filtered. The filtrate was
concentrated under reduced pressure to give the crude product,
which was used for the next step without further purification.
[2773] Mass Spectral Analysis m/z=487.2 (M+H).sup.+
Preparation of 22.2
[2774] To a solution of 22.1 (5.0 g, as of 9.5 mmol, 1.0 eq) in dry
dichloroethane (100 mL) was added sulfur trioxide
N,N-dimethylformamide complex (4.3) (2.18 g, 14.25 mmol, 1.5 eq)
portion wise. The mixture was heated under reflux for 10 h and then
cooled to 0-10.degree. C. at which point oxalyl chloride (1.33 mL,
15.2 mmol, 1.6 eq) was added drop wise. The mixture was then
stirred at 70.degree. C. for another 3 h and quenched with ice
water (1:1) (150 mL) at room temperature. Dichloromethane (100 mL)
was added to the reaction mixture and the two phases were
separated. The aqueous phase was further extracted with
dichloromethane (3.times.50 mL) and the combined organic layers
were dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[2775] Yield: 84% over two steps
[2776] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.88 (m, 1H), 7.70
(m, 1H), 7.48 (m, 2H), 7.35 (m, 2H), 7.08 (d, 1H), 5.716 &
5.706 (2s, 1H), 4.03-3.26 (m, 8H), 2.49-2.21 (m, 3H), 2.03-1.72 (m,
3H), 1.33-1.11 (m, 6H)
[2777] Mass Spectral Analysis m/z=585.2 (M+H).sup.+
Preparation of 22.3a
[2778] To a solution of 22.2 (0.6 g, 1.02 mmol, 1.0 eq) in dry
dichloromethane (30 mL) at 0.degree. C. was added triethylamine
(0-71 mL, 5.10 mmol, 5.0 eq) and methylamine (3.4b) hydrochloride
salt (0.21 g, 3.06 mmol, 3.0 eq) in one portion. The reaction
mixture was slowly warmed to room temperature and stirred for 10 h
at room temperature. Water (50 mL) and dichloromethane (50 mL) were
added to the mixture and the two phases were separated. The aqueous
phase was further extracted with dichloromethane (3.times.50 mL)
and the combined organic layers were dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography (eluent: hexane/ethyl
acetate mixtures of increasing polarity).
[2779] Yield: 89%
[2780] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.71 (dd, 1H),
7.51 (t, 1H), 7.45 (m, 2H), 7.34 (m, 2H), 7.02 (d, 1H), 5.665 &
5.657 (2s, 1H), 4.29 (m, 1H), 4.02-3.25 (m, 8H), 2.63 (d, 3H),
2.47-2.19 (m, 3H), 1.99-1.68 (m, 3H), 1.22 (m, 6H)
[2781] Mass Spectral Analysis m/z=580.3 (M+H).sup.+
Preparation of 22A
[2782] To a solution of 22.3a (0.53 g, 0.91 mmol, 1.0 eq) in a
mixture of methanol (20 mL) and water (5 mL) at 0.degree. C. was
added potassium carbonate (0.75 g, 5.46 mmol, 6.0 eq) portion wise.
The reaction mixture was warmed to room temperature and stirred for
10 h at room temperature. Brine (50 mL) and chloroform (50 mL) were
added to the reaction mixture and the two phases were separated.
The aqueous phase was extracted with chloroform (3.times.50 mL) and
the combined organic layers were dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography (eluent:
dichloromethane/methanol mixtures of increasing polarity). The
desired fractions were combined and concentrated under reduced
pressure. To a cold (0.degree. C.) solution of the resulting oil in
anhydrous dichloromethane was added drop wise a 2.0M solution of
hydrogen chloride in diethyl ether (0.91 mL, 1.82 mmol, 2.0 eq).
The mixture was stirred for 1 h at room temperature, concentrated
under reduced pressure, and dried under vacuum.
[2783] Yield: 82%
[2784] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.04 (brs, 2H),
7.64 (dd, 1H), 7.49-7.34 (m, 6H), 7.17 (d, 1H), 6.04 (s, 1H), 3.45
(m, 2H), 3.31-3.15 (m, 5H), 3.09 (m, 1H), 2.35 (d, 3H), 2.28 (m,
2H), 2.18 (m, 1H), 1.99 (m, 2H), 1.80 (m, 1H), 1.12 (m, 6H)
[2785] Mass Spectral Analysis m/z=484.2 (M+H).sup.+
[2786] Elemental analysis:
[2787] C.sub.26H.sub.33N.sub.3O.sub.4S, 1HCl, 1.2H.sub.2O
[2788] Theory: % C, 57.65; % H, 6.77; % N, 7.76.
[2789] Found: % C, 57.69; % H, 6.62; % N, 7.71.
[2790] [.alpha.].sub.D.sup.25=-0.42 (c. 9.4 mg/mL, MeOH)
Example 22B
[2791] 22B was obtained according to a procedure similar to the one
described for 22A, with the following exception:
Step 22.3: 3.4b was replaced by 3.4c.
[2792] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.98 (brs, 1H),
7.65 (dd, 1H), 7.44 (m, 5H), 7.37 (d, 1H), 7.16 (d, 1H), 6.04 (s,
1H), 3.45 (m, 2H), 3.32-3.05 (m, 6H), 2.71 (m, 2H), 2.35-1.75 (m,
6H), 1.12 (m, 6H), 0.94 (t, 3H)
[2793] Mass Spectral Analysis m/z=498.3 (M+H).sup.+
[2794] Elemental analysis:
[2795] C.sub.27H.sub.35N.sub.3O.sub.4S, 1HCl, 1.1H.sub.2O
[2796] Theory: % C, 58.54; % H, 6.95; % N, 7.59.
[2797] Found: % C, 58.55; % H, 6.82; % N, 7.55.
[2798] [.alpha.].sub.D.sup.25=-0.51 (c=9.25 mg/ml, MeOH)
Example 22C
[2799] 22C was obtained according to a procedure similar to the one
described for 22A, with the following exception:
Step 22.3: 3.4b was replaced by 3.4d.
[2800] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.05 (brs, 2H),
7.65 (dd, 1H), 7.56 (t, 1H), 7.43 (m, 4H), 7.37 (d, 1H), 7.16 (d,
1H), 6.04 (s, 1H), 3.53-3.04 (m, 8H), 2.63 (m, 2H), 2.35-1.75 (m,
6H), 1.33 (m, 2H), 1.12 (m, 6H), 0.77 (t, 3H)
[2801] Mass Spectral Analysis m/z=512.4 (M+H).sup.+
[2802] Elemental analysis:
[2803] C.sub.28H.sub.37N.sub.3O.sub.4S, 1HCl, 0.5H.sub.2O
[2804] Theory: % C, 60.36; % H, 7.06; % N, 7.54.
[2805] Found: % C, 60.28; % H, 7.10; % N, 7.53.
[2806] [.alpha.].sub.D.sup.25=-0.60 (c=9.55 mg/ml, MeOH)
Example 22D
[2807] 22D was obtained according to a procedure similar to the one
described for 22A, with the following exception:
Step 22.3: 3.4b was replaced by 3.4g.
[2808] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.0 (brs, 2H),
7.66 (m, 2H), 7.42 (m, 5H), 7.16 (d, 1H), 6.04 (s, 1H), 3.45 (m,
2H), 3.22 (m, 6H), 2.59 (m, 2H), 2.35-1.75 (m, 6H), 1.12 (m, 6H),
0.75 (m, 1H), 0.32 (m, 2H), 0.03 (m, 2H)
[2809] Mass Spectral Analysis m/z=524.3 (M+H).sup.+
[2810] Elemental analysis:
[2811] C.sub.29H.sub.37N.sub.3O.sub.4S, 1HCl, 0.66H.sub.2O
[2812] Theory: % C, 60.88; % H, 6.93; % N, 7.34.
[2813] Found: % C, 60.92; % H, 6.96; % N, 7.37.
[2814] [.alpha.].sub.D.sup.25=-0.59 (c=9.35 mg/ml, MeOH)
Example 22E
Preparation of 22.4
[2815] To a solution of 22.2 (0.86 g, 1.47 mmol, 1.0 eq) in
tetrahydrofuran (5 mL) at 0.degree. C. was added a 1.0M solution of
hydrazine in tetrahydrofuran (5.1) (15 mL, 15 mmol, 15.0 eq) in one
portion. The reaction mixture was stirred at 0.degree. C. for 30
min. Water (50 mL) and dichloromethane (100 mL) were added and the
two phases were separated. The aqueous phase was extracted with
dichloromethane (3.times.50 mL) and the combined organic layers
were dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[2816] Yield: 72%
[2817] Mass Spectral Analysis m/z=581.2 (M+H).sup.+
Preparation of 22.5
[2818] To a suspension of 22.4 (0.62 g, 1.06 mmol, 1.0 eq) in
ethanol (10 mL) was added sodium acetate (0.58 g, 7.1 mmol, 6.7 eq)
and iodomethane (2.8c) (0.37 mL, 5.8 mmol, 5.5 eq). The reaction
mixture was heated under reflux for 10 h. Water (100 mL) and
dichloromethane (100 mL) were added and the two phases were
separated. The aqueous phase was extracted with dichloromethane
(3.times.50 mL) and the combined organic layers were dried over
sodium sulfate, filtered, and concentrated under reduced pressure.
The crude product was purified by column chromatography (eluent:
hexane/ethyl acetate mixtures of increasing polarity).
[2819] Yield: 78%
[2820] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.78 (m, 1H), 7.61
(t, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.06 (d, 1H), 5.685 &
5.675 (2s, 1H), 4.01-3.42 (m, 6H), 3.33 (brs, 2H), 3.00 (s, 3H),
2.46-2.22 (m, 3H), 2.00-1.69 (m, 3H), 1.22 (m, 6H)
[2821] Mass Spectral Analysis m/z=565.3 (M+H).sup.+
Preparation of 22E
[2822] To a solution of 22.5 (0.45 g, 0.8 mmol, 1.0 eq) in a
mixture of methanol (20 mL) and water (5 mL) at 0.degree. C. was
added potassium carbonate (0.86 g, 4.8 mmol, 6.0 eq) portion wise.
The reaction mixture was warmed to room temperature and stirred for
10 h at room temperature. Brine (50 mL) and chloroform (50 mL) were
added and the two phases were separated. The aqueous phase was
extracted with chloroform (3.times.50 mL) and the combined organic
layers were dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The crude product was purified by column
chromatography (eluent: dichloromethane/methanol mixtures of
increasing polarity). The desired fractions were combined and
concentrated under reduced pressure. To a cold (0.degree. C.)
solution of the resulting oil in anhydrous dichloromethane was
added dropwise a 2.0M solution of hydrogen chloride in diethyl
ether (0.8 mL, 1.6 mmol, 2.0 eq). The mixture was then stirred for
1 h at room temperature, concentrated under reduced pressure, and
dried under vacuum.
[2823] Yield: 86%
[2824] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.01 (brs, 2H),
7.80 (dd, 1H), 7.46 (m, 5H), 7.22 (d, 1H), 6.06 (s, 1H), 3.45 (m,
2H), 3.32-3.03 (m, 9H), 2.29 (m, 2H), 2.18 (m, 1H), 1.99 (m, 2H),
1.81 (m, 1H), 1.12 (m, 6H)
[2825] Mass Spectral Analysis m/z=469.2 (M+H).sup.+
[2826] Elemental analysis:
[2827] C.sub.26H.sub.32N.sub.2O.sub.4S, 1HCl
[2828] Theory: % C, 61.83; % H, 6.59; % N, 5.55.
[2829] Found: % C, 61.82; % H, 6.60; % N, 5.51.
[2830] [.alpha.].sub.D.sup.25=-0.45 (c. 10.3 mg/mL, MeOH)
Example 23A
[2831] 23A was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: Method 1B was used and 1.2 was replaced by 23.1a (see
also step 23.1). Step 1.3: Method 1C was used (see also step 23.3).
Step 1.4: Method 1E was used (see also step 23.4).
[2832] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.20 (m, 2H),
7.40 (m, 4H), 7.22 (m, 1H), 7.04 (m, 2H), 6.91 (m, 1H), 5.66 (s,
1H), 3.85-3.50 (m, 5H), 3.31 (m, 3H), 2.60 (m, 1H), 2.13 (m, 1H),
1.27 (m, 3H), 1.16 (m, 3H)
[2833] Mass Spectral Analysis m/z=363.2 (M+H).sup.+
Example 23B
[2834] 23B was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: Method 1B was used and 1.2 was replaced by 23.1b (see
also step 23.1). Step 1.3: Method 1C was used (see also step 23.3).
Step 1.4: Method 1E was used (see also step 23.4).
[2835] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.33 (m, 1H),
9.21 (m, 1H), 7.39 (m, 5H), 7.21 (m, 1H), 6.98 (m, 1H), 6.87 (m,
1H), 5.50 (s, 1H), 3.55 (m, 4H), 3.34 (m, 2H), 2.93 (m, 2H), 2.44
(m, 1H), 2.33 (m, 1H), 1.83 (m, 1H), 1.70 (m, 1H), 1.26 (m, 3H),
1.16 (m, 3H)
[2836] Mass Spectral Analysis m/z=377.0 (M+H).sup.+
Example 23C
[2837] 23C was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.1: Method 1B was used and 1.2 was replaced by 23.5 (see also
step 23.5). Step 1.3: Method 1C was used (see also step 23.7). Step
1.4: Method 1E was used (see also step 23.8).
[2838] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.28 (brm, 2H),
7.43 (d, 2H), 7.35 (d, 2H), 7.27 (m, 1H), 7.01 (d, 1H), 6.97 (m,
2H), 5.57 (s, 1H), 4.01 (brs, 2H), 3.44 (brs, 2H), 3.22 (brs, 2H),
2.36 (m, 2H), 2.27 (m, 4H), 2.04 (m, 2H), 1.12 (brd, 6H)
[2839] Mass Spectral Analysis m/z=403.2 (M+H).sup.+
Example 24A
Preparation of 24.2
[2840] To a solution of 24.1 (9.37 g, 60 mmol, 1.0 eq) in dry
methanol (100 mL) was added pyrrolidine (10 mL, 120 mmol, 2.0 eq)
followed by 2'-hydroxyacetophenone (1.1a) (7.22 mL, 60 mmol, 1.0
eq). The reaction mixture was heated under reflux for 10 h. The
volatiles were removed under reduced pressure and the residue was
dissolved in ethyl acetate (200 mL). The mixture was washed with a
1M aqueous solution of hydrochloric acid (3.times.50 mL), with a 1M
aqueous solution of sodium hydroxide (3.times.50 mL) and brine. The
organic extracts were dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: hexane/ethyl acetate mixtures of
increasing polarity).
[2841] Yield: 100%
[2842] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.86 (dd, 1H),
7.48 (m, 1H), 6.98 (m, 2H), 3.96 (m, 4H), 2.71 (s, 2H), 2.12 (m,
2H), 1.99 (m, 2H), 1.74 (m, 2H), 1.61 (m, 2H)
Preparation of 24.3
[2843] To an oven-dried two-neck 500 mL flask charged with a
solution of 24.2 (16.46 g, 60 mmol, 1.0 eq) in dry tetrahydrofuran
(100 mL) at -78.degree. C. under nitrogen was added a 1.0M solution
of lithium bis(trimethylsilyl)amide in tetrahydrofuran (72 mL, 72
mmol, 1.2 eq) over a 30 min time period. The mixture was kept at
-78.degree. C. for 1 h and a solution of
N-phenylbis(trifluoromethanesulfonamide) (1.4) (25.72 g, 72 mmol,
1.2 eq) in tetrahydrofuran (100 mL) was added to the mixture over a
30 min time period. The reaction mixture was kept at -78.degree. C.
for 1 h, and was slowly warmed to room temperature and stirred for
10 h at room temperature. Ice water (100 mL) was added to quench
the reaction and the product was extracted with diethyl ether (200
mL). The organic phase was then washed with a 1M aqueous solution
of hydrochloric acid (3.times.100 mL), with a 1M aqueous solution
of sodium hydroxide (3.times.100 mL) and brine, dried over sodium
sulfate and filtered. The filtrate was concentrated under reduced
pressure and the crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[2844] Yield: 90%
[2845] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.34-7.19 (m, 2H),
6.97 (m, 1H), 6.89 (m, 1H), 5.60 (s, 1H), 4.03-3.91 (m, 4H), 2.20
(m, 2H), 2.09-1.97 (m, 2H), 1.81 (m, 2H), 1.62 (m, 2H)
Preparation of 24.4
[2846] To a solution of 24.3 (22 g, 54.14 mmol, 1.0 eq) in
dimethoxyethane (200 mL) under nitrogen was added sequentially a 2M
aqueous solution of sodium carbonate (81.2 mL, 162.42 mmol, 3.0
eq), lithium chloride (6.88 g, 162.42 mmol, 3.0 eq),
tetrakis(triphenylphosphine)palladium(0) (1.25 g, 1.08 mmol, 0.02
eq), and 4-N,N-diethylphenylboronic acid (1.6) (13.16 g, 59.55
mmol, 1.1 eq). The reaction mixture was heated under reflux for 10
h. Water (200 mL) and diethyl ether (300 mL) were added and the two
phases were separated. The aqueous phase was further extracted with
diethyl ether (2.times.100 mL) and the combined organic extracts
were washed with brine, dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: hexane/ethyl acetate mixtures of
increasing polarity).
[2847] Yield: 95%
[2848] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.38 (m, 4H), 7.18
(m, 1H), 6.99 (m, 1H), 6.93 (m, 1H), 6.85 (m, 1H), 5.62 (s, 1H),
3.99 (m, 4H), 3.57 (brs, 2H), 3.32 (brs, 2H), 2.24-2.02 (m, 4H),
1.80 (m, 2H), 1.65 (m, 2H), 1.21 (m, 6H)
Preparation of 24A
[2849] To a cold (0.degree. C.) solution of 24.4 (22.32 g, 51.48
mmol, 1.0 eq) in tetrahydrofuran (200 mL) was added a 1.0M aqueous
solution of hydrochloric acid (155 mL, 155 mmol, 3.0 eq). The
mixture was stirred at room temperature for 10 h and then
concentrated under reduced pressure. The resulting solid was
collected by filtration, washed with hexane/ethyl acetate mixture
(20:1), and dried under vacuum.
[2850] Yield: 85%
[2851] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.40 (m, 4H), 7.23
(m, 1H), 7.04 (d, 1H0, 7.00 (d, 1H), 6.91 (m, 1H), 5.62 (s, 1H),
3.57 (brs, 2H), 3.32 (brs, 2H), 2.87 (m, 2H), 2.50 (m, 2H), 2.33
(m, 2H), 1.94 (m, 2H), 1.21 (m, 6H)
[2852] Mass Spectral Analysis m/z=390.2 (M+H).sup.+
Example 24B/Example 24C
Preparation of 24B/24C
[2853] To a solution of 24A (0.51 g, 1.3 mmol, 1.0 eq) in dry
tetrahydrofuran (30 mL) at 0.degree. C. was added sodium
borohydride (50 mg, 1.3 mmol, 1.0 eq) in one portion under a
nitrogen atmosphere. The reaction mixture was stirred at room
temperature for 1 h. Water (50 mL) and diethyl ether (100 mL) were
added and the two phases were separated. The aqueous phase was
further extracted with diethyl ether (2.times.50 mL) and the
combined organic layers were washed with brine, dried over sodium
sulfate, filtered, and concentrated to give the mixture of two
isomers. The crude product was purified by preparative liquid
chromatography affording 24B and 24C.
[2854] (24B) .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (m,
4H), 7.18 (m, 1H), 6.97 (m, 2H), 6.85 (m, 1H), 5.55 (s, 1H), 3.73
(m, 1H), 3.58 (brs, 2H), 3.33 (brs, 2H), 2.51 (brs, 4H), 2.21 (m,
2H), 1.52 (m, 2H), 1.22 (brd, 6H)
[2855] Mass Spectral Analysis m/z=392.2 (M+H).sup.+
[2856] (24C) .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (m,
4H), 7.18 (m, 1H), 7.01-6.81 (m, 3H), 5.73 & 5.55 (2s, 1H),
4.07 & 3.74 (2m, 1H), 3.59 (brs, 2H), 3.34 (brs, 2H), 3.16
(brs, 4H), 2.31-1.89 (m, 2H), 1.68-1.46 (m, 2H), 1.22 (m, 6H)
[2857] Mass Spectral Analysis m/z=392.2 (M+H).sup.+
Example 24D/Example 24E
Preparation of 24D/24E
[2858] To a stirred solution of 24A (0.63 mL, 1.62 mmol, 2.0 eq) in
dry dichloromethane (20 mL) was added sequentially n-propylamine
(3.4d) (0.16 g, 1.94 mmol, 1.2 eq), acetic acid (0.11 mL, 1.94
mmol, 1.2 eq), and sodium cyanoborohydride (0.153 g, 2.43 mmol, 1.5
eq). The reaction mixture was stirred at room temperature for 10 h.
Water (40 mL) was added and the aqueous layer was basified to pH=10
with a 1M aqueous solution of sodium hydroxide. The two phases were
separated and the aqueous phase was saturated with sodium chloride
and extracted with dichloromethane (3.times.50 mL). The combined
organic extracts were dried over sodium sulfate, filtered, and
concentrated under reduced pressure to give the crude mixture,
which was purified by column chromatography (eluent:
dichloromethane/methanol mixtures of increasing polarity).
[2859] (24D) .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.38 (m,
4H), 7.17 (m, 1H), 6.99 (dd, 1H), 6.90 (dd, 1H), 6.84 (m, 1H), 5.91
(s, 1H), 3.57 (brs, 2H), 3.31 (brs, 2H), 2.75 (brs, 1H), 2.65 (t,
2H), 2.11 (m, 2H), 1.98 (m, 2H), 1.82-1.46 (m, 7H), 1.21 (m, 6H),
0.95 (t, 3H)
[2860] Mass Spectral Analysis m/z=433.2 (M+H).sup.+
[2861] (24E) .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.38 (m,
4H), 7.16 (m, 1H), 6.98 (dd, 1H), 6.93 (dd, 1H), 6.83 (m, 1H), 5.54
(s, 1H), 3.57 (brs, 2H), 3.31 (brs, 2H), 2.64 (t, 2H), 2.53 (m,
1H), 2.20 (m, 2H), 1.83-1.42 (m, 7H), 1.21 (m, 6H), 0.94 (t,
3H)
[2862] Mass Spectral Analysis m/z=433.2 (M+H).sup.+
Example 24F
[2863] 24F was obtained according to a procedure similar to the one
described for 24D, with the following exception:
Step 24.6: 3.4d was replaced by 3.4j.
[2864] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.38 (m, 4H), 7.17
(m, 1H), 6.96 (m, 2H), 6.84 (m, 1H), 5.54 (s, 1H), 3.57 (m, 2H),
3.32 (m, 2H), 2.35 (s, 6H), 2.25 (m, 3H), 1.79 (m, 4H), 1.46 (m,
2H), 1.26 (m, 3H), 1.16 (m, 3H)
[2865] Mass Spectral Analysis m/z=419.2 (M+H).sup.+
Example 24G
[2866] 24G was obtained according to a procedure similar to the one
described for 24E, with the following exception:
Step 24.6: 3.4d was replaced by 3.4j.
[2867] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.40 (m, 4H), 7.18
(m, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 6.85 (m, 1H), 5.89 (s, 1H),
3.57 (m, 2H), 3.32 (m, 2H), 2.51 (m, 7H), 2.20 (m, 2H), 2.06 (m,
2H), 1.76 (m, 4H), 1.26 (m, 3H), 1.16 (m, 3H)
[2868] Mass Spectral Analysis m/z=419.2 (M+H).sup.+
Example 25A
[2869] 25A was obtained according to a procedure similar to the one
described for compound 1.8a with the following exception:
Step 1.1: 1.2 was replaced by 25.1 (see also step 25.1).
[2870] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.42 (d, 2H),
7.38 (d, 2H), 7.19 (m, 1H), 6.97 (m, 2H), 6.86 (m, 1H), 5.62 (s,
1H), 3.96 (m, 2H), 3.79 (m, 2H), 3.57 (brs, 2H), 3.32 (brs, 2H),
2.03 (d, 2H), 1.84 (m, 2H), 1.21 (brd, 6H)
[2871] Mass Spectral Analysis m/z=378.2 (M+H).sup.+
Example 26A
Preparation of 26.2
[2872] To a solution of 1.5a (2.08 g, 4.63 mmol, 1 eq) in dry
tetrahydrofuran (40 mL) was added
tetrakis(triphenylphosphine)palladium(0) (0.535 g, 0.463 mmol, 0.1
eq), followed by 4-cyanobenzylzinc bromide (26.1) (0.5M solution in
tetrahydrofuran, 23.16 mL, 11.58 mmol, 2.5 eq) drop wise under a
nitrogen atmosphere. The reaction mixture was stirred at room
temperature for 10 h. A saturated aqueous solution of ammonium
chloride (40 mL) was added to quench the reaction and diethyl ether
(50 mL) was added to partition the two phases. The aqueous phase
was extracted with diethyl ether (3.times.50 mL) and the combined
organic layers were washed with brine, dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography (eluent: hexane/ethyl
acetate mixture of increasing polarity).
[2873] Yield: 62%
[2874] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.59 (d, 2H), 7.34
(d, 2H), 7.14 (m, 1H), 7.00 (dd, 1H), 6.88 (dd, 1H), 6.82 (m, 1H),
5.28 (s, 1H), 3.95-3.75 (m, 4H), 3.28 (m, 2H), 1.99 (m, 2H), 1.59
(m, 2H), 1.46 (s, 9H)
[2875] Mass Spectral Analysis m/z=417 (M+H).sup.+
Preparation of 26.3a & 26.3b
[2876] A mixture of 26.2 (1.2 g, 2.88 mmol) in concentrated
hydrochloric acid (30 mL) was heated under reflux for 10 h and then
concentrated under reduced pressure to give the crude mixture of
26.3a and 26.3b. A 80 mg quantity of the mixture was purified by
preparative liquid chromatography. The remaining mixture
(26.3a/26.3b) was used for the next step without further
purification.
[2877] 26.3a: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.87 (s,
b, 1H), 8.58 (m, 2H), 7.86 (m, 2H), 7.41 (m, 2H), 7.21-7.12 (m,
2H), 6.92 (dd, 1H), 6.86 (m, 1H), 5.70 (s, 1H), 3.85 (s, 2H), 3.19
(m, 4H), 2.06 (m, 2H), 1.86 (m, 2H)
[2878] Mass Spectral Analysis m/z=336.2 (M+H).sup.+
[2879] 26.3b: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.00 (s,
b, 1H), 8.68 (m, 1H), 8.29 (m, 1H), 7.97 (m, 2H), 7.84 (dd, 1H),
7.50 (m, 2H), 7.41 (s, 1H), 7.27 (m, 1H), 7.03-6.94 (m, 2H),
3.19-3.00 (m, 4H), 2.82 (s, 2H), 1.91 (m, 2H), 1.63 (m, 2H)
[2880] Mass Spectral Analysis m/z=336.2 (M+H).sup.+
Preparation of 26.4a & 26.4b
[2881] To a solution of the mixture of 26.3a and 26.3b (1 g, 2.69
mmol) in methanol (50 mL) was slowly added a 4.0M solution of
hydrogen chloride in dioxane (20 mL). The reaction mixture was
stirred at room temperature for 10 h and concentrated under reduced
pressure. The residue was dissolved in ethyl acetate (100 mL),
washed with a 1M aqueous solution of sodium carbonate (4.times.50
mL), brine, dried over sodium sulfate, filtered, and concentrated
under reduced pressure to give the crude mixture of 26.4a and
26.4b. A small amount (150 mg) of the crude mixture was purified by
column chromatography (eluent: hexane/ethyl acetate mixture of
increasing polarity) and repurified preparative liquid
chromatography. The remaining mixture (26.4a/26.4b) was used for
the next step without further purification.
[2882] Yield: 90%
[2883] 26.4a: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.05 (s, b,
1H), 8.72 (s, b, 1H), 7.98 (d, 2H), 7.29 (d, 2H), 7.17 (m, 1H),
7.11 (m, 1H), 6.93-6.85 (m, 2H), 5.29 (s, 1H), 3.91 (s, 3H), 3.80
(s, 2H), 3.37 (m, 4H), 2.24 (m, 2H), 1.95 (m, 2H)
[2884] Mass Spectral Analysis m/z=350.2 (M+H).sup.+
[2885] 26.4b: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.42 (s, b,
1H), 8.95 (s, b, 1H), 8.05 (d, 2H), 7.66 (d, 1H), 7.40-7.22 (m,
4H), 7.00 (m, 1H), 6.92 (d, 1H), 3.94 (s, 3H), 3.25 (m, 4H), 2.78
(s, 2H), 2.04 (m, 2H), 1.75 (m, 2H)
[2886] Mass Spectral Analysis m/z=350.2 (M+H).sup.+
Preparation of 26.5a & 26.5b
[2887] To a solution of the mixture of 26.4a and 26.4b (0.5 g, 1.5
mmol, 1 eq) in dry dichloromethane (30 mL) at 0.degree. C. was
slowly added triethylamine (0.42 mL, 3 mmol, 2 eq) and a solution
of di-tert-butyl-dicarbonate 4.7 (0.38 g, 1.74 mmol, 1.2 eq) in
dichloromethane (10 mL) drop wise. The reaction mixture was slowly
warmed up to room temperature and stirred at room temperature for
10 h. Dichloromethane (50 mL) was added and the mixture was washed
with a 1N aqueous solution of hydrochloric acid (3.times.50 mL),
brine, dried over sodium sulfate, filtered, and concentrated under
reduced pressure to give the crude mixture of 26.5a and 26.5b,
which was used for the next step without purification.
Preparation of 26.6a & 26.6b
[2888] To a solution of the mixture of 26.5a and 26.5b (0.57 g,
1.26 mmol, 1 eq) in a mixture methanol (15 mL), tetrahydrofuran (15
mL) and water (15 mL) was added lithium hydroxide monohydrate (0.21
g, 5 mmol, 4 eq) in one portion. The reaction mixture was stirred
at room temperature for 10 h. The volatiles were removed under
reduced pressure and the remaining aqueous solution was acidified
to pH=3 with a 1N aqueous solution of hydrochloric acid while
stirring. The mixture was stirred for 1 h at room temperature and
left at room temperature for 10 h. The resulting solid was
collected by filtration, washed with water, and dried under vacuum
to give the mixture of 26.6a and 26.6b, which was used for the next
step without further purification.
Preparation of 26.7a & 26.7b
[2889] To a stirred solution of the mixture of 26.6a and 26.6b
(0.49 g, 1.12 mmol, 1 eq) in acetonitrile (20 mL) was slowly added
diisopropylethylamine (0.46 mL, 2.69 mmol, 2.4 eq), diethylamine
1.12 (0.24 g, 3.36 mmol, 3 eq) at room temperature. The mixture was
stirred for 10 min at room temperature. The mixture was cooled to
0.degree. C. and O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU) (0.43 g, 1.34 mmol, 1.2 eq) was added
portion wise. The reaction mixture was slowly warmed up to room
temperature and stirred at room temperature for an additional 10 h.
The volatiles were removed under reduced pressure and the residue
was partitioned between ethyl acetate (100 mL) and a 1M aqueous
solution of sodium bicarbonate (100 mL). The organic phase was
washed with a 1M aqueous solution of sodium bicarbonate (2.times.50
mL), a 1M aqueous solution of hydrochloric acid (3.times.50 mL),
brine, dried over sodium sulfate, filtered, and concentrated under
reduced pressure to give the crude mixture of 26.7a and 26.7b. The
crude mixture was purified by column chromatography (eluent:
hexane/ethyl acetate mixture of increasing polarity). A small
amount (85 mg) of the purified mixture was separated by preparative
liquid chromatography. The remaining mixture (26.7a/26.7b) was used
for the next step without further purification.
[2890] Yield: 81% over three steps
[2891] 26.7a: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.33-7.24
(m, 4H), 7.15-7.07 (m, 2H), 6.89-6.80 (m, 2H), 5.25 (s, 1H), 3.84
(m, 2H), 3.74 (s, 2H), 3.55 (m, 2H), 3.28 (m, 4H), 1.98 (m, 2H),
1.57 (m, 2H), 1.46 (s, 9H), 1.18 (m, 6H)
[2892] Mass Spectral Analysis m/z=491.1 (M+H).sup.+
[2893] 26.7b: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.63 (dd,
1H), 7.39 (m, 2H), 7.31 (m, 2H), 7.22 (m, 1H), 7.17 (s, 1H), 6.95
(m, 1H), 6.90 (dd, 1H), 3.81 (m, 2H), 3.58 (m, 2H), 3.34 (m, 2H),
3.17 (m, 2H), 2.71 (s, 2H), 1.82 (m, 2H), 1.43 (s, 9H), 1.38 (m,
2H), 1.22 (m, 6H)
[2894] Mass Spectral Analysis m/z=491.1 (M+H).sup.+
Preparation of 26A
[2895] To a cold (0.degree. C.) stirred solution of the mixture of
26.7a and 26.7b (0.36 g, 0.73 mmol, 1 eq) in dry dichloromethane
(20 mL) was added dropwise a 4.0 M solution of hydrogen chloride in
dioxane (1.8 mL, 7.2 mmol, 10 eq). The mixture was stirred at room
temperature for 10 h and concentrated under reduced pressure to
give the crude mixture of 26A and 26.8. The crude mixture was
purified by preparative liquid chromatography.
[2896] Yield: 85%
[2897] 26A: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.35 (s, b,
1H), 9.00 (s, b, 1H), 7.30 (m, 4H), 7.14 (m, 2H), 6.87 (m, 2H),
5.28 (s, 1H), 3.76 (s, 2H), 3.55 (m, 2H), 3.24 (m, 6H), 2.11 (m,
2H), 1.93 (m, 2H), 1.20 (m, 6H)
[2898] Mass Spectral Analysis m/z=391.0 (M+H).sup.+
[2899] 26.8: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.12 (s, b,
1H), 8.71 (s, b, 1H), 7.65 (d, 1H), 7.39 (d, 2H), 7.31 (d, 2H),
7.28-7.19 (m, 2H), 7.00 (m, 1H), 6.92 (d, 1H), 3.59 (m, 2H), 3.29
(m, 6H), 2.78 (s, 2H), 2.05 (m, 2H), 1.78 (m, 2H), 1.23 (m, 6H)
[2900] Mass Spectral Analysis m/z=391.0 (M+H).sup.+
Example 26B
Preparation of 26B
[2901] To a stirred solution of 26.8 (0.12 g, 0.26 mmol, 1 eq) in
methanol (10 mL) was added palladium [24 mg, 10 wt. % (dry basis)
on activated carbon, 20% wt. eq]. The reaction mixture was stirred
under hydrogen atmosphere using a hydrogen balloon at room
temperature for 10 h. The palladium on activated carbon was
filtered off on a celite pad and the filtrate was concentrated
under reduced pressure. The crude product was purified by column
chromatography (eluent: dichloromethane/methanol/ammonium hydroxide
mixture of increasing polarity). The desired fractions were
combined and concentrated under reduced pressure. To a cold
(0.degree. C.) solution of the resulting oil in dichloromethane was
added dropwise a 2.0M solution of hydrogen chloride in diethyl
ether (0.26 mL, 0.52 mmol, 2 eq). The mixture was then stirred for
1 h at room temperature, concentrated under reduced pressure, and
dried under vacuum.
[2902] Yield: 88%
[2903] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.41 (s, b, 1H),
8.95 (s, b, 1H), 7.40 (m, 1H), 7.33 (m, 2H), 7.25-7.14 (m, 3H),
6.97 (m, 1H), 6.86 (m, 1H), 3.62-3.04 (m, 10H), 2.63 (m, 1H),
2.03-1.49 (m, 6H), 1.20 (m, 6H)
[2904] Mass Spectral Analysis m/z=393.0 (M+H).sup.+
Example 27A
Preparation of 27A
[2905] A solution of 1A (0.66 g, 1.75 mmol, 1.0 eq) in anhydrous
methanol (13 mL) was hydrogenated at atmospheric pressure in the
presence of palladium hydroxide [Pd(OH).sub.2: Pearlman's catalyst]
(0.120 g, 0.09 mmol, 0.05 eq) for 10 h. The mixture was then
filtered through celite. The filtrate was concentrated and was
hydrogenated at atmospheric pressure in the presence of palladium
hydroxide (0.120 g) for an additional 10 h. The mixture was
filtered through celite and the filtrate was concentrated to
dryness under reduced pressure. To a cold (0.degree. C.) solution
of the resulting oil in anhydrous dichloromethane was added drop
wise a 2.0M solution of anhydrous hydrochloric acid in diethyl
ether (5 mL). The mixture was then stirred for 1 h at room
temperature and concentrated under reduced pressure. Diethyl ether
was added. The resulting precipitate was collected by filtration
and washed with diethyl ether and ethyl acetate.
[2906] Yield: 63%
[2907] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.15 (m, 2H),
7.30 (m, 4H), 7.10 (m, 1H), 6.90 (m, 1H), 6.75 (m, 1H), 6.60 (m,
1H), 4.20 (m, 1H), 3.40 (m, 3H), 3.20 (m, 4H), 3.00 (m, 1H), 2.15
(m, 1H), 1.95 (m, 5H), 1.05 (m, 6H)
[2908] Mass Spectral Analysis m/z=379.1 (M+H).sup.+
[2909] Elemental analysis:
[2910] C.sub.24H.sub.30N.sub.2O.sub.2, 1HCl, 0.75H.sub.2O
[2911] Theory: % C, 67.28; % H, 7.65; % N, 6.54.
[2912] Found: % C, 67.32; % H, 7.63; % N, 6.37.
Example 27B
Preparation of 27B
[2913] 27A (racemic mixture) (10 g, 24.10 mmol, 1.0 eq) was
resolved using Chiral HPLC method:
Column: Chiralpak AD-H, 4.6.times.250 mm, 51, Chiral Technologies
PN#19325
[2914] Column temperature: room temperature Detection: UV photo
diode array, 200 to 300 nm, extract at 275 nm Injection volume: 40
.mu.L of 2 mg/mL sample in EtOH:MeOH (80:20) Flow: 1 mL/minute
Mobile Phase: 85% Solution A, 15% Solution B
Solution A: 0.1% Di-isopropylethylamine in Hexane (HPLC Grade)
[2915] Solution B: 80% Ethanol, 20% Methanol (both HPLC Grade)
Note: Methanol is miscible in Hexane only if first dissolved in
Ethanol. Solution B should be pre-mixed Run time: 25 min. HPLC:
Waters Alliance 2695 (system dwell volume is .about.350 .mu.L)
Detector: Waters 996 (resolution: 4.8 mm, scan rate: 1 Hz)
Yield: 40%
[2916] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.10 (m, 2H),
7.28 (m, 4H), 7.14 (m, 1H), 6.90 (d, 1H), 6.80 (m, 1H), 6.63 (d,
1H), 4.25 (m, 1H), 3.42 (m, 3H), 3.24 (m, 4H), 2.97 (m, 1H), 2.20
(m, 1H), 1.97 (m, 5H), 1.10 (m, 6H)
[2917] Mass Spectral Analysis m/z=379.4 (M+H).sup.+
[2918] Chiral HPLC Method: t.sub.R=8.64 min. (ee=97%)
[2919] Elemental analysis:
[2920] C.sub.24H.sub.30N.sub.2O.sub.2, 1HCl, 0.25H.sub.2O
[2921] Theory: % C, 68.72; % H, 7.57; % N, 6.68.
[2922] Found: % C, 68.87; % H, 7.52; % N, 6.68.
[2923] [.alpha.].sub.D.sup.25=+58.40 (c. 0.01, MeOH)
Determination of Absolute Configuration of Example 27B
Preparation of 27.3
[2924] Compound 27.2 (0.45 g, 1.78 mmol, 1.1 eq) was added at
0.degree. C. to a solution of 27B (0.67 g, 1.61 mmol, 1 eq) and
triethylamine (0.74 mL, 5.33 mmol, 3.3 eq) in dichloromethane (6
mL). The reaction was warmed to room temperature and stirred
overnight at room temperature. The mixture was washed with a
saturated aqueous solution of sodium hydrogenocarbonate and brine,
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The crude product was purified by column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity).
[2925] Yield: 64%
[2926] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.30 (m, 4H),
7.11 (t, 1H), 6.90 (d, 1H), 6.77 (t, 1H), 6.61 (d, 1H), 4.23 (m,
1H), 3.39 (br m, 9H), 2.93 (d, 1H), 2.37 (m, 2H), 2.24 (m, 1H),
2.06 (m, 2H), 1.93 (m, 6H), 1.53 (m, 1H), 1.41 (m, 1H), 1.10 (m,
6H), 1.03 (s, 3H), 0.83 (s, 3H)
[2927] Mass Spectral Analysis m/z=593.4 (M+H).sup.+
[2928] Elemental analysis:
[2929] C.sub.33H.sub.44N.sub.2O.sub.5S, 0.25H.sub.2O
[2930] Theory: % C, 68.37; % H, 7.51; % N, 4.69.
[2931] Theory: % C, 68.38; % H, 7.50; % N, 4.55.
X-Ray Crystallography Data:
[2932] Single crystals were grown as needles by dissolving 27.3 (10
mg, 0.017 mmol, 1 eq) in isopropanol (1 mL) and letting sit still
at room temperature for 72 h.
Crystal data and structure refinement for 27.3: Identification
code: ptut001 Empirical formula: C.sub.34H.sub.44N.sub.2O.sub.5S
Formula weight: 592.77
Temperature: 120(2) K
Wavelength: 0.71073 A
[2933] Crystal system, space group: Monoclinic, P2(1) Unit cell
dimensions: a=15.135(2) A, alpha=90 deg b=6.1924(10) A,
beta=91.802(2) deg c=16.602(3) A, gamma=90 deg
Volume: 1555.2(4) A.sup.3
[2934] Z, Calculated density: 2, 1.266 Mg/m.sup.3 Absorption
coefficient: 0.148 mm.sup.-1
F(000): 636
[2935] Crystal size: 0.30.times.0.08.times.0.04 mm Theta range for
data collection: 1.79 to 27.79 deg Limiting indices:
-18<=h<=19, -7<=k<=7, -20<=1<=21 Reflections
collected/unique: 12166/6251 [R (int)=0.0168] Completeness to
theta=27.79: 91.9% Absorption correction: Semi-empirical from
equivalents Max. and min. transmission: 0.9941 and 0.9569
Refinement method: Full-matrix least-squares on F.sup.2
Data/restraints/parameters: 6251/1/383
Goodness-of-fit on F.sup.2: 1.040
[2936] Final R indices [I>2sigma(I)]: R1=0.0392, wR2=0.1030 R
indices (all data): R1=0.0401, wR2=0.1041 Absolute structure
parameter: -0.03(6) Largest diff. peak and hole: 0.365 and -0.200
e.A.sup.-3
Example 27C
Preparation of 27C
[2937] 27A (racemic mixture) (10 g, 24.10 mmol, 1 eq) was resolved
using Chiral HPLC method:
Column: Chiralpak AD-H, 4.6.times.250 mm, 5.mu., Chiral
Technologies PN#19325
[2938] Column temperature: room temperature Detection: UV photo
diode array, 200 to 300 nm, extract at 275 nm Injection volume: 40
.mu.L of 2 mg/mL sample in EtOH:MeOH (80:20) Flow: 1 mL/minute
Mobile phase: 85% Solution A, 15% Solution B
Solution A: 0.1% Di-isopropylethylamine in Hexane (HPLC Grade)
[2939] Solution B: 80% Ethanol, 20% Methanol (both HPLC Grade) Run
time: 25 min HPLC: Waters Alliance 2695 (system dwell volume is
.about.350 .mu.L.)
Detector: Waters 996 (Resolution: 4.8 nm, Scan Rate: 1 Hz)
Yield: 40%
[2940] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.12 (m, 2H),
7.28 (m, 4H), 7.14 (m, 1H), 6.90 (d, 1H), 6.79 (m, 1H), 6.63 (d,
1H), 4.25 (m, 1H), 3.44 (m, 3H), 3.24 (m, 4H), 2.96 (m, 1H), 2.18
(m, 1H), 1.97 (m, 5H), 1.10 (m, 6H)
[2941] Mass Spectral Analysis m/z=379.4 (M+H).sup.+
[2942] Chiral HPLC Method: t.sub.R=11.914 min. (ee=100%)
[2943] Elemental analysis:
[2944] C.sub.24H.sub.30N.sub.2O.sub.2, 1HCl, 0.25H.sub.2O
[2945] Theory: % C, 68.72; % H, 7.57; % N, 6.68.
[2946] Found: % C, 68.79; % H, 7.55; % N, 6.68.
[2947] [.alpha.].sub.D.sup.25=-63.59 (c. 0.01, MeOH)
Example 27D
[2948] 27D was obtained according to a procedure similar to the one
described for 27A, with the following exception:
Step 27.3: Method 27A was used and 1A was replaced by 1D.
[2949] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9-05 (m, 2H),
7.31 (q, 4H), 6.98 (m, 2H), 6.36 (dd, 1H), 6.47 (dd, 1H), 3.51-3.33
(m, 2H), 3.29-3.11 (m, 5H), 2.96 (m, 1H), 2.19 (m, 1H), 2.05-1.82
(m, 5H), 1.20-1.00 (m, 6H)
[2950] Mass Spectral Analysis m/z=397.3 (M+H).sup.+
Example 27E
[2951] 27E was obtained from 27D by chiral HPLC chromatography
[2952] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.82 (m, 2H),
7.31 (m, 4H), 6.97 (m, 2H), 6.37 (m, 1H), 4.27 (m, 1H), 3.42 (m,
2H), 3.23 (m, 5H), 2.97 (m, 1H), 2.20 (m, 1H), 1.94 (m, 5H), 1.11
(m, 6H)
[2953] Mass Spectral Analysis m/z=397.4 (M+H).sup.+
[2954] Elemental analysis:
[2955] C.sub.24H.sub.29FN.sub.2O.sub.2, 1HCl, 0.33H.sub.2O
[2956] Theory: % C, 65.71; % H, 7.09; % N, 6.36.
[2957] Found: % C, 65.68; % H, 7.07; % N, 6.41.
[2958] [.alpha.].sub.D.sup.25=+6.53 (c=9.85 mg/mL, MeOH)
Example 27F
[2959] 27F was obtained from 27D by chiral HPLC chromatography
[2960] .sup.1H NMR (400MHz, DMSO d.sub.6) .delta. 8.92 (m, 2H),
7.32 (m, 4H), 6.98 (m, 2H), 6.37 (m, 1H), 4.27 (m, 1H), 3.42 (m,
2H), 3.24 (m, 5H), 2.97 (m, 1H), 2.20 (m, 1H), 1.95 (m, 5H), 1.11
(m, 6H)
[2961] Mass Spectral Analysis m/z=397.3 (M+H).sup.+
[2962] Elemental analysis:
[2963] C.sub.24H.sub.29FN.sub.2O.sub.2, 1HCl, 0.2H.sub.2O
[2964] Theory: % C, 66.03; % H, 7.02; % N, 6.42.
[2965] Found: % C, 66.07; % H, 6.99; % N, 6.34.
[2966] [.alpha.].sub.D.sup.25=-6.54 (c=9.75 mg/mL, MeOH)
Example 27G
[2967] 27G was obtained according to a procedure similar to the one
described for 27A, with the following exception:
Step 27.3: Method 27A was used and 1A was replaced by 2C.
[2968] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.12 (brs, 1H),
8.97 (brs, 1H), 7.32 (d, 2H), 7.27 (d, 2H), 6.84 (d, 1H), 6.73 (dd,
1H), 6.12 (d, 1H), 4.21 (m, 1H), 3.55 (m, 3H), 3.42 (brs, 1H), 3.20
(brm, 5H), 2.94 (m, 1H), 2.16 (m, 1H), 1.92 (m, 5H), 1.09 (m, 7H),
0.46 (m, 2H), 0.18 (m, 2H)
[2969] Mass Spectral Analysis m/z=449.3 (M+H).sup.+
[2970] Elemental analysis:
[2971] C.sub.28H.sub.36N.sub.2O.sub.3, 1HCl, 1H.sub.2O
[2972] Theory: % C, 66.85; % H, 7.81; % N, 5.57; % Cl, 7.05.
[2973] Found: % C, 67.02; % H, 7.51; % N, 5.54; % Cl, 7.25.
Example 27H
[2974] 27H was obtained according to a procedure similar to the one
described for 27A, with the following exception:
Step 27.3: Method 27A was used and 1A was replaced by 1N.
[2975] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.07 (m, 1.5H),
8.53 (d, 1H), 7.70 (dd, 1H), 7.52 (d, 1H), 7.16 (m, 1H), 6.93 (dd,
1H), 6.82 (m, 1H), 6.63 (d, 1H), 4.36 (dd, 1H), 3.45 (q, 2H),
3.33-3.15 (m, 5H), 2.98 (m, 1H), 2.22 (m, 1H), 2.07-1.85 (m, 5H),
1.15 (t, 3H), 1.09 (t, 3H)
[2976] Mass Spectral Analysis m/z=380.2 (M+H).sup.+
Example 27I
[2977] 27I was obtained from 27H by chiral HPLC chromatography
[2978] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.89 (m, 2H),
8.52 (d, 1H), 7.68 (dd, 1H), 7.51 (d, 1H), 7.16 (m, 1H), 6.94 (m,
1H), 6.82 (m, 1H), 6.62 (m, 1H), 4.35 (m, 1H), 3.44 (q, 2H), 3.26
(m, 5H), 2.98 (m, 1H), 2.23 (m, 1H), 1.95 (m, 5H), 1.15 (t, 3H),
1.09 (t, 3H)
[2979] Mass Spectral Analysis m/z=380.2 (M+H).sup.+
[2980] Elemental analysis:
[2981] C.sub.23H.sub.29N.sub.3O.sub.2, 1.3HCl, 1.4H.sub.2O
[2982] Theory: % C, 61.10; % H, 7.38; % N, 9.29; % Cl, 10.19.
[2983] Found: % C, 61.01; % H, 7.35; % N, 9.21; % Cl, 10.41.
[2984] [.alpha.].sub.D.sup.25=+4.46 (c=9.65 mg/mL, MeOH)
Example 27J
[2985] 27J was obtained from 27H by chiral HPLC chromatography
[2986] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.08 (m, 2H),
8.53 (d, 1H), 7.70 (dd, 1H), 7.52 (d, 1H), 7.16 (m, 1H), 6.93 (m,
1H), 6.82 (m, 1H), 6.63 (m, 1H), 4.36 (m, 1H), 3.45 (q, 2H), 3.25
(m, 5H), 2.97 (m, 1H), 2.22 (m, 1H), 1.97 (m, 5H), 1.15 (t, 3H),
1.09 (t, 3H)
[2987] Mass Spectral Analysis m/z=380.2 (M+H).sup.+
[2988] Elemental analysis:
[2989] C.sub.23H.sub.29N.sub.3O.sub.2, 2HCl, 1.75H.sub.2O
[2990] Theory: % C, 57.08; % H, 7.19; % N, 8.68; % Cl, 14.65.
[2991] Found: % C, 56.92; % H, 7.15; % N, 8.58; % Cl, 15.02.
[2992] [.alpha.].sub.D.sup.25=-3.55 (c=10.3 mg/ml, MeOH)
Example 27K
[2993] 27K was obtained according to a procedure similar to the one
described for 27A, with the following exception:
Step 27.3: Method 27A was used and 1A was replaced by 10.
[2994] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.17-8.85 (m,
2H), 8.53 (d, 1H), 7.70 (dd, 1H), 7.52 (d, 1H), 7.06-6.94 (m, 2H),
6.41 (dd, 1H), 4.37 (dd, 1H), 3.49-3.35 (m, 2H), 3.32-3.14 (m, 5H),
2.97 (m, 1H), 2.23 (m, 1H), 2.05-1.82 (m, 5H), 1.15 (t, 3H), 1.09
(t, 3H)
[2995] Mass Spectral Analysis m/z=398.3 (M+H).sup.+
Example 27L
[2996] 27L was obtained from 27K by chiral HPLC chromatography
[2997] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.15 (m, 2H),
8.54 (d, 1H), 7.72 (dd, 1H), 7.54 (d, 1H), 7.00 (m, 2H), 6.42 (dd,
1H), 4.38 (m, 1H), 3.45 (q, 2H), 3.25 (m, 5H), 2.96 (m, 1H), 2.22
(m, 1H), 1.96 (m, 5H), 1.15 (t, 2H), 1.09 (t, 3H)
[2998] Mass Spectral Analysis m/z=398.3 (M+H).sup.+
[2999] Elemental analysis:
[3000] C.sub.23H.sub.28FN.sub.3O.sub.2, 2HCl, 1.75H.sub.2O
[3001] Theory: % C, 55.04; % H, 6.73; % Cl, 14.13; % N, 8.37.
[3002] Found: % C, 54.85; % H, 6.53; % Cl, 14.28; % N, 8.45.
[3003] [.alpha.].sub.D.sup.25=+4.19 (c=10.2 mg/mL, MeOH)
Example 27M
[3004] 27M was obtained from 27K by chiral HPLC chromatography
[3005] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.14 (m, 2H),
8.54 (d, 1H), 7.79 (dd, 1H), 7.54 (d, 1H), 7.00 (m, 2H), 6.42 (dd,
1H), 4.38 (m, 1H), 3.45 (q, 2H), 3.25 (m, 5H), 2.96 (m, 1H), 2.23
(m, 1H), 1.96 (m, 5H), 1.15 (t, 3H), 1.09 (t, 3H)
[3006] Mass Spectral Analysis m/z=398.3 (M+H).sup.+
[3007] Elemental analysis:
[3008] C.sub.23H.sub.28FN.sub.3O.sub.2, 2HCl, 1.75H.sub.2O
[3009] Theory: % C, 55.04; % H, 6.73; % N, 8.37; % Cl, 14.13.
[3010] Found: % C, 54.85; % H, 6.66; % N, 8.37; % Cl, 14.31.
[3011] [.alpha.].sub.D.sup.25=-4.09 (c=10.25 mg/mL, MeOH)
Example 27N
[3012] 27N was obtained according to a procedure similar to the one
described for 27A, with the following exception:
Step 27.3: 1A was replaced by 1S.
[3013] Mass Spectral Analysis m/z=408.3 (M+H).sup.+
Example 27O
[3014] 27O was obtained from 27N by chiral HPLC chromatography
[3015] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.93 (brs, 1H),
8.75 (brs, 1H), 8.50 (d, 1H), 7.65 (dd, 1H), 7.50 (d, 1H), 6.74 (s,
1H), 6.37 (s, 1H), 4.26 (m, 1H), 3.45 (q, 2H), 3.24 (m, 5H), 2.94
(m, 1H), 2.18 (m, 1H), 2.14 (s, 3H), 1.99 (s, 3H), 1.90 (m, 5H),
1.15 (t, 3H), 1.08 (t, 3H)
[3016] Mass Spectral Analysis m/z=408.3 (M+H).sup.+
[3017] Elemental analysis:
[3018] C.sub.25H.sub.33N.sub.3O.sub.2, 1.25HCl, 1.63H.sub.2O
[3019] Theory: % C, 62.25; % H, 7.84; % N, 8.70; % Cl, 9.19.
[3020] Found: % C, 62.52; % H, 7.64; % N, 8.30; % Cl, 8.80.
Example 27P
[3021] 27P was obtained from 27N by chiral HPLC chromatography
[3022] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.00 (brs, 1H),
8.82 (brs, 1H), 8.50 (d, 1H), 7.65 (dd, 1H), 7.50 (d, 1H), 6.74 (s,
1H), 6.37 (s, 1H), 4.26 (m, 1H), 3.45 (q, 2H), 3.24 (m, 5H), 2.94
(m, 1H), 2.18 (m, 1H), 2.13 (s, 3H), 1.99 (s, 3H), 1.88 (m, 5H),
1.15 (t, 3H), 1.09 (t, 3H)
[3023] Mass Spectral Analysis m/z=408.3 (M+H).sup.+
[3024] Elemental analysis:
[3025] C.sub.25H.sub.33N.sub.3O.sub.2, 1.2HCl, 1.6H.sub.2O
[3026] Theory: % C, 62.54; % H, 7.85; % N, 8.75; % Cl, 8.86.
[3027] Found: % C, 62.61; % H, 7.73; % N, 8.44; % Cl, 8.52.
Example 27Q
Preparation of 27.6
[3028] A solution of 2.7a (15.00 g, 30.45 mmol, 1 eq) in anhydrous
dichloromethane (50 mL) and anhydrous methanol (100 mL) was
hydrogenated at 1 atm, in the presence of palladium, 10 weight %
(dry basis) on activated carbon, wet, Degussa type E101 NE/W (3.24
g, 1.52 mmol, 0.05 eq) for 10 h. The mixture was then filtered
through celite and the filtrate was concentrated to dryness under
reduced pressure. The product was used without further
purification.
[3029] Yield: 99%
[3030] Mass Spectral Analysis m/z=495.4 (M+H).sup.+
Preparation of 27Q
[3031] A 4.0M solution of hydrochloric acid in dioxane (41.9 mL,
167.46 mmol, 5.5 eq) was added drop wise to a cooled (0.degree. C.)
solution of 27.6 (15.06 g, 30.45 mmol, 1 eq) in anhydrous methanol
(50 mL). The mixture was warmed to room temperature and stirring
was continued for an additional 10 h at room temperature. The
mixture was concentrated under reduced pressure. Diethyl ether (100
mL) was added to the solution. The resulting precipitate was
collected by filtration and washed with diethyl ether.
[3032] Yield: 85%
[3033] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.03 (m, 1H),
8.90 (m, 1H), 8.80 (s, 1H), 7.28 (m, 4H), 6.71 (d, 1H), 6.53 (m,
1H), 6.05 (d, 1H), 4.16 (m, 1H), 3.43 (m, 3H), 3.21 (m, 5H), 2.92
(m, 1H), 2.11 (m, 1H), 1.98 (m, 1H), 1.90 (m, 4H), 1.11 (m, 6H)
[3034] Mass Spectral Analysis m/z=395.4 (M+H).sup.+
[3035] Elemental analysis:
[3036] C.sub.24H.sub.30N.sub.2O.sub.2, 1HCl, 0.75H.sub.2O
[3037] Theory: % C, 64.85, % H, 7.37, % N, 6.30.
[3038] Found: % C, 65.12, % H, 7.43, % N, 6.18.
Example 27R
Preparation of 27R
[3039] 27R was obtained from 27Q by chiral HPLC chromatography
[3040] 27Q (racemic mixture) (10 g, 23.20 mmol, 1 eq) was resolved
using Chiral HPLC method:
Column: Chiralpak AD-H, 4.4.times.250 mm
[3041] Column temperature: 25.degree. C.
Detection: UV at 230 nm
[3042] Flow: 2.0 mL/minute Mobile phase: 80% carbon dioxide, 20%
ethanol, 0.1% ethane sulfonic acid Run time: 24 min.
[3043] The relevant fractions were combined and concentrated under
reduced pressure. An aqueous 1N solution of sodium hydroxide was
added to the resulting oil until the solution was basic using pH
paper. The aqueous mixture was extracted with dichloromethane. The
organic extracts were combined, dried over sodium sulfate, filtered
and concentrated under reduced pressure. To a cold (0.degree. C.)
solution of the resulting oil in anhydrous methanol was added drop
wise a 4M solution of anhydrous hydrochloric acid in dioxane (5.5
eq). The mixture was then stirred for 1 hour at room temperature
and concentrated under reduced pressure. The crude product was
purified by column chromatography (eluent: dichloromethane/methanol
mixtures of increasing polarity).
[3044] Yield: 30%
[3045] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.19 (m, 1H),
9.05 (m, 1H), 7.31 (m, 4H), 6.73 (d, 1H), 6.54 (m, 1H), 6.05 (d,
1H), 4.16 (m, 1H), 3.42 (br s, 2H), 3.17 (br m, 6H), 2.91 (m, 1H),
2.11 (m, 1H), 1.98 (m, 1H), 1.90 (m, 4H), 1.10 (m, 6H)
[3046] Mass Spectral Analysis m/z=395.1 (M+H).sup.+
[3047] Chiral HPLC purity: t.sub.R=9.932 min. (ee =>99%)
[3048] [.alpha.].sub.D.sup.24.2=+21.49 (c. 0.01, MeOH)
Example 27S
Preparation of 27S
[3049] 27S was obtained from 27Q by chiral HPLC chromatography
[3050] 27Q (racemic mixture) (10 g, 23.20 mmol, 1 eq) was resolved
using Chiral HPLC method:
Column: Chiralpak AD-H, 4.4.times.250 mm
Column Temperature: 25.degree. C.
Detection: UV at 230 nm
[3051] Flow: 2.0 mL/minute Mobile Phase: 80% carbon dioxide, 20%
ethanol, 0.1% ethane sulfonic acid
Run Time: 24 min.
[3052] The relevant fractions were combined and concentrated under
reduced pressure. An aqueous 1N solution of sodium hydroxide was
added to the resulting oil until the solution was basic using pH
paper. The aqueous mixture was extracted with dichloromethane. The
organic extracts were combined, dried over sodium sulfate, filtered
and concentrated under reduced pressure. To a cold (0.degree. C.)
solution of the resulting oil in anhydrous methanol was added drop
wise a 4M solution of anhydrous hydrochloric acid in dioxane (5.5
eq). The mixture was then stirred for 1 h at room temperature and
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: dichloromethane/methanol mixtures
of increasing polarity).
[3053] Yield: 18%
[3054] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.03 (m, 1H),
8.87 (m, 1H), 8.80 (s, 1H), 7.31 (m, 4H), 6.71 (d, 1H), 6.55 (d,
1H), 6.05 (m, 1H), 4.18 (m, 1H), 3.36 (m, 2H), 3.18 (m, 5H), 2.93
(m, 1H), 2.11 (m, 1H), 1.98 (m, 1H), 1.87 (m, 4H), 1.10 (m, 6H)
[3055] Mass Spectral Analysis m/z=395.1 (M+H).sup.+
[3056] Chiral HPLC prity: t.sub.R=13.371 min. (ee=98.1%)
[3057] [.alpha.].sub.D.sup.24.2=-25.96 (c. 0.01, MeOH)
Example 27T
Preparation of 27.1
[3058] A solution of 11.6a (15.00 g, 27.95 mmol, 1 eq) in anhydrous
methanol (100 mL) was hydrogenated at 70 psi in the presence of
palladium hydroxide [Pd(OH).sub.2: Pearlman's catalyst] (1.96 g,
1.40 mmol, 0.05 eq) for 10 h. The mixture was filtered through
celite. The filtrate was concentrated under reduced pressure and
was hydrogenated at 70 psi in the presence of palladium hydroxide
(1.96 g) for an additional 10 h. The mixture was filtered through
celite and the filtrate was concentrated to dryness under reduced
pressure. The crude product was used without further
purification.
[3059] Yield: 84%
[3060] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.23 (d, 2H),
7.11 (m, 3H), 6.60 (d, 1H), 6.52 (d, 1H), 4.85 (d, 1H), 4.74 (d,
1H), 4.16 (m, 1H), 3.61 (m, 2H), 3.30 (br m, 6H), 2.83 (s, 3H),
2.24 (m, 1H), 1.75 (m, 2H), 1.64 (m, 1H), 1.52 (m, 2H), 1.39 (s,
9H), 1.06 (m, 6H)
[3061] Mass Spectral Analysis m/z=539.5 (M+H).sup.+
Preparation of 27T
[3062] To a cold (0.degree. C.) solution of 27.1 (2.00 g, 3.71
mmol, 1.0 eq) in anhydrous methanol (40 mL) was added drop wise a
4M solution of anhydrous hydrochloric acid in dioxane (9.3 mL,
37.20 mmol, 10.0 eq). The mixture was then stirred for 10 h at room
temperature and concentrated under reduced pressure. Diethyl ether
was added. The resulting precipitate was collected by filtration
and washed with diethyl ether.
[3063] Yield: 99%
[3064] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.30 (br s, 1H),
9.03 (br s, 1H), 8.96 (br s, 1H), 7.21 (d, 2H), 7.14 (d, 2H), 6.99
(t, 1H), 6.43 (d, 1H), 6.35 (d, 1H), 4.15 (m, 1H), 3.87 (br s, 3H),
3.39 (m, 2H), 3.15 (m, 5H), 2.90 (m, 1H), 2.25 (m, 1H), 1.83 (br m,
5H), 1.09 (m, 6H)
[3065] Mass Spectral Analysis m/z=395.3 (M+H).sup.+
Example 27U
Preparation of 27.4
[3066] Compound 27.1 (racemic mixture) (10 g, 18.56 mmol, 1 eq) was
resolved using
Chiral HPLC method:
Column: Chiralpak AD-H, 4.4.times.250 mm
[3067] Column temperature: 25.degree. C.
Detection: UV at 280 nm
[3068] Flow: 2.0 mL/minute Mobile phase: 75% carbon dioxide, 25%
isopropanol Run time: 10 minutes.
[3069] The relevant fractions were combined and concentrated under
reduced pressure. The crude product was used without further
purification.
[3070] Yield: 79%
[3071] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.21 (d, 2H),
7.11 (m, 3H), 6.60 (d, 1H), 6.55 (d, 1H), 4.83 (d, 1H), 4.74 (d,
1H), 4.16 (m, 1H), 3.62 (m, 2H), 3.15 (br m, 6H), 2.83 (s, 3H),
2.24 (m, 1H), 1.75 (m, 2H), 1.61 (m, 1H), 1.50 (m, 2H), 1.39 (s,
9H), 1.06 (m, 6H)
[3072] Mass Spectral Analysis m/z=539.1 (M+H).sup.+
[3073] Chiral HPLC purity: t.sub.R=4.728 min. (ee =>99%)
[3074] [.alpha.].sub.D.sup.24.1=32.97 (c. 0.01, MeOH)
Preparation of 27U
[3075] To a cold (0.degree. C.) solution of 27.4 (1.00 g, 1.86
mmol, 1 eq) in anhydrous methanol was added drop wise a 4M solution
of anhydrous hydrochloric acid in dioxane (2.5 mL, 10.21 mmol, 5.5
eq). The mixture was stirred for 10 hours at room temperature and
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: dichloromethane/methanol mixtures
of increasing polarity).
[3076] Yield: 88%
[3077] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.30 (s, 1H),
9.00 (m, 2H), 7.21 (d, 2H), 7.14 (d, 2H), 6.99 (t, 1H), 6.41 (d,
1H), 6.35 (d, 1H), 4.15 (m, 1H), 3.42 (br s, 5H), 3.12 (m, 2H),
2.90 (m, 1H), 2.24 (m, 1H), 1.83 (m, 4H), 1.72 (m, 1H), 1.09 (m,
6H)
[3078] Mass Spectral Analysis m/z=395.1 (M+H).sup.+
[3079] [.alpha.].sub.D.sup.24.2=+3.24 (c. 0.01, MeOH)
Example 27V
Preparation of 27.5
[3080] 27.1 (racemic mixture) (10 g, 18.56 mmol, 1 eq) was resolved
using Chiral HPLC method:
Column: Chiralpak AD-H, 4.4.times.250 mm
[3081] Column temperature: 25.degree. C.
Detection: UV at 280 nm
[3082] Flow: 2.0 mL/minute Mobile phase: 75% carbon dioxide, 25%
isopropanol Run time: 10 minutes.
[3083] The relevant fractions were combined and concentrated under
reduced pressure. The crude product was used without further
purification.
[3084] Yield: 83%
[3085] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.23 (d, 2H),
7.11 (m, 3H), 6.58 (d, 1H), 6.54 (d, 1H), 4.85 (d, 1H), 4.73 (d,
1H), 4.16 (m, 1H), 3.63 (m, 2H), 3.16 (br m, 6H), 2.83 (s, 3H),
2.24 (m, 1H), 1.75 (m, 2H), 1.61 (m, 1H), 1.52 (m, 2H), 1.39 (s,
9H), 1.05 (m, 6H)
[3086] Mass Spectral Analysis m/z=539.1 (M+H).sup.+
[3087] Chiral HPLC Method: t.sub.R=5.943 min. (ee=98.7%)
[3088] [.alpha.].sub.D.sup.24.0=+29.88 (c. 0.01, MeOH)
Preparation of 27V
[3089] To a cold (0.degree. C.) solution of 27.5 (1.00 g, 1.86
mmol, 1 eq) in anhydrous methanol was added drop wise a 4M solution
of anhydrous hydrochloric acid in dioxane (2.5 mL, 10.21 mmol, 5.5
eq). The mixture was then stirred for 10 h at room temperature and
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: dichloromethane/methanol mixtures
of increasing polarity).
[3090] Yield: 92%
[3091] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.32 (s, 1H),
9.09 (br s, 2H), 7.21 (d, 2H), 7.12 (d, 2H), 6.99 (t, 1H), 6.41 (d,
1H), 6.38 (d, 1H), 4.16 (m, 1H), 3.36 (m, 5H), 3.13 (brm, 2H), 2.90
(m, 1H), 2.24 (m, 1H), 1.81 (br m, 5H), 1.09 (m, 6H)
[3092] Mass Spectral Analysis m/z=395.1 (M+H).sup.+
[3093] [.alpha.].sub.D.sup.24.3=-6.35 (c. 0.01, MeOH)
Example 27W
[3094] 27W was obtained according to a procedure similar to the one
described for 27A, with the following exception:
Step 27.3: 1A was replaced by 1E.
[3095] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.34 (d, 2H), 7.18
(d, 2H), 6.96 (d, 1H), 6.78 (d, 1H), 6.54 (s, 1H), 4.06 (m, 1H),
3.72 (q, 1H), 3.55 (brm, 3H), 3.28 (brm, 3H), 3.17 (m, 1H), 3.03
(m, 1H), 2.14 (m, 5H), 1.97 (m, 2H), 1.49 (t, 1H), 1.20 (brd,
6H)
[3096] Mass Spectral Analysis m/z=393.4 (M+H).sup.+
Example 28A
Preparation of 28.2
[3097] To a solution of benzyl 4-oxopiperidine-1-carboxylate (19.1)
(37.26 g, 160 mmol) in toluene (450 mL) were added ethyl
cyanoacetate (28.1) (18.8 g, 166 mmol, 1.04 eq), acetic acid (2 mL)
and ammonium acetate (1.24 g, 16 mmol, 0.1 eq). The reaction
mixture was refluxed for 2 h with azeotropic removal of water
formed during the reaction using a Dean-Stark trap. Additional
ethyl cyanoacetate (10 g, 88.4 mmol, 0.55 eq), acetic acid (2 mL)
and ammonium acetate (1.24 g, 6 mmol, 0.0375 eq) was added to the
reaction mixture, which was then refluxed for 1.5 h. Additional
ethyl cyanoacetate (10 g, 88.4 mmol, 0.55 eq), acetic acid (2 mL)
and ammonium acetate (1.24 g, 6 mmol, 0.0375 eq) were added, and
refluxed for an additional 1 h. The reaction mixture was cooled to
room temperature and washed with a saturated aqueous solution of
sodium bicarbonate, and dried over sodium sulfate. The mixture was
filtered and the filtrate was concentrated under vacuum. To the
residue was added hexane (300 mL) and ethyl acetate (20 mL). The
mixture was kept at room temperature overnight. The solid was
collected by filtration, washed with hexane and dried under
vacuum.
[3098] Yield: 87.7%
[3099] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.35 (m, 5H), 5.19
(s, 2H), 4.30 (q, 2H), 3.70 (m, 2H), 3.63 (m, 2H), 3.18 (m, 2H),
2.80 (m, 2H), 1.39 (t, 3H)
Preparation of 28.4a
[3100] To a suspension of copper (I) cyanide (17.3 g, 193.2 mmol,
2.0 eq) in anhydrous tetrahydrofuran (400 mL) was added drop wise a
2.0 M solution of benzylmagnesium chloride (28.3a) (192 mL, 384
mmol, 4.0 eq) in tetrahydrofuran under a nitrogen atmosphere at
0.degree. C. After the reaction mixture was stirred at room
temperature for 2 h, a solution of compound 28.2 (31.5 g, 96 mmol)
in tetrahydrofuran (100 mL) was added dropwise at -30.degree. C.
After the addition, the reaction mixture was stirred at room
temperature overnight, and then quenched with a saturated aqueous
solution of ammonium chloride, and filtered. The filtrate was
extracted by diethyl ether and the combined organic extracts were
dried over sodium sulfate. The organics were concentrated under
reduced pressure and the residue was purified by column
chromatography (eluent: hexane/methylene chloride/ethyl acetate,
4:1:1).
[3101] Yield: 100%
[3102] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.35-7.20 (m,
10H), 5.11 (s, 2H), 4.25 (q, 2H), 3.72-3.50 (m, 5H), 3.06 (d, 1H),
2.91 (d, 1H), 1.90-1.65 (m, 4H), 1.32 (t, 3H)
Preparation of 28.6a
[3103] Concentrated sulfuric acid (210 mL) was added slowly to
28.4a (38 g, 90.5 mmol) at 0.degree. C. The mixture was warmed to
room temperature, stirred for 30 min at room temperature, and then
heated at 90.degree. C. overnight. The reaction mixture was cooled
in an ice bath and carefully basified to pH=9-10 with a 6 N aqueous
solution of sodium hydroxide. The mixture was extracted with
methylene chloride, and the organic extracts were combined, dried
over sodium sulfate and concentrated under vacuum. The residue was
dissolved in methylene chloride (500 mL). To this solution was
added triethylamine (30 mL, 215.6 mmol, 2.4 eq) followed by drop
wise addition of benzyl chloroformate (21.8) (16 mL, 106.5 mmol,
1.2 eq) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 1 h and then washed with a saturated aqueous
solution of sodium bicarbonate. The organic layer was dried over
sodium sulfate and concentrated under vacuum. The residue was
purified by column chromatography (eluent: hexane/methylene
chloride/ethyl acetate, 4:1:1).
[3104] Yield: 41.2%
[3105] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.00 (d, 1H), 7.50
(t, 1H), 7.33-7.23 (m, 7H), 5.11 (s, 2H), 2.98 (s, 2H), 2.62 (s,
2H), 1.50 (m, 4H)
Preparation of 28.7a
[3106] A 1.0 M solution of lithium bis(trimethylsilyl)amide in
tetrahydrofuran (3.6 mL, 3.6 mmol, 1.2 eq) was added at -78.degree.
C. to a solution of 28.6a (1.047 g, 3.0 mmol) in tetrahydrofuran
(30 mL). After 45 min, a solution of 1.4 (1.3 g, 3.6 mmol, 1.2 eq)
in tetrahydrofuran (8 mL) was added drop wise to the reaction
mixture. The reaction mixture was then warmed to room temperature
and stirred for 2.5 h, quenched by addition of water (40 mL), and
extracted with a mixture of hexane and diethyl ether (1:1). The
organic extracts were combined and washed with water, brine and
dried over sodium sulfate. Evaporation of the solvent gave the
crude product, which was used for the next step without further
purification.
[3107] Yield: 100%
[3108] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.35-7.18 (m, 9H),
5.98 (s, 1H), 5.11 (s, 2H), 3.70 (m, 2H), 3.40 (m, 2H), 2.83 (s,
2H), 1.66-1.56 (m, 4H)
Preparation of 28.8a
[3109] To the solution of crude 28.7a (3 mmol) in dimethoxyethane
(25 mL) was added sequentially a 2 N aqueous solution of sodium
carbonate (5 mL, 10 mmol, 3.3 eq), lithium chloride (424 mg, 10
mmol, 3.3 eq), 4-(N,N-diethylaminocarbonyl)phenylboronic acid (796
mg, 3.6 mmol, 1.2 eq) and tetrakis(triphenylphosphine)palladium(0)
(104 mg, 0.09 mmol, 0.03 eq). The reaction mixture was refluxed
overnight, cooled to room temperature, diluted with water (30 mL)
and extracted with diethyl ether. The combined organic extracts
were dried over sodium sulfate and concentrated under vacuum. The
residue was purified by column chromatography (eluent:
hexane/methylene chloride/ethyl acetate, 2:1:1).
[3110] Yield: 91.9%
[3111] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.36-7.12 (m,
12H), 7.00 (d, 1H), 6.00 (s, 1H), 5.13 (s, 2H), 3.70 (m, 2H), 3.58
(m, 2H), 3.45 (m, 2H), 3.30 (m, 2H), 2.82 (s, 2H), 1.65-1.52 (m,
4H), 1.21 (m, 6H)
Preparation of 28A
[3112] Iodotrimethylsilane (0.29 mL, 2 mmol, 2 eq) was added to a
solution of 28.8a (508 mg, 1 mmol) in anhydrous methylene chloride
(10 mL) under a nitrogen atmosphere. The reaction mixture was
stirred at room temperature for 2 h and quenched with a 1N aqueous
solution of hydrochloric acid (30 mL) and extracted with diethyl
ether. The aqueous phase was basified to pH=9-10 with a 3N aqueous
solution of sodium hydroxide, and extracted with methylene
chloride. The organic extracts were combined, dried over sodium
sulfate and concentrated under vacuum. The residue was dissolved in
methylene chloride (3 mL) and diluted with diethyl ether (15 mL).
To this solution was added a 2.0 M solution of anhydrous
hydrochloric acid in diethyl ether (1.5 mL, 3 mmol, 3.0 eq) and the
reaction was stirred at room temperature for 30 min. The solid was
collected by filtration, washed with diethyl ether and dried under
vacuum.
[3113] Yield: 92.7%
[3114] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.90 (m, 2H),
7.40-7.20 (m, 7H), 6.97 (d, 1H), 6.20 (s, 1H), 3.42 (m, 2H), 3.20
(m, 6H), 2.82 (s, 2H), 1.70 (m, 4H), 1.10 (m, 6H)
[3115] Mass Spectral Analysis m/z=375.1 (M+H).sup.+
Example 28B
Preparation of 28.4b
[3116] Compound 28.4b was prepared as described for 28.4a except
28.3a was replaced by 23.8b.
Preparation of 28.9
[3117] To a solution of compound 28.4b (29 g, 64.4 mmol) in
dimethylsulfoxide (200 mL) was added sodium chloride (1.5 g, 25.6
mmol, 0.4 eq) and water (3.0 mL, 167 mmol, 2.6 eq). The reaction
mixture was heated at 160.degree. C. for 2 h and then cooled to
room temperature. Water (600 mL) was added to the mixture and the
crude product was extracted with diethyl ether. The organic
extracts were combined, washed with water and brine, dried over
sodium sulfate, and concentrated under vacuum. The residue was
purified by column chromatography (eluent: hexane/methylene
chloride/ethyl acetate, 4:1:1).
[3118] Yield: 94.8%
[3119] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.35 (m, 5H), 7.08
(d, 2H), 6.83 (d, 2H), 5.12 (s, 2H), 3.80 (s, 3H), 3.68 (m, 2H),
3.40 (m, 2H), 2.74 (s, 2H), 2.21 (s, 2H), 1.60-1.52 (m, 4H)
Preparation of 28.10
[3120] To a solution of compound 28.9 (7.56 g, 20 mmol) in methanol
(200 mL) was added concentrated sulfuric acid (40 mL). The mixture
was heated at reflux for 2 days. The reaction mixture was cooled to
0.degree. C., basified to pH=9 by slow addition of a 6 N aqueous
solution of sodium hydroxide, and then concentrated under vacuum to
remove the methanol. The mixture was extracted with methylene
chloride. The organic extracts were combined, dried over sodium
sulfate, filtered and concentrated under vacuum. The residue was
dissolved in methylene chloride (80 mL) and cooled to 0.degree. C.
To this solution was added triethylamine (9.6 mL, 69 mmol, 3.5 eq)
and followed by drop wise addition of benzyl chloroformate (21.8)
(6.4 mL, 95%, 42.7 mmol, 2.1 eq). The reaction mixture was stirred
at 0.degree. C. for 1 h, washed with a saturated aqueous solution
of sodium bicarbonate, dried over sodium sulfate, filtered and
concentrated under vacuum. The residue was purified by column
chromatography (eluent: hexane/methylene chloride/ethyl acetate,
4:1:1).
[3121] Yield: 94.8%
[3122] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.38 (m, 5H), 7.10
(d, 2H), 6.80 (d, 2H), 5.12 (s, 2H), 3.80 (s, 3H), 3.75 (m, 2H),
3.70 (s, 3H), 3.32 (m, 2H), 2.73 (s, 2H), 2.30 (s, 2H), 1.50 (m,
4H)
Preparation of 28.11
[3123] Compound 28.10 (2.06 g, 5 mmol) was dissolved in mixture of
methanol (40 mL), tetrahydrofuran (40 mL) and water (40 mL). To
this solution was added lithium hydroxide (1.52 g, 36 mmol, 7.2 eq)
in one portion. The reaction mixture was stirred at room
temperature overnight, concentrated under vacuum, acidified with a
3 N aqueous solution of hydrochloric acid and extracted with
methylene chloride. The combined organic extracts were dried over
sodium sulfate, filtered and concentrated under vacuum. The crude
product was used for the next step without further
purification.
[3124] Yield: 100%
[3125] .sup.1H NMR (400 MHz, DMSO d.sub.6) 12.22 (brs, 1H), 7.33
(m, 5H), 7.10 (d, 2H), 6.86 (d, 2H), 5.06 (s, 2H), 3.73 (s, 3H),
3.60 (m, 2H), 3.32 (m, 2H), 2.69 (s, 2H), 2.17 (s, 2H), 1.45-1.35
(m, 4H)
Preparation of 28.6b
[3126] To a solution of 28.11 (1.98 g, 5 mmol) in anhydrous
methylene chloride (10 mL) was added a 2.0 M solution of oxalyl
chloride in methylene chloride (20 mL, 40 mmol, 8.0 eq) followed by
2 drops of anhydrous N,N-dimethylformamide. The reaction mixture
was stirred at room temperature for 4 h and then concentrated under
vacuum. The resulting acyl chloride was dissolved in anhydrous
methylene chloride (100 mL) and aluminum chloride (1.35 g, 10 mmol,
2.0 eq) was added in one portion. The reaction mixture was stirred
at room temperature overnight and then quenched with water (60 mL)
followed by addition of concentrated ammonium hydroxide to basify
the aqueous layer. The organic layer was separated and the aqueous
layer was further extracted with methylene chloride. The combined
organic extracts were dried over sodium sulfate, filtered and
concentrated under vacuum. The residue was then dissolved in
methylene chloride (60 mL) and cooled to 0.degree. C. To this
solution was added triethylamine (3.0 mL, 21.6 mmol, 4.3 eq)
followed by benzyl chloroformate (21.8) (2.0 mL, 13.3 mmol, 2.7
eq). The reaction mixture was stirred at 0.degree. C. for 1 h and
then washed with a saturated aqueous solution of sodium
bicarbonate, dried over sodium sulfate, filtered and concentrated
under vacuum. The residue was purified by column chromatography
(eluent: hexane/methylene chloride/ethyl acetate, 4:1:1).
[3127] Yield: 89.7%
[3128] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.48 (d, 1H), 7.35
(m, 5H), 7.16 (d, 1H), 7.10 (dd, 1H), 5.11 (s, 2H), 3.81 (s, 3H),
3.50 (m, 4H), 2.90 (s, 2H), 2.60 (s, 2H), 1.50 (m, 4H)
Preparation of 28B
[3129] 28B was obtained from 28.6b according to a procedure similar
to the one described for 28A.
[3130] .sup.1H NMR (DMSO d.sub.6) .delta. 8.90 (m, 2H), 7.48 (d,
2H), 7.40 (d, 2H), 7.26 (d, 1H), 6.85 (dd, 1H), 6.45 (d, 1H), 6.20
(s, 1H), 3.64 (s, 3H), 3.42 (m, 4H), 3.18 (m, 4H), 2.78 (s, 2H),
1.70 (m, 4H), 1.11 (m, 6H)
[3131] Mass Spectral Analysis m/z=405.1 (M+H).sup.+
Example 28C
Preparation of 28C
[3132] Compound 28.8a (800 mg, 1.58 mmol) was dissolved in a
mixture of methylene chloride (5 mL) and methanol (50 mL), and the
reaction mixture was hydrogenated in the presence of 10% Pd/C (240
mg) using a hydrogen balloon. After 2 days at room temperature, the
reaction mixture was filtered through celite and the filtrate was
concentrated under vacuum. The residue was dissolved in methylene
chloride (10 ml) and added 2.0 M solution of anhydrous hydrochloric
acid in diethyl ether (2 mL, 4 mmol, 2.5 eq). The mixture was
stirred for 1 h at room temperature and then concentrated under
vacuum.
[3133] Yield: 100%
[3134] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.12 (brs, 2H),
7.28-7.03 (m, 7H), 6.66 (d, 1H), 4.10 (m, 1H), 3.40 (m, 2H),
3.20-3.08 (m, 6H), 2.85 (d, 1H), 2.78 (d, 1H), 2.10 (m, 1H), 1.60
(m, 5H), 1.10 (m, 6H).
[3135] Mass Spectral Analysis m/z=377.1 (M+H).sup.+
Example 28D
[3136] 28D was obtained according to a procedure similar to the one
described for 28C, with the following exception:
Step 28.12: 28.8a was replaced by 28.8b.
[3137] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.77 (m, 2H),
7.28 (m, 4H), 7.89 (d, 1H), 6.75 (dd, 1H), 6.16 (d, 1H), 4.09 (m,
1H), 3.55 (s, 3H), 3.49-3.00 (m, 8H), 2.73 (m, 2H), 2.10 (m, 1H),
1.59 (m, 5H), 1.10 (m, 6H)
[3138] Mass Spectral Analysis m/z=407.3 (M+H).sup.+
Example 28E
[3139] 28E was obtained according to a procedure similar to the one
described for 28A, with the following exception:
Step 28.10:1.6 was replaced by 1.7 (see also step 28.13).
[3140] .sup.1H NMR (400 MHz, DMSO d.sub.6) 8.91 (m, 2H), 8.61 (s,
1H), 7.89 (d, 1H), 760 (d, 1H), 7.31-7.20 (m, 3H), 6.90 (d, 1H),
6.33 (s, 1H), 3.45-3.15 (m, 8H), 2.83 (s, 2H), 1.70 (m, 4H), 1.12
(m, 6H)
[3141] Mass Spectral Analysis m/z=376.4 (M+H).sup.+
[3142] Elemental analysis:
[3143] C.sub.24H.sub.29N.sub.30, 4/3HCl, 1H.sub.2O
[3144] Theory: % C, 65.20; % H, 7.37; % N, 9.50; % Cl, 0.69.
[3145] Found: % C, 64.94; % H, 7.06; % N, 9.36; % Cl, 10.56.
Example 29A
Preparation of 29.2
[3146] To a solution of crude compound 28.7a (12 mmol) in anhydrous
tetrahydrofuran (200 mL) at room temperature was added a 0.5 M
solution of 4-(ethoxycarbonyl)phenylzinc iodide (29.1) in
tetrahydrofuran (60 mL, 30 mmol, 2.5 eq) followed by
tetrakis(triphenylphosphine)palladium(0) (833 mg, 0.72 mmol, 0.06
eq). The reaction mixture was heated at 40.degree. C. for 2 days
and then cooled to room temperature. The reaction was quenched by
addition of a saturated aqueous solution of ammonium chloride and
extracted with ethyl acetate. The organic extracts were combined,
dried over sodium sulfate and filtered. The organic extracts were
concentrated under reduced pressure and the residue was purified by
column chromatography (eluent: hexane/ethyl acetate, 5:1).
[3147] Yield: 86.6%
[3148] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.05 (d, 2H),
7.40-7.10 (m, 10H), 6.96 (d, 1H), 6.00 (s, 1H), 5.13 (s, 2H), 4.40
(q, 2H), 3.70 (m, 2H), 3.48 (m, 2H), 2.82 (s, 2H), 1.66-1.53 (m,
6H), 1.40 (t, 3H)
Preparation of 29.3
[3149] Lithium hydroxide (3.36 g, 80 mmol, 8.0 eq) was added to a
solution of 29.2 (4.81 g, 10 mmol) in a mixture of methanol (100
mL), tetrahydrofuran (100 mL) and water (100 mL). The reaction
mixture was stirred at room temperature overnight, concentrated
under vacuum and acidified to pH=1-2 with a 3N aqueous solution of
hydrochloric acid. The acidified solution was extracted with
methylene chloride and the organic extracts were combined, dried
over sodium sulfate, filtered and concentrated under vacuum. The
crude product was used for the next step without further
purification.
[3150] Yield: 100%
[3151] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 13.00 (brs, 1H),
7.99 (d, 2H), 7.48 (d, 2H), 7.38-7.15 (m, 8H), 6.91 (d, 1H), 6.18
(s, 1H), 5.10 (s, 2H), 3.60-3.46 (m, 4H), 2.82 (s, 2H), 1.53 (m,
2H), 1.42 (m, 2H)
Preparation of 29.5a
[3152] To a solution of 29.3 (680 mg, 1.5 mmol, 1.0 eq)) in
methylene chloride (40 mL) was added isopropylamine (3.4h) (0.26
mL, 3 mmol, 2.0 eq) followed by triethylamine (0.84 ml, 6 mmol, 4.0
eq) and the Mukaiyama acylating reagent
(2-chloro-1-methylpyridinium iodide) (461 mg, 1.8 mmol, 1.2 eq).
The reaction mixture was stirred at room temperature overnight,
washed with a saturated aqueous solution of sodium bicarbonate,
dried over sodium sulfate, and filtered. The organic extracts were
concentrated under reduced pressure and the residue was purified by
column chromatography (eluent: hexane/methylene chloride/ethyl
acetate, 2:1:1).
[3153] Yield: 95.8%
[3154] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.78 (d, 2H),
7.40-7.10 (m, 10H), 6.94 (d, 1H), 6.00 (s, 1H), 5.95 (d, 1H), 5.12
(s, 2H), 4.31 (m, 1H), 3.70 (m, 2H), 3.46 (m, 2H), 2.81 (s, 2H),
1.62-1.52 (m, 6H), 1.30 (d, 6H)
Preparation of 29A
[3155] Iodotrimethylsilane (0.37 mL, 2.6 mmol, 2.0 eq) was added to
a solution 29.5 (620 mg, 1.26 mmol) in anhydrous methylene chloride
(20 mL) under a nitrogen atmosphere. The reaction mixture was
stirred at room temperature for 2 h, quenched with a 1N aqueous
solution of hydrochloric acid (40 mL), and the mixture was
extracted with diethyl ether. The aqueous phase was basified to
pH=9-10 with a 3N aqueous solution of sodium hydroxide and
extracted with methylene chloride. The organic extracts were
combined, dried over sodium sulfate, filtered and concentrated
under vacuum. The residue was dissolved in methylene chloride (4
mL) and diluted with diethyl ether (20 mL). To this solution was
added a 2.0 M solution of anhydrous hydrochloric acid in diethyl
ether (2.0 mL, 4 mmol, 3.2 eq) and the mixture was stirred at room
temperature for 30 min. The resulting precipitate was collected by
filtration, washed with diethyl ether and dried under vacuum.
[3156] Yield: 100%
[3157] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.90 (brd, 2H),
8.29 (d, 1H), 7.90 (d, 2H), 7.43 (d, 2H), 7.31-7.16 (m, 3H), 6.90
(d, 1H), 6.18 (s, 1H), 4.11 (m, 1H), 3.16 (m, 4H), 2.86 (s, 2H),
1.70 (m, 4H), 1.20 (d, 6H)
[3158] Mass Spectral Analysis m/z=361.0 (M+H).sup.+
Example 29B
[3159] 29B was obtained according to a procedure similar to the one
described for 29A, with the following exception:
Step 29.3: 3.4h was replaced by 29.4.
[3160] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.89 (m, 2H),
8.10 (d, 1H), 7.92 (d, 2H), 7.45 (d, 2H), 7.31 (d, 1H), 7.25 (t,
1H), 7.20 (t, 1H), 6.90 (d, 1H), 6.18 (s, 1H), 3.80 (m, 1H), 3.20
(m, 4H), 2.88 (s, 2H), 1.60 (m, 8H), 0.90 (t, 6H)
[3161] Mass Spectral Analysis m/z=389.1 (M+H).sup.+
Example 29C
Preparation of 29.7
[3162] To a solution of the carboxylic acid 29.3 (1.82 g, 4 mmol)
in a mixture of dioxane (18 mL) and tert-butyl alcohol (18 mL) was
added triethylamine (0.78 mL, 5.6 mmol, 1.4 eq) and
diphenylphosphoryl azide (29.6) (1.12 mL, 5.2 mmol, 1.3 eq). The
reaction mixture was refluxed overnight and concentrated under
vacuum. The residue was purified by column chromatography (eluent:
hexane/methylene chloride/ethyl acetate, 5:1:1) to afford the
desired crude carbamate 29.7, which was used for the next step
without further purification.
[3163] Yield: 33.4%
Preparation of 29.8
[3164] To a solution of the crude carbamate 29.7 (700 mg) in
methylene chloride (15 mL) was added a 2.0 M solution of anhydrous
hydrochloric acid in diethyl ether (15 mL, 30 mmol). The reaction
mixture was stirred at room temperature overnight and then diethyl
ether was added to the reaction mixture, which was stirred for an
additional 2 h at room temperature. The resulting precipitate was
collected by filtration and used for the next step without further
purification.
[3165] Yield: 57%
[3166] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.15 (brs, 3H),
7.40-7.15 (12H), 6.89 (d, 1H), 6.10 (s, 1H), 5.10 (s, 2H), 3.59 (m,
2H), 3.46 (m, 2H), 2.81 (s, 2H), 1.54 (m, 2H), 1.41 (m, 2H)
Preparation of 29.10
[3167] Triethylamine (0.42 mL, 3 mmol) was added to a suspension of
29.8 (300 mg, 0.65 mmol) in methylene chloride (20 mL) at 0.degree.
C. followed by drop wise addition of propionyl chloride (29.9)
(0.12 mL, 1.3 mmol, 2.0 eq). The reaction mixture was stirred at
room temperature for 6 h and washed with a saturated aqueous
solution of sodium bicarbonate. The organic layer was dried over
sodium sulfate, filtered and concentrated under vacuum. The residue
was purified by column chromatography (eluent: hexane/methylene
chloride/ethyl acetate, 2:1:1).
[3168] Yield: 89.5%
[3169] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.54 (d, 2H),
7.38-7.10 (m, 1H), 7.00 (d, 1H), 5.95 (s, 1H), 5.12 (s, 2H), 3.70
(m, 2H), 3.44 (m, 2H), 2.80 (s, 2H), 2.42 (q, 2H), 1.60 (m, 2H),
1.50 (m, 2H), 1.28 (t, 3H)
Preparation of 29C
[3170] Iodotrimethylsilane (0.21 mL, 1.47 mmol, 2.0 eq) was added
to a solution of compound 29.10 (220 mg, 0.46 mmol) in anhydrous
methylene chloride (8 mL) under a nitrogen atmosphere. The reaction
mixture was stirred at room temperature for 2 h and quenched with a
1 N aqueous solution of hydrochloric acid (15 mL). The crude
product was extracted with diethyl ether. The aqueous layer was
basified to pH=9-10 with a 3M aqueous solution of sodium hydroxide
and the mixture was extracted with methylene chloride. The organic
extracts were combined, dried over sodium sulfate and concentrated
under vacuum. The residue was dissolved in methylene chloride (3
mL) and diluted with diethyl ether (10 mL). To this solution was
added a 2.0 M solution of anhydrous hydrochloric acid in diethyl
ether (0.7 mL, 1.4 mmol, 3.0 eq) and the mixture was stirred at
room temperature for 30 min. The solid was collected by filtration,
washed with diethyl ether and dried under vacuum.
[3171] Yield: 83.9%
[3172] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.05 (s, 1H),
8.94 (brd, 2H), 7.66 (d, 2H), 7.30-7.20 (m, 5H), 6.96 (d, 1H), 6.08
(s, 1H), 3.15 (m, 4H), 2.82 (s, 2H), 2.34 (q, 2H), 1.68 (m, 4H),
1.10 (t, 3H)
[3173] Mass Spectral Analysis m/z=347.0 (M+H).sup.+
Example 29D
Preparation of 29.11
[3174] Methanesulfonyl chloride (7.4) (0.051 mL, 0.66 mmol, 2.0 eq)
was added to a solution of 29.8 (150 mg, 0.326 mmol) in pyridine (6
mL) at 0.degree. C. The reaction mixture was stirred at room
temperature overnight, diluted with methylene chloride (40 mL) and
washed with a 1N aqueous solution of hydrochloric acid and brine.
The organic layer was dried over sodium sulfate and concentrated
under vacuum. The residue was purified by column chromatography
(eluent: hexane/ethyl acetate, 1:1).
[3175] Yield: 97.7%
[3176] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.38-7.13 (m,
12H), 6.99 (d, 1H), 6.50 (s, 1H), 5.96 (s, 1H), 5.12 (s, 2H), 3.70
(m, 2H), 3.46 (m, 2H), 3.08 (s, 3H), 2.81 (s, 2H), 1.62-1.52 (m,
4H)
Preparation of 29D
[3177] Iodotrimethylsilane (0.14 mL, 0.98 mmol, 3.5 eq) was added
to a solution of 29.11 (140 mg, 0.28 mmol) in anhydrous methylene
chloride (6 mL) under a nitrogen atmosphere. The reaction mixture
was stirred at room temperature for 2 h and quenched with a 1N
aqueous solution of hydrochloric acid (10 mL). The crude product
was extracted with diethyl ether. The aqueous layer was basified to
pH=9-10 with a 3N aqueous solution of sodium hydroxide and
extracted with methylene chloride. The organic extracts were
combined, dried over sodium sulfate, filtered and concentrated
under vacuum. The residue was dissolved in methylene chloride (3
mL) and diluted with diethyl ether (10 mL). To this solution was
added a 2.0 M solution of anhydrous hydrochloric acid in diethyl
ether (0.42 mL, 0.84 mmol, 3.0 eq) and the mixture was stirred at
room temperature for 30 min. The solid was collected by filtration,
washed with diethyl ether and dried under vacuum.
[3178] Yield: 90.5%
[3179] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.88 (s, 1H), 8.91 (brd, 2H), 7.35-7.18
(m, 7H), 6.96 (d, 1H), 6.09 (s, 1H), 3.12 (m, 4H), 3.02 (s, 3H),
2.82 (s, 2H), 1.68 (m, 4H)
[3180] Mass Spectral Analysis m/z=368.9 (M+H).sup.+
Example 30A
Preparation of 30.3
[3181] A mixture of 30.1 (10.2 g, 0.050 mol, 1.0 eq) and 30.2 (25
g, 0.075 mol, 1.5 eq) in toluene (100 mL) under nitrogen was
refluxed for 2 h. The mixture was concentrated under reduced
pressure and the crude product was purified by column
chromatography (eluent: hexane/ethyl acetate, 1:1).
[3182] Yield: 92%
[3183] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.42 (s, 5H), 5.78
(brs, 1H), 3.83 (brs, 2H), 3.70 (s, 3H), 3.49 (brs, 2H), 3.02 (brm,
2H), 2.37 (brm, 2H)
[3184] Mass Spectral Analysis m/z=259.9 (M+H).sup.+
Preparation of 30.5
[3185] A solution of 30.3 (5.0 g, 19.3 mmol, 1.0 eq), 30.4 (16.39
g, 149 mmol, 7.7 eq), and triethylamine (3.90 g, 38.6 mmol, 2.0 eq)
in tetrahydrofuran (100 mL) was refluxed for 12 h. The mixture was
concentrated under reduced pressure and the crude product was
purified by column chromatography (eluent: hexane/ethyl acetate,
60:40).
[3186] Yield: 98%
[3187] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.56 (m, 2H), 7.37
(m, 8H), 4.40 (brs, 1H), 3.72 (s, 3H), 3.58 (brm, 3H), 2.56 (s,
2H), 1.76 (brm, 4H)
[3188] Mass Spectral Analysis m/z=369.9 (M+H).sup.+
Preparation of 30.6
[3189] A solution of 30.5 (10.0 g, 27.07 mmol, 1.0 eq) and
concentrated sulfuric acid (50 mL) was stirred at room temperature
for 18 h. The mixture was poured onto ice water (1:1) (200 mL) and
the crude product was extracted with ethyl acetate. The combined
organic extracts were dried over magnesium sulfate, concentrated
under reduced pressure and the crude product was purified by column
chromatography (eluent: hexane/ethyl acetate, 70:30).
[3190] Yield: 22%
[3191] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.08 (dd, 1H),
7.40 (m, 7H), 7.20 (m, 1H), 4.47 (brs, 1H), 3.44 (brm, 3H), 2.97
(brd, 2H), 1.92 (brm, 4H)
[3192] Mass Spectral Analysis m/z=337.9 (M+H).sup.+
Preparation of 30.7
[3193] To a solution of 30.6 (1.2 g, 3.56 mmol, 1.0 eq) in acetic
acid (5 mL) was added at room temperature a 30% aqueous solution of
hydrogen peroxide (2 mL). The solution was heated at 90.degree. C.
for 2 h and then cooled to room temperature. The mixture was
concentrated to 1/3 of its volume under reduced pressure. Water was
added and the crude product was extracted with methylene chloride.
The combined organic extracts were then washed with a saturated
sodium thiosulfate solution, brine, dried over magnesium sulfate
and filtered. The filtrate was concentrated under reduced pressure.
The crude product was purified by column chromatography (eluent:
hexane/ethyl acetate, 1:1).
[3194] Yield: 84%
[3195] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.10 (m, 2H), 7.87
(m, 1H), 7.77 (m, 1H), 7.41 (m, 5H), 4.34 (brs, 1H), 3.90 (brm,
1H), 3.50 (brm, 4H), 2.36 (brs, 2H), 1.80 (brm, 2H)
[3196] Mass Spectral Analysis m/z=369.8 (M+H).sup.+
Preparation of 30.8
[3197] A mixture of 30.7 (1.1 g, 2.98 mmol, 1.0 eq) and a 6N
aqueous solution of hydrochloric acid (5 mL) in ethanol (20 mL) was
heated at 90.degree. C. for 12 h. The mixture was concentrated
under reduced pressure and used for the next step without further
purification.
[3198] Yield: 100%
[3199] Mass Spectral Analysis m/z=265.8 (M+H).sup.+
Preparation of 30.9
[3200] To a solution of 30.8 (0.9 g, 2.98 mmol, 1.0 eq) in
tetrahydrofuran (10 mL) at 0.degree. C. was added triethylamine
(1.2 g, 11.92 mmol, 4.0 eq) and 4.7 (0.78 g, 3.58 mmol, 1.2 eq).
The mixture was stirred at 0.degree. C. for 1 h and at room
temperature for 1 h. Water (20 mL) was added and the crude mixture
was extracted with ethyl acetate. The combined organics were washed
with water, brine, dried over magnesium sulfate and filtered. The
filtrate was concentrated under reduced pressure. The crude product
was purified by column chromatography (eluent: eluent: hexane/ethyl
acetate, 1:1).
[3201] Yield: 79%
[3202] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.09 (m, 2H), 7.86
(m, 1H), 7.76 (m, 1H), 3.97 (brs, 2H), 3.39 (s, 2H), 3.20 (brm,
2H), 2.29 (m, 2H), 1.76 (brm, 2H), 1.46 (s, 9H)
Preparation of 30.10
[3203] To a solution of 30.9 (0.84 g, 2.30 mmol, 1.0 eq) in
tetrahydrofuran (10 mL) at -78.degree. C. under a nitrogen
atmosphere was added drop wise a 1.0M solution of LiHMDS in
tetrahydrofuran (2.76 mL, 2.76 mmol, 1.2 eq). The mixture was
stirred for 45 min at -78.degree. C. A solution of 1.4 (0.986 g,
2.76 mmol, 1.2 eq) in tetrahydrofuran (3 mL) was added drop wise to
the reaction mixture. The mixture was stirred for 3 h at 0.degree.
C. and at room temperature for 16 h. The mixture was poured into
ice water (20 mL) and the crude product was extracted with ethyl
acetate. The combined organic extracts were washed with water,
brine, dried over magnesium sulfate and filtered. The crude product
was purified by column chromatography (eluent: 85/15 hexane/ethyl
acetate mixture).
[3204] Yield: 52%
[3205] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.09 (dd, 1H),
7.76 (m, 1H), 7.69 (m, 1H), 7.61 (d, 1H), 6.36 (s, 1H), 4.17 (brs,
2H), 3.06 (brs, 2H), 2.24 (m, 2H), 1.82 (m, 2H), 1.47 (s, 9H)
Preparation of 30.11
[3206] To a solution of 30.10 (0.15 g, 0.30 mmol, 1.0 eq) in
dimethoxyethane (DME) (30 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (0.45 mL, 0.90 mmol, 3.0 eq), lithium
chloride (0.038 g, 0.90 mmol, 3.0 eq), 1.6 (0.106 g, 0.33 mmol, 1.1
eq) and tetrakis(triphenylphosphine)palladium(0) (0.007 g, 0.006
mmol, 0.02 eq). The mixture was refluxed for 16 h under a nitrogen
atmosphere. The mixture was then cooled to room temperature and ice
water (20 mL) was added. The mixture was extracted with ethyl
acetate. The combined organic extracts were further washed with
water, brine, dried over magnesium sulfate and filtered. The
filtrate was concentrated under reduced pressure. The crude product
was purified by column chromatography (eluent: hexane/ethyl
acetate, 70:30).
[3207] Yield: 86%
[3208] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.09 (m, 1H), 7.56
(m, 2H), 7.44 (d, 2H), 7.38 (d, 2H), 7.15 (m, 1H), 6.22 (s, 1H),
4.16 (brs, 2H), 3.58 (brs, 2H), 3.30 (brs, 2H), 3.14 (brs, 2H),
2.23 (m, 2H), 1.88 (m, 2H), 1.47 (s, 9H), 1.23 (brd, 6H)
[3209] Mass Spectral Analysis m/z=525.9 (M+H).sup.+
Preparation of 30A
[3210] To a solution of 30.11 (0.440 g, 0.84 mmol, 1.0 eq) in
anhydrous methylene chloride (20 mL) was added a 2.0M solution of
anhydrous hydrochloric acid in diethyl ether (8.0 mL, 16 mmol, 19
eq). The mixture was stirred for 48 h at room temperature. The
mixture was concentrated under reduced pressure and treated with
diethyl ether. The resulting precipitate was collected by
filtration.
[3211] Yield: 100%
[3212] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.37 (brm, 1H),
8.80 (brm, 1H), 8.05 (d, 1H), 7.73 (m, 2H), 7.53 (d, 2H), 7.44 (d,
2H), 7.21 (d, 1H), 6.58 (s, 1H), 3.36 (brm, 8H), 2.26 (brm, 2H),
1.95 (brd, 2H), 1.13 (brd, 6H)
[3213] Mass Spectral Analysis m/z=425.3 (M+H).sup.+
Example 31A
Preparation of 13.2a
[3214] To a solution of 1.5a (7.80 g, 17.35 mmol, 1.0 eq) in
dimethoxyethane (75 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (26.03 mL, 52.06 mmol, 3.0 eq),
lithium chloride (2.21 g, 52.06 mmol, 3.0 eq), 13.1 (3.44 g, 19.09
mmol, 1.1 eq) and tetrakis(triphenylphosphine)palladium(0) (0.40 g,
0.35 mmol, 0.02 eq). The mixture was refluxed overnight under
nitrogen. The mixture was then cooled to room temperature and water
(250 mL) was added. The mixture was extracted with ethyl acetate.
The organic layer was further washed with brine and dried over
sodium sulfate. The mixture was filtered and the filtrate was
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: hexane/ethyl acetate mixtures of
increasing polarity).
[3215] Yield: 64%
[3216] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.02 (d, 2H),
7.49 (d, 2H), 7.23 (m, 1H), 6.99 (d, 1H), 6.92 (m, 2H), 5.92 (s,
1H), 3.88 (s, 3H), 3.70 (m, 2H), 3.27 (m, 2H), 1.89 (m, 2H), 1.71
(m, 2H), 1.42 (s, 9H)
[3217] Mass Spectral Analysis m/z=436.0 (M+H).sup.+
Preparation of 31A
[3218] 31A was obtained according to a procedure similar to the one
described for 1A, with the following exceptions:
Step 1.4: method 1E was used; 1.8a was replaced by 13.2a (see also
step 31.2).
[3219] .sup.1H NMR (DMSO d.sub.6) .delta. 8.81 (m, 2H), 8.00 (m,
2H), 7.45 (m, 2H), 7.24 (m, 1H), 7.03 (m, 1H), 6.91 (m, 2H), 5.99
(s, 1H), 3.90 (s, 3H), 3.22 (m, 4H), 2.06 (m, 2H), 1.98 (m,
2H),
[3220] Mass Spectral Analysis m/z=336.0 (M+H).sup.+
[3221] Elemental analysis:
[3222] C.sub.21H.sub.21NO.sub.3, 1HCl, 0.2H.sub.2O
[3223] Theory: % C, 67.18; % H, 6.01; % N, 3.73.
[3224] Found: % C, 67.32; % H, 5.98; % N, 3.77.
Example 31B
[3225] 31B was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 14.1. Step 31.2: Method 1F was
used.
[3226] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.92 (m, 2H),
7.94 (d, 2H), 7.59 (d, 2H), 7.29 (m, 1H), 7.06 (m, 1H), 6.94 (m,
2H), 6.02 (s, 1H), 3.22 (m, 4H), 2.05 (m, 4H)
[3227] Mass Spectral Analysis m/z=303.1 (M+H).sup.+
[3228] Elemental analysis:
[3229] C.sub.20H.sub.18N.sub.2O, 1HCl, 0.8H.sub.2O
[3230] Theory: % C, 68.00; % H, 5.88; % N, 7.93.
[3231] Found: % C, 67.89; % H, 5.59; % N, 7.79.
Example 31C
[3232] 31C was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 16.1. Step 31.2: Method 1F was
used.
[3233] .sup.1H NMR (400 MHz, DMSO d.sub.6) 9.10 (brs, 1H), 7.90 (s,
2H), 7.65 (m, 2H), 7.25 (t, 1H), 7.10 (d, 1H), 6.00 (s, 1H), 3.20
(m, 4H), 2.00 (m, 4H)
[3234] Mass Spectral Analysis m/z=303.1 (M+H).sup.+
Example 31D
[3235] 31D was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1a. Step 31.2: Method 1E was
used.
[3236] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.18 (m, 2H),
7.51 (m, 1H), 7.41 (m, 2H), 7.26 (m, 2H), 7.05 (m, 1H), 6.94 (m,
2H), 5.92 (s, 1H), 3.46 (m, 2H), 3.20 (m, 6H), 2.06 (m, 4H), 1.11
(m, 6H)
[3237] Mass Spectral Analysis m/z=377.4 (M+H).sup.+
Example 31E
[3238] 31E was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1b. Step 31.2: Method 1F was
used.
[3239] .sup.1H NMR (DMSO d.sub.6) .delta. Done See Provisional Ex.
13
[3240] Mass Spectral Analysis m/z=356.1 (M+H).sup.+
Example 31F
[3241] 31F was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1c. Step 31.2: Method 1F was
used.
[3242] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.60 (m, 2H),
7.41 (m, 4H), 7.26 (m, 1H), 7.03 (m, 1H), 6.95 (m, 2H), 5.89 (s,
1H), 4.11 (s, 2H), 3.23 (m, 4H), 2.09 (m, 2H), 1.94 (m, 2H)
[3243] Mass Spectral Analysis m/z=317.0 (M+H).sup.+
Example 31G
[3244] 31G was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1d. Step 31.2: Method 31A was
used.
[3245] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.16 (brs, 2H),
7.30 (d, 2H), 7.24 (m, 1H), 7.02 (m, 4H), 6.93 (m, 1H), 5.80 (s,
1H), 3.80 (s, 3H), 3.20 (brm, 4H), 2.03 (brm, 4H)
[3246] Mass Spectral Analysis m/z=308.0 (M+H).sup.+
Example 31H
[3247] 31H was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1e. Step 31.2: Method 1F was
used.
[3248] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.07 (m, 2H),
7.26 (m, 5H), 6.98 (m, 3H), 5.82 (s, 1H), 3.21 (m, 4H), 2.35 (s,
3H), 2.03 (m, 4H)
[3249] Mass Spectral Analysis m/z=292.1 (M+H).sup.+
Example 31I
[3250] 31I was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1f. Step 31.2: Method 1F was
used.
[3251] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.76 (m, 1H), 9.29 (m,
1H), 7.69 (m, 1H), 7.46 (m, 1H), 7.27 (brm, 4H), 6.96 (m, 2H), 5.64
(m, 1H), 3.44 (m, 2H), 3.30 (m, 2H), 2.29 (m, 2H), 2.11 (m, 2H)
[3252] Mass Spectral Analysis m/z=346.1 (M+H).sup.+
Example 31J
[3253] 31J was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1g. Step 31.2: Method 31A was
used.
[3254] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.92 (brs,
1.5H), 7.44 (m, 3H), 7.36 (m, 2H), 7.25 (m, 1H), 7.04 (d, 1H), 6.95
(m, 2H), 5.87 (s, 1H), 3.22 (brm, 4H), 2.09 (brm, 2H), 1.97 (brm,
2H)
[3255] Mass Spectral Analysis m/z=278.1 (M+H).sup.+
Example 31K
[3256] 31K was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1h. Step 31.2: Method 31A was
used.
[3257] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.66 (brs, 1H),
8.96 (brs, 2H), 7.50 (brm, 1H), 7.18 (brm, 3H), 6.97 (brm, 3H),
6.82 (brm, 1H), 5.67 (s, 1H), 3.18 (brm, 4H) 2.02 (brm, 4H)
[3258] Mass Spectral Analysis m/z=294.0 (M+H).sup.+
Example 31L
[3259] 31L was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1i. Step 31.2: Method 31A was
used.
[3260] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.93 (brs, 2H),
7.37 (t, 1H), 7.25 (t, 1H), 6.97 (brm, 6H), 5.89 (s, 1H), 3.79 (s,
3H), 3.21 (brm, 4H), 2.03 (brm, 4H)
[3261] Mass Spectral Analysis m/z=308.0 (M+H).sup.+
Example 31M
[3262] 31M was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1j. Step 31.2: Method 31A was
used.
[3263] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.60 (s, 1H),
9.05 (brs, 2H), 7.24 (m, 2H), 7.02 (m, 2H), 6.94 (m, 1H), 6.82 (d,
1H), 6.76 (m, 2H), 5.82 (s, 1H), 3.20 (brm, 4H), 2.03 (brm, 4H)
[3264] Mass Spectral Analysis m/z=294.0 (M+H).sup.+
Example 31N
[3265] 31N was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1k. Step 31.2: Method 1F was
used.
[3266] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.10 (brm,
1.5H), 8.20 (s, 1H), 8.05 (s, 2H), 7.29 (m, 1H), 7.08 (d, 1H), 6.97
(t, 1H), 6.90 (dd, 1H), 6.16 (s, 1H), 3.23 (brm, 4H), 2.08 (brm,
4H)
[3267] Mass Spectral Analysis m/z=414.1 (M+H).sup.+
Example 31O
[3268] 31O was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.11. Step 31.2: Method 31A was
used.
[3269] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.88 (brs, 2H),
7.42 (m, 1H), 7.07 (brm, 5H), 6.83 (t, 1H), 6.60 (d, 1H), 5.73 (s,
1H), 3.65 (s, 3H), 3.18 (brm, 4H), 2.08 (brm, 2H), 1.96 (brm,
2H)
[3270] Mass Spectral Analysis m/z=308.0 (M+H).sup.+
Example 31P
[3271] 31P was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1m. Step 31.2: Method 31A was
used.
[3272] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.46 (s, 1H),
9.02 (brs, 2H), 7.22 (t, 1H), 7.16 (t, 1H), 7.10 (d, 1H), 6.93 (m,
2H), 6.84 (m, 2H), 6.70 (d, 1H), 5.71 (s, 1H), 3.20 (brm, 4H), 2.11
(brm, 2H), 1.97 (brm, 2H)
[3273] Mass Spectral Analysis m/z=294.0 (M+H).sup.+
Example 31Q
[3274] 31Q was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1n. Step 31.2: Method 1E was
used.
[3275] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.75 (m, 2H), 7.85
(m, 1H), 7.78 (m, 1H), 7.49 (m, 1H), 7.37 (m, 3H), 7.28 (m, 1H),
6.99 (m, 2H), 5.88 (s, 1H), 3.42 (m, 4H), 2.27 (m, 4H)
[3276] Mass Spectral Analysis m/z=333.9 (M+H).sup.+
Example 31R
[3277] 31R was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1o. Step 31.2: Method 1F was
used.
[3278] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.04 (m, 2H),
7.66 (m, 3H), 7.34 (m, 4H), 7.10 (m, 2H), 6.48 (m, 1H), 3.23 (m,
4H), 2.09 (m, 4H)
[3279] Mass Spectral Analysis m/z=318.1 (M+H).sup.+
Example 31S
[3280] 31S was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1p. Step 31.2: Method 31A was
used.
[3281] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.81 (brs, 1H),
9.40 (brs, 1H), 8.76 (brs, 2H), 7.98 (d, 1H), 7.67 (brs, 1H), 7.29
(m, 1H), 7.01 (d, 1H), 6.95 (t, 1H), 6.91 (d, 1H), 5.70 (s, 1H),
3.43 (m, 2H), 3.34 (m, 2H), 2.29 (m, 2H), 2.15 (m, 2H)
[3282] Mass Spectral Analysis m/z=279.1 (M+H).sup.+
Example 31T
[3283] 31T was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1q. Step 31.2: Method 1E was
used.
[3284] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.71 (m, 2H),
7.44-7.21 (m, 3H), 7.11 (m, 2H), 6.96 (m, 2H), 5.75 (s, 1H), 3.39
(m, 4H), 2.24 (m, 4H)
[3285] Mass Spectral Analysis m/z=283.9 (M+H).sup.+
Example 31U
[3286] 31U was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1r. Step 31.2: Method 1F was
used.
[3287] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.04 (brm,
1.5H), 7.66 (m, 1H), 7.62 (m, 1H), 7.26 (m, 1H), 7.20 (m, 2H), 7.03
(d, 1H), 6.97 (t, 1H), 5.96 (s, 1H), 3.20 (brm, 4H), 2.07 (brm,
2H), 1.98 (brm, 2H)
[3288] Mass Spectral Analysis m/z=284.1 (M+H).sup.+
Example 31V
[3289] 31V was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1s. Step 31.2: Method 1F was
used.
[3290] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.71 (brs, 1H),
9.29 (brs, 1H), 7.52 (m, 3H), 6.99 (m, 2H), 6.59 (m, 1H), 6.49 (m,
1H), 5.95 (s, 1H), 3.42 (m, 2H), 3.32 (m, 2H), 2.25 (m, 2H), 2.10
(m, 2H)
[3291] Mass Spectral Analysis m/z=268.1 (M+H).sup.+
Example 31W
[3292] 31W was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1t. Step 31.2: Method 1F was
used.
[3293] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.34 (brm,
1.5H), 8.12 (d, 1H), 7.60 (m, 6H), 7.42 (t, 1H), 7.32 (t, 1H), 7.22
(t, 1H), 7.02 (d, 1H), 6.89 (m, 2H), 6.81 (d, 1H), 5.98 (s, 1H),
3.41 (brs, 2H), 2.20 (brm, 6H)
[3294] Mass Spectral Analysis m/z=457.1 (M+H).sup.+
Example 31X
[3295] 31X was obtained according to a procedure similar to the one
described for 31A, with the following exceptions:
Step 31.1: 13.1 was replaced by 31.1u. Step 31.2: Method 1E was
used.
[3296] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.93 (m, 2H),
8.03 (d, 1H), 7.42 (d, 1H), 7.32 (m, 2H), 7.05 (m, 2H), 6.25 (s,
1H), 3.22 (m, 4H), 2.03 (m, 4H)
[3297] Mass Spectral Analysis m/z=308.8 (M+H).sup.+
Example 31Y
Preparation of 31Y
[3298] A solution of 16.2 (0.200 g, 0.0046 mol, 1.0 eq) in
tetrahydrofuran (50 mL) was added drop wise to a cold (0.degree.
C.) suspension of lithium aluminum hydride (1.05 g, 0.027 mol, 6.0
eq) in tetrahydrofuran (50 mL). The mixture was allowed to warm to
room temperature and was refluxed for 12 h under a nitrogen
atmosphere. The reaction was cooled to room temperature and
quenched by careful addition of water (3 mL). The mixture was
stirred for 1 h at room temperature and filtered through celite.
The celite was further rinsed with hot ethyl acetate. Evaporation
of the filtrate afforded an oil which was dissolved in diethyl
ether (20 mL). A 2.0M solution of hydrochloric acid in anhydrous
diethyl ether (6.9 mL, 0.0138 mol, 3-0 eq) was added to the
mixture. The resulting precipitate was collected by filtration and
washed with diethyl ether.
[3299] Yield: 70%
[3300] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.60 (m, 1H),
8.40 (m, 2H), 7.50 (m, 3H), 7.35 (m, 1H), 7.25 (m, 1H), 6.90-7.10
(m, 3H), 5.80 (s, 1H), 4.10 (m, 2H), 3.30 (m, 7H), 2.10 (m, 4H)
[3301] Mass Spectral Analysis m/z=321.1 (M+H).sup.+
Example 31Z
Preparation of 31Z
[3302] Acetyl chloride (0.14 mL, 0.0019 mol, 1.5 eq) was added drop
wise to a cold solution of 31Y (dihydrochloric acid salt) (0.500 g,
0.0012 mol, 1.0 eq) and triethylamine (0.90 mL, 0.006 mol, 5.0 eq)
in dichloromethane (10 mL). The mixture was allowed to warm to room
temperature and stirring was continued for 12 h at room
temperature. The mixture was poured into water and ethyl acetate
(30 mL) was added. The organic layer was separated, washed with
brine, dried over sodium sulfate, filtered and evaporated. The
crude product was purified by column chromatography (eluent:
dichloromethane/methanol, mixtures of increasing polarity). The
purified compound was dissolved in diethyl ether (20 mL). A 2.0M
solution of anhydrous hydrochloric acid in diethyl ether (1.8 mL,
0.0036 mol, 3.0 eq) was added to the mixture. The resulting
precipitate was collected by filtration and washed with diethyl
ether.
[3303] Yield: 31%
[3304] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.70 (m, 1H),
8.35 (m, 1H), 7.35 (m, 1H), 7.20-7.30 (m, 3H), 7.05 (m, 1H), 6.90
(m, 3H), 5.75 (s, 1H), 4.20 (s, 2H), 3.30 (m, 4H), 2.80 (s, 3H),
2.15 (m, 4H), 1.85 (s, 3H)
[3305] Mass Spectral Analysis m/z=363.1 (M+H).sup.+
Example 31AA
Preparation of 31AA
[3306] Methane sulfonyl chloride (0.15 mL, 0.0019 mol, 1.5 eq) was
added drop wise to a cold solution of 31Y (dihydrochloric acid
salt) (0.500 g, 0.0012 mol, 1.0 eq) and triethylamine (0.90 mL,
0.006 mol, 5.0 eq) in dichloromethane (10 mL). The mixture was
allowed to warm to room temperature and stirring was continued for
12 h at room temperature. The mixture was poured into water and
ethyl acetate (30 mL) was added. The organic layer was separated,
washed with brine, dried over sodium sulfate, filtered and
evaporated. The crude product was purified by column chromatography
(eluent: dichloromethane/methanol mixtures of increasing polarity).
The purified compound was dissolved in diethyl ether (20 mL). A
2.0M solution of anhydrous hydrochloric acid in diethyl ether (1.8
mL, 0.0036 mol, 3.0 eq) was added to the mixture. The resulting
precipitate was collected by filtration and washed with diethyl
ether.
[3307] Yield: 30%
[3308] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 10.90 (m, 1H),
7.40 (m, 2H), 7.35 (m, 1H), 7.30 (m, 2H), 7.10 (m, 1H), 7.00 (m,
2H), 5.75 (s, 1H), 4.20 (d, 2H), 3.30 (m, 4H), 2.90 (s, 3H), 2.80
(s, 3H), 2.10 (m, 4H)
[3309] Mass Spectral Analysis m/z=399.1 (M+H).sup.+
Example 32A
Preparation of 32.1
[3310] To a solution of Bis(pinacolato)diboron 1.14 (14.7 g, 57.8
mmol, 2.0 eq) in N,N-dimethylformamide (200 mL) at room temperature
under a nitrogen atmosphere was added
1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride complex
with dichloromethane (710 mg, 0.867 mmol, 0.03 eq) followed by
addition of potassium acetate (8.58 g, 86.7 mmol, 3.0 eq.) The
mixture was heated to 80.degree. C. followed by drop wise addition
of a solution of the enol triflate 1.5a (13.0 g, 28.9 mmol, 1.0 eq)
in N,N-dimethylformamide (100 mL). After the addition was complete,
the reaction mixture was heated at 80.degree. C. for an additional
16 h. The solvent was evaporated under vacuum and the residue was
added to a 1N aqueous solution of hydrochloric acid. The aqueous
residue was extracted with ethyl acetate. The organic extracts were
washed with brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure to afford a brown semisolid.
The crude product was purified by column chromatography (eluent:
hexane/ethyl acetate mixtures of increasing polarity).
[3311] Yield: 96.0%
[3312] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.71 (d, 1H), 7.11
(t, 1H), 6.90 (t, 1H), 6.83 (d, 1H), 6.28 (s, 1H), 3.84 (brs, 2H),
3.27 (brm, 2H), 1.96 (d, 2H), 1.60 (m, 2H), 1.34 (s, 9H), 1.26 (s,
12H)
[3313] Mass Spectral Analysis m/z=428.0 (M+H).sup.+
Preparation of 32.2a
[3314] To a solution of 4-bromophenylacetic acid (32.4) (3.21 g, 15
mmol) in methylene chloride (300 mL) was added diethylamine (1.12)
(3.2 mL, 30 mmol, 2.0 eq) followed by triethylamine (8.4 ml, 60
mmol, 4.0 eq) and the Mukaiyama acylating reagent
(2-chloro-1-methylpyridinium iodide) (4.61 mg, 18 mmol, 1.2 eq).
The reaction mixture was stirred at room temperature overnight and
the mixture was washed with a saturated aqueous solution of sodium
bicarbonate, dried over sodium sulfate and filtered. The filtrate
was concentrated under reduced pressure and the residue was
purified by column chromatography (eluent: hexane/methylene
chloride/ethyl acetate, 2:1:1).
[3315] Yield: 89.2%
[3316] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.43 (d, 2H), 7.15
(d, 2H), 3.63 (s, 2H), 3.40 (q, 2H), 3.30 (q, 2H), 1.10 (t, 3H)
Preparation of 32.3a
[3317] To a solution of 32.1 (2.14 g, 5 mmol) in dimethoxyethane
(DME) (40 mL) was added sequentially a 2 N aqueous solution of
sodium carbonate (8 mL, 16 mmol, 3.2 eq), lithium chloride (679 mg,
16 mmol, 3.2 eq.), 32.2a (1.62 mg, 6 mmol, 1.2 eq) and
tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.15 mmol, 0.03
eq). The mixture was refluxed overnight under a nitrogen
atmosphere. The mixture was then cooled to room temperature and
water (50 mL) was added. The mixture was extracted with ethyl
acetate. The organic layer was further washed with brine, dried
over sodium sulfate and concentrated under vacuum. The crude
product was purified by column chromatography (eluent: hexane/ethyl
acetate, 1:1).
[3318] Yield: 61%
[3319] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.29 (s, 4H), 7.18
(t, 1H), 7.03 (d, 1H), 6.95 (d, 1H), 5.86 (t, 1H), 5.53 (s, 1H),
3.86 (m, 2H), 3.72 (s, 2H), 3.39 (m, 6H), 2.05 (m, 2H), 1.68 (m,
2H), 1.49 (s, 9H), 1.16 (m, 6H)
Preparation of 32A
[3320] To a solution of 32.3a (1.4 g, 3.38 mmol) in methylene
chloride (15 mL) was added a 2.0 M solution of anhydrous
hydrochloric acid in diethyl ether (50 mL). The mixture was stirred
at room temperature for 24 h and diluted by addition of diethyl
ether was added. The resulting precipitate was collected by
filtration and washed with diethyl ether.
[3321] Yield: 92%
[3322] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.20 (m, 2H),
7.20 (s, 4H), 7.24 (m, 1H), 7.00 (m, 3H), 5.83 (s, 1H), 3.40-3.20
(m, 8H), 2.03 (m, 4H), 1.08 (m, 6H)
[3323] Mass Spectral Analysis m/z=391.3 (M+H).sup.+
Example 32B
[3324] 32B was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2b and Method 1C was used.
Note: 32.2b was obtained according to a procedure similar to the
one described for 32.2e (see 32E) except 13.4b was replaced by 1.12
in step 32.8.
[3325] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.02 (brs, 2H),
8.88 (s, 2H), 8.57 (s, 2H), 7.23 (s, 1H), 7.05 (s, 1H), 6.91 (s,
2H), 6.00 (s, 1H), 3.32 (s, 4H), 3.12 (brs, 4H), 2.08 (m, 4H), 1.02
(brd, 6H)
[3326] Mass Spectral Analysis m/z=454.0 (M+H).sup.+
[3327] Elemental analysis:
[3328] C.sub.23H.sub.28N.sub.2O.sub.3S, 1HCl, 1/3H.sub.2O
[3329] Theory: % C, 60.71; % H, 6.57; % N, 6.16.
[3330] Found: % C, 60.64; % H, 6.36; % N, 6.16.
Example 32C
[3331] 32C was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2c and Method 1D was used.
Note: 32.2c was obtained according to a procedure similar to the
one described for 32.2e (see 32E) except 13.4b was replaced by 3.4c
in step 32.8.
[3332] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.00 (brs, 2H),
7.86 (d, 2H), 7.68 (t, 1H), 7.60 (d, 2H), 7.28 (m, 1H), 7.06 (d,
1H), 6.96 (d, 2H), 6.01 (s, 1H), 3.21 (brm, 4H), 2.81 (m, 2H), 2.10
(brm, 2H), 2.01 (brm, 2H), 1.00 (t, 3H)
[3333] Mass Spectral Analysis m/z=385.3 (M+H).sup.+
[3334] Elemental analysis:
[3335] C.sub.21H.sub.24N.sub.2O.sub.3S, 1HCl, 0.25H.sub.2O
[3336] Theory: % C, 59.28; % H, 6.04; % N, 6.58.
[3337] Found: % C, 59.06; % H, 5.92; % N, 6.44.
Example 32D
[3338] 32D was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2d. Note: 32.2d was obtained
according to a procedure similar to the one described for 32.2e
(see 32E) except 13.4b was replaced by 32.6 in step 32.8.
[3339] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.13 (brs, 2H),
7.90 (d, 2H), 7.64 (s, 1H), 7.56 (d, 2H), 7.27 (m, 1H), 7.06 (d,
1H), 6.95 (m, 2H), 6.01 (s, 1H), 3.22 (brm, 4H), 2.07 (brm, 4H),
1.12 (s, 9H)
[3340] Mass Spectral Analysis m/z=413.3 (M+H).sup.+
Example 32E
Preparation of 32.2e
[3341] 13.4b (7.33 mL, 64.58 mmol, 3.3 eq) was added at room
temperature to a solution of 32.5 (5 g, 19.57 mmol, 1 eq) in
tetrahydrofuran (20 mL). The reaction was stirred at room
temperature overnight. The mixture was concentrated under reduced
pressure and dichloromethane was added. The mixture was washed with
water, a saturated aqueous solution of sodium bicarbonate and
brine, and then dried over sodium sulfate and filtered. The organic
extracts were concentrated under reduced pressure and the crude
product was used for the next step without further
purification.
[3342] Yield: 40%
[3343] .sup.1H NMR (400 MHz, DMSO d.sub.6) .quadrature. 7.82 (s,
4H), 7.25 (s, 4H), 4.58 (s, 4H)
[3344] Mass Spectral Analysis m/z=337.9 (M+H).sup.+
Preparation of 32E
[3345] 32E was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2e.
[3346] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.06 (brs, 2H),
7.94 (d, 2H), 7.60 (d, 2H), 7.26 (m, 5H), 7.04 (d, 1H), 6.90 (m,
2H), 5.97 (s, 1H), 4.62 (s, 4H), 3.19 (brm, 4H), 2.03 (brm, 4H)
[3347] Mass Spectral Analysis m/z=459.3 (M+H).sup.+
Example 32F
[3348] 32F was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2f. Note: 32.2f was obtained
according to a procedure similar to the one described for 32.2e
except 13.4b was replaced by 3.4e in step 32.8.
[3349] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.04 (brs, 2H),
7.86 (d, 2H), 7.72 (t, 1H), 7.59 (d, 2H), 7.28 (m, 1H), 7.06 (d,
1H), 6.95 (d, 2H), 6.01 (s, 1H), 3.22 brm, 4H), 2.57 (t, 2H), 2.10
(brm, 2H), 2.02 (brm, 2H), 1.65 (m, 1H), 0.83 (d, 6H)
[3350] Mass Spectral Analysis m/z=413.3 (M+H).sup.+
[3351] Elemental analysis:
[3352] C.sub.23H.sub.28N.sub.2O.sub.3S, 1HCl, 0.5H.sub.2O
[3353] Theory: % C, 60.31; % H, 6.60; % N, 6.12.
[3354] Found: % C, 60.67; % H, 6.33; % N, 6.10.
Example 32G
[3355] 32G was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2g and Method 1D was used.
[3356] 32.2 g was obtained according to a procedure similar to the
one described for 32.2e except 13.4b was replaced by 3.4h in step
32.8.
[3357] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.16 (brs, 2H),
7.87 (d, 2H), 7.70 (d, 1H), 7.59 (d, 2H), 7.28 (m, 1H), 7.06 (d,
1H), 6.95 (m, 2H), 6.01 (s, 1H), 3.24 (brm, 5H), 2.07 (brm, 4H),
0.98 (d, 6H)
[3358] Mass Spectral Analysis m/z=399.4 (M+H).sup.+
[3359] Elemental analysis:
[3360] C.sub.22H.sub.26N.sub.2O.sub.3S, 1HCl
[3361] Theory: % C, 60.75; % H, 6.26; % N, 6.44.
[3362] Found: % C, 60.58; % H, 6.29; % N, 6.36.
Example 32H
[3363] 32H was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2h.
[3364] 32.2h was obtained according to a procedure similar to the
one described for 32.2e except 13.4b was replaced by 3.4o in step
32.8.
[3365] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.09 (brs, 2H),
7.89 (d, 2H), 7.58 (d, 2H), 7.28 (m, 1H), 7.06 (d, 1H), 6.94 (m,
2H), 6.02 (s, 1H), 3.76 (m, 2H), 3.22 (brm, 4H), 2.05 (brm, 4H),
1.20 (d, 12H)
[3366] Mass Spectral Analysis m/z=441.4 (M+H).sup.+
Example 32I
[3367] 32I was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2i.
[3368] 32.2i was obtained according to a procedure similar to the
one described for 32.2e except 13.4b was replaced by 13.4c in step
32.8.
[3369] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.03 (brs, 2H),
7.66 (d, 2H), 7.38 (d, 2H), 7.08 (m, 1H), 6.86 (d, 1H), 6.74 (m,
2H), 5.81 (s, 1H), 3.00 (brm, 6H), 2.82 (d, 2H), 1.87 (brm, 4H),
1.37 (m, 2H), 0.71 (m, 1H), 0.65 (t, 3H), 0.27 (m, 2H), 0.01 (m,
2H)
[3370] Mass Spectral Analysis m/z=453.3 (M+H).sup.+
Example 32J
Preparation of 32J
[3371] Trifluoroacetic acid (5 mL, 64.90 mmol, 10.0 eq) was added
drop wise to 32.3b (3.83 g, 7.47 mmol, 1.0 eq) at 0.degree. C. The
mixture was warmed to room temperature and stirring was continued
for an additional 10 h at room temperature. The mixture was
concentrated under reduced pressure. A saturated solution of sodium
bicarbonate (50 mL) was added to the mixture, which was then
extracted with dichloromethane. The organic phase was separated,
washed with brine, dried over sodium sulfate, filtered and the
filtrate was concentrated under reduced pressure. To a cold
(0.degree. C.) solution of the resulting oil in anhydrous
dichloromethane (35 mL) was added drop wise a 2.0M solution of
anhydrous hydrochloric acid in diethyl ether (17 mL, 35.70 mmol,
5.5 eq). The mixture was then stirred for 1 h at room temperature
and concentrated under reduced pressure. Diethyl ether was added.
The resulting precipitate was collected by filtration and washed
with diethyl ether. The crude product was purified by column
chromatography (eluent: dichloromethane/methanol mixtures of
increasing polarity).
[3372] Yield: 10%
[3373] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.08 (m, 2H),
7.90 (m, 2H), 7.56 (m, 2H), 7.46 (m, 2H), 7.28 (m, 1H), 7.07 (m,
1H), 6.94 (m, 2H), 5.98 (s, 1H), 3.46 (m, 2H), 3.17 (m, 2H), 2.05
(m, 4H)
[3374] Mass Spectral Analysis m/z=357.4 (M+H).sup.+
[3375] Elemental analysis:
[3376] C.sub.19H.sub.20N.sub.2O.sub.3S, 1HCl, 1H.sub.2O
[3377] Theory: % C, 55.54; % H, 5.64; % N, 6.82.
[3378] Found: % C, 55.30; % H, 5.28; % N, 6.55.
Example 32K
Preparation of 32.9a
[3379] Triethylamine (0.96 mL, 6.88 mmol, 1.3 eq) was added to a
solution of 20.2a (0.40 mL, 5.29 mmol, 1.0 eq) and 32.7 (1.0 g,
5.29 mmol, 1.0 eq) in acetonitrile (60 mL). The solution was
refluxed for 1 h and then concentrated under reduced pressure.
Methylene chloride was added and the organic mixture was washed
with water. The organic mixture was dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The crude
product was used for the next step without further
purification.
[3380] Yield: 93%
[3381] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.40 (d, 2H), 7.18
(d, 2H), 2.92 (q, 2H), 1.31 (t, 3H)
Preparation of 32.2j
[3382] To a solution of 32.9a (1.07 g, 4.93 mmol, 1.0 eq) in acetic
acid (7 mL) was added a 30% aqueous solution of hydrogen peroxide
(3 mL). The mixture was heated at 90.degree. C. for 2 h. The
mixture was cooled to room temperature. Water was added and the
mixture was extracted with methylene chloride. The organic mixture
was then washed with a saturated aqueous sodium thiosulfate
solution and brine. The organic mixture was dried over sodium
sulfate and filtered. The filtrate was concentrated under reduced
pressure. The crude product was used for the next step without
further purification.
[3383] Yield: 92%
[3384] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.78 (d, 2H), 7.72
(d, 2H), 3.11 (q, 2H), 1.28 (t, 3H)
Preparation of 32K
[3385] 32K was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2j and Method 1D was used.
[3386] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.86 (brs, 1H),
7.96 (d, 2H), 7.66 (d, 2H), 7.29 (m, 1H), 7.07 (d, 1H), 6.96 (d,
2H), 6.04 (s, 1H), 3.37 (m, 2H), 3.22 (m, 4H), 2.10 (m, 2H), 2.00
(m, 2H), 1.13 (t, 3H)
[3387] Mass Spectral Analysis m/z 370.2 (M+H).sup.+
[3388] Elemental analysis:
[3389] C.sub.21H.sub.23NO.sub.3S, 1HCl, 0.33H.sub.2O
[3390] Theory: % C, 61.23; % H, 6.04; % N, 3.40; % S, 7.78.
[3391] Found: % C, 61.15; % H, 5.92; % N, 3.39; % S, 7.68.
Example 32L
[3392] 32L was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2k and Method 12A was used.
Note: 32.2k was obtained according to a procedure similar to the
one described for 32.2j except 20.2a was replaced by 20.2b in step
32.6.
[3393] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.92 (brs, 1H),
7.96 (d, 2H), 7.66 (d, 2H), 7.29 (m, 1H), 7.07 (d, 1H), 6.96 (d,
2H), 6.04 (s, 1H), 3.31 (m, 2H), 3.22 (m, 4H), 2.10 (m, 2H), 2.00
(m, 2H), 1.58 (m, 2H), 0.94 (t, 3H)
[3394] Mass Spectral Analysis m/z=384.2 (M+H).sup.+
[3395] Elemental analysis:
[3396] C.sub.22H.sub.25NO.sub.3S, 1HCl, 0.5H.sub.2O
[3397] Theory: % C, 61.60; % H, 6.34; % N, 3.27; % S, 7.47.
[3398] Found: % C, 61.88; % H, 6.28; % N, 3.36; % S, 7.36.
Example 32M
[3399] 32M was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2l and Method 12A was used.
Note: 32.2l was obtained according to a procedure similar to the
one described for 32.2j except 20.2a was replaced by 2.8a in step
32.6.
[3400] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.93 (brs, 1H),
7.97 (d, 2H), 7.65 (d, 2H), 7.29 (m, 1H), 7.07 (d, 1H), 6.95 (m,
2H), 6.04 (s, 1H), 3.32 (m, 2H), 3.22 (m, 4H), 2.10 (m, 2H), 2.01
(m, 2H), 0.87 (m, 1H), 0.47 (m, 2H), 0.13 (m, 2H)
[3401] Mass Spectral Analysis m/z=396.2 (M+H).sup.+
[3402] Elemental analysis:
[3403] C.sub.23H.sub.25NO.sub.3S, 1HCl
[3404] Theory: % C, 63.95; % H, 6.07; % N, 3.24; % S, 7.42.
[3405] Found: % C, 63.94; % H, 6.03; % N, 3.32; % S, 7.32.
Example 32N
[3406] 32N was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2m and Method 12A was used.
Note: 32.2m was obtained according to a procedure similar to the
one described for 32.2j except 20.2a was replaced by 32.8a in step
32.6.
[3407] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.91 (brs, 1H),
7.98 (d, 2H), 7.66 (d, 2H), 7.29 (m, 1H), 7.07 (d, 1H), 6.96 (m,
2H), 6.04 (s, 1H), 3.32 (m, 2H), 3.22 (m, 4H), 2.10 (m, 2H), 2.02
(m, 2H), 1.62 (m, 1H), 1.46 (m, 2H), 0.84 (d, 6H)
[3408] Mass Spectral Analysis m/z=412.2 (M+H).sup.+
[3409] Elemental analysis:
[3410] C.sub.24H.sub.29NO.sub.3S, 1HCl, 0.33H.sub.2O
[3411] Theory: % C, 63.49; % H, 6.81; % N, 3.08.
[3412] Found: % C, 63.45; % H, 6.71; % N, 3.39.
Example 32O
[3413] 32O was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2n and Method 12A was used.
Note: 32.2n was obtained according to a procedure similar to the
one described for 32.2p (see 32Q) except 32.8d was replaced by
32.8b in step 32.6.
[3414] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.93 (brm, 1H),
7.98 (d, 2H), 7.64 (d, 2H), 7.29 (m, 1H), 7.07 (d, 1H), 6.94 (m,
2H), 6.02 (s, 1H), 3.32 (m, 2H), 3.22 (m, 4H), 2.10 (m, 2H), 2.01
(m, 2H), 1.10 (s, 9H)
[3415] Mass Spectral Analysis m/z=412.2 (M+H).sup.+
[3416] Elemental analysis:
[3417] C.sub.24H.sub.29NO.sub.3S, 1HCl, 0.33H.sub.2O
[3418] Theory: % C, 63.49; % H, 6.81; % N, 3.08; % S, 7.06.
[3419] Found: % C, 63.49; % H, 6.70; % N, 3.25; % S, 6.78.
Example 32P
[3420] 32P was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2o and Method 12A was used.
Note: 32.2o was obtained according to a procedure similar to the
one described for 32.2p (see 32Q) except 32.8d was replaced by
32.8c in step 32.6.
[3421] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.82 (brs, 2H),
7.93 (d, 2H), 7.66 (d, 2H), 7.29 (m, 1H), 7.07 (d, 1H), 6.96 (m,
2H), 6.05 (s, 1H), 3.47 (m, 1H), 3.23 (m, 4H), 2.10 (m, 2H), 2.00
(m, 2H), 1.19 (d, 6H)
[3422] Mass Spectral Analysis m/z=384.2 (M+H).sup.+
[3423] Elemental analysis:
[3424] C.sub.22H.sub.25NO.sub.3S, 1HCl
[3425] Theory: % C, 62.92; % H, 6.24; % N, 3.34; % S, 7.63.
[3426] Found: % C, 63.18; % H, 6.26; % N, 3.46; % S, 7.54.
Example 32Q
Preparation of 32.9b
[3427] To a suspension of sodium hydride (0.33 g, 13.75 mmol, 1.3
eq) in N,N-dimethylformamide (10 mL) at 0.degree. C. under nitrogen
was added drop wise a solution of 32.7 (2.0 g, 10.58 mmol, 1.0 eq)
in N,N-dimethylformamide (5 mL). The mixture was stirred for 10 min
at 0.degree. C. and 32.8d (1.48 mL, 10.58 mmol, 1.0 eq) was added
drop wise. The mixture was allowed to warm to room temperature and
stirring continued for a further 16 h at room temperature. The
reaction was carefully quenched with water and the mixture was
extracted with diethyl ether. The organic extracts were combined,
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The crude product was used for the next step without
further purification.
[3428] Yield: 87%
[3429] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.38 (d, 2H), 7.18
(d, 2H), 2.87 (d, 2H), 1.45 (m, 5H), 0.88 (t, 6H)
Preparation of 32.2p
[3430] To a solution of 32.9b (2.53 g, 9.26 mmol, 1.0 eq) in acetic
acid (14 mL) was added a 30% aqueous solution of hydrogen peroxide
(6 mL). The mixture was heated at 90.degree. C. for 2 h. The
mixture was cooled to room temperature. Water was added and the
crude product was extracted with methylene chloride. The organic
mixture was washed with a saturated aqueous sodium thiosulfate
solution and brine. The mixture was dried over sodium sulfate and
filtered. The filtrate was concentrated under reduced pressure. The
crude product was used for the next step without further
purification.
[3431] Yield: 80%
[3432] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.78 (d, 2H), 7.71
(d, 2H), 3.00 (d, 2H), 1.88 (m, 1H), 1.46 (m, 4H), 0.82 (t, 6H)
Preparation of 32Q
[3433] 32Q was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2p and Method 12A was used.
[3434] (32Q) .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.97 (brs,
2H), 7.99 (d, 2H), 7.65 (d, 2H), 7.29 (m, 1H), 7.07 (d, 1H), 6.94
(m, 2H), 6.03 (s, 1H), 3.23 (m, 6H), 2.10 (m, 2H), 2.02 (m, 2H),
1.73 (m, 1H), 1.40 (m, 4H), 0.77 (t, 6H)
[3435] Mass Spectral Analysis m/z=426.2 (M+H).sup.+
[3436] Elemental analysis:
[3437] C.sub.25H.sub.31NO.sub.3S, 1HCl, 0.33H.sub.2O
[3438] Theory: % C, 64.15; % H, 7.03; % N, 2.99; % S, 6.85.
[3439] Found: % C, 64.26; % H, 6.91; % N, 3.20; % S, 6.35.
Example 32R
Preparation of 32.2q
[3440] To a solution 4-bromo-N-methylaniline of (32.10) (0.74 g, 4
mmol, 1.0 eq) in dry dichloromethane (50 mL) at 0.degree. C. was
slowly added triethylamine (2.23 mL, 8 mmol, 2.0 eq). The mixture
was stirred for 10 min at room temperature and 19.8a (0.63 mL, 6
mmol, 1.5 eq) was added drop wise to the reaction mixture. The
reaction mixture was slowly warmed to room temperature and was
stirred for 10 h at room temperature. Dichloromethane (100 mL) was
added to the mixture which was washed with a 1M aqueous solution of
hydrochloric acid (3.times.50 mL), a saturated aqueous sodium
bicarbonate (2.times.50 mL) and brine. The organic extracts were
dried over sodium sulfate, filtered, and concentrated under reduced
pressure to give the crude product, which was used for next step
without purification.
[3441] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.56 (m, 2H), 7.08
(m, 2H), 3.23 (s, 3H), 2.49 (m, 1H), 1.02 (d, 6H)
[3442] Mass Spectral Analysis m/z=256.15 (M+H).sup.+
Preparation of 32R
[3443] 32R was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2q and Method 1D was used.
[3444] .sup.1H NMR (400 MHz, DMSO (16) .delta. 8.91 (brs, 2H), 7.43
(m, 4H), 7.27 (m, 1H), 7.01 (m, 3H), 5.96 (s, 1H), 3.40-3.14 (m,
8H), 2.04 (m, 4H), 0.96 (m, 6H)
[3445] Mass Spectral Analysis m/z=377.3 (M+H).sup.+
[3446] Elemental analysis:
[3447] C.sub.24H.sub.28N.sub.2O.sub.3, 1HCl, 2/3H.sub.2O
[3448] Theory: % C, 67.83; % H, 7.19; % N, 6.59.
[3449] Found: % C, 67.78; % H, 7.19; % N, 6.50.
Example 32S
[3450] 32S was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2r and Method 1D was used.
Note: 32.2r was obtained according to a procedure similar to the
one described for 32.2q except 19.8a was replaced by 19.8b in step
32.9.
[3451] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.98 (brs, 2H),
7.47 (m, 2H), 7.33 (m, 2H), 7.27 (m, 1H), 7.00 (m, 3H), 5.96 (s,
1H), 3.40-3.12 (m, 7H), 2.25-1.94 (m, 5H), 1.48 (m, 2H), 1.30 (m,
2H), 0.76 (m, 6H)
[3452] Mass Spectral Analysis m/z=405.4 (M+H).sup.+
[3453] Elemental analysis:
[3454] C.sub.26H.sub.32N.sub.2O.sub.2, 1HCl, 1/5H.sub.2O
[3455] Theory: % C, 70.24; % H, 7.57; % N, 6.30.
[3456] Found: % C, 70.20; % H, 7.50; % N, 6.19.
Example 32T
[3457] 32T was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2s and Method 1D was used.
Note: 32.2s was obtained according to a procedure similar to the
one described for 32.2q except 19.8a was replaced by 32.11a in step
32.9.
[3458] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.95 (brs, 2H),
7.44 (m, 2H), 7.37 (m, 2H), 7.27 (m, 1H), 7.00 (m, 3H), 5.96 (s,
1H), 3.21 (m, 7H), 2.03 (m, 7H), 0.81 (m, 6H)
[3459] Mass Spectral Analysis m/z=391.3 (M+H).sup.+
[3460] Elemental analysis:
[3461] C.sub.25H.sub.30N.sub.2O.sub.2, 1HCl, 0.1H.sub.2O
[3462] Theory: % C, 70.03; % H, 7.33; % N, 6.53.
[3463] Found: % C, 69.97; % H, 7.33; % N, 6.57.
Example 32U
[3464] 32U was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2t and Method 1D was used.
Note: 32.2t was obtained according to a procedure similar to the
one described for 32.2q except 19.8a was replaced by 6.7 in step
32.9.
[3465] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.95 (m, 2H),
7.42 (m, 4H), 7.26 (m, 1H), 7.00 (m, 3H), 5.93 (s, 1H), 3.20 (m,
7H), 2.04 (m, 4H), 1.83 (s, 3H)
[3466] Mass Spectral Analysis m/z=349.2 (M+H).sup.+
[3467] Elemental analysis:
[3468] C.sub.22H.sub.24N.sub.2O.sub.2, 1HCl, 1.4H.sub.2O
[3469] Theory: % C, 64.43; % H, 6.83; % N, 6.83.
[3470] Found: % C, 64.49; % H, 6.87; % N, 6.89.
Example 32V
[3471] 32V was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2u and Method 1D was used.
Note: 32.2u was obtained according to a procedure similar to the
one described for 32.2q except 19.8a was replaced by 32.11b in step
32.9.
[3472] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.95 (m, 2H),
7.42 (m, 4H), 7.26 (m, 1H), 7.05 (m, 1H), 6.96 (m, 2H), 5.94 (s,
1H), 3.20 (m, 7H), 2.05 (m, 6H), 1.38 (m, 3H), 0.74 (m, 6H)
[3473] Mass Spectral Analysis m/z=405.3 (M+H).sup.+
[3474] Elemental analysis:
[3475] C.sub.26H.sub.32N.sub.2O.sub.2, 1HCl, 1.5H.sub.2O
[3476] Theory: % C, 66.72; % H, 7.75; % N, 5.99.
[3477] Found: % C, 66.57; % H, 7.67; % N, 5.93.
Example 32W
[3478] 32W was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2v and Method 1D was used.
Note: 32.2v is commercially available.
[3479] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.91 (brs, 2H),
7.74 (m, 2H), 7.37 (m, 2H), 7.25 (m, 1H), 7.02 (m, 2H), 6.94 (m,
1H), 5.86 (s, 1H), 3.87 (t, 2H), 3.20 (m, 4H), 2.52 (t, 2H), 2.08
(m, 4H), 1.99 (m, 2H)
[3480] Mass Spectral Analysis m/z=361.2 (M+H).sup.+
[3481] Elemental analysis:
[3482] C.sub.23H.sub.24N.sub.2O.sub.2, 1HCl, 0.5H.sub.2O
[3483] Theory: % C, 68.06; % H, 6.46; % N, 6.90.
[3484] Found: % C, 68.10; % H, 6.42; % N, 6.96.
Example 32X
[3485] 32X was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2w and Method 1D was used.
Note: 32.2w is commercially available.
[3486] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.82 (brs, 2H),
8.07 (d, 1H), 7.24 (m, 2H), 7.14 (d, 1H), 7.02 (m, 2H), 6.94 (m,
1H), 5.82 (s, 1H), 4.13 (t, 2H), 3.19 (m, 6H), 2.18 (s, 3H), 2.06
(m, 2H), 1.96 (m, 2H)
[3487] Mass Spectral Analysis m/z=361.3 (M+H).sup.+
[3488] Elemental analysis:
[3489] C.sub.23H.sub.24N.sub.2O.sub.2, 1HCl, 0.4H.sub.2O
[3490] Theory: % C, 68.36; % H, 6.44; % N, 6.93.
[3491] Found: % C, 68.41; % H, 6.23; % N, 6.93.
Example 32Y
[3492] 32Y was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2x and Method 1D was used.
Note: 32.2x was obtained according to a procedure similar to the
one described for 32.2q except 19.8a was replaced by 32.11c in step
32.9.
[3493] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.04 (brs, 2H),
7.41 (m, 4H), 7.26 (m, 1H), 7.00 (m, 3H), 5.94 (s, 1H), 3.20 (m,
7H), 2.05 (m, 6H), 1.49 (m, 2H), 3.79 (m, 3H)
[3494] Mass Spectral Analysis m/z=377.4 (M+H).sup.+
[3495] Elemental analysis:
[3496] C.sub.24H.sub.28N.sub.2O.sub.2, 1HCl, 1.1H.sub.2O
[3497] Theory: % C, 66.61; % H, 7.27; % N, 6.47.
[3498] Found: % C, 66.51; % H, 7.20; % N, 6.39.
Example 32Z
[3499] 32Z was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 32.2y and Method 1D was used.
Note: 32.2y was obtained according to a procedure similar to the
one described for 32.2q except 19.8a was replaced by 32.11d in step
32.9.
[3500] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.98 (brs, 2H),
7.41 (m, 4H), 7.26 (m, 1H), 7.00 (m, 3H), 5.94 (s, 1H), 3.20 (m,
7H), 2.05 (m, 6H), 1.46 (m, 2H), 1.18 (m, 2H), 3.79 (m, 3H)
[3501] Mass Spectral Analysis m/z=391.4 (M+H).sup.+
[3502] Elemental analysis:
[3503] C.sub.25H.sub.30N.sub.2O.sub.2, 1HCl, 0.9H.sub.2O
[3504] Theory: % C, 67.75; % H, 7.46; % N, 6.32.
[3505] Found: % C, 67.71; % H, 7.45; % N, 6.30.
Example 33A
[3506] 33A was obtained according to a procedure similar to the one
described for 32A, with the following exception:
Step 32.2: 32.2a was replaced by 33.1a (see also step 33.2). Note:
33.1a was commercially available.
[3507] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.98 (d, 1H),
7.89 (dd, 1H), 7.84 (d, 1H), 7.29 (m, 1H), 7.01 (m, 2H), 6.42 (s,
1H), 3.07 (m, 4H), 1.95 (m, 4H)
[3508] Mass Spectral Analysis m/z=284.9 (M+H).sup.+
Example 33B
[3509] 33B was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 33.1b and Method 33A was used (see
also step 33.2). Note: 33.1b was commercially available.
[3510] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.19 (m, 3H),
8.86 (m, 2H), 7.29 (m, 1H), 7.07 (m, 1H), 6.97 (m, 2H), 6.15 (s,
1H), 3.22 (m, 4H), 2.08 (m, 4H)
[3511] Mass Spectral Analysis m/z=279.9 (M+H).sup.+
Example 33C
[3512] 33C was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 33.1c and Method 33A was used (see
also step 33.2). Note: 33.1c is commercially available.
[3513] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.73 (m, 1H),
7.21 (m, 1H), 6.90 (m, 5H), 5.94 & 5.88 (2s, 1H rotamer),
3.6-2.7 (m, 7H), 1.91 (m, 4H)
[3514] Mass Spectral Analysis m/z=282.0 (M+H).sup.+
Example 33D
[3515] 33D was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 33.1d and Method 33A was used (see
also step 33.2). Note: 33.1d is commercially available.
[3516] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.87 (m, 2H),
7.80 (s, 2H), 7.56 (m, 1H), 7.32 (m, 2H), 7.26 (m, 1H), 7.15 (m,
2H), 6.18 (s, 1H), 3.30-3.07 (m, 4H), 2.03 (m, 4H)
[3517] Mass Spectral Analysis m/z=362.9 (M+H).sup.+
Example 33E
[3518] 33E was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 33.1e and Method 33A was used (see
also step 33.2). Note: 33.1e is commercially available.
[3519] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.99 (brs, 2H),
8.80 (s, 1H), 8.15 (m, 1H), 8.08 (m, 1H), 7.30 (m, 1H), 7.07 (m,
1H), 6.96 (m, 2H), 6.17 (s, 1H), 3.23 (m, 4H), 2.08 (m, 4H)
[3520] Mass Spectral Analysis m/z=303.9 (M+H).sup.+
Example 33F
Preparation of 33.1f
[3521] To a stirred solution of 33.3 (3 g, 14.85 mmol, 1.0 eq) in
acetonitrile (20 mL) was slowly added diisopropylethylamine (6.2
mL, 35.64 mmol, 2.4 eq) and diethylamine (1.12) (3.1 mL, 29.70
mmol, 2 eq) at room temperature. The mixture was stirred for 10 min
at room temperature, cooled to 0.degree. C. and
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) (5.72 g, 17.82 mmol, 1.2 eq) was added portion wise. The
reaction mixture was slowly warmed to room temperature and stirred
for 10 h at room temperature. The volatiles were removed under
reduced pressure and the residue was partitioned between ethyl
acetate (200 mL) and a 1M aqueous solution of sodium bicarbonate
(100 mL). The organic phase was washed with a 1M aqueous solution
of sodium bicarbonate (2.times.50 mL), a 1M aqueous solution of
hydrochloric acid (3.times.50 mL) and brine. The organic phase was
dried over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity).
[3522] Yield: 100%
[3523] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.72 (d, 1H), 8.55
(d, 1H), 7.87 (m, 1H), 3.56 (q, 2H), 3.27 (q, 2H), 1.26 (t, 3H),
1.16 (t, 3H)
[3524] Mass Spectral Analysis m/z=256.81 (M+H).sup.+
Preparation of 33F
[3525] 33F was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 33.1f and Method 33A was used (see
also step 33.2).
[3526] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.07 (brs, 2H),
8.65 (m, 2H), 7.80 (m, 1H), 7.29 (m, 1H), 7.07 (m, 1H), 6.96 (m,
2H), 6.09 (s, 1H), 3.52-3.10 (m, 8H), 2.05 (m, 4H), 1.12 (m,
6H)
[3527] Mass Spectral Analysis m/z=378.3 (M+H).sup.+
Example 33G
Preparation of 33.1g
[3528] To a stirred solution of 33.4 (3 g, 14.85 mmol, 1.0 eq) in
acetonitrile (20 mL) was slowly added diisopropylethylamine (6.2
mL, 35.64 mmol, 2.4 eq) and diethylamine (1.12) (3.1 mL, 29.70
mmol, 2 eq) at room temperature. The mixture was stirred for 10
min, cooled to 0.degree. C. and
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) (5.72 g, 17.82 mmol, 1.2 eq) was added portion wise. The
reaction mixture was slowly warmed to room temperature and stirred
for 10 h at room temperature. The volatiles were removed under
reduced pressure and the residue was partitioned between ethyl
acetate (200 mL) and a 1M aqueous solution of sodium bicarbonate
(100 mL). The organic phase was washed with a 1M aqueous solution
of sodium bicarbonate (2.times.50 mL), a 1M aqueous solution of
hydrochloric acid (3.times.50 mL) and brine. The organic phase was
dried over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity).
[3529] Yield: 100%
[3530] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.64 (d, 1H), 7.59
(dd, 1H), 7.52 (dd, 1H), 3.54 (q, 2H), 3.38 (q, 2H), 1.25 (m,
6H)
[3531] Mass Spectral Analysis m/z=256.7 (M+H).sup.+
Preparation of 33G
[3532] 33G was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 33.1g and Method 33A was used (see
also step 33.2).
[3533] (33G) .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.01 (m,
2H), 8.01 (m, 1H), 7.59 (m, 2H), 7.26 (m, 1H), 7.13 (m, 1H), 7.04
(m, 1H), 6.93 (m, 1H), 6.11 (s, 1H), 3.51-3.11 (m, 8H), 2.05 (m,
4H), 1.15 (t, 3H), 1.06 (t, 3H)
[3534] Mass Spectral Analysis m/z=378.2 (M+H).sup.+
Example 33H
[3535] 33H was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced with 33.1h and Method 1D was used
(see also step 33.2). Note: 33.1h was obtained according to a
procedure similar to the one described for 1.13 (see 1N) except
1.12 was replaced by 3.4j in step 1.8 (see also step 33.9).
[3536] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.99 (brs, 1H),
8.61 (d, 1H), 7.91 (dd, 1H), 7.64 (d, 1H), 7.29 (m, 1H), 7.06 (d,
1H), 6.97 (m, 2H), 6.09 (s, 1H), 3.23 (m, 4H), 3.04 (s, 3H), 2.99
(s, 3H), 2.11 (m, 2H), 2.02 (m, 2H)
[3537] Mass Spectral Analysis m/z=350.2 (M+H).sup.+
[3538] Elemental analysis:
[3539] C.sub.21H.sub.23N.sub.3O.sub.2, 1.35HCl, 0.8H.sub.2O
[3540] Theory: % C, 61.06; % H, 6.33; % N, 10.17; % Cl, 11.59.
[3541] Found: % C, 60.72; % H, 6.23; % N, 10.05; % Cl, 11.26.
Example 33I
[3542] 33I was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced with 33.1i and Method 1D was used
(see also step 33.2). Note: 33.1i was obtained according to a
procedure similar to the one described for 1.13 (see 1N) except
1.12 was replaced by 3.4c in step 1.8 (see also step 33.9).
[3543] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.87 (m, 2H),
8.62 (d, 1H), 8.11 (d, 1H), 7.99 (dd, 1H), 7.30 (m, 1H), 7.08 (d,
1H), 6.96 (m, 2H), 6.10 (s, 1H), 3.35 (m, 2H), 3.24 (m, 4H), 2.11
(m, 2H), 2.02 (m, 2H), 1.14 (t, 3H)
[3544] Mass Spectral Analysis m/z=350.2 (M+H).sup.+
[3545] Elemental analysis:
[3546] C.sub.21H.sub.23N.sub.3O.sub.2, 1.4HCl, 1.8H.sub.2O
[3547] Theory: % C, 58.26; % H, 6.52; % N, 9.71; % Cl, 11.47.
[3548] Found: % C, 58.26; % H, 6.23; % N, 9.59; % Cl, 11.83.
Example 33J
[3549] 33J was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced with 33.1j and Method 1D was used
(see also step 33.2). Note: 33.1j was obtained according to a
procedure similar to the one described for 1.13 (see 1N) except
1.12 was replaced by 3.4b in step 1.8 (see also step 33.9).
[3550] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.94 (brs, 1H),
8.83 (m, 1H), 8.62 (d, 1H), 8.11 (d, 1H), 7.98 (dd, 1H), 7.30 (m,
1H), 7.08 (d, 1H), 6.96 (m, 2H), 6.10 (s, 1H), 3.22 (m, 4H), 2.84
(d, 3H), 2.11 (m, 2H), 2.02 (m, 2H)
[3551] Mass Spectral Analysis m/z=336.2 (M+H).sup.+
[3552] Elemental analysis:
[3553] C.sub.20H.sub.21N.sub.3O.sub.2, 1.1HCl, 0.8H.sub.2O
[3554] Theory: % C, 61.61; % H, 6.13; % N, 10.78; % Cl, 10.00.
[3555] Found: % C, 61.84; % H, 5.90; % N, 10.75; % Cl, 10.01.
Example 33K
Preparation of 33.6
[3556] To a mixture of a 2.5M solution of n-butyl lithium in
hexanes (0.84 mL, 2.1 mmol, 1.05 eq) and toluene (4 mL) at
-78.degree. C. was added a solution of 33.5 (0.57 g, 2.0 mmol, 1.0
eq) in toluene (2 mL). The reaction was stirred for 1 h at
-78.degree. C. The reaction was quenched with freshly crushed dry
ice. The mixture was warmed slowly to room temperature and was
stirred for 2 h at room temperature. The mixture was concentrated
under reduced pressure and the resulting solid was treated with
acetic acid. The solid was collected by filtration, dried under
vacuum and used for the next step without further purification.
[3557] Yield: 62%
[3558] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.90 (s, 2H)
Preparation of 33.7
[3559] To a solution of 33.6 (0.055 g, 0.27 mmol, 1.0 eq) in
methylene chloride (5 mL) was added oxalyl chloride (0.050 mL, 0.58
mmol, 2.1 eq). The mixture was refluxed for 1 h and concentrated
under reduced pressure. The crude acyl chloride was used for the
next step without further purification.
Preparation of 33.1k
[3560] To a solution of 33.7 (0.060 g, 0.27 mmol, 1.0 eq) in
tetrahydrofuran (2.5 mL) was added 1.12 (0.11 mL, 1.06 mmol, 4.0
eq). The mixture was stirred for 16 h and then diluted with ethyl
acetate. The organic mixture was washed with water, with a
saturated aqueous solution of sodium bicarbonate, a 1N aqueous
solution of hydrochloric acid and brine. The organic mixture was
dried over sodium sulfate, filtered, concentrated under reduced
pressure and the crude product was used for the next step without
further purification. Note: the product was isolated with a 17%
impurity corresponding to
N,N-diethyl-2-iodopyrimidine-5-carboxamide.
[3561] Yield: 86%
[3562] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.82 (s, 2H), 3.56
(q, 2H), 3.20 (q, 2H), 1.28 (t, 3H), 1.18 (t, 3H)
Preparation of 33K
[3563] 33K was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 33.1k and Method 12A (see was used
(see also step 33.2).
[3564] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.81 (m, 2H),
7.18 (m, 1H), 6.92 (m, 2H), 6.85 (m, 1H), 6.06 (s, 0.8H), 6.04 (s,
0.2H), 3.41 (q, 2H), 3.06 (q, 2H), 2.86 (m, 2H), 2.76 (m, 2H), 1.73
(brm, 4H), 1.10 (t, 3H), 1.00 (t, 3H)
[3565] Mass Spectral Analysis m/z=379.3 (M+H).sup.+
Example 33L
Preparation of 33L
[3566] To a solution of 33.2a (0.27 g, 0.67 mmol, 1 eq) in dry
dichloromethane (15 mL) was added dropwise a 4.0M solution of
hydrogen chloride in dioxane (1.34 mL, 5.35 mmol, 8 eq). The
reaction mixture was stirred at room temperature for 10 h and
concentrated under reduced pressure. The crude mixture (containing
a mixture of 33E and 33L) was purified by column chromatography
(eluent: dichloromethane/methanol/ammonium hydroxide mixture of
increasing polarity), affording the 33L in a pure form.
[3567] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.59 (d, 1H),
8.17 (s, 1H), 8.09 (d, 1H), 7.95 (dd, 1H), 7.71 (s, 1H), 7.23 (m,
1H), 6.97 (d, 1H), 6.91 (m, 2H), 6.02 (s, 1H), 2.91 (m, 2H), 2.77
(m, 2H), 1.82 (m, 2H), 1.73 (m, 2H)
[3568] Mass Spectral Analysis m/z=321.9
Example 34A
Preparation of 34.1a
[3569] To a stirred solution of 34.3 (2.5 g, 12.38 mmol, 1.0 eq) in
acetonitrile (20 mL) was slowly added diisopropylethylamine (4.74
mL, 27.24 mmol, 2.2 eq) and diethylamine (1.12) (2.56 mL, 24.76
mmol, 2.0 eq) at room temperature. The mixture was stirred for 10
min at room temperature, cooled to 0.degree. C. and
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) (4.37 g, 13.62 mmol, 1.1 eq) was added portion wise to the
reaction mixture. The reaction mixture was slowly warmed to room
temperature and stirred for 10 h at room temperature. The volatiles
were removed under reduced pressure and the residue was partitioned
between ethyl acetate (200 mL) and 1M aqueous sodium bicarbonate
(100 mL). The organic phase was washed with a 1M aqueous solution
of sodium bicarbonate (2.times.50 mL), with a 1M aqueous solution
of hydrochloric acid (3.times.50 mL) and brine. The organic phase
was dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[3570] Yield: 78%
[3571] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.41 (m, 1H), 7.59
(m, 1H), 7.55 (m, 1H), 3.55 (q, 2H), 3.27 (q, 2H), 1.25 (t, 3H),
1.15 (t, 3H)
[3572] Mass Spectral Analysis m/z=257.04 (M+H).sup.+
Preparation of 34A
[3573] 34A was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1a (see also step 34.2).
[3574] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.94 (brm, 2H),
8.64 (s, 1H), 7.92 (dd, 1H), 7.65 (d, 1H), 7.29 (m, 2H), 7.05 (d,
1H), 6.96 (t, 1H), 6.22 (s, 1H), 3.48 (m, 2H), 3.24 (brm, 6H), 2.05
(brm, 4H), 1.14 (brd, 6H)
[3575] Mass Spectral Analysis m/z=378.4 (M+H).sup.+
[3576] Elemental analysis:
[3577] C.sub.23H.sub.27N.sub.3O.sub.2, 1HCl, 1.3H.sub.2O
[3578] Theory: % C, 63.16; % H, 7.05; % N, 9.61.
[3579] Found: % C, 63.05; % H, 6.75; % N, 9.50.
Example 34B
[3580] 34B was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1b (see also step 34.2). Note:
34.1b was obtained according to a procedure similar to the one
described for 34.1a except 1.12 was replaced by 3.4o in step
34.4.
[3581] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.04 (brs, 2H),
8.59 (d, 1H), 7.85 (dd, 1H), 7.64 (d, 1H), 7.28 (m, 2H), 7.05 (d,
1H), 6.96 (t, 1H), 6.21 (s, 1H), 3.67 (m, 2H), 3.22 (brm, 4H), 2.06
(brm, 4H), 1.45 (brs, 6H), 1.15 (brs, 6H)
[3582] Mass Spectral Analysis m/z=406.4 (M+H).sup.+
[3583] Elemental analysis:
[3584] C.sub.25H.sub.31N.sub.3O.sub.2, 1.5HCl, 0.66H.sub.2O
[3585] Theory: % C, 63.59; % H, 7.22; % N, 8.90; % Cl, 11.26.
[3586] Found: % C, 63.68; % H, 7.21; % N, 8.99; % Cl, 11.28.
Example 34C
Preparation of 34.1c
[3587] To a stirred solution of 34.4 (2.1 g, 10 mmol, 1.0 eq) in
acetonitrile (20 mL) was slowly added diisopropylethylamine (4.2
mL, 24 mmol, 2.4 eq) and diethylamine (1.12) (2.1 mL, 20 mmol, 2
eq) at room temperature. The mixture was stirred for 10 min at room
temperature, cooled to 0.degree. C. and
O-benzotriazol-1-yl-N,N,N'-tetramethyluronium tetrafluoroborate
(TBTU) (3.85 g, 12 mmol, 1.2 eq) was added portion wise. The
reaction mixture was slowly warmed to room temperature and stirred
for 10 h at room temperature. The volatiles were removed under
reduced pressure and the residue was partitioned between ethyl
acetate (200 mL) and a 1M aqueous solution of sodium bicarbonate
(100 mL). The organic phase was washed with a 1M aqueous solution
of sodium bicarbonate (2.times.50 mL), with a 1N aqueous solution
of hydrochloric acid (3.times.50 mL) and brine, dried over sodium
sulfate and filtered. The filtrate was concentrated under reduced
pressure. The crude product was used for next step without further
purification.
[3588] Mass Spectral Analysis m/z=262.1 (M+H).sup.+
Preparation of 34C
[3589] 34C was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1c (see also step 34.2).
[3590] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.07 (brs, 2H),
7.41 (d, 1H), 7.37 (d, 1H), 7.31 (t, 1H), 7.22 (d, 1H), 7.07 (d,
1H), 7.02 (t, 1H), 6.12 (s, 1H), 3.50 (brm, 4H), 3.21 (brm, 4H0,
2.03 (brm, 4H), 1.18 (brt, 6H)
[3591] Mass Spectral Analysis m/z=383.3 (M+H).sup.+
[3592] Elemental analysis:
[3593] C.sub.22H.sub.26N.sub.2O.sub.2S, 1HCl
[3594] Theory: % C, 63.07; % H, 6.50; % N, 6.69.
[3595] Found: % C, 63.03; % H, 6.52; % N, 6.61.
Example 34D
[3596] 34D was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1d (see also step 34.2). Note:
34.1d was obtained according to a procedure similar to the one
described for 34.1c except 1.12 was replaced by 3.4o in step
34.5.
[3597] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.93 (brs, 2H),
7.38 (d, 1H), 7.31 (t, 1H), 7.26 (d, 1H), 7.19 (d, 1H), 7.07 (d,
1H), 7.02 (t, 1H), 6.10 (s, 1H), 3.97 (brs, 2H), 3.21 (brm, 4H),
2.07 (brm, 2H), 1.97 (brm, 2H), 1.31 (brd, 12H)
[3598] Mass Spectral Analysis m/z=411.4 (M+H).sup.+
[3599] Elemental analysis:
[3600] C.sub.24H.sub.30N.sub.2O.sub.2S, 1HCl,
[3601] Theory: % C, 64.48; % H, 6.99; % N, 6.27.
[3602] Found: % C, 64.25; % H, 7.01; % N, 6.22.
Example 34E
Preparation of 34.1e
[3603] To a stirred solution of 34.5 (4.58 g, 17.5 mmol, 1.0 eq) in
dichloromethane (100 mL) at 0.degree. C. was slowly added
triethylamine (7.32 mL, 52.5 mmol, 3 eq) followed by drop wise
addition of diethylamine (1.12) (3.64 mL, 35.0 mmol, 2.0 eq). The
reaction mixture was kept at 0.degree. C. for 30 min. and then
stirred at room temperature for 3 h. The mixture was washed with a
1N aqueous solution of hydrochloric acid (3.times.50 mL) and brine.
The organic phase was dried over sodium sulfate, filtered and
concentrated under reduced pressure to give the crude product,
which was used for the next step without further purification.
[3604] Yield: 100%
[3605] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30 (d, 1H), 7.05
(d, 1H), 3.24 (q, 4H), 1.19 (t, 6H)
[3606] Mass Spectral Analysis m/z=297.92 (M+H).sup.+
Preparation of 34E
[3607] 34E was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1e (see also step 34.2).
[3608] (34E) .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.98 (brs,
2H), 7.68 (d, 1H), 7.34 (brm, 3H), 7.06 (m, 2H), 6.23 (s, 1H), 3.22
(brm, 8H), 2.03 (brm, 4H), 1.12 (m, 6H)
[3609] Mass Spectral Analysis m/z=419.2 (M+H).sup.+
Example 34F
Preparation of 34.1f
[3610] To a stirred solution of 34.6 (2 g, 10.47 mmol, 1.0 eq) in
acetonitrile (20 mL) was slowly added diisopropylethylamine (4 mL,
23.03 mmol, 2.2 eq) and diethylamine (1.12) (2.1 mL, 20.94 mmol,
2.0 eq) at room temperature. The mixture was stirred for 10 min at
room temperature, cooled to 0.degree. C. and
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) (3.7 g, 11.52 mmol, 1.1 eq) was added portion wise. The
reaction mixture was slowly warmed to room temperature and stirred
for 10 h at room temperature. The volatiles were removed under
reduced pressure and the residue was partitioned between ethyl
acetate (200 mL) and a 1M aqueous solution of sodium bicarbonate
(100 mL). The organic phase was washed with a 1M aqueous solution
of sodium bicarbonate (2.times.50 mL), a 1M aqueous solution of
hydrochloric acid (3.times.50 mL) and brine. The organic phase was
dried over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity).
[3611] Yield: 91%
[3612] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.99 (d, 1H), 6.41
(d, 1H), 3.54 (brs, 4H), 1.26 (brs, 6H)
[3613] Mass Spectral Analysis m/z=246.0 (M+H).sup.+
Preparation of 34F
[3614] 34F was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1f (see also step 34.2).
[3615] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.05 (brs, 2H),
7.52 (d, 1H), 7.32 (t, 1H), 7.07 (brm, 3H), 6.91 (d, 1H), 6.26 (s,
1H), 3.50 (brs, 4H), 3.20 (brm, 4H), 2.05 (brm, 4H), 1.17 (brs,
6H)
[3616] Mass Spectral Analysis m/z=367.3 (M+H).sup.+
Example 34G
[3617] 34G was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1g (see also step 34.2). Note:
34.1g was obtained according to a procedure similar to the one
described for 34.1f except 1.12 was replaced by 3.4o in step
34.8.
[3618] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.89 (brs, 2H),
7.52 (d, 1H), 7.32 (t, 1H), 7.07 (m, 2H), 6.92 (d, 1H), 6.87 (d,
1H), 6.24 (s, 1H), 4.02 (brs, 2H), 3.20 (brm, 4H), 2.03 (brm, 4H),
1.31 (brs, 12H),
[3619] Mass Spectral Analysis m/z=395.5 (M+H).sup.+
Example 34H
Preparation of 34.1h
[3620] To a stirred solution of 34.7 (2.1 g, 10 mmol, 1.0 eq) in
acetonitrile (20 mL) was slowly added diisopropylethylamine (4.2
mL, 24 mmol, 2.4 eq) and diethylamine (1.12) (2.1 mL, 20 mmol, 2
eq) at room temperature. The mixture was stirred for 10 min at room
temperature, cooled to 0.degree. C. and
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) (3.85 g, 12 mmol, 1.2 eq) was added portion wise. The
reaction mixture was slowly warmed to room temperature and stirred
for 10 h at room temperature. The volatiles were removed under
reduced pressure and the residue was partitioned between ethyl
acetate (200 mL) and a 1M aqueous solution of sodium bicarbonate
(100 mL). The organic phase was washed with a 1M aqueous solution
of sodium bicarbonate (2.times.50 mL), a 1M aqueous solution of
hydrochloric acid (3.times.50 mL) and brine. The organic phase was
dried over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity).
[3621] Yield: 87%
[3622] Mass Spectral Analysis m/z=262.15 (M+H).sup.+
Preparation of 34H
[3623] 34H was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1h (see also step 34.2).
[3624] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.01 (brs, 2H),
7.80 (s, 1H), 7.41 (s, 1H), 7.27 (t, 1H), 7.19 (d, 1H), 7.04 (d,
1H), 6.99 (t, 1H), 6.04 (s, 1H), 3.48 (brm, 4H), 3.21 (brm, 4H),
2.02 (brm, 4H), 1.16 (brt, 6H)
[3625] Mass Spectral Analysis m/z=383.4 (M+H).sup.+
Example 34I
[3626] 34I was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1i (see also step 34.2).
[3627] 34.1i was obtained according to a procedure similar to the
one described for 34.1h except 1.12 was replaced by 3.4o in step
34.7.
[3628] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.99 (brs, 2H),
7.73 (d, 1H), 7.27 (m, 2H), 7.21 (dd, 1H), 7.04 (d, 1H), 6.99 (t,
1H), 6.04 (s, 1H), 3.90 (brs, 2H), 3.21 (brm, 4H), 2.07 (brm, 2H),
1.98 (brm, 2H), 1.30 (brd, 12H)
[3629] Mass Spectral Analysis m/z=411.4 (M+H).sup.+
Example 34J
[3630] 34J was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1j (see also step 34.2). Note:
34.1j was obtained according to a procedure similar to the one
described for 34.1k (see 34K) except 34.8b was replaced by 34.8a in
step 34.9.
[3631] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.85 (brs, 2H),
7.43 (t, 1H), 7.35 (d, 1H), 7.27 (m, 2H), 7.04 (m, 2H), 6.97 (m,
1H), 6.03 (s, 1H), 3.48 (q, 2H), 3.22 (brm, 6H), 2.04 (brm, 4H),
1.16 (t, 3H), 1.04 (t, 3H)
[3632] Mass Spectral Analysis m/z=395.0 (M+H).sup.+
[3633] Elemental analysis:
[3634] C.sub.24H.sub.27FN.sub.2O.sub.2, 1HCl, 0.25H.sub.2O
[3635] Theory: % C, 66.20; % H, 6.60; % N, 6.43.
[3636] Found: % C, 65.97; % H, 6.48; % N, 6.21.
Example 34K
Preparation of 34.1k
[3637] To a stirred solution of 34.8b (5.0 g, 22.83 mmol, 1.0 eq)
in acetonitrile (50 mL) was added N,N-diisopropylethylamine (8.35
mL, 47.94 mmol, 2.1 eq), 1.12 (2.6 mL, 25.11 mmol, 1.1 eq) and
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) (8.06 g, 25.11 mmol, 1.1 eq). The reaction mixture was
stirred at room temperature for 16 h. The mixture was concentrated
under reduced pressure and the residue was dissolved in ethyl
acetate. The mixture was washed with a saturated aqueous solution
of sodium bicarbonate, dried over sodium sulfate and filtered. The
filtrate was concentrated under reduced pressure and the crude
product was purified by column chromatography (eluent: hexane/ethyl
acetate mixtures of increasing polarity).
[3638] Yield: 91%
[3639] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30 (m, 2H), 7.03
(m, 1H), 3.53 (q, 2H), 3.24 (q, 2H), 1.27 (t, 3H), 1.13 (t, 3H)
Preparation of 34K
[3640] 34K was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1k (see also step 34.2).
[3641] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.92 (brs, 2H),
7.29 (m, 3H), 7.13 (s, 1H), 7.05 (d, 1H), 6.98 (m, 2H), 6.01 (s,
1H), 3.43 (brm, 2H), 3.23 (brm, 6H), 2.04 (brm, 4H), 1.10 (brd,
6H)
[3642] Mass Spectral Analysis m/z=395.0 (M+H).sup.+
[3643] Elemental analysis:
[3644] C.sub.24H.sub.27FN.sub.2O.sub.2, 1HCl, 0.25H.sub.2O
[3645] Theory: % C, 66.20; % H, 6.60; % N, 6.43.
[3646] Found: % C, 66.17; % H, 6.57; % N, 6.32.
Example 34L
[3647] 34L was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.11 (see also step 34.2). Note:
34.1l was obtained according to a procedure similar to the one
described for 34.1k except 34.8b was replaced by 34.8c in step
34.9.
[3648] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.76 (brs, 1H),
9.63 (brs, 1H), 7.20 (m, 4H), 7.05 (dd, 1H), 6.93 (m, 2H), 5.60 (s,
1H), 3.76 (brs, 2H), 3.42 (brm, 4H), 3.18 (q, 2H), 2.32 (s, 3H),
2.21 (brm, 4H), 1.28 (t, 3H), 1.08 (t, 3H)
[3649] Mass Spectral Analysis m/z=391.0 (M+H).sup.+
[3650] Elemental analysis:
[3651] C.sub.25H.sub.30N.sub.2O.sub.2, 1HCl
[3652] Theory: % C, 70.32; % H, 7.32; % N, 6.56.
[3653] Found: % C, 69.92; % H, 7.27; % N, 6.49.
Example 34M
[3654] 34M was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1m (see also step 34.2). Note:
34.1m was obtained according to a procedure similar to the one
described for 34.1k except 34.8b was replaced by 34.8d in step
34.9.
[3655] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.78 (brs, 1H),
9.62 (brs, 1H), 7.22 (m, 3H), 7.13 (d, 1H), 6.92 (d, 1H), 6.84 (t,
1H), 6.63 (dd, 1H), 5.48 (s, 1H), 3.42 (brm, 8H), 2.36 (brm, 2H),
2.21 (m, 2H), 2.13 (s, 3H), 1.21 (brd, 6H)
[3656] Mass Spectral Analysis m/z=391.0 (M+H).sup.+
[3657] Elemental analysis:
[3658] C.sub.25H.sub.30N.sub.2O.sub.2, 1HCl
[3659] Theory: % C, 70.32; % H, 7.32; % N, 6.56.
[3660] Found: % C, 70.01; % H, 7.30; % N, 6.57.
Example 34N
[3661] 34N was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1n (see also step 34.2). Note:
34.1n was obtained according to a procedure similar to the one
described for 34.1k except 34.8b was replaced by 34.8e in step
34.9.
[3662] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.78 (brs, 1H),
9.68 (brs, 1H), 7.28 (m, 1H), 7.03 (dd, 1H), 6.95 (m, 4H), 5.64 (s,
1H), 3.62 (q, 2H), 3.41 (brm, 4H), 3.28 (q, 2H), 2.26 (brm, 4H),
1.28 (t, 3H), 1.05 (t, 3H)
[3663] Mass Spectral Analysis m/z=413.0 (M+H).sup.+
[3664] Elemental analysis:
[3665] C.sub.24H.sub.26F.sub.2N.sub.2O.sub.2, 1HCl,
0.25H.sub.2O
[3666] Theory: % C, 63.57; % H, 6.11; % N, 6.18.
[3667] Found: % C, 63.54; % H, 6.09; % N, 6.20.
Example 34O
[3668] 34O was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1o (see also step 34.2). Note:
34.1o was obtained according to a procedure similar to the one
described for 34.1k except 34.8b was replaced by 34.8f in step
34.9.
[3669] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.78 (brs 1H),
9.66 (brs, 1 h), 7.38 (s, 1H), 7.33 (d 1H), 7.25 (m, 2H), 7.02 (d,
1H), 6.95 (m, 2H), 5.63 (s, 1H), 3.81 (brs, 1H), 3.42 (brm 5H),
3.21 (brm, 2H), 2.26 (brm, 4H), 1.28 (t, 3H), 1.12 (t, 3H)
[3670] Mass Spectral Analysis m/z=411.0 (M+H).sup.+
[3671] Elemental analysis:
[3672] C.sub.24H.sub.27ClN.sub.2O.sub.2, 1HCl
[3673] Theory: % C, 64.43; % H, 6.31; % N, 6.26.
[3674] Found: % C, 64.34; % H, 6.35; % N, 6.28.
Example 34P
[3675] 34P was obtained according to a procedure similar to the one
described for 32A, with the following exceptions:
Step 32.2: 32.2a was replaced by 34.1p (see also step 34.2). Note:
34.1p was obtained according to a procedure similar to the one
described for 34.1k except 34.8b was replaced by 34.9 in step 34.9
(see also step 34.10).
[3676] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.10 (brs, 2H),
7.47 (m, 2H), 7.34 (m, 1H), 7.27 (m, 1H), 7.20 (m, 1H), 6.98 (m,
1H), 6.87 (m, 1H), 6.76 (m, 1H), 5.69 (s, 1H), 3.29 (m, 2H), 3.18
(m, 4H), 3.01 (m, 2H), 2.04 (m, 2H), 1.93 (m, 2H), 0.96 (m, 6H)
[3677] Mass Spectral Analysis m/z=377.4 (M+H).sup.+
Example 35A
Preparation of 35.2
[3678] To a solution of 35.1 (41.44 g, 0.3 mol, 1.0 eq) in ammonium
hydroxide (105 mL, 30% solution in H.sub.2O) was added drop wise a
solution of 12 (61.23 g, 0.24 mol, 0.8 eq) and KI (47.71 g, 0.287
mol, 0.96 eq) in water (300 mL) over a 20 min period. The mixture
was stirred at room temperature for 1 h, and the mixture was
concentrated under reduced pressure to half of its volume. The pH
was adjusted to 3-4 with a 6N aqueous solution of hydrochloric
acid. The white solid was collected by filtration and washed by a
small amount of water. The solid was re-crystallized from
water/EtOH (2:1), and dried under high vacuum.
[3679] Yield: 22%
[3680] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.96 (b, 1H),
10.70 (s, 1H), 7.80 (d, 1H), 7.42 (s, 1H), 7.12 (d, 1H)
Preparation of 35.3
[3681] To an acidic methanolic solution, which was prepared by drop
wise addition of acetyl chloride (0.5 mL) to anhydrous methanol (75
mL) was added 35.2 (20.0 g, 75.8 mmol). The mixture was heated to
reflux for 18 h. The reaction mixture was allowed to cool to room
temperature, and was concentrated under reduced pressure. The
residue was diluted in ethyl acetate (100 mL), washed by water (100
mL), brine (100 mL), dried over Na.sub.2SO.sub.4. The solution was
filtered and the filtrate was concentrated under reduced pressure.
The crude product was dried under vacuum.
[3682] Yield: 92%
[3683] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.10.79 (s, 1H),
7.85 (d, 1H), 7.46 (s, 1H), 7.15 (d, 1H), 3.84 (s, 3H)
Preparation of 35.4
[3684] A mixture of 35.3 (2.0 g, 7.19 mmol, 1.0 eq), 2.8c (4.08 g,
28.8 mmol, 4.0 eq) and potassium carbonate (9.94 g, 71.9 mmol, 10.0
eq) in acetone (100 mL) was refluxed for 16 h. The reaction was
cooled to room temperature and the solid was collected by
filtration. The volume of the filtrate was reduced to 15 mL and
this solution was taken on to the next step without further
purification.
Preparation of 35.5
[3685] To a solution of 35.4 (2.10 g, 7.19 mmol, 1.0 eq) in acetone
(115 mL) was added lithium hydroxide (1.2 g, 28.8 mmol, 4.0 eq) and
a 1:1 tetrahydrofuran/water solution (30 mL). The mixture was
stirred at room temperature for 16 h. The mixture was reduced to
half of its volume under reduced pressure and was acidified with a
6N aqueous solution of hydrochloric acid (5 mL). The crude mixture
was extracted with ethyl acetate. The organic layer was washed with
brine, dried over magnesium sulfate, and filtered. The filtrate was
concentrated under reduced pressure. The crude product was used for
the next step without further purification.
[3686] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.91 (d, 1H), 7.49
(d, 1H), 7.45 (dd, 1H), 3.96 (s, 3H)
Preparation of 35.6
[3687] To a mixture of 35.5 (2.0 g, 7.19 mmol, 1.0 eq) and
O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) (2.54 g, 7.91 mmol, 1.1 eq) in acetonitrile (75 mL) at
0.degree. C. was added 1.12 (0.58 g, 7.91 mmol, 1.1 eq) and
N,N-diisopropylethylamine (1.95 g, 15.1 mmol, 2.1 eq). The mixture
was warmed to room temperature, stirred for 16 h at room
temperature and concentrated under reduced pressure. The crude
mixture was dissolved in ethyl acetate. The mixture was washed with
a saturated aqueous solution of sodium bicarbonate, dried over
magnesium sulfate and filtered. The filtrate was concentrated under
reduced pressure. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixture, 60:40).
[3688] Yield: 96%
[3689] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.78 (d, 1H), 6.84
(d, 1H), 6.70 (dd, 1H), 3.90 (s, 3H), 3.54 (brs, 2H), 3.26 (brs,
2H), 1.19 (brd, 6H)
[3690] Mass Spectral Analysis m/z=334.1 (M+H).sup.+
Preparation of 35.9
[3691] To a solution of 35.6 (1.34 g, 4.02 mmol, 1.0 eq) in
dimethoxyethane (DME) (20 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (6.03 mL, 12.06 mmol, 3-0 eq), lithium
chloride (0.511 g, 12.06 mmol, 3.0 eq), 32.1 (2.06 g, 4.83 mmol,
1.2 eq) and tetrakis(triphenylphosphine)palladium(0) (0.232 g, 0.20
mmol, 0.05 eq). The Suzuki coupling reaction was conducted under
microwave conditions (A. 25.degree. C. to 170.degree. C. for 10
min; B. 170.degree. C. for 7 min). The crude mixture was dissolved
in ethyl acetate, washed with water, dried over sodium sulfate and
filtered. The filtrate was concentrated under reduced pressure. The
crude product was purified by column chromatography (eluent:
hexane/ethyl acetate mixtures of increasing polarity).
[3692] Yield: 74%
[3693] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.18 (d, 1H), 7.13
(m, 1H), 6.98 (m, 2H), 6.90 (d, 1H), 6.79 (m, 1H), 6.70 (dd, 1H),
5.53 (s, 1H), 3.84 (brs, 2H), 3.72 (s, 3H), 3.56 (brs, 2H), 3.33
(brs, 4H), 2.07 (brm, 2H), 1.67 (brm, 2H), 1.47 (s, 9H), 1.22 (brd,
6H)
[3694] Mass Spectral Analysis m/z=507.3 (M+H).sup.+
Preparation of 35A
[3695] Compound 35.9 (1.50 g, 2.96 mmol, 1.0 eq) was dissolved in a
4.0M anhydrous solution of hydrochloric acid in dioxane (15 mL, 60
mmol, 20 eq) and the mixture was stirred at room temperature for 16
h. The mixture was concentrated under reduced pressure. The residue
was dissolved in a minimum amount (until complete dissolution of
the product) of methylene chloride, and ethyl acetate was added
until the solution became cloudy. The mixture was stirred for 2 h
at room temperature. The resulting precipitate was collected by
filtration.
[3696] Yield: 77%
[3697] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.75 (brs, 1H),
9.58 (brs, 1H), 7.16 (m, 2H), 6.98 (m, 2H), 6.90 (d, 1H), 6.83 (m,
1H), 6.72 (dd, 1H), 5.56 (s, 1H), 3.72 (s, 3H), 3.50 (brm, 8H),
2.35 (brm, 2H), 2.16 (brm, 2H), 1.23 (brd, 6H)
[3698] Mass Spectral Analysis m/z=407.0 (M+H).sup.+
[3699] Elemental analysis:
[3700] C.sub.25H.sub.30N.sub.2O.sub.3, 1HCl, 0.5H.sub.2O
[3701] Theory: % C, 66.43; % H, 7.14; % N, 6.20.
[3702] Found: % C, 66.28; % H, 7.10; % N, 5.94.
Example 35B
Preparation of 35.7
[3703] To a solution of 35.6 (1.10 g, 3.30 mmol, 1.0 eq) in
methylene chloride (30 mL) at 0.degree. C. was added a 1.0M
solution of boron tribromide in methylene chloride (5.0 mL, 5.0
mmol, 1.5 eq). The reaction was warmed to room temperature and
stirred for 16 h at room temperature. A saturated aqueous solution
of sodium bicarbonate was added to the mixture and the crude
product was extracted with methylene chloride. The combined organic
extracts were dried over sodium sulfate, filtered and the filtrate
was concentrated under reduced pressure. The crude product was used
for the next step without further purification.
[3704] Yield: 87%
[3705] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.28 (brs, 1H),
7.64 (d, 1H), 6.95 (d, 1H), 6.56 (dd, 1H), 3.54 (q, 2H), 3.25 (q,
2H), 1.24 (t, 3H), 1.10 (t, 3H)
[3706] Mass Spectral Analysis m/z=320.0 (M+H).sup.+
Preparation of 35.8
[3707] To a solution of 35.7 (0.90 g, 2.82 mmol, 1.0 eq) and
N,N-diisopropylethylamine (2.91 g, 22.6 mmol, 8.0 eq) in methylene
chloride (25 mL) at 0.degree. C. under nitrogen was added drop wise
11.3 (0.86 mL, 11.3 mmol, 4.0 eq). The mixture was warmed to room
temperature and stirred for 48 h at room temperature. The mixture
was concentrated under reduced pressure, dissolved in ethyl acetate
and the solution was washed with a saturated aqueous solution of
sodium bicarbonate. The organic layer was dried over sodium
sulfate, filtered and the filtrate was concentrated under reduced
pressure. The crude product was used for the next step without
further purification.
[3708] Mass Spectral Analysis m/z=364.1 (M+H).sup.+
Preparation of 35.10
[3709] To a solution of 35.8 (1.02 g, 2.82 mmol, 1.0 eq) in
dimethoxyethane (DME) (20 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (4.23 mL, 8.46 mmol, 3.0 eq), lithium
chloride (0.359 g, 8.46 mmol, 3.0 eq), 32.1 (1.44 g, 3.38 mmol, 1.2
eq) and palladium on carbon (10%, 50% water) (0.038 g, 0.007 mmol,
0.0025 eq). The reaction was conducted under microwave conditions
(A. 25.degree. C. to 170.degree. C. for 10 min; B. 170.degree. C.
for 7 min). The mixture was dissolved in ethyl acetate, washed with
water, dried over sodium sulfate. The mixture was filtered and the
filtrate was concentrated under reduced pressure. The crude product
was purified by column chromatography (eluent: hexane/ethyl acetate
mixtures of increasing polarity).
[3710] Yield: 50%
[3711] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.21 (m, 2H), 7.13
(m, 1H), 7.06 (dd, 1H), 6.90 (d, 1H), 6.76 (m, 2H), 5.53 (s, 1H),
5.04 (s, 2H), 3.87 (brs, 2H), 3.55 (brs, 2H), 3.34 (brs, 4H), 3.30
(s, 3H), 2.08 (brm, 2H), 1.67 (brm, 2H), 1.48 (s, 9H), 1.24 (brm,
6H)
[3712] Mass Spectral Analysis m/z=537.3 (M+H).sup.+
Preparation of 35B
[3713] To a solution of 35.10 (0.647 g, 1.21 mmole, 1 eq) in
methanol (3 mL) was added an excess of a 4.0M solution of anhydrous
hydrochloric acid in dioxane (20 mL). The mixture was stirred at
room temperature for 16 h. The mixture was concentrated under
reduced pressure and treated with a mixture of methylene chloride
(15 mL) and ethyl acetate (25 mL). The resulting precipitate was
collected by filtration and dried under vacuum.
[3714] Yield: 77%
[3715] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.75 (s, 1H),
8.84 (brm, 2H), 7.16 (m, 2H), 6.96 (d, 1H), 6.84 (m, 3H), 6.72 (d,
1H), 5.78 (s, 1H), 3.42 (brs, 2H), 3.22 (brs, 6H), 2.10 (brm, 2H),
1.96 (brm, 2H), 1.12 (brs, 6H)
[3716] Mass Spectral Analysis m/z=393.3 (M+H).sup.+
Example 36A
Preparation of 36.3
[3717] To a mixture of copper (II) bromide (8.8 g, 39.4 mmol, 1.2
eq) in acetonitrile (50 mL) under a nitrogen atmosphere was added
36.2 (5.1 g, 49.5 mmol, 1.5 eq). The mixture was cooled to
0.degree. C. and 36.1 (5.0 g, 32.6 mmol, 1.0 eq) was added in small
portions. Additional amount of acetonitrile (25 mL) was added to
the mixture, which was stirred at 0.degree. C. for 2 h. The mixture
was poured onto a 20% aqueous solution of hydrochloric acid (200
mL) and extracted with diethyl ether. The combined organic extracts
were washed with a 20% aqueous solution of hydrochloric acid, dried
over magnesium sulfate, filtered, and concentrated under reduced
pressure. The residue was dissolved in diethyl ether. The mixture
was extracted with a 15% aqueous solution of sodium hydroxide. The
aqueous portion was washed with diethyl ether, acidified to pH 1
with a 6N aqueous solution of hydrochloric acid and the mixture was
extracted with diethyl ether. The combined organic extracts were
washed with brine, dried over magnesium sulfate, filtered and
concentrated under reduced pressure. The residue was treated with
chloroform and the resulting precipitate was collected by
filtration. The product was used for the next step without further
purification.
[3718] Mass Spectral Analysis m/z=215.1 (M-H).sup.-
Preparation of 36.4
[3719] To a mixture of 1.12 (0.85 g, 11.58 mmol, 2.5 eq),
O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) (1.93 g, 6.02 mmol, 1.3 eq) and N,N-diisopropylethylamine
(1.25 g, 9.72 mmol, 2.1 eq) in acetonitrile (50 mL) at 0.degree. C.
was added drop wise a solution of 36.3 (1.0 g, 4.63 mmol, 1.0 eq)
in acetonitrile (10 mL). The mixture was warmed to room temperature
and stirred for 48 h at room temperature. An additional portion of
TBTU (1.04 g, 3.24 mmol, 0.7 eq) was added to the mixture which was
heated at 60.degree. C. for 5 h. The mixture was concentrated under
reduced pressure, and the residue was dissolved in ethyl acetate.
The mixture was washed by water, brine, dried over magnesium
sulfate and filtrate. The solution was concentrated under reduced
pressure. The crude product was purified by column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity)
[3720] Yield: 63%
[3721] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.08 (s, 1H),
7.17 (d, 1H), 7.12 (d, 1H), 6.98 (dd, 1H), 3.50 (q, 4H), 1.27 (t,
6H)
[3722] Mass Spectral Analysis m/z=270.1 (M-H).sup.-
Preparation of 36.5
[3723] To a solution of 36.4 (0.30 g, 1.11 mmol, 1.0 eq) in
dimethoxyethane (DME) (10 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (1.66 mL, 3.32 mmol, 3.0 eq), lithium
chloride (0.141 g, 3.32 mmol, 3.0 eq), 32.1 (0.57 g, 1.33 mmol, 1.2
eq) and tetrakis(triphenylphosphine)palladium(0) (0.128 g, 0.11
mmol, 0.1 eq). The reaction was conducted under microwave
conditions (A. 25.degree. C. to 170.degree. C. for 10 min; B.
170.degree. C. for 10 min). The crude mixture was dissolved in
ethyl acetate. The mixture was washed with a 0.5N aqueous solution
of hydrochloric acid, brine, and dried over magnesium sulfate. The
mixture was filtered and the filtrate was concentrated under
reduced pressure. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[3724] Yield: 37%
[3725] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.94 (s, 1H), 7.29
(d, 1H), 7.18 (m, 1H), 7.06 (dd, 1H), 7.00 (d, 1H), 6.94 (d, 1H),
6.85 (m, 2H), 5.59 (s, 1H), 3.85 (brs, 2H), 3.55 (q, 4H), 3.34
(brs, 2H), 2.04 (brm, 2H), 1.66 (m, 2H), 1.48 (s, 9H), 1.30 (t,
6H)
[3726] Mass Spectral Analysis m/z=493.2 (M+H).sup.+
Preparation of 36A
[3727] To a solution of 36.5 (0.20 g, 0.406 mmol, 1.0 eq) in
methylene chloride (2 mL) was added a 1.0M solution of anhydrous
hydrochloric acid in diethyl ether (10 mL, 10 mmol, 25 eq). The
mixture was stirred at room temperature for 16 h. The mixture was
concentrated under reduced pressure and treated with diethyl ether.
The resulting precipitate was collected by filtration. By LC/MS
some starting material remained; therefore, so the precipitate was
treated with an excess of a 4.0M solution of anhydrous hydrochloric
acid in dioxane. This mixture was stirred at room temperature for
16 h. The mixture was concentrated under reduced pressure and the
crude product was purified by column chromatography (eluent:
methylene chloride/methanol mixtures of increasing polarity).
[3728] Yield: 66%
[3729] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.91 (brs, 1H),
9.08 (brs, 2H), 7.26 (m, 1H), 7.13 (d, 1H), 7.04 (m, 2H), 6.95 (m,
1H), 6.84 (m, 2H), 5.87 (s, 1H), 3.66 (brs, 4H), 3.20 (brm, 4H),
2.05 (brm, 4H), 1.08 (brd, 6H)
[3730] Mass Spectral Analysis m/z=393.4 (M+H).sup.+
[3731] Elemental analysis:
[3732] C.sub.24H.sub.28N.sub.2O.sub.3, 1HCl, 1.5H.sub.2O
[3733] Theory: % C, 63.22; % H, 7.07; % N, 6.14.
[3734] Found: % C, 63.45; % H, 6.88; % N, 6.09.
Example 36B
Preparation of 36.8
[3735] To a solution of 36.6 (13.0 mL, 89.41 mmol, 1.0 eq) and
triethylamine (13.71 mL, 98.35 mmol, 1.1 eq) in methylene chloride
(100 mL) at 0.degree. C. under a nitrogen atmosphere was added drop
wise ethyl chloroformate (9.40 mL, 98.35 mmol, 1.1 eq). The mixture
was warmed to room temperature and stirred for 1 h at room
temperature. Water and methylene chloride were added to the
reaction mixture and the layers were separated. The organic layer
was dried over sodium sulfate, filtered and concentrated under
reduced pressure. The crude product was used for the next step
without further purification.
[3736] Yield: 100%
[3737] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.22 (t, 1H), 6.76
(m, 3H), 4.66 (brs, 1H), 4.11 (q, 2H), 3.80 (s, 3H), 3.43 (m, 2H),
2.78 (m, 2H), 1.23 (t, 3H)
[3738] Mass Spectral Analysis m/z=224.1 (M+H).sup.+
Preparation of 36.9
[3739] A mixture of 36.8 (20 g, 89.58 mmol, 1.0 eq) and
polyphosphoric acid (90 g) was heated at 120.degree. C. under a
nitrogen atmosphere for 1.5 h. The mixture was cooled to room
temperature. Water (200 mL) was added to the mixture which was
extracted with ethyl acetate. The organic extracts were combined,
dried over sodium sulfate, filtered and concentrated under reduced
pressure. The crude product was purified by column chromatography
(eluent: ethyl acetate). Polyphosphoric acid was still present in
the purified sample; therefore the residue was dissolved in ethyl
acetate and the solution was washed with a saturated aqueous
solution of sodium bicarbonate. The mixture was dried over sodium
sulfate, filtered and concentrated under reduced pressure. Ethyl
acetate (15 mL) was added to the mixture. The resulting precipitate
was collected by filtration and was used for the next step without
further purification.
[3740] Yield: 30%
[3741] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.02 (d, 1H), 6.86
(dd, 1H), 6.71 (d, 1H), 6.22 (brs, 1H), 3.85 (s, 3H), 3.55 (m, 2H),
2.97 (t, 2H)
[3742] Mass Spectral Analysis m/z=178.1 (M+H).sup.+
Preparation of 36.11
[3743] To a suspension of NaH (0.81 g, 33.86 mmol, 6.0 eq) in
tetrahydrofuran (30 mL) under a nitrogen atmosphere was added drop
wise a solution of 36.9 (1.0 g, 5.64 mmol, 1.0 eq) in
tetrahydrofuran (15 mL). To this mixture was added drop wise 36.10
(2.28 mL, 28.22 mmol, 5.0 eq) and stirring was continued for 16 h
at room temperature. A thick precipitate formed; therefore
additional amount of tetrahydrofuran (15 mL) and 36.10 (1.0 mL,
12.39 mmol, 2.2 eq) were added and stirring was continued for an
additional 24 h at room temperature. The reaction was quenched by
addition of a 1N aqueous solution of hydrochloric acid followed by
ethyl acetate and water. The layers were separated. The organic
phase was dried over sodium sulfate, filtered and concentrated
under reduced pressure. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity).
[3744] Yield: 83%.
[3745] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.03 (d, 1H), 6.84
(dd, 1H), 6.65 (d, 1H), 3.84 (s, 3H), 3.61 (q, 2H), 3.53 (t, 2H),
2.95 (t, 2H), 1.21 (t, 3H)
[3746] Mass Spectral Analysis m/z=206.1 (M+H).sup.+
Preparation of 36.12
[3747] To a solution of 36.11 (0.96 g, 4.68 mmol, 1.0 eq) in
anhydrous methylene chloride (30 mL) at -78.degree. C. under a
nitrogen atmosphere was added drop wise a 1.0M solution of boron
tribromide in methylene chloride (9.35 mL, 9.35 mmol, 2.0 eq). The
reaction was warmed to room temperature and stirred for 16 h at
room temperature. The mixture was cooled in an ice bath, quenched
with methanol (10 mL) and concentrated under reduced pressure. The
crude mixture was dissolved in ethyl acetate and the solution was
washed with a 1N aqueous solution of hydrochloric acid and then
brine. The organic phase was dried over sodium sulfate, filtered
and concentrated under reduced pressure. The crude solid was
triturated in a ethyl acetate/hexane (1:1). The precipitate was
collected by filtration.
[3748] Yield: 74%.
[3749] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.89 (d, 1H), 6.82
(dd, 1H), 6.68 (d, 1H), 3.63 (q, 2H), 3.54 (t, 2H), 2.91 (t, 2H),
1.22 (t, 3H)
[3750] Mass Spectral Analysis m/z=192.1 (M+H).sup.+
Preparation of 36.14
[3751] To a solution of 36.12 (0.38 g, 1.99 mmol, 1.0 eq) and
pyridine (0.32 mL, 3.98 mmol, 2.0 eq) in methylene chloride (10 mL)
at 0.degree. C. under a nitrogen atmosphere was added 36.13 (0.40
mL, 2.38 mmol, 1.2 eq). The reaction was warmed to room temperature
and stirred for 2 h at room temperature. Methylene chloride was
added to the mixture which was washed with a 1N aqueous solution of
hydrochloric acid, and with a 1N aqueous solution of sodium
hydroxide. The organic phase was dried over sodium sulfate,
filtered and concentrated under reduced pressure. The crude product
was purified by column chromatography (eluent: hexane/ethyl
acetate, 1:1).
[3752] Yield: 45%.
[3753] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.18 (d, 1H), 7.23
(dd, 1H), 7.11 (d, 1H), 3.62 (m, 4H), 3.04 (t, 2H), 1.23 (t,
3H)
[3754] Mass Spectral Analysis m/z=324.1 (M+H).sup.+
Preparation of 36.15
[3755] To a solution of 36.14 (0.100 g, 0.309 mmol, 1.0 eq) in
N,N-dimethylformamide (5 mL) under a nitrogen atmosphere was added
32.1 (0.145 g, 0.340 mmol, 1.1 eq), potassium acetate (0.091 g,
0.928 mmol, 3.0 eq) and
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II),
dichloromethane complex (0.005 g, 0.006 mmol, 0.02 eq). The
reaction was stirred at 65.degree. C. for 16 h. The mixture was
cooled to room temperature. Water was added and the mixture was
extracted with ethyl acetate. The organic phase was dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The crude product was purified by column chromatography (eluent:
hexane/ethyl acetate mixtures of increasing polarity).
[3756] Yield: 45%.
[3757] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.11 (d, 1H), 7.31
(dd, 1H), 7.19 (m, 1H), 7.15 (s, 1H), 6.96 (m, 2H), 6.86 (m, 1H),
5.58 (s, 1H), 3.86 (brm, 2H), 3.65 (q, 2H), 3.59 (t, 2H), 3.34 (m,
2H), 3.01 (t, 2H), 2.05 (m, 2H), 1.67 (m, 2H), 1.48 (s, 9H), 1.26
(t, 3H)
[3758] Mass Spectral Analysis m/z=475.3 (M+H).sup.+
Preparation of 36B
[3759] To a solution of 36.15 (0.150 g, 0.316 mmol, 1.0 eq) in
anhydrous methylene chloride (5 mL) at 0.degree. C. under a
nitrogen atmosphere was added a 1.0M solution of anhydrous
hydrochloric acid in diethyl ether (1.26 mL, 1.26 mmol, 4.0 eq).
The reaction was warmed to room temperature and stirred for 4 days
at room temperature. Diethyl ether was added (5 mL) and the
resulting precipitate was collected by filtration.
[3760] Yield: 27%.
[3761] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.80 (brs, 2H),
7.92 (d, 1H), 7.29 (m, 3H), 7.05 (d, 1H), 6.97 (m, 2H), 5.94 (s,
1H), 3.54 (m, 4H), 3.23 (brm, 4H), 3.00 (t, 2H), 2.08 (brm, 2H),
1.97 (brm, 2H), 1.13 (t, 3H)
[3762] Mass Spectral Analysis m/z=375.3 (M+H).sup.+
[3763] Elemental analysis:
[3764] C.sub.24H.sub.26N.sub.2O.sub.2, 1HCl, 1H.sub.2O
[3765] Theory: % C, 67.20; % H, 6.81; % N, 6.53.
[3766] Found: % C, 67.52; % H, 6.46; % N, 6.54.
Example 37A
Preparation of 37.2 and 37.3
[3767] To a solution of 37.1 (5.0 g, 24.60 mmol, 1.0 eq) and 1.1a
(2.56 mL, 24.60 mmol, 1.0 eq) in methanol (100 mL) was added
pyrrolidine (5.53 mL, 66.90 mmol, 2.72 eq). The mixture was
refluxed for 16 h. The mixture was concentrated under reduced
pressure, dissolved in ethyl acetate and the mixture was washed
with a 1N aqueous solution of sodium hydroxide and brine. The
organic phase was dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude mixture was purified
by column chromatography (eluent: hexane/ethyl acetate mixtures of
increasing polarity) to give a mixture of 37.2/37.3 (1/1.7).
[3768] Yield: 80%
[3769] (37.2) .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.82 (dd,
1H), 7.47 (m, 1H), 7.28 (m, 5H), 6.96 (m, 2H), 3.50 (q, 2H), 2.76
(q, 2H), 2.64 (brm, 1H), 2.40 (brm, 1H), 2.18 (brm, 2H), 2.00 (brm,
1H), 1.82 (brm, 1H), 1.70 (brm, 1H), 1.07 (brd, 3H)
[3770] Mass Spectral Analysis m/z=322.3 (M+H).sup.+
[3771] (37.3) .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.84 (dd,
1H), 7.48 (m, 1H), 7.29 (m, 5H), 6.98 (m, 2H), 3.51 (m, 2H), 3.15
(d, 1H), 2.65 (m, 1H), 2.55 (m, 1H), 2.34 (m, 2H), 2.24 (m, 1H),
2.15 (m, 1H), 1.91 (m, 1H), 1.56 (m, 1H), 1.02 (d, 3H)
[3772] Mass Spectral Analysis m/z=322.3 (M+H).sup.+
Preparation of 37.4
[3773] To a solution of 37.2 (2.30 g, 7.16 mmol, 1.0 eq) in
methanol (25 mL) was added 10% Pd/C (0.50 g). The mixture was
shaken for 6 h under 55 psi of hydrogen. The mixture was filtered
through celite, and concentrated under reduced pressure. The crude
product was used for the next step without further
purification.
[3774] Yield: 99%
[3775] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.83 (dd, 1H),
7.48 (m, 1H), 6.97 (m, 2H), 3.18 (dd, 1H), 3.02 (m, 1H), 2.77 (m,
2H), 2.55 (m, 1H), 2.06 (m, 1H), 1.80 (brm, 3H), 1.06 (d, 3H)
[3776] Mass Spectral Analysis m/z=232.3 (M+H).sup.+
Preparation of 37.5
[3777] To a solution of 37.4 (1.65 g, 7.13 mmol, 1.0 eq) in
tetrahydrofuran (50 mL) was added triethylamine (2.98 mL, 21.40
mmol, 3.0 eq) and 4.7 (1.87 g, 8.56 mmol, 1.2 eq). The mixture was
stirred for 2 h at room temperature. Water (100 mL) was added and
the crude mixture was extracted with ethyl acetate and washed with
brine. The organic phase was dried over sodium sulfate, filtered
and concentrated under reduced pressure. The crude product was
purified by column chromatography (eluent: hexane/ethyl acetate,
70/30).
[3778] Yield: 100%
[3779] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85 (dd, 1H),
7.50 (m, 1H), 6.99 (m, 2H), 3.80 (brs, 1H), 3.56 (brm, 2H), 3.30
(brs, 1H), 2.73 (m, 2H), 2.12 (brs, 1H), 1.82 (brm, 2H), 1.46 (s,
9H), 1.03 (d, 3H)
[3780] Mass Spectral Analysis m/z=332.3 (M+H).sup.+
Preparation of 37.6
[3781] To a solution of 37.5 (2.70 g, 8.15 mmol, 1.0 eq) in
tetrahydrofuran (20 mL) at -78.degree. C. under a nitrogen
atmosphere was added drop wise a 1.0M solution of LiHMDS in
tetrahydrofuran (9.78 mL, 9.78 mmol, 1.2 eq). The mixture was
stirred for 45 min at -78.degree. C. A solution of 1.4 (3.49 g,
9.78 mmol, 1.2 eq) in tetrahydrofuran (10 mL) was added drop wise
to the mixture, which was warmed slowly to room temperature and
stirred for 16 h at room temperature. The mixture was then poured
into ice water. A 1N aqueous solution of hydrochloric was added and
the crude mixture was extracted with ethyl acetate. The organic
extracts were washed with a 1N aqueous solution of sodium
hydroxide, brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: hexane/ethyl acetate mixtures of
increasing polarity).
[3782] Yield: 62%
[3783] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.31 (m, 1H),
7.15 (m, 1H), 6.95 (m, 1H), 6.85 (m, 1H), 6.25 (s, 0.6H), 5.83 (s,
0.4H), 3.54 (brs, 2H), 3.19 (brm, 2H), 1.96 (brm, 2H), 1.55 (brm,
1H), 1.33 (s, 9H), 0.83 (d, 3H)
[3784] Mass Spectral Analysis m/z=464.2 (M+H).sup.+
Preparation of 37.7
[3785] To a solution of 37.6 (1.17 g, 2.52 mmol, 1.0 eq) in dioxane
(20 mL) was added sequentially 1.6 (0.61 g, 2.78 mmol, 1.1 eq),
potassium phosphate (0.80 g, 3.79 mmol, 1.5 eq) and potassium
bromide (0.33 g, 2.78 mmol, 1.1 eq). The mixture was placed under
vacuum, flushed with nitrogen and then the process was repeated.
Tetrakis(triphenylphosphine)palladium(0) (0.146 g, 0.13 mmol, 0.05
eq) was added and the mixture was heated at 100.degree. C. for 16 h
under a nitrogen atmosphere. The mixture was cooled to room
temperature, dissolved in ethyl acetate and the mixture was washed
with water. The organic phase was dried over sodium sulfate,
filtered and concentrated under reduced pressure. The crude product
was purified by column chromatography (eluent: hexane/ethyl acetate
mixtures of increasing polarity).
[3786] Yield: 53%
[3787] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.42 (d, 2H), 7.37
(d, 2H), 7.18 (m, 1H), 6.99 (d, 1H), 6.92 (d, 1H), 6.84 (m, 1H),
5.70 (s, 1H), 3.65 (brm, 5H), 3.32 (brs, 3H), 2.15 (brs, 1H), 2.04
(m, 1H), 1.77 (brs, 1H), 1.48 (s, 9H), 1.22 (brd, 6H), 1.02 (d,
3H)
[3788] Mass Spectral Analysis m/z=491.5 (M+H).sup.+
Preparation of 37 A
[3789] To a solution of 37.7 (0.65 g, 1.33 mmol, 1.0 eq) in
anhydrous methylene chloride (10 mL) at 0.degree. C. under a
nitrogen atmosphere was added a 1.0M solution of anhydrous
hydrochloric acid in diethyl ether (5.31 mL, 5.31 mmol, 4.0 eq).
The mixture was warmed to room temperature and stirred for 5 days
at room temperature. The mixture was concentrated under reduced
pressure and dissolved in methylene chloride (5 mL). Diethyl ether
(10 mL) was added drop wise to the mixture which was stirred for 1
h at room temperature. The resulting precipitate was collected by
filtration and dried under vacuum.
[3790] Yield: 82%
[3791] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.46 (brm,
1.5H), 7.71 (d, 2H), 7.67 (d, 2H), 7.48 (m, 1H), 7.21 (m, 2H), 7.15
(m, 1H), 6.44 (s, 1H), 3.70 (brs, 2H), 3.42 (brm, 6H), 2.52 (brm,
1H), 2.44 (brm, 1H), 2.13 (brm, 1H), 1.36 (brd, 6H), 1.22 (d,
3H)
[3792] Mass Spectral Analysis m/z=391.3 (M+H).sup.+
[3793] Elemental analysis:
[3794] C.sub.25H.sub.30N.sub.2O.sub.2, 1HCl, 0.25H.sub.2O
[3795] Theory: % C, 69.59; % H, 7.36; % N, 6.49.
[3796] Found: % C, 69.29; % H, 7.28; % N, 6.40.
Example 37B
[3797] 37B was obtained according to a procedure similar to the one
described for 37A, with the following exceptions:
Step 37.2: 37.2 was replaced by 37.3 (see also step 37.5).
[3798] .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 9.40 (brm,
1.5H), 7.66 (s, 4H) 7.48 (m, 1H), 7.27 (d, 1H), 7.21 (m, 1H), 7.15
(m, 1H), 6.03 (s, 1H), 3.69 (brs, 2H), 3.43 (brm, 4H), 3.24 (brm,
2H), 2.47 (brm, 1H), 2.35 (brm, 1H), 2.08 (brm, 1H), 1.37 (brd,
6H), 1.20 (d, 3H)
[3799] Mass Spectral Analysis m/z=391.3 (M+H).sup.+
[3800] Elemental analysis:
[3801] C.sub.25H.sub.30N.sub.2O.sub.2, 1HCl, 0.25H.sub.2O
[3802] Theory: % C, 69.59; % H, 7.36; % N, 6.49.
[3803] Found: % C, 69.69; % H, 7.18; % N, 6.49.
Methods of Preparation for Final Compounds found in Examples
Z1-Z14
[3804] The compounds prepared in Examples Z1-Z14 and depicted in
Table Z1 were prepared according to the Schemes Z1-Z6. The
preparation of spiro[2H-1-benzopyran-2,4'-piperidine] derivatives
15 (Example Z1), 16 (Example Z2) and 18 (Example Z3) is outlined in
Scheme Z1. The 2'-hydroxyacetophenone derivatives 1, 2 and 3
(commercially available from Aldrich Chemical Company) were
condensed with 1-Boc-4-piperidone 4 in methanol in the presence of
pyrrolidine to provide
N-Boc-spiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one derivatives
5-7 respectively. Compounds 12-14 were prepared by conversion of
the ketones 5-7 to the enol triflate derivatives 8-10 and
subsequent Suzuki coupling reaction with
4-(N,N-diethylaminocarbonyl)phenylboronic acid 11. The Boc
protecting groups of 12-14 were subsequently removed using
trifluoroacetic acid to generate the corresponding
spiro[2H-1-benzopyran-2,4'-piperidine] derivatives 15 (Example Z1),
16 (Example Z2) and 17. Demethylation of the methyl ether 17 using
boron tribromide in anhydrous dichloromethane afforded the phenolic
derivative 18 (Example Z3). Hydrogenation of 15 in methanol in the
presence of palladium hydroxide (Pearlman's catalyst) afforded the
3,4-dihydrospiro[2H,1-benzopyran-2,4'-piperidine] derivative 19
(Example Z4) (Scheme Z2). Treatment of 15 with formaldehyde in the
presence of sodium cyanoborohydride gave the N-methyl derivative 20
(Example Z5) (Scheme Z2).
##STR00480## ##STR00481##
[3805] The compounds prepared in Examples Z6-Z9 were prepared
according to Scheme Z3. Suzuki type coupling of the enol triflate
derivative 8 (Scheme Z1) with 4-(methoxycarbonyl)phenylboronic acid
21 in dimethoxyether in the presence of tetrakis
triphenylphosphine, lithium chloride and an aqueous solution of
sodium carbonate afforded the methyl ester 22 which was hydrolyzed
under basic conditions to provide the carboxylic acid derivative
23. Coupling of the carboxylic acid 23 with primary amine (2) or
secondary amine derivatives (25-7) using TBTU as peptide coupling
agent afforded the amides 28-31 which were converted to the
spiro[2H-1-benzopyran-2,4'-piperidine] derivatives 32-34 (Examples
Z6-Z8) and 35 under acidic conditions. Hydrolysis of the ethyl
ester 35 in the presence of sodium hydroxide afforded the
carboxylic acid 36 (Example Z9).
##STR00482##
[3806] Suzuki type coupling of the enol triflate derivative 8
(Scheme Z1) with 4-cyanophenylboronic acid 37 in dimethoxyether in
the presence of tetrakis triphenylphosphine palladium (0), lithium
chloride and an aqueous solution of sodium carbonate afforded the
cyanide 38 which was converted to the tetrazole 39 using sodium
azide and zinc bromide in a 1:1 solution of isopropanol/water
(Scheme Z4). The Boc protecting group of 39 was subsequently
removed using trifluoroacetic acid to generate the corresponding
spiro[2H-1-benzopyran-2,4'-piperidine]derivative 40 (Example Z10).
Alkylation of 39 with ethyl bromopropionate in dimethylformamide in
the presence of triethylamine afforded the two regioisomers 42
(minor isomer) and 43 (major isomer) separated by silica gel column
chromatography. The Boc protecting group of 43 was subsequently
removed using trifluoroacetic acid to generate the corresponding
spiro[2H-1-benzopyran-2,4'-piperidine] derivative 44. Hydrolysis of
the ethyl ester 44 in the presence of sodium hydroxide afforded the
carboxylic acid 45 (Example Z11) (Scheme Z4).
##STR00483## ##STR00484##
[3807] Suzuki type coupling of the enol triflate derivative 8
(Scheme Z1) with 3-pyridylboronic acid 46 in dimethoxyether in the
presence of tetrakis triphenylphosphine palladium (0), lithium
chloride and an aqueous solution of sodium carbonate afforded
compound 47 which was converted to the corresponding
spiro[2H-1-benzopyran-2,4'-piperidine] derivative 48 (Example Z12)
under acidic conditions (Scheme Z5).
[3808] Suzuki type coupling of the enol triflate derivative 8
(Scheme Z1) with 4-methanesulfonylphenylboronic acid 49 in
dimethoxyether in the presence of tetrakis triphenylphosphine
palladium(0), lithium chloride and an aqueous solution of sodium
carbonate afforded the compound 50 which was converted to the
corresponding spiro[2H-1-benzopyran-2,4'-piperidine] derivative 51
(Example Z13) under acidic conditions (Scheme Z5).
##STR00485## ##STR00486##
[3809] The preparation of spiro[2H-1-benzopyran-2,4'-nortropine]
derivative 56 (Example Z14) is outlined in Scheme 6.
2'-hydroxyacetophenone (1) was condensed with 1-Boc-4-nortropinone
(52) in methanol in the presence of pyrrolidine to provide
N-Boc-spiro[2H-1-benzopyran-2,4'-nortropine]-4(3H)-one derivative
53. Compound 55 were prepared by conversion of the ketone 53 to the
enol triflate derivative 54 and subsequent Suzuki coupling reaction
with 4-(N,N-diethylaminocarbonyl)phenylboronic acid 11. The Boc
protecting group of 55 was subsequently removed using
trifluoroacetic acid to generate the corresponding
spiro[2H-1-benzopyran-2,4'-nortropine] derivatives 56 (Example
Z14).
##STR00487##
##STR00488##
Materials: All chemicals were reagent grade and used without
further purification. Analytical: Thin-layer chromatography (TLC)
was performed on silica gel 60 flexible backed plates (250 microns)
from Alltech and visualized by UV 254 irradiation and iodine. Flash
chromatography was conducted using the ISCO CombiFlash with RediSep
silica gel cartridges (4 g, 12 g, 40 g, 120 g). All .sup.1H NMR
spectra were recorded at ambient temperature on a Bruker-400 MHz
spectrometer. They are reported in ppm on the .delta. scale, from
TMS. LC-MS data were obtained using a Thermo-Finnigan Surveyor HPLC
and a Thermo-Finnigan AQA MS using either positive or negative
electrospray ionization. Program (positive) Solvent A: 10 mM
ammonium acetate, pH 4.5, 1% acetonitrile; solvent B: acetonitrile;
column: Michrom Bioresources Magic C18 Macro Bullet, detector: PDA
k=220-300 nm. Gradient: 96% A-100% B in 3.2 minutes, hold 100% B
for 0.4 minutes. Program (negative) Solvent A: 1 mM ammonium
acetate, pH 4.5, 1% acetonitrile; solvent B: acetonitrile; column:
Michrom Bioresources Magic C18 Macro Bullet, detector: PDA
.lamda.=220-300 nm. Gradient: 96% A-100% B in 3.2 minutes, hold
100% B for 0.4 minutes.
Example Z1
Preparation of
4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-piperid-
ine]hydrochloride (15)
Step 1:
[3810] Pyrrolidine (42 mL, 2 eq) was added drop wise at room
temperature to a solution of 1-Boc-4-piperidone (4) (49.8 g, 0.249
mol) and 2'-hydroxyacetophenone (1) (34 g, 0.184 mol, 1 eq) in
anhydrous methanol (400 mL). The solution was refluxed overnight
and then concentrated under reduced pressure. Diethyl ether (500
mL) was added. The organic mixture was washed with a 1N aqueous
solution of hydrochloric acid, a 1N aqueous solution of sodium
hydroxide, brine and dried over sodium sulfate. Hexane (300 mL) was
added to the mixture. The resulting precipitate was collected by
filtration, washed with hexane, and used for the next step without
further purification (56.6 g, 72%).
[3811] 5: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85 (d, 1H),
7.45 (t, 1H), 7.00 (m, 2H), 3.85 (m, 2H), 3.20 (m, 2H), 2.70 (s,
1H), 2.00 (d, 2H), 1.60 (m, 2H), 1.40 (s, 9H); Mass Spectral
Analysis m/z=318.0 (M+H).sup.+ t.sub.R=2.42 minutes.
Step 2:
[3812] To a solution of 5 (25 g, 0.078 mol) in tetrahydrofuran (250
mL) at -78.degree. C. under nitrogen was added drop wise a 1.0M
solution of LiHMDS in tetrahydrofuran (94.5 mL). The mixture was
stirred for 1 hour at -78.degree. C. A solution of
N-phenyltrifluoromethanesulfonimide (33.8 g, 1.2 eq) in
tetrahydrofuran (150 mL) was added drop wise. The mixture was
warmed slowly to room temperature and stirring was continued for a
further 12 hours at room temperature. The mixture was then poured
into ice water and the 2 phases were separated. The organic phase
was washed with a 1N aqueous solution of hydrochloric acid, a 1N
aqueous solution of sodium hydroxide, brine and dried over sodium
sulfate. The crude product was purified by column chromatography
(eluent: hexane/ethyl acetate mixtures of increasing polarity) (25
g, 70%)
[3813] 8: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.45-7.20 (m,
2H), 7.00 (m, 2H), 6.15 (s, 1H), 3.70 (m, 2H), 3.20 (m, 2H), 1.90
(m, 2H), 1.75 (m, 2H), 1.40 (s, 9H); Mass Spectral Analysis
m/z=450.1 (M+H).sup.+ t.sub.R=2.95 minutes.
Step 3:
[3814] To a solution of 8 (15 g, 33.37 mmol, 1 eq) in
dimethoxyethane (DME) (100 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (50.06 mL, 100.12 mmol, 3 eq), lithium
chloride (4.24 g, 100.12 mmol, 3 eq.),
4-(N,N-diethylaminocarbonyl)phenylboronic acid) 11 (8.12 g, 36.71
mmol, 1.1 eq) and tetrakis(triphenylphosphine)palladium(0) (0.77 g,
0.67 mmol, 0.02 eq). The mixture was refluxed for 10 hours under
nitrogen. The mixture was then cooled to room temperature and water
(250 mL) was added. The mixture was extracted with ethyl acetate.
The organic layer was further washed with brine and dried over
sodium sulfate. The crude product was purified by column
chromatography (eluent: hexane/ethyl acetate mixtures of increasing
polarity) (11.5 g, 73%).
[3815] 12: .sup.1H NMR (400 MHz, CDCl.sub.3) .quadrature. 7.35 (m,
4H), 7.15 (t, 1H), 7.00-6.80 (m, 3H), 5.55 (s, 1H), 3.85 (m, 2H),
3.55 (m, 2H), 3.30 (m, 4H), 2.00 (m, 2H), 1.65 (m, 2H), 1.40 (s,
9H); 1.20 (m, 6H); Mass Spectral Analysis m/z=477.2 (M+H).sup.+
t.sub.R=2.82 minutes.
Step 4:
[3816] Trifluoroacetic acid (10.33 mL, 134.09 mmol, 5.5 eq) was
added drop wise to a cold (0.degree. C.) solution of 12 (11.62 g,
24.38 mmol, 1 eq) in anhydrous dichloromethane (50 mL). The mixture
was warmed to room temperature and stirring was continued for an
additional 10 hours at room temperature. The mixture was then
concentrated under reduced pressure. A saturated solution of sodium
bicarbonate (100 mL) was added to the mixture that was extracted
with dichloromethane. The organic phase was separated, washed with
brine, dried over sodium sulfate, and concentrated under reduced
pressure. To a cold (0.degree. C.) solution of the resulting oil in
anhydrous dichloromethane was added drop wise a 2 M solution of
anhydrous hydrochloric acid in diethyl ether (3 eq, 0.073 mol, 36.5
mL). The mixture was then stirred for 1 hour at room temperature
and concentrated under reduced pressure. Diethyl ether was added.
The resulting precipitate was collected by filtration and washed
with diethyl ether (9.9 g, 99%).
[3817] 15 (Example Z1): .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta.
9.1 (m, 2H), 7.40 (s, 4H), 7.20 (t, 1H), 7.00 (m, 3H), 5.95 (s,
1H), 3.45 (m, 2H), 3.20 (m, 6H), 2.00 (m, 4H), 1.10 (m, 6H); Mass
Spectral Analysis m/z=377.2 (M+H).sup.+ t.sub.R=1.77 minutes.
Example Z2
Preparation of
4-[(4-N,N-diethylaminocarbonyl)phenyl]-6-fluoro-spiro[2H,1-benzopyran-2,4-
'-piperidine]hydrochloride (16)
Step 1:
[3818] The compound 6 was prepared using the same procedure as
described for the preparation of 5
(5'-fluoro-2'-hydroxyacetophenone was used as starting material)
(71% yield).
[3819] 6: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.45 (m, 2H),
7.15 (d, 1H), 3.70 (m, 2H), 3.10 (m, 2H), 2.85 (s, 1H), 1.85 (m,
2H), 1.60 (m, 2H), 1.40 (s, 9H); Mass Spectral Analysis m/z=377.0
(M+H+CH.sub.3CN).sup.+ t.sub.R=2.42 minutes.
Step 2:
[3820] The compound 9 was prepared using the same procedure as
described for the preparation of 8 from 5 (83% yield).
[3821] 9: Mass Spectral Analysis m/z=509.0 (M+H+CH.sub.3CN).sup.+
t.sub.R=2.93 minutes.
Step 3:
[3822] The compound 13 was prepared using the same procedure as
described for the preparation of 12 from 8 (66% yield).
[3823] 13: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.40 (s,
4H), 7.05 (m, 2H), 6.70 (m, 1H), 5.95 (s, 1H), 3.70 (m, 2H), 3.45
(m, 2H), 3.20 (m, 4H), 1.85 (m, 2H), 1.60 (m, 2H), 1.40 (s, 9H);
1.10 (m, 6H); Mass Spectral Analysis m/z=495.2 (M+H).sup.+
t.sub.R=2.83 minutes.
Step 4:
[3824] The compound 16 was prepared using the same procedure as
described for the preparation of 15 from 12 (37% yield).
[3825] 16 (Example Z2): .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta.
8.95 (m, 2H), 7.40 (s, 4H), 7.10 (m, 1H), 6.70 (m, 1H), 6.00 (s,
1H), 3.40 (m, 2H), 3.30 (m, 2H), 3.20 (m, 4H), 2.00 (m, 4H), 1.10
(m, 6H); Mass Spectral Analysis m/z=395.2 (M+H).sup.+ t.sub.R=1.87
minutes.
Example Z3
Preparation of
4-[(4-N,N-diethylaminocarbonyl)phenyl]-6-hydroxyspiro[2H,1-benzopyran-2,4-
'-piperidine]hydrochloride (1)
Step 1:
[3826] The compound 7 was prepared using the same procedure as
described for the preparation of 5
(5'-methoxy-2'-hydroxyacetophenone was used as starting material)
(75% yield).
[3827] 7: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30 (s, 1H),
7.10 (m, 1H), 6.90 (m, 1H), 3.85 (m, 2H), 3.75 (s, 3H), 3.20 (m,
2H), 2.70 (s, 2H), 2.00 (d, 2H), 1.55 (m, 2H), 1.40 (s, 9H); Mass
Spectral Analysis m/z=348.0 (M+H).sup.+ t.sub.R=2.43 minutes.
Step 2:
[3828] The compound 10 was prepared using the same procedure as
described for the preparation of 8 from 5 (96% yield).
[3829] 10: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 6.95 (m,
2H), 6.70 (s, 1H), 6.15 (s, 1H), 3.70 (m, 5H), 3.15 (m, 2H), 1.85
(m, 2H), 1.70 (m, 2H), 1.40 (s, 9H); Mass Spectral Analysis
m/z=480.0 (M+H).sup.+ t.sub.R=3.01 minutes.
Step 3:
[3830] The compound 14 was prepared using the same procedure as
described for the preparation of 12 from 8 (96% yield).
[3831] 14: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.40 (s,
4H), 6.90 (d, 1H), 6.80 (m, 1H), 6.45 (s, 1H), 5.90 (s, 1H), 3.70
(m, 2H), 3.60 (s, 3H), 3.55 (m, 2H), 3.40 (m, 2H), 3.20 (m, 4H),
1.80 (m, 2H), 1.65 (m, 2H), 1.40 (s, 9H); 1.10 (m, 6H); Mass
Spectral Analysis m/z=507.1 (M+H).sup.+ t.sub.R=2.86 minutes.
Step 4:
[3832] The compound 17 was prepared using the same procedure as
described for the preparation of 15 from 12 (98% yield).
[3833] 17: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.80 (m,
2H), 7.40 (m, 4H), 7.00 (d, 1H), 6.85 (m, 1H), 6.45 (s, 1H), 5.95
(s, 1H), 3.60 (m, 5H), 3.40 (m, 2H), 3.20 (m, 4H), 2.00 (m, 4H),
1.10 (m, 6H); Mass Spectral Analysis m/z=407.2 (M+H).sup.+
t.sub.R=1.74 minutes.
Step 5:
[3834] A solution of 17 (1 g, 2.46 mmol, 1 eq) in anhydrous
dichloromethane (40 mL) was added drop wise at -78.degree. C. to a
1 M solution of boron tribromide in anhydrous dichloromethane
(13.53 mL, 13.53 mmol, 5.5 eq). The mixture was warmed slowly to
room temperature and stirring was continued for 1 hour. The mixture
was cooled to 0.degree. C., water was added drop wise followed by
an aqueous saturated solution of sodium bicarbonate. The mixture
was stirred for 1 hour at room temperature and made basic using
additional amount of an aqueous saturated solution of sodium
bicarbonate. The phases were separated and the aqueous phase was
further extracted with dichloromethane. The combined organic
extracts were washed with brine, dried over sodium sulfate, and
concentrated under reduced pressure. The crude product was purified
by column chromatography (eluent: dichloromethane/methanol mixtures
of increasing polarity (0.21 g, 22%).
[3835] 18 (Example Z3): .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta.
9.05 (s, 1H), 8.60 (m, 2H), 7.40 (m, 4H), 6.80 (d, 1H), 6.60 (m,
1H), 6.40 (s, 1H), 5.90 (s, 1H), 3.40 (m, 4H), 3.20 (m, 4H), 2.05
(m, 2H), 1.90 (m, 2H), 1.10 (m, 6H); Mass Spectral Analysis
m/z=393.2 (M+H).sup.+ t.sub.R=1.54 minutes.
Example Z4
Preparation of
4-[(4-N,N-diethylaminocarbonyl)phenyl]-3,4-dihydrospiro[2H,1-benzopyran-2-
,4'-piperidine]hydrochloride (19)
[3836] A solution of 15 (0.66 g) in anhydrous methanol was
hydrogenated at atmospheric pressure in the presence of palladium
hydroxide [Pd(OH).sub.2: Pearlman's catalyst] (0.120 g) for 10
hours. The mixture was then filtered through celite. The filtrate
was concentrated and was hydrogenated at atmospheric pressure in
the presence of palladium hydroxide (0.120 g) for an additional 10
hours. The mixture was filtered through celite and the filtrate was
concentrated to dryness under reduced pressure. To a cold
(0.degree. C.) solution of the resulting oil in anhydrous
dichloromethane was added drop wise a 2M solution of anhydrous
hydrochloric acid in diethyl ether (5 mL). The mixture was then
stirred for 1 hour at room temperature and concentrated under
reduced pressure. Diethyl ether was added. The resulting
precipitate was collected by filtration and washed with diethyl
ether and ethyl acetate (0.457 g, 63%).
[3837] 19 (Example Z4): .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta.
9.15 (s, 1H), 8.60 (m, 2H), 7.30 (m, 4H), 7.10 (m, 1H), 6.90 (m,
1H), 6.75 (m, 1H), 6.60 (m, 1H), 4.20 (m, 1H), 3.40 (m, 2H), 3.20
(m, 5H), 3.00 (m, 1H), 2.15 (m, 2H), 1.95 (m, 5H), 1.05 (m, 6H);
Mass Spectral Analysis m/z=379.1 (M+H).sup.+ t.sub.R=1.74
minutes.
Example Z5
Preparation of
4-[(4-N,N-diethylaminocarbonyl)phenyl]-N-methyl-spiro[2H,1-benzopyran-2,4-
'-piperidine]hydrochloride (20)
[3838] Triethylamine (0.37 mL, 2.66 mmol, 2.2 eq.) was added to a
solution of 15 (HCl salt, 0.500 g, 1.21 mmol, 1 eq.) in anhydrous
tetrahydrofuran (4 mL). Anhydrous methanol (4 g) was then added
followed by formaldehyde (0.20 mL, 2.42 mmol, 2 eq). Sodium
cyanoborohydride (0.090 g, 1.45 mmol, 1.2 eq) was then added to the
reaction mixture that was stirred for 30 min at room temperature
under nitrogen. The mixture was concentrated under reduced
pressure. Dichloromethane (30 mL) and water (10 mL) were added and
the suspension was stirred at room temperature for 10 minutes. The
phases were separated. The organic phase was further washed with
water, brine, dried over sodium sulfate and concentrated under
reduced pressure. To a cold (0.degree. C.) solution of the
resulting oil in anhydrous dichloromethane was added drop wise a 2
M solution of anhydrous hydrochloric acid in diethyl ether (5 mL).
The mixture was then stirred for 1 hour at room temperature and
concentrated under reduced pressure. Diethyl ether was added. The
resulting precipitate was collected by filtration and washed with
diethyl ether. (0.340 g, 65%).
[3839] 20 (Example Z5): .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta.
10.5 (m, 1H), 7.40 (m, 4H), 7.25 (m, 1H), 7.10 (m, 1H), 6.95 (m,
2H), 5.85 (s, 1H), 3.60-3.10 (m, 8H), 2.80 (s, 3H), 2.10 (m, 4H),
1.10 (m, 6H); Mass Spectral Analysis m/z=391.2 (M+H).sup.+
t.sub.R=1.82 minutes.
Example Z6
Preparation of
4-[(4-N-ethylaminocarbonyl)phenyl]spiro[2H,1-benzopyran-2,4'-piperidine]h-
ydrochloride (32)
Steps 1, 2:
[3840] See preparation of 8 from 1.
Step 3:
[3841] The compound 22 was prepared using the same procedure as
described for the preparation of 12 from 8 (64% yield).
[4-(methoxycarbonyl)phenylboronic acid) 21 was used in place of
4-(N,N-diethylaminocarbonyl)phenylboronic acid) 11].
[3842] 22: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.00 (d,
2H), 7.45 (d, 2H), 7.20 (m, 1H), 7.00 (m, 1H), 6.90 (m, 2H), 5.90
(s, 1H), 3.90 (s, 3H), 3.70 (m, 2H), 3.25 (m, 2H), 1.85 (m, 2H),
1.70 (m, 2H), 1.40 (s, 9H); Mass Spectral Analysis m/z=436.0
(M+H).sup.+ t.sub.R=3.12 minutes.
Step 4:
[3843] Lithium hydroxide (0.54 g, 12.98 mmol, 1.2 eq) was added to
a solution of 22 (4.71 g, 10.81 mmol, 1 eq) in tetrahydrofuran (30
mL) and water (30 mL). The mixture was stirred for 10 hours at room
temperature and acidified to pH 1 using a 2N aqueous solution of
hydrochloric acid. The mixture was concentrated under reduced
pressure. Ethyl acetate was added and the phases were separated.
The aqueous layer was further extracted with ethyl acetate. The
combined organic extracts were washed with water, brine, dried over
sodium sulfate and evaporated to afford the carboxylic acid 23 used
for the next step without further purification. (99%).
[3844] 23: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 13.00 (s,
1H), 8.00 (d, 2H), 7.50 (d, 2H), 7.20 (m, 1H), 7.00-6.85 (m, 3H),
5.90 (s, 1H), 3.70 (m, 2H), 3.30 (m, 2H), 1.85 (m, 2H), 1.70 (m,
2H), 1.40 (s, 9H); Mass Spectral Analysis m/z=420.1 (M-H).sup.+
t.sub.R=2.10 minutes.
Steps 5-6:
[3845] To a solution of 23 (0.18 g, 0.43 mmol, 1 eq.) in
acetonitrile (5 mL) was added consecutively diisopropylethylamine
(0.17 mL, 0.94 mmol, 2.2 eq), ethylamine hydrochloride (0.08 g,
0.94 mmol, 2.2 eq.) and TBTU (0.15 g, 0.47 mmol, 1.1 eq.). The
mixture was stirred at room temperature under nitrogen for 10
hours. The mixture was then poured into a saturated aqueous
solution of sodium bicarbonate and extracted with ethyl acetate.
The organic extracts were washed with brine, dried over sodium
sulfate and concentrated under reduced pressure to afford the crude
amide 28 used for the next step without further purification.
Trifluoroacetic acid (1.20 mL, 5.5 eq) was added drop wise to a
cold (0.degree. C.) solution of 28 obtained previously in anhydrous
dichloromethane (10 mL). The mixture was warmed to room temperature
and stirring was continued for an additional 10 hours. The mixture
was then concentrated under reduced pressure. A saturated solution
of sodium bicarbonate (100 mL) was added to the mixture, which was
extracted with dichloromethane. The organic phase was separated,
washed with brine, dried over sodium sulfate, and concentrated
under reduced pressure. To a cold (0.degree. C.) solution of the
resulting oil in anhydrous dichloromethane was added drop wise a 2
M solution of anhydrous hydrochloric acid in diethyl ether (3 eq.,
0.073 mol, 36.5 mL). The mixture was then stirred for 1 hour at
room temperature and concentrated under reduced pressure. Diethyl
ether was added. The resulting precipitate was collected by
filtration and washed with diethyl ether. (0.033 g, 21%).
[3846] 32 (Example Z6): .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta.
8.50 (m, 1H), 7.90 (d, 2H), 7.40 (d, 2H), 7.20 (m, 1H), 6.90 (m,
3H), 5.85 (s, 1H), 3.30 (m, 2H), 2.90 (m, 2H), 2.70 (m, 2H),
1.85-1.70 (m, 4H), 1.10 (t, 3H); Mass Spectral Analysis m/z=349.2
(M+H).sup.+ t.sub.R=1.56 minutes.
Example Z7
Preparation of
4-[(4-N-propyl-N-cyclopropylmethylaminocarbonyl)phenyl]-spiro[2H,1-benzop-
yran-2,4'-piperidine]hydrochloride (33)
Steps 1-2:
[3847] See preparation of 8 from 1.
Steps 3-4:
[3848] See preparation of 23 from 8.
Steps 5-6:
[3849] The compound 33 was prepared using the same procedure
described for the preparation of 32 from 23 (30% yield).
[N-propyl-N-cyclopropyl amine 25 was used in place of ethylamine
24].
[3850] 33 (Example Z7): .sup.1H NMR (400 MHz, DMSO d.sub.6) 9.00
(m, 1H), 7.40 (m, 4H), 7.25 (m, 1H), 7.00 (m, 3H), 5.90 (s, 1H),
3.55-3.05 (m, 8H), 2.05 (m, 4H), 1.60 (m, 2H), 1.10 (m, 1H), 0.90
(m, 2H), 0.65 (m, 1H), 0.40 (m, 2H), 0.15 (m, 1H), 0.10 (m, 1H);
Mass Spectral Analysis m/z=417.2 (M+H).sup.+ t.sub.R=2.03
minutes.
Example Z8
Preparation of
4-[4-(isoindolineaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-piperid-
ine]hydrochloride (3)
Steps 1-2:
[3851] See preparation of 8 from 1.
Steps 3-4:
[3852] See preparation of 23 from 8.
Steps 5-6:
[3853] The compound 34 was prepared using the same procedure as
described for the preparation of 32 from 23 (44% yield).
[isoindoline 26 was used in place of ethylamine 24].
[3854] 34 (Example Z8): .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta.
8.90 (m, 2H), 7.70 (d, 2H), 7.50 (d, 2H), 7.40 (m, 1H), 7.30 (m,
4H), 7.00 (m, 3H), 5.95 (s, 1H), 4.90 (s, 2H), 4.80 (s, 2H), 3.30
(s, 4H), 2.05 (m, 4H); Mass Spectral Analysis m/z=423.2 (M+H).sup.+
t.sub.R=1.94 minutes.
Example Z9
Preparation of
4-[4-(4-carboxypiperidineaminocarbonyl)phenyl]-spiro[2H,1-benzopyran-2,4'-
-piperidine]hydrochloride (36)
Steps 1-2:
[3855] See preparation of 8 from 1.
Steps 3-4:
[3856] See preparation of 23 from 8.
Steps 5-6:
[3857] The compound 35 was prepared using the same procedure as
described for the preparation of 32 from 23 (63% yield).
[4-ethoxycarbonylpiperidine 27 was used in place of ethylamine
24].
[3858] 35: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.65 (m,
2H), 7.45 (m, 4H), 7.25 (t, 1H), 7.00 (m, 3H), 5.95 (s, 1H), 4.35
(m, 1H), 4.10 (q, 2H), 3.95-3.55 (m, 3H), 3.25 (m, 4H), 2.65 (m,
1H), 2.15-1.75 (m, 6H), 1.50 (m, 2H), 1.20 (t, 3H); Mass Spectral
Analysis m/z=461.2 (M+H).sup.+ t.sub.R=1.86 minutes.
Step 7:
[3859] A 2N aqueous solution of sodium hydroxide (1.0 mL, 2 mmol,
9.2 eq.) was added to a solution of 35 (0.100 g, 0.22 mmol, 1 eq.)
in tetrahydrofuran (5 mL) and anhydrous absolute ethanol (5 mL).
The mixture was stirred for 10 hours at room temperature and
acidified to pH 6 using a 2 N aqueous solution of hydrochloric
acid. The mixture was concentrated under reduced pressure. The
mixture was then stirred for 1 hour at room temperature. The
resulting precipitate was collected by filtration, washed several
times with water and diethyl ether (0.054 mg, 60%).
[3860] 36 (Example Z9): .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta.
7.40 (m, 4H), 7.20 (m, 1H), 6.95 (m, 3H), 5.90 (s, 1H), 4.30 (m,
1H), 3.65-2.90 (m, 8H), 2.10-1.70 (m, 6H), 1.50 (m, 2H); Mass
Spectral Analysis m/z=433.1 (M+H).sup.+ t.sub.R=1.39 minutes.
Example Z10
Preparation of
4-[4-(2H-tetrazolyl)phenyl]-spiro[2H,1-benzopyran-2,4'-piperidine]trifluo-
roacetic acid salt (40)
[3861] Steps 1-2: See preparation of 8 from 1.
Step 3:
[3862] To a solution of 8 (7.80 g, 17.35 mmol, 1 eq) in
dimethoxyethane (DME) (75 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (26.03 mL, 52.06 mmol, 3 eq), lithium
chloride (2.21 g, 52.06 mmol, 3 eq), 4-cyanophenylboronic acid 37
(2.81 g, 19.09 mmol, 1.1 eq) and
tetrakis(triphenylphosphine)palladium(0) (0.40 g, 0.35 mmol, 0.02
eq). The mixture was refluxed for 10 h under nitrogen. The mixture
was then cooled to room temperature and water (250 mL) was added.
The mixture was extracted with ethyl acetate. The organic layer was
further washed with brine and dried over sodium sulfate. The crude
product was purified by column chromatography (eluent: hexane/ethyl
acetate mixtures of increasing polarity) (5.20 g, 74%).
[3863] 38: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.90 (d,
2H), 7.50 (d, 2H), 7.20 (m, 1H), 7.00 (m, 1H), 6.90 (m, 2H), 5.95
(s, 1H), 3.70 (m, 2H), 3.25 (m, 2H), 1.85 (m, 2H), 1.70 (m, 2H),
1.40 (s, 9H); Mass Spectral Analysis m/z=403.1 (M+H).sup.+
t.sub.R=2.98 minutes.
Step 4:
[3864] A mixture of 38 (4.95 g, 0.0122 mol, 1 eq), sodium azide
(1.60 g, 0.024 mol, 2 eq) and zinc bromide (1.38 g, 0.0061 mol, 0.5
eq) in isopropanol (100 mL) and water (80 mL) was refluxed for 3
days. The reaction mixture was then cooled to 0.degree. C. and
acidified to pH 1 using a 3N aqueous solution of hydrochloric acid.
The mixture was extracted with ethyl acetate. The organic phase was
washed with brine, dried over sodium sulfate, and concentrated
under reduced pressure. Diethyl ether (30 mL) was added. The
resulting precipitate was collected by filtration and washed with
diethyl ether. The crude compound was used for the next step
without further purification (3.25 g, 59%).
[3865] 39: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.10 (d,
2H), 7.55 (d, 2H), 7.20 (m, 1H), 7.00 (m, 2H), 6.90 (m, 1H), 5.90
(s, 1H), 3.70 (m, 2H), 3.30 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H),
1.40 (s, 9H); Mass Spectral Analysis m/z=446.1 (M+H).sup.+
t.sub.R=2.22 minutes.
Step 5:
[3866] Trifluoroacetic acid (0.18 mL, 0.0023 mol, 5 eq) was added
drop wise to a cold (0.degree. C.) solution of 39 (0.206 g, 0.00046
mol, 1 eq) in anhydrous dichloromethane (10 mL). The mixture was
warmed to room temperature and stirring was continued for an
additional 10 h at room temperature. The precipitate was collected
by filtration and washed with diethyl ether (0.112 g, 52%).
[3867] 40 (Example Z10): .sup.1H NMR (400 MHz, DMSO d.sub.6)
.delta. 8.60 (m, 1H), 8.10 (d, 2H), 7.60 (d, 2H), 7.25 (m, 1H),
7.00 (m, 3H), 6.00 (s, 1H), 3.40 (m, 2H), 3.25 (m, 2H), 2.10 (m,
2H), 1.95 (m, 2H); Mass Spectral Analysis m/z=346.1 (M+H).sup.+
t.sub.R=1.33 minutes.
Example Z11
Preparation of
4-[4-(4-carboxypropyl-tetrazol-2-yl)phenyl]-spiro[2H,1-benzopyran-2,4'-pi-
peridine] (4)
Steps 1-2:
[3868] See preparation of 8 from 1.
Steps 3-4:
[3869] See preparation of 39 from 8.
Step 5:
[3870] Ethyl bromobutyrate (4) (0.40 mL, 0.0028 mol, 2.5 eq) was
added drop wise to a solution of 39 (0.500 g, 0.0011 mol, 1 eq) and
triethylamine (0.40 mL, 0.0028 mol, 2.5 eq) in anhydrous
dimethylformamide and the mixture was stirred at room temperature
for 3 days. The mixture was poured into water (50 mL) and extracted
with ethyl acetate. The organic phase was washed with brine, dried
over sodium sulfate, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography (eluent:
hexane/ethyl acetate mixtures of increasing polarity). The minor
regioisomer 42 was isolated in 6% yield (40 mg); the major
regioisomer 43 was isolated in 82% (0.520 g).
[3871] 42: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.90 (d,
2H), 7.60 (d, 2H), 7.20 (m, 1H), 7.00 (m, 2H), 6.90 (m, 1H), 5.95
(s, 1H), 4.55 (t, 2H), 4.00 (q, 2H), 3.70 (m, 2H), 3.30 (m, 2H),
2.40 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1.40 (s,
9H), 1.10 (t, 3H); Mass Spectral Analysis m/z=560.2 (M+H).sup.+
t.sub.R=2.83 minutes.
[3872] 43: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.10 (d,
2H), 7.50 (d, 2H), 7.20 (m, 1H), 7.00 (m, 2H), 6.90 (m, 1H), 5.90
(s, 1H), 4.70 (t, 2H), 4.00 (q, 2H), 3.70 (m, 2H), 3.30 (m, 2H),
2.40 (m, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1.40 (s,
9H), 1.15 (t, 3H); Mass Spectral Analysis m/z=560.3 (M+H).sup.+
t.sub.R=3.09 minutes.
Step 6:
[3873] A 2 M anhydrous solution of hydrochloric acid in diethyl
ether (10 mL) was added drop wise to a cold (0.degree. C.) solution
of 43 (0.520 g, 0.00092 mol, 1 eq) in anhydrous dichloromethane (10
mL). The mixture was warmed to room temperature and stirring was
continued for an additional 10 hours at room temperature. An
additional amount (10 mL) of a 2M anhydrous solution of
hydrochloric acid in diethyl ether was added to the mixture, which
was stirred for an additional 6 hours at room temperature. The
mixture was concentrated under reduced pressure. Diethyl ether was
added. The resulting precipitate was collected by filtration and
washed with diethyl ether. (0.321 g, 70%).
[3874] 44: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 8.80 (m,
1H), 8.15 (d, 2H), 7.60 (d, 2H), 7.25 (m, 1H), 7.00 (m, 3H), 6.00
(s, 1H), 4.80 (t, 2H), 4.00 (q, 2H), 3.35 (m, 2H), 3.20 (m, 2H),
2.40 (m, 2H), 2.20 (m, 2H), 2.10 (m, 2H), 1.95 (m, 2H), 1.15 (t,
3H); Mass Spectral Analysis m/z=460.2 (M+H).sup.+ t.sub.R=2.08
minutes.
Step 7:
[3875] A 2 N aqueous solution of sodium hydroxide (1.8 mL, 0.0036
mol, 5.5 eq.) was added to a solution of 44 (0.300 g, 0.00060 mol,
1 eq) in tetrahydrofuran (10 mL) and absolute ethanol (1 mL). The
mixture was stirred for 10 hours at room temperature and acidified
to pH 6 using a 2N aqueous solution of hydrochloric acid. The
mixture was concentrated under reduced pressure. The mixture was
then stirred for 1 hour at room temperature. The resulting
precipitate was collected by filtration, washed several times with
water and diethyl ether (0.258 mg, 98%).
[3876] 45 (Example Z11): .sup.1H NMR (400 MHz, DMSO
d.sub.6+CF.sub.3CO.sub.2d) .delta. 8.80 (m, 1H), 8.20 (m, 2H), 7.70
(m, 2H), 7.30 (m, 1H), 7.00 (m, 3H), 6.00 (s, 1H), 4.80 (m, 2H),
3.30 (m, 4H), 2.60-1.95 (m, 8H); Mass Spectral Analysis m/z=432.1
(M+H).sup.+ t.sub.R=1.65 minutes.
Example Z12
Preparation of
4-(3-pyridyl)-spiro[2H,1-benzopyran-2,4'-piperidine]hydrochloride
(48)
Steps 1-2:
[3877] See preparation of 8 from 1.
Steps 3-4:
[3878] To a solution of 8 (0.5 g, 1 eq.) in dimethoxyethane (DME)
(3.5 mL) was added sequentially a 2 N aqueous solution of sodium
carbonate (1.67 mL, 3 eq.), lithium chloride (0.141 g, 3 eq),
3-pyridylboronic acid 46 (0.199 g, 1.1 eq) and
tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.02 eq). The
reaction mixture was heated using a MicroSynth Microwave Lab
Station (Milestone) using the following temperature conditions: the
temperature was increased from 25.degree. C. to 160.degree. C. for
15 min; the temperature was stabilized at 160.degree. C. for 15
min; the temperature was decreased from 160.degree. C. to
25.degree. C. for 15 minutes. Dichloromethane (10 mL) and a 1 N
aqueous solution of sodium hydroxide (10 mL) were added to the
reaction mixture. The phases were separated. The organic phase was
dried over sodium sulfate and filtered. Trifluoroacetic acid (3 mL)
was added to the filtrate and the mixture was stirred at room
temperature for 10 hours. The mixture was then concentrated under
reduced pressure. A saturated solution of sodium bicarbonate (100
mL) was added to the mixture, which was extracted with
dichloromethane. The organic phase was separated, washed with
brine, dried over sodium sulfate, and concentrated under reduced
pressure. The crude product was purified by column chromatography
[eluent: dichloromethane/methanol (containing 1% of ammonium
hydroxide) employing solvent mixtures of increasing polarity. To a
cold (0.degree. C.) solution of the resulting oil in anhydrous
dichloromethane was added drop wise a 2 M solution of anhydrous
hydrochloric acid in diethyl ether (3 eq., 1.67 mL). The mixture
was then stirred for 1 hour at room temperature and concentrated
under reduced pressure. Diethyl ether was added. The resulting
precipitate was collected by filtration and washed with diethyl
ether. (0.189 g, 61%).
[3879] 48 (Example Z12): .sup.1H NMR (400 MHz, DMSO d.sub.6)
.delta. 9.50 (m, 2H), 8.90 (m, 2H), 8.40 (m, 1H), 8.00 (m, 1H),
7.25 (m, 1H), 7.10 (m, 1H), 6.95 (m, 2H), 6.20 (s, 1H), 3.20 (m,
4H), 2.10 (m, 4H); Mass Spectral Analysis m/z=279.1 (M+H).sup.+
t.sub.R=1.42 minutes.
Example Z13
Preparation of
4-[4-(methanesulfonyl)-phenyl]-spiro[2H,1-benzopyran-2,4'-piperidine]hydr-
ochloride (1)
Steps 1-2:
[3880] See preparation of 8 from 1.
Steps 3-4:
[3881] To a solution of 8 (0.5 g, 1 eq.) in dimethoxyethane (DME)
(3.5 mL) was added sequentially a 2 N aqueous solution of sodium
carbonate (1.67 mL, 3 eq.), lithium chloride (0.141 g, 3 eq),
4-methanesulfonylphenylboronic acid 49 (0.244 g, 1.1 eq) and
tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.02 eq). The
reaction mixture was heated using a MicroSynth Microwave Lab
Station (Milestone) using the following temperature conditions: the
temperature was increased from 25.degree. C. to 160.degree. C. for
15 min; the temperature was stabilized at 160.degree. C. for 15
min; the temperature was decreased from 160.degree. C. to
25.degree. C. for 15 minutes. Dichloromethane (10 mL) and a 1 N
aqueous solution of sodium hydroxide (10 mL) were added to the
reaction mixture. The phases were separated. The organic phase was
dried over sodium sulfate and filtered. Trifluoroacetic acid (3 mL)
was added to the filtrate and the mixture was stirred at room
temperature for 10 h. The mixture was then concentrated under
reduced pressure. A saturated solution of sodium bicarbonate (100
mL) was added to the mixture, which was extracted with
dichloromethane. The organic phase was separated, washed with
brine, dried over sodium sulfate, and concentrated under reduced
pressure. The crude product was purified by column chromatography
[eluent: dichloromethane/methanol (containing 1% of ammonium
hydroxide) employing solvent mixtures of increasing polarity. To a
cold (0.degree. C.) solution of the resulting oil in anhydrous
dichloromethane was added drop wise a 2 M solution of anhydrous
hydrochloric acid in diethyl ether (3 eq., 1.67 mL). The mixture
was then stirred for 1 hour at room temperature and concentrated
under reduced pressure. Diethyl ether was added. The resulting
precipitate was collected by filtration and washed with diethyl
ether. (0.269 g, 68%).
[3882] 51 (Example Z13): .sup.1H NMR (400 MHz, DMSO d.sub.6)
.delta. 8.95 (m, 2H), 8.00 (d, 2H), 7.65 (d, 2H), 7.25 (m, 1H),
7.05 (m, 2H), 6.95 (m, 1H), 6.00 (s, 1H), 3.30 (s, 3H), 3.20 (m,
4H), 2.10 (m, 4H); Mass Spectral Analysis m/z=356.1 (M+H).sup.+
t.sub.R=1.54 minutes.
Example Z14
Preparation of
4-[(4-N,N-diethylaminocarbonyl)phenyl]spiro[2H,1-benzopyran-2,4'-nortropi-
ne]hydrochloride (56)
Step 1:
[3883] Pyrrolidine (1.83 mL, 0.022 mol, 2 eq.) was added drop wise
at room temperature to a solution of 1-Boc-4-nortropinone (2) (2.5
g, 0.011 mol, 1 eq) and 2'-hydroxyacetophenone (1.51 g, 0.011 mol,
1 eq) in anhydrous methanol (15 mL).
[3884] The solution was refluxed for 3 days and then concentrated
under reduced pressure. Diethyl ether (200 mL) was added. The
organic mixture was washed with a 1N aqueous solution of
hydrochloric acid, a 1N aqueous solution of sodium hydroxide, brine
and dried over sodium sulfate. The crude product was purified by
column chromatography employing solvent mixtures of increasing
polarity (eluent: hexane/ethyl acetate, 0.80 g, 30%).
[3885] 53: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.70 (m,
1H), 7.60 (m, 1H), 7.00 (m, 2H), 4.10 (s, 2H), 2.65 (s, 2H), 2.00
(m, 4H), 1.90 (m, 2H), 1.75 (m, 2H), 1.40 (s, 9H); Mass Spectral
Analysis m/z=385.0 (M+H+CH.sub.3CN).sup.+ t.sub.R=2.51 minutes.
Step 2:
[3886] To a solution of 53 (0.75 g, 0.00218 mol) in tetrahydrofuran
(10 mL) at -78.degree. C. under nitrogen was added drop wise a 1.0
M solution of LiHMDS in tetrahydrofuran (2.62 mL, 0.00262 mol, 1.2
eq). The mixture was stirred for 1 hour at -78.degree. C. A
solution of N-phenyltrifluoromethanesulfonimide (0.936 g, 0.00262
mol, 1.2 eq) in tetrahydrofuran (10 mL) was added drop wise. The
mixture was warmed slowly to room temperature and stirring was
continued for a further 12 h at room temperature. The mixture was
then poured into ice water and the 2 phases were separated. The
organic phase was washed with a 1N aqueous solution of hydrochloric
acid, a 1N aqueous solution of sodium hydroxide, brine and dried
over sodium sulfate. The crude product was purified by column
chromatography employing solvent mixtures of increasing polarity
(eluent: hexane/ethyl acetate 0.76 g, 69%).
[3887] 54: Mass Spectral Analysis m/z=517.0 (M+H+CH.sub.3CN).sup.+
t.sub.R=3.05 minutes.
Step 3:
[3888] To a solution of 54 (0.760 g, 0.001598, 1 eq) in
dimethoxyethane (DME) (10 mL) was added sequentially a 2N aqueous
solution of sodium carbonate (2.4 mL, 0.00479 mol, 3 eq), lithium
chloride (0.203 g, 0.00479 mol, 3 eq),
4-(N,N-diethylaminocarbonyl)phenylboronic acid) 11 (0.388 g,
0.00175 mol, 1.1 eq) and tetrakis(triphenylphosphine)palladium(0)
(0.037 g, 0.0000319 mol, 0.02 eq). The mixture refluxed for 10
hours under nitrogen. The mixture was then cooled to room
temperature and water (250 mL) was added. The mixture was extracted
with ethyl acetate. The organic layer was further washed with brine
and dried over sodium sulfate. The crude product was triturated in
hexane. The resulting precipitate was collected by filtration and
washed with hexane (0.5 g, 62%).
[3889] 55: .sup.1H NMR (400 MHz, DMSO d.sub.6) .delta. 7.40 (m,
4H), 7.20 (t, 1H), 7.00 (m, 3H), 5.60 (s, 1H), 4.10 (m, 2H), 3.45
(m, 2H), 3.20 (m, 2H), 2.15 (m, 4H), 1.90 (m, 4H), 1.40 (s, 9H);
1.10 (m, 6H); Mass Spectral Analysis m/z=503.2 (M+H).sup.+
t.sub.R=2.96 minutes.
Step 4:
[3890] Trifluoroacetic acid (0.19 mL, 0.00248 mol, 5 eq.) was added
drop wise to a cold (0.degree. C.) solution of 55 (0.250 g, 0.00049
mol, 1 eq.) in anhydrous dichloromethane (10 mL). The mixture was
warmed to room temperature and stirring was continued for an
additional 10 h. The mixture was then concentrated under reduced
pressure. A saturated solution of sodium bicarbonate (20 mL) was
added to the mixture, which was extracted with dichloromethane. The
organic phase was separated, washed with brine, dried over sodium
sulfate and concentrated under reduced pressure. To a cold
(0.degree. C.) solution of the resulting oil in anhydrous
dichloromethane was added drop wise a 2 M solution of anhydrous
hydrochloric acid in diethyl ether (3 eq., 0.00149 mol, 0.75 mL).
The mixture was then stirred for 1 hour at room temperature and
concentrated under reduced pressure. Diethyl ether was added. The
resulting precipitate was collected by filtration and washed with
diethyl ether (0.125 g, 57%).
[3891] 56 (Example Z14): .sup.1H NMR (400 MHz, DMSO d.sub.6)
.delta. 9.4 (m, 2H), 7.40 (d, 2H), 7.30 (d, 2H), 7.20 (t, 1H), 6.95
(m, 3H), 5.55 (s, 1H), 4.00 (s, 2H), 3.40 (m, 2H), 3.20 (m, 2H),
2.25 (m, 6H), 2.00 (m, 2H), 1.10 (m, 6H); Mass Spectral Analysis
m/z=403.2 (M+H).sup.+ t.sub.R=1.91 minutes.
TABLE-US-00003 TABLE Z1 Example Name [M + H].sup.+ Z1 4-[(4-N,N-
377 diethylaminocarbonyl)phenyl]-
spiro[2H,1-benzopyran-2,4'-piperidine] Z2 4-[(4-N,N- 395
diethylaminocarbonyl)phenyl]-6-fluoro-
spiro[2H,1-benzopyran-2,4'-piperidine] hydrochloride Z3 4-[(4-N,N-
393 diethylaminocarbonyl)phenyl]-6-hydroxy-
spiro[2H,1-benzopyran-2,4'-piperidine] Z4 4-[(4-N,N- 379
diethylaminocarbonyl)phenyl]-3,4-dihydro-
spiro[2H,1-benzopyran-2,4'-piperidine] hydrochloride Z5 4-[(4-N,N-
391 diethylaminocarbonyl)phenyl]-
spiro[2H,1-benzopyran-2,4'-(1'-methyl- piperidine)] Z6
4-[(4-N-ethyl- 349 aminocarbonyl)phenyl]spiro[2H,1-
benzopyran-2,4'-piperidine] Z7 4-[(4-N-propyl-N- 417
cyclopropylmethylaminocarbonyl)phenyl]-
spiro[2H,1-benzopyran-2,4'-piperidine] Z8 4-[4- 423
(isoindolineaminocarbonyl)phenyl]-
spiro[2H,1-benzopyran-2,4'-piperidine] Z9 4-[4-(4- 433
carboxypiperidineaminocarbonyl)phenyl]-
spiro[2H,1-benzopyran-2,4'-piperidine] Z10
4-[4-(2H-tetrazol-5-yl)phenyl]- 346
spiro[2H,1-benzopyran-2,4'-piperidine] Z11 4-[4-(4-carboxypropyl-
432 tetrazol-2-yl)phenyl]- spiro[2H,1-benzopyran-2,4'-piperidine]
Z12 4-(3-pyridyl)-spiro[2H,1- 279 benzopyran-2,4'-piperidine] Z13
4-[4-(methanesulfonyl)-phenyl]- 356
spiro[2H,1-benzopyran-2,4'-piperidine] Z14 4-[(4-N,N- 403
diethylaminocarbonyl)phenyl]spiro[2H,1-
benzopyran-2,4'-nortropine]
Biological Activity
[3892] The potencies of the final compounds found in Examples
Z1-Z14 and listed in Table Z1 were determined by testing the
ability of a range of concentrations of each compound to inhibit
the binding of the non-selective opioid antagonist,
[.sup.3H]diprenorphine, to the cloned human .mu., and .delta.
opioid receptors, expressed in separate cell lines. IC.sub.50
values were obtained by nonlinear analysis of the data using
GraphPad Prism version 3.00 for Windows (GraphPad Software, San
Diego). K; values were obtained by Cheng-Prusoff corrections of
IC.sub.50 values.
Receptor Binding
[3893] The receptor binding method (DeHaven and DeHaven-Hudkins,
1998) was a modification of the method of Raynor et al. (1994).
After dilution in buffer A and homogenization as before, membrane
proteins (10-80 .mu.g) in 250 .mu.L were added to mixtures
containing test compound and [.sup.3H]diprenorphine (0.5 to 1.0 nM,
40,000 to 50,000 dpm) in 250 .mu.L of buffer A in 96-well deep-well
polystyrene titer plates (Beckman). After incubation at room
temperature for one hour, the samples were filtered through GF/B
filters that had been presoaked in a solution of 0.5% (w/v)
polyethylenimine and 0.1% (w/v) bovine serum albumin in water. The
filters were rinsed 4 times with 1 mL of cold 50 mM Tris HCl, pH
7.8 and radioactivity remaining on the filters determined by
scintillation spectroscopy. Nonspecific binding was determined by
the minimum values of the titration curves and was confirmed by
separate assay wells containing 10 .mu.M naloxone. K.sub.i values
were determined by Cheng-Prusoff corrections of IC.sub.50 values
derived from nonlinear regression fits of 12 point titration curves
using GraphPad Prism.RTM. version 3.00 for Windows (GraphPad
Software, San Diego, Calif.).
[3894] To determine the equilibrium dissociation constant for the
inhibitors (K.sub.i), radioligand bound (cpm) in the presence of
various concentrations of test compounds was measured. The
concentration to give half-maximal inhibition (EC.sub.50) of
radioligand binding was determined from a best nonlinear regression
fit to the following equation,
Y = Bottom + ( Top - Bottom ) 1 + 10 X - LogEC 50 ##EQU00005##
where Y is the amount of radioligand bound at each concentration of
test compound, Bottom is the calculated amount of radioligand bound
in the presence of an infinite concentration of test compound, Top
is the calculated amount of radioligand bound in the absence of
test compound, X is the logarithm of the concentration of test
compound, and LogEC.sub.50 is the log of the concentration of test
compound where the amount of radioligand bound is half-way between
Top and Bottom. The nonlinear regression fit was performed using
the program Prism.RTM. (GraphPad Software, San Diego, Calif.). The
K.sub.i values were then determined from the EC.sub.50 values by
the following equation,
K i = EC 50 1 + [ ligand ] K d ##EQU00006##
where [ligand] is the concentration of radioligand and K.sub.d is
the equilibrium dissociation constant for the radioligand.
Receptor-Mediated [.sup.35S]GTP.quadrature.S Binding
[3895] The potency and efficacy of compounds at each of the
receptors are assessed by modifications of the methods of Selley et
al., 1997 and Traynor and Nahorski, 1995 using receptor-mediated
[.sup.35S]GTP.gamma.S binding in the same membrane preparations
used to measure receptor binding. Assays are carried out in 96-well
FlashPlates.RTM. (Perkin Elmer Life Sciences, Inc, Boston, Mass.).
Membranes prepared from CHO cells expressing the appropriate
receptor (50-100 .mu.g of protein) are added to assay mixtures
containing agonist with or without antagonists, 100 pM
[.sup.35S]GTP.quadrature.S (approx. 100,000 dpm), 3.0 .mu.M GDP, 75
mM NaCl, 15 mM MgCl.sub.2, 1.0 mM ethylene
glycol-bis(.beta.-aminoethyl ether)-N,N,N',N'-tetracetic acid, 1.1
mM dithiothreitol, 10 .mu.g/mL leupeptin, 10 .mu.g/mL pepstatin A,
200 .mu.g/mL bacitracin, and 0.5 .mu.g/mL aprotinin in 50 mM
Tris-HCl buffer, pH 7.8. After incubation at room temperature for
one hour, the plates are sealed, centrifuged at 800.times.g in a
swinging bucket rotor for 5 min and bound radioactivity determined
with a TopCount microplate scintillation counter (Packard
Instrument Co., Meriden, Conn.).
[3896] EC.sub.50 values for agonists are determined from nonlinear
regression fits of 8- or 12-point titration curves to the
4-parameter equation for a sigmoidal dose-response with a slope
factor of 1.0 using GraphPad Prism.RTM. version 3.00 for Windows
(GraphPad Software, San Diego, Calif.).
[3897] To determine IC.sub.50 values, the concentrations to give
half-maximal inhibition of agonist-stimulated
[.sup.35S]GTP.quadrature.S binding, the amount of
[.sup.35S]GTP.quadrature.S bound in the presence of a fixed
concentration of agonist and various concentrations of antagonist
was measured. The fixed concentration of agonist was the EC.sub.80,
the concentration to give 80% of the relative maximum stimulation
of [.sup.35S]GTP.quadrature.S binding. The agonists loperamide (100
nM), U50,488 (50 nM), and BW373U86 (2.0 nM) were used to stimulate
[.sup.35S]GTP.quadrature.S binding via the .quadrature.,
.quadrature., and .quadrature. opioid receptors, respectively. The
IC.sub.50 value was determined from a best nonlinear regression fit
of the data to the 4-parameter equation for a sigmoidal
dose-response with a slope factor of 1.0 using GraphPad Prism.RTM.
version 3.00 for Windows.
In Vivo Assays
Castor Oil-Induced Diarrhea
[3898] Mice were fasted overnight with water ad libitum. Mice were
weighed, dosed orally with 0.6 mL of castor oil and placed in
individual cubicles (11 cm.times.10 cm) lined with a pre-weighed
sheet of absorbent paper. Thirty min after receiving castor oil,
mice were injected s.c with tested compound. Seventy-five min after
dosing with castor oil, the mice and absorbent paper were reweighed
and the number of mice with diarrhea (defined as wet, unformed
stool) was determined.
[3899] Percent inhibition by tested compounds in castor oil-induced
diarrhea assay was determined by the following formula:
1 - ( agonist response ) ( vehicle response ) .times. 100
##EQU00007##
[3900] Example Z1 reduced incidence of diarrhea in a time-dependent
manner: ED.sub.50 (s.c.)=8.7 mg/kg.
Freunds Complete Adjuvant (FCA)-Induced Hyperalgesia
[3901] Rats were injected intraplantar with FCA and 24 h later
treated with tested compounds administered orally. Paw Pressure
Thresholds (PPT) was assessed 30, 60, 120, and 240 minutes after
drug treatment. Example Z1 significantly increased PPT by 170-180%
in the inflamed paw 1-2 h after oral administration (ED.sub.50=2.5
mg/kg p.o.). Example Z1 produced a similar increase in PPT in the
uninflamed paw at the 2 h time point, a change that is generally
associated with effects mediated within the central nervous
system.
Acetic Acid-Induced Writhing
[3902] Male ICR mice weighing 20-25 g are injected s.c. with either
vehicle or test compound 15 minutes before they are injected
intraperitoneally with 0.6% acetic acid. At 5 minutes after
treatment with acetic acid, the number of writhes is counted for 10
minutes. Dose response curves are expressed as the percent
inhibition of acetic acid induced writhing, when compared to the
mean number of writhes observed in the vehicle-treated mice. The
mean percent inhibition (% I) of acetic acid-induced writhing for
drug-treated mice is calculated according to the following
formula:
% I = ( Mean vehicle response - Mean individual response ) ( Mean
vehicle response ) .times. 100 ##EQU00008##
The mean individual response is the mean number of writhes in mice
treated with test compound. The mean vehicle response is the mean
number of writhes in mice treated with vehicle.
[3903] Example Z1 produces 69% inhibition of acetic acid-induced
writhing at 30 mg/kg (s.c.)
Results and Discussions
[3904] The potencies of the compounds were determined by testing
the ability of a range of concentrations of each compound to
inhibit the binding of the non-selective opioid antagonist,
[.sup.3H]diprenorphine, to the cloned human .mu., .kappa., and
.delta. opioid receptors, expressed in separate cell lines. All the
compounds tested (Examples Z1-Z14, Table Z2) bind with high
affinity to the human cloned .quadrature. opioid receptor. These
compounds display high selectivity .delta./.kappa. and
.delta./.mu.. The potencies of the ligands were assessed by their
abilities to stimulated [.sup.35S]GTP.gamma.S binding to membranes
containing the cloned human .delta. opioid receptors. All the
compounds tested were agonists at .delta.opioid receptor with
EC.sub.50 values in the nanomolar range (Table Z2).
TABLE-US-00004 TABLE Z2 K.sub.i(.kappa.)(nM) or K.sub.i(.mu.)(nM)
or K.sub.i(.delta.) EC.sub.50(.delta.) % Inhibition % Inhibition
Example (nM) (nM) at 10 .mu.M at 10 .mu.M Z1 0.93 9.1 32% 980 Z2
2.6 70 17% 4500 Z3 0.36 1.4 790 50% Z4 1.5 14 19% 34% Z5 5.8 140
23% 17% Z6 6.1 130 750 2900 Z7 1.7 29 51% 2500 Z8 0.53 36 890 450
Z9 15 160 24% 17% Z10 2.7 22 1.3% 29% Z11 8 140 -3.3% 3.7% Z12 54
NA 44% 36% Z13 28 NA 17% 41% Z14 26 NA 8% 24%
[3905] The disclosures of each patent, patent application and
publication cited or described in this document are hereby
incorporated herein by reference, in their entirety.
[3906] Those skilled in the art will appreciate that numerous
changes and modifications can be made to the preferred embodiments
of the invention and that such changes and modifications can be
made without departing from the spirit of the invention. It is,
therefore, intended that the appended claims cover all such
equivalent variations as fall within the true spirit and scope of
the invention.
* * * * *