U.S. patent application number 10/807113 was filed with the patent office on 2005-01-27 for kappa agonist compounds and pharmaceutical formulations thereof.
This patent application is currently assigned to Adolor Corporation. Invention is credited to Chang, Michael An-Chih, Gaul, Forrest, Guo, Deqi, Kumar, Virendra, Marella, Michael Anthony, Maycock, Alan L., Zhang, Wei Yuan.
Application Number | 20050020576 10/807113 |
Document ID | / |
Family ID | 27617951 |
Filed Date | 2005-01-27 |
United States Patent
Application |
20050020576 |
Kind Code |
A1 |
Zhang, Wei Yuan ; et
al. |
January 27, 2005 |
Kappa agonist compounds and pharmaceutical formulations thereof
Abstract
Compounds having kappa opioid agonist activity, compositions
containing them and method of using them as analgesics are
provided. The compounds of formulae I, II, IIA, III, IIIA, IIIB,
IIB-i, IV and IVA have the structure: 12 wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4; and X, X.sub.4, X.sub.5, X.sub.7, X.sub.9; Y, Z
and n are as described in the specification.
Inventors: |
Zhang, Wei Yuan;
(Collegeville, PA) ; Maycock, Alan L.; (Wayne,
PA) ; Marella, Michael Anthony; (Limerick, PA)
; Kumar, Virendra; (Paoli, PA) ; Gaul,
Forrest; (Glen Moore, PA) ; Chang, Michael
An-Chih; (Rochester, MN) ; Guo, Deqi;
(Phoenixville, PA) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
ONE LIBERTY PLACE, 46TH FLOOR
1650 MARKET STREET
PHILADELPHIA
PA
19103
US
|
Assignee: |
Adolor Corporation
|
Family ID: |
27617951 |
Appl. No.: |
10/807113 |
Filed: |
March 23, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10807113 |
Mar 23, 2004 |
|
|
|
10146693 |
May 15, 2002 |
|
|
|
6750216 |
|
|
|
|
10146693 |
May 15, 2002 |
|
|
|
09478482 |
Jan 6, 2000 |
|
|
|
6391910 |
|
|
|
|
09478482 |
Jan 6, 2000 |
|
|
|
09150369 |
Sep 9, 1998 |
|
|
|
6303611 |
|
|
|
|
09150369 |
Sep 9, 1998 |
|
|
|
09034661 |
Mar 3, 1998 |
|
|
|
5945443 |
|
|
|
|
09034661 |
Mar 3, 1998 |
|
|
|
08899086 |
Jul 23, 1997 |
|
|
|
5744458 |
|
|
|
|
08899086 |
Jul 23, 1997 |
|
|
|
08796078 |
Feb 5, 1997 |
|
|
|
5688955 |
|
|
|
|
08796078 |
Feb 5, 1997 |
|
|
|
08612680 |
Mar 8, 1996 |
|
|
|
5646151 |
|
|
|
|
Current U.S.
Class: |
514/217.12 ;
514/317; 514/408; 540/609; 546/234; 548/571 |
Current CPC
Class: |
C07D 241/04 20130101;
C07D 207/12 20130101; A61K 45/06 20130101; C07D 403/06 20130101;
C07D 295/073 20130101; C07D 209/42 20130101; A61K 31/404 20130101;
C07D 213/56 20130101; A61K 31/4439 20130101 |
Class at
Publication: |
514/217.12 ;
514/317; 514/408; 540/609; 546/234; 548/571 |
International
Class: |
A61K 031/55; A61K
031/445; A61K 031/40 |
Claims
1-19. (canceled)
20. A compound of the formula IIIA or a pharmaceutically acceptable
salt thereof: 361wherein: n is 1 to 3; R.sub.1 and R.sub.2 are
independently CH.sub.3 or together form --(CH.sub.2).sub.m--,
--CH.sub.2CH(OR)(CH.sub.2- ).sub.2--,
--CH.sub.2CH(F)(CH.sub.2).sub.2--, --(CH.sub.2).sub.2O(CH.sub.2-
).sub.2-- or --(CH.sub.2).sub.2CH.dbd.CHCH.sub.2--; R is H, alkyl,
acyl or aroyl; Ar is mono- or di-substituted phenyl, wherein said
substituents are selected from the group consisting of halogen,
OCH.sub.3, OH, SO.sub.2CH.sub.3, CF.sub.3, NH.sub.2, alkyl, CN,
unsubstituted and substitued sulfamoyl groups; Ar may also be
substituted with NH(CH.sub.2).sub.uCO.sub.2R',
NH(CH.sub.2).sub.u(CH.dbd.CH).sub.u(CH.sub.- 2)CO.sub.2R',
NHCO(CH.sub.2).sub.u(CH.dbd.CH).sub.u(CH.sub.2).sub.uCO.sub.- 2R',
NHP(O)(OBn).sub.2, NHP(O)(OR').sub.2,
(CH.sub.2).sub.uNHSO.sub.2CH.su- b.3,
(CH.sub.2).sub.uNHC(S)NHCH(CO.sub.2R')(CH.sub.2).sub.uCO.sub.2R',
CONHOH, or (CH.sub.2).sub.uCONHOH; or Ar is substituted with
362R.sub.6 is H or Ac; R.sub.7 is NH(CH.sub.2).sub.vCO.sub.2H,
NH(CH.sub.2).sub.vCH(NH.sub.2)(CO.sub.2H),
NHCH(CO.sub.2H)(CH.sub.2).sub.- vNH.sub.2.
NH(CH.sub.2).sub.vSO.sub.3H, NH(CH.sub.2).sub.vPO.sub.3H,
NH(CH.sub.2).sub.vNHC(NH)NH.sub.2, or
NHCH(CO.sub.2H)(CH.sub.2).sub.vCO.s- ub.2H; R' is H or lower alkyl;
X.sub.7 is H, halogen, OH, OCH.sub.3, CF.sub.3, NO.sub.2, NH.sub.2,
amino substituted with acyl, carbamate, alkyl or aryl sulfonates,
or COR"; R" is OH, amide, alkoxy, aryloxy or heteroaryloxy; X.sub.8
is CO.sub.2H, NHSO.sub.2CH.sub.3, NHP(O)(OBn).sub.2,
NHP(O)(OH).sub.2, OP(O)(OBn).sub.2, or OP(O)(OH).sub.2; m is 4 to
8; u is 0 to 5; and v is 1 to 20.
21. A compound which is selected from the group consisting of
N-[(4-Trifluoromethylphenyl)-N-methyl-{[1S-1-phenyl-2-[1-pyrrolidinyl)]et-
hyl}-acetamido]glycine hydrochloride;
2-(3,4-Dichlorophenyl)-N-methyl-N-[(-
1R,S)-1-(3-sulfamidophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide
hydrochloride; 2-(4-Trifluoromethylphenyl)-N-methyl-N-{[1
S]-1-[3-[(methylsulfonyl)amino]-phenyl]-2-[1-pyrrolidinyl]ethyl}acetamide
hydrochloride;
2-(4-Methanesulfonylphenyl)-N-methyl-N-{[1S]-1-[3-[(methyl-
sulfonyl)amino]-phenyl]-2-[1-pyrrolidinyl]ethyl}acetamide
methanesulfonate;
2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-[3-[(methylsu-
lfonyl)amino]phenyl]-2-[1-pyrrolidinyl]ethyl}acetamide
hydrochloride;
2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-[3-(diethyl
phosphoryl)amino]phenyl)-2-(1-pyrrolidinyl)ethyl]acetamide
hydrochloride;
2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-[3-[(4-oxo-butenoate)]amino]phe-
nyl)-2-(1-pyrrolidinyl)ethyl]acetamide;
2-(3,4-Dichlorophenyl)-N-methyl-N--
{(1S)-1-[3-(3-(((iso-butoxycarbonyl)-methyl)aminocarbonyl)propionamido)phe-
nyl]-2-(1-pyrrolidinyl)ethyl}acetamide hydrochloride;
2-(3,4-Dichlorophenyl)-N-methyl-N-{(1R,S)-1-[3-(3-(((hydroxycarbonyl)-met-
hyl)aminocarbonyl)propionamido)phenyl]-2-(1-pyrrolidinyl)ethyl}acetamide
hydrochloride;
2-[(2-N-Phenylsulfonamido)phenyl)]-N-methyl-N-[(1S)-1-phen-
yl-2-(1-pyrrolidinyl)ethyl]acetamide methane sulfonate;
2-[3-(N-Methylsulfamoyl)-4-chlorophenyl]-N-methyl-N-{[1
S]-1-phenyl-2-[1-pyrrolidinyl]ethyl}acetamide hydrochloride;
2-(3-Sulfamoyl-4-chlorophenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-pyrrolidiny-
l]-ethyl}acetamide methanesulfonate;
2-(3-Sulfamoyl-4-chlorophenyl)-N-meth-
yl-N-{[1S]-1-[3-[(methylsulfonyl)amino]-phenyl]-2-[1-pyrrolidinyl]ethyl}ac-
etamide methanesulfonate;
2-[3-(N-Methylsulfamoyl)-4-fluorophenyl]-N-methy-
l-N-{[1S]-1-phenyl-2-[1-pyrrolidinyl]ethyl}acetamide hydrochloride;
2-[2&4-(N-Methylsulfamoyl)phenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-pyrrolid-
inyl)-ethyl]acetamide hydrochloride;
3-(N-Methylsulfamoyl)phenyl-N-methyl--
N-[(1S)-phenyl-2-(1-pyrrolidinyl)ethyl]-acetamide hydrochloride;
2-[N-Methylsulfamoyl)-4-bromophenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-pyrro-
lidinyl]ethyl acetamide hydochloride;
2-[2&4-(N-Methylsulfamoyl)phenyl]-N-- methyl-N-{[1
S]-1-phenyl-2-[1-(3S)-3-hydroxypyrrolidinyl]ethyl}acetamide
hydrochloride;
2-[2-Methoxy-3-(N-methylsulfamoyl)phenyl]-N-methyl-N-{[1S]-
-1-phenyl-2-(1-pyrrolidinyl)ethyl}acetamide hydrochloride;
(Z)-4-[2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-(3S)-3-hydroxypy-
rrolidinyl]ethyl]acetamido]-4-oxo-2-butenoic acid;
(Z)-4-[2-(2-Amino-4,5-d-
ichlorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]ethyl]acetamid-
o]-4-oxo-butanoic acid;
(Z)-4-[2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[-
(1S)-1-phenyl)-2-[1-pyrrolidinyl]ethyl]acetamido]-4-oxo-2-butenoic
acid; (E) Ethyl
4-[2-(2-amino-4,5-dichorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[-
1-pyrrolidinyl]ethyl]acetamido]-4-oxo-2-butenoate hydrochloride;
(Z)-4-[2-(2-Amino-4-trifluoromethylphenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[-
1-pyrrolidinyl]ethyl]acetamido]-4-oxo-2-butenoic acid;
(Z)-4-[2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]-et-
hyl]acetamido]-4-oxo-2-butenoic acid hemimaleate; 2-(N,N-Bisacetic
acid-2-amino-.alpha.,.alpha.,.alpha.,-trifluoro-4-tolyl)-N-methyl-N-[(1S)-
-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride;
3-[2-N-Methylsulfonamido)phenyl]-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidi-
nyl)-ethyl]acetamide hydrochloride;
2-(O-Butylacetate)phenyl-N-methyl-N-[(-
1S)-1-phenyl-2-[1-pyrrolidinyl]ethyl acetamide hydrochloride;
2-[Phenoxy-acetyl]methylamino(1-pyrrolidinyl)
ethyl]acetamide]hydrochlori- de;
2-[4-Trifluoromethylphenyl]-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-3-hydr-
oxy-pyrrolidinyl]ethyl}acetamide hydrochloride;
2-(2-Pyridyl)-N-methyl-N-{- [1
S]-1-phenyl-2-[1-(3S)-3-hydroxypyrrolidinyl]ethyl}-acetamide
dihydrochloride;
2-(5-Bromo-3-pyridyl)-N-methyl-N-[(1S)-1-phenyl-2-pyrrol- idinyl
ethyl]acetamide hydrochloride;
2-(5-Bromo-3-pyridyl)-N-methyl-N-{[1-
S]-1-phenyl-2-[1-(3S)-3-hydroxy-pyrrolidinyl]ethyl}acetamide
hydrochloride;
2-(9-Anthracenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidi-
nyl)ethyl}acetamide hydrochloride;
2-(2-Carboxyphenyl)-N-methyl-N-{[1
S]-1-phenyl-2-(1-pyrrolidinyldethyl}acetamide hydrochloride;
[2-(2-Phenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}acetamido-
]-2-oxo-glycine hydrochloride; Methyl
N-[2-(2-phenyl)-N-methyl-N-{[1S]-1-p-
henyl-2-(1-pyrrolidinyl)ethyl}-acetamido]-2-oxo-glycinate
hydrochloride; 2-(3,4-Dihydroxyphenyl)-N-methyl-N-{[1
S]-1-phenyl-2-(1-pyrrolidinyl)ethy- l}-acetamide hydrochloride;
2-(3,4-Dimethoxyphenyl)-N-methyl-N-{[1
S]-phenyl-2-(1-pyrrolidinyl)ethyl}-acetamide hydrochloride;
2-(2-Methanesulfonamidophenyl-N-methyl-N-[(1S)-1-(3-methanesulfonamidophe-
nyl-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride;
2-(2-Iso-butyramidophenyl)-N-methyl-N-[(1S)-1-(3-isobutyramido-phenyl)-2--
(1-pyrrolidinyl)ethyl]acetamide methanesulfonic acid salt;
4-[4-N-Methylsulfonamido-phenyl]-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethy-
l]acetamide hydrochloride;
2-(3,4-Dichlorocinnamyl)-N-methyl-N-[(1S)-1-phe-
nyl-2-(1-pyrrolidinyl)-ethyl]acetamide hydrochloride;
2-(2-Nitrocinnamyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)
ethyl]acetamide hydrochloride;
(R,S)-1-[2-(Methanesulfonylamino)-phenyl-N-
-methylacetamido]-1-(3-methoxy-phenyl)-2-(1-pyrrolidino)-ethane,
methanesulfonic acid salt;
(R,S)-1-[2-(Methanesulfonylamino)-phenyl-N-met-
hylacetamido]-1-(3-hydroxy-phenyl)-2-(1-pyrrolidino)ethane,
methanesulfonic acid salt;
2-(3-Indolyl)-N-methyl-N-[(1S)-1-phenyl-2-[(3S-
)-1-pyrrolidin-3-ol]ethyl]-acetamide hydrochloride;
2-(2-N-Benzyl-2-N-methylsulfamoyl-3,4-dimethoxyphenyl)-N-methyl-N-[(1S)-1-
-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride;
2-(N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-[(1R)-1-phenyl-2-(1-pyrr-
olidinyl)ethyl]acetamide methane sulfonate;
(R,S)-1-(4-Trifluoromethylphen-
yl-N-methylacetamido)-1-(3-methoxyphenyl)-2-(1-pyrrolidino)-ethane,
methanesulfonic acid salt;
(R,S)-1-(4-Trifluoromethylphenyl-N-methylaceta-
mido)-1-(3-hydroxyphenyl)-2-(1-pyrrolidino)-ethane, methanesulfonic
acid salt;
2-Fluorophenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]-a-
cetamide hydrochloride;
4-Fluorophenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrr-
olidinyl)ethyl]acetamide hydrochloride; and
(E)-4-[2-(2-Amino-4,5-dichloro-
phenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrrolidinyl]ethyl]acetamido]-4-ox-
o-2-butenoic acid hydrochloride.
22. A pharmaceutical composition comprising a compound of claim 20
in a pharmaceutically acceptable carrier.
23. A pharmaceutical composition comprising a compound of claim 21
in a pharmaceutically acceptable carrier.
24. A method of treating hyperalgesia in a patient comprising
administereing to said patient an effective amount of a compound of
claim 20.
25. A method of treating hyperalgesia in a patient comprising
administereing to said patient an effective amount of a compound of
claim 21.
26. A method of treating hyperalgesia in a patient comprising
administereing to said patient an effective amount of the
pharmaceutical composition of claim 22.
27. A method of treating hyperalgesia in a patient comprising
administereing to said patient an effective amount of the
pharmaceutical composition of claim 23.
28. A pharmaceutical composition comprising a compound of claim 20
and an antibiotic, antiviral, antifungal, anti-inflammatory agent,
or a mixture thereof in a pharmaceutically acceptable carrier.
29. A pharmaceutical composition comprising a compound of claim 21
and an antibiotic, antiviral, antifungal, anti-inflammatory agent,
or a mixture thereof in a pharmaceutically acceptable carrier.
30. A compound of the formula IVA or a pharmaceutically acceptable
salt thereof: 363wherein: n is 1 to 3; R.sub.1 and R.sub.2 are
independently CH.sub.3 or together form --(CH.sub.2).sub.m--,
--CH.sub.2CH(OR)(CH.sub.2- ).sub.2--,
--CH.sub.2CH(F)(CH.sub.2).sub.2--, --(CH.sub.2).sub.2O(CH.sub.2-
).sub.2-- or --(CH.sub.2).sub.2CH.dbd.CHCH.sub.2--; R is H, alkyl,
acyl or aroyl; R.sub.3 and R.sub.4 are independently H, OCH.sub.3,
alkyl or --O(CH.sub.2).sub.2--; each X.sub.9 is independently
selected from the group consisting of halogen, CF.sub.3, OH,
OCH.sub.3, SO.sub.2NH(CH.sub.2).sub.qCH.sub.3,
NH(CH.sub.2).sub.qCO.sub.2R',
NH(CH.sub.2).sub.q(CH.dbd.CH).sub.q(CH.sub.2).sub.qCO.sub.2R',
NH(CH.sub.2).sub.q(CH.ident.CH).sub.q(CH.sub.2).sub.qCO.sub.2R',
NHCO(CH.sub.2).sub.q(CH.dbd.CH).sub.q(CH.sub.2).sub.qCO.sub.2R',
and
NHCO(CH.sub.2).sub.q(CH.ident.CH).sub.q(CH.sub.2).sub.qCO.sub.2R';
R' is OH, lower alkyl, aryl ester or aryl amide; q is 0 to 20; and
y is 1 to 4.
31. A compound which is selected from the group consisting of
(Z)-4-[2-((.+-.)-trans-2-Amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl-
)-cyclohexyl]phenylaetamido)]-4-oxo-2-butenoic acid;
(Z)-4-[2-((.+-.)-trans-2-Amino-4-trifluoromethyl-N-methyl-N-[2-(1-pyrroli-
dinyl)-cyclohexyl]-phenylaetamido)]-4-oxo-2-butenoic acid;
(.+-.)-trans-2-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-pyridylacetamide
dihydrochloride;
(.+-.)-trans-3-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-
-5-bromo-pyridylacetamide hydrochloride;
(.+-.)-trans-3,5-Di-Trifluorometh-
yl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide
hydrochloride;
(.+-.)-trans-3-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-(-
trans-3-furyl)acetamide hydrochloride;
(.+-.)-trans-2-Methoxy-3-methylsulf-
amoyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide
hydrochloride;
(.+-.)-trans-3-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]in-
doleacetamide hydrochloride;
(.+-.)-trans-4-Fluoro-3-methylsulfamoyl-N-met-
hyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamide hydrochloride;
N-[1
S,2S-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-ph-
enylacetamido]glycine hydrochloride; and N-[1
R,2R-trans-4-Trifluoromethyl-
-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamido]glycine
hydrochloride.
32. A pharmaceutical composition comprising a compound of claim 30
in a pharmaceutically acceptable carrier.
33. A pharmaceutical composition comprising a compound of claim 31
in a pharmaceutically acceptable carrier.
34. A method of treating hyperalgesia in a patient comprising
administering to said patient an effective amount of a compound of
claim 30.
35. A method of treating hyperalgesia in a patient comprising
administering to said patient an effective amount of a compound of
claim 31.
36. A method of treating hyperalgesia in a patient comprising
administering to said patient an effective amount of the
pharmaceutical composition of claim 32.
37. A method of treating hyperalgesia in a patient comprising
administering to said patient an effective amount of the
pharmaceutical composition of claim 33.
38. A pharmaceutical composition comprising a compound of claim 30
and an antibiotic, antiviral, antifungal, anti-inflammatory agent,
or a mixture thereof in a pharmaceutically acceptable carrier.
39. A pharmaceutical composition comprising a compound of claim 31
and an antibiotic, antiviral, antifungal, anti-inflammatory agent,
or a mixture thereof in a pharmaceutically acceptable carrier.
Description
[0001] This application is a continuation-in-part of application
Ser. No. 09/478,482, filed Jan. 6, 2000, now allowed, which in turn
is a divisional of application Ser. No. 09/150,369, filed Sep. 9,
1998, now U.S. Pat. No. 6,303,611, which in turn is a
continuation-in-part of application Ser. No. 09/034,661 filed Mar.
3, 1998, now U.S. Pat. No. 5,945,443, which in turn is a divisional
of application Ser. No. 08/899,086 filed on Jul. 23, 1997, now U.S.
Pat. No. 5,744,458, which in turn is a divisional of application
Ser. No. 08/796,078, filed on Feb. 5, 1997, now U.S. Pat. No.
5,688,955, which in turn is a continuation-in-part of application
Ser. No. 08/612,680, filed on Mar. 8, 1996, now U.S. Pat. No.
5,646,151. The disclosures of each of the foregoing applications is
hereby incorporated herein by reference, in their entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to compounds, to processes of their
preparation, to pharmaceutical compositions containing them and to
their medical use as agonists at kappa opioid receptors.
[0004] 2. Reported Developments
[0005] Opium and its derivatives are potent analgesics that also
have other pharmacological effects, and exert their effects by
interacting with high-affinity receptors.
[0006] It has been shown by investigators that there are at least
three major opioid receptor types in the central nervous system
(hereinafter CNS) and in the periphery. These receptors, known as
mu (.mu.), delta (.delta.) and kappa (.kappa.), have distinct
pharmacological profiles, anatomical distributions and functions.
[See, for example: Wood, P. L., Neuropharmacology, 21, 487497,
1982; Simon, E. J., Med. Res. Rev., 11, 357-374, 1991; Lutz et al,
J. Recept. Res. 12, 267-286; and Mansour et al, Opioid I, ed. Herz,
A. (Springer, Berlin) pp. 79-106, 1993.] The .delta. receptors are
abundant in CNS and mediate analgesia, gastrointestinal motility
and various hormonal functions. The .mu. receptors bind
morphine-like drugs and mediate the opiate phenomena associated
with morphine, including analgesia, opiate dependence,
cardiovascular and respiratory functions, and several
neuroendocrine effects.
[0007] The .kappa. receptors have a wide distribution in CNS and
mediate a spectrum of functions including the modulation of
drinking, water balance, food intake, gut motility, temperature
control and various endocrine functions. They also produce
analgesia. [See, for example: Leander et al, J. Pharmacol. Exp.
Ther. 234, 463-469, 1985; Morley et al, Peptides 4, 797-800, 1983;
Manzanares et al, Neuroendocrinology 52, 200-205, 1990; and Iyengar
et al, J. Pharmacol. Exp. Ther, 238, 429-436, 1986.]
[0008] Most clinically used opioid analgesics such as morphine and
codeine act as J receptor agonists. These opioids have well-known,
undesirable and potentially dangerous dependence forming side
effects. Compounds which are .kappa.-receptor agonists act as
analgesics through interaction with .kappa. opioid receptors. The
advantage of these agonists over the classical .mu. receptor
agonists, such as morphine, lies in their ability to cause
analgesia while being devoid of morphine-like behavioral effects
and addiction liability.
[0009] A large number of classes of compounds which act as agonists
at .kappa. opioid receptors have been described in the art
including the following illustrative classes of compounds.
[0010] U.S. Pat. No. 4,065,573 discloses
4-amino-4-phenylcyclohexane ketal compounds having analgesic
activity.
[0011] U.S. Pat. No. 4,212,878 discloses phenylacetamide
derivatives having analgesic properties and reduced physical
dependence liability properties, relative to morphine and
methadone.
[0012] U.S. Pat. No. 4,145,435 discloses
N-(2-amino-cycloaliphatic)-phenyl- acetamide compounds having
analgesic activity and narcotic antagonist activity.
[0013] U.S. Pat. No. 4,098,904 discloses
N-(2-amino-cycloaliphatic)-benzoa- mides and naphthamides useful
for relieving pain.
[0014] U.S. Pat. No. 4,359,476 discloses substituted
cycloalkane-amides useful as analgesic and having low abuse
liability.
[0015] U.S. Pat. No. 4,438,130 discloses 1-oxa-, aza- and
thia-spirocyclic compounds having analgesic activity, low physical
dependence and abuse liability properties and little dysphoric
inducing properties.
[0016] U.S. Pat. No. 4,663,343 discloses substituted
naphthalenyloxy-1,2-diaminocyclohexyl amides as analgesics.
[0017] U.S. Pat. No. 4,906,655 discloses 1,2-cyclohexylaminoaryl
amides having high kappa-opioid affinity, selectivity and potency
and useful as analgesics, diuretics, anti-inflammatory and
psychotherapeutic agents.
SUMMARY OF THE INVENTION
[0018] Compounds having kappa opioid agonist activity, compositions
containing them and method of using them as analgesics are
provided.
[0019] In its compound aspect, the present invention provides a
compound of the formulae I, II, IIA, III, IIIA, IIIB, IIIB-i, IV
and IVA, or a pharmaceutically acceptable salt thereof.
[0020] The compounds of formula (I) have the following structure:
3
[0021] wherein
[0022] n is an integer from 1 to 3, with 1 being preferred;
[0023] R.sub.1 and R.sub.2 are together --(CH.sub.2).sub.m-- where
m is an integer from 4 to 8, with 4 being preferred;
--CH.sub.2CH(OH)(CH.sub.2).s- ub.2--;
--CH.sub.2CH(F)(CH.sub.2).sub.2--; --(CH.sub.2).sub.2O(CH.sub.2).s-
ub.2--; or --(CH.sub.2).sub.2CH.dbd.CHCH.sub.2--;
[0024] Ar is unsubstituted or mono- or di-substituted phenyl
wherein said substituents are selected from the group consisting of
halogen, OCH.sub.3, SO.sub.2CH.sub.3, CF.sub.3, amino, alkyl, and
3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl
methyl; or 9-fluorene;
[0025] Z is --P(O)(OBn).sub.2; --P(O)(OH).sub.2;
--(CH.sub.2).sub.pC(O)NHO- H; --(CH.sub.2).sub.pCO.sub.2H;
--SO.sub.2CH.sub.3; --SO.sub.2NH.sub.2;
--CO(CH.sub.2).sub.pCH(NH.sub.2)(CO.sub.2H);
--COCH(NH.sub.2)(CH.sub.2).s- ub.pCO.sub.2H; --CO.sub.2CH.sub.3;
--CONH.sub.2; --(CH.sub.2).sub.pO(CH.su- b.2).sub.pCO.sub.2H;
--(CH.sub.2).sub.pO(CH.sub.2).sub.pCONHOH;
--(CH.sub.2).sub.pNHSO.sub.2CH.sub.3;
--(CH.sub.2).sub.pNHC(S)NHCH(CO.sub- .2H)(CH.sub.2).sub.pCO.sub.2H;
--(CH.sub.2).sub.pSO.sub.3H; or 4
[0026] wherein
[0027] p is an integer from 0 to 20;
[0028] R.sub.3 is --H or -Ac;
[0029] X.sub.2 is --CO.sub.2H; --NHSO.sub.2CH.sub.3;
NHP(O)(OBn).sub.2; NHP(O)(OH).sub.2; --OP(O)(OBn).sub.2; or
OP(O)(OH).sub.2;
[0030] X and Y are independently --CH.sub.2NHSO.sub.2CH.sub.3,
--CH.sub.2NHP(O)(OBn).sub.2, --CH.sub.2NHP(O)(OH).sub.2,
--CH.sub.2OP(O)(OBn).sub.2, --CH.sub.2OP(O)(OH).sub.2,
--(CH.sub.2).sub.qO(CH.sub.2).sub.qCO.sub.2H,
--(CH.sub.2).sub.qO(CH.sub.- 2).sub.qSO.sub.3H,
--(CH.sub.2).sub.qO(CH.sub.2).sub.2CHNHOH,
--CH.sub.2NHC(S)NHCH(CO.sub.2H)(CH.sub.2).sub.qCO.sub.2H or 5
[0031] wherein
[0032] q is an integer from 1 to 20;
[0033] r is an integer from 1 to 20
[0034] R.sub.4 is --H or -Ac
[0035] X.sub.3 is --CO.sub.2H; --NHSO.sub.2CH.sub.3;
--NHP(O)(OBn).sub.2; --NHP(O)(OH).sub.2; --OP(O)(OBn).sub.2; or
--OP(O)(OH).sub.2.
[0036] The compounds of formula II have the following structure:
6
[0037] wherein
[0038] n is an integer from 1 to 3, with 1 being preferred;
[0039] R.sub.1 and R.sub.2 are together --(CH.sub.2).sub.m--, where
m is an integer from 4 to 8, with 4 being preferred;
--CH.sub.2CH(OH)(CH.sub.2- ).sub.2--;
CH.sub.2CH(F)(CH.sub.2).sub.2--; --(CH.sub.2).sub.2O(CH.sub.2).-
sub.2--; or --(CH.sub.2).sub.2CH.dbd.CHCH.sub.2--;
[0040] Ar is unsubstituted or mono- or di-substituted phenyl
wherein said substituents are selected from the group consisting of
halogen, OCH.sub.3, SO.sub.2CH.sub.3, CF.sub.3, amino, alkyl, and
3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl
methyl; or 9-fluorene;
[0041] X.sub.4 and X.sub.5 are independently --OP(O)(OBn).sub.2;
--OP(O)(OH); --CO.sub.2H; --SO.sub.3H;
--O(CH.sub.2).sub.sCO.sub.2H; --NHSO.sub.2CH.sub.3;
--CONH(CH.sub.2).sub.sCO.sub.2H; or
--SO.sub.2NH(CH.sub.2).sub.sCO.sub.2H; wherein s is an integer from
1 to 5
[0042] or X.sub.4 and X.sub.5 are independently 7
[0043] wherein
[0044] t is an integer from 1 to 20
[0045] R.sub.5 is --H or -Ac
[0046] X.sub.6 is --CO.sub.2H; --NHSO.sub.2CH.sub.3;
--NHP(O)(OBn).sub.2; --NHP(O)(OH).sub.2; --OP(O)(OBn).sub.2; or
--OP(O)(OH).sub.2.
[0047] The compounds of formula IIA have the following structure:
8
[0048] wherein
[0049] n is an integer from 1 to 3, with 1 being preferred;
[0050] R.sub.1 and R.sub.2 are together (CH.sub.2).sub.m, where m
is an integer from 4 to 8, with 4 being preferred;
--CH.sub.2CH(OR)(CH.sub.2).s- ub.2-- wherein R is H, alkyl, acyl or
aroyl; CH.sub.2CH(F)(CH.sub.2).sub.2- --;
--(CH.sub.2).sub.2(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2CH.dbd.CHCH- .sub.2--;
[0051] Ar is unsubstituted or mono- or di-substituted phenyl;
wherein said substituents are selected from the group consisting of
halogen, OCH.sub.3, OH, SO.sub.2CH.sub.3, CF.sub.3, NH.sub.2,
alkyl, CN, unsubstituted and substituted sulfamoyl groups;
[0052] Ar may also be substituted with
--NH(CH.sub.2).sub.uCO.sub.2R';
--NH(CH.sub.2).sub.u(CH.dbd.CH).sub.u(CH.sub.2)CO.sub.2R';
--NHCO(CH.sub.2).sub.u(CH.dbd.CH).sub.u(CH.sub.2).sub.uCO.sub.2R';
--NHP(O)(OBn).sub.2; --NHP(O)(OR').sub.2;
--(CH.sub.2).sub.uNHSO.sub.2CH.- sub.3;
--(CH.sub.2).sub.uNHC(S)NHCH(CO.sub.2R')(CH.sub.2).sub.uCO.sub.2R';
--CONHOH; or --(CH.sub.2).sub.uCONHOH;
[0053] wherein
[0054] u is an integer from 0 to 5;
[0055] R' is H or lower alkyl;
[0056] or Ar is 9
[0057] R.sub.6 is --H or -Ac
[0058] X.sub.6 is --CO.sub.2H; --NHSO.sub.2CH.sub.3;
--NHP(O)(OBn).sub.2; --NHP(O)(OH).sub.2; --OP(O)(OBN).sub.2; or
--OP(O)(OH).sub.2;
[0059] R.sub.7 is --NH(CH.sub.2).sub.vCO.sub.2H;
--NH(CH.sub.2).sub.vCH(NH- .sub.2)(CO.sub.2H);
--NHCH(CO.sub.2H)(CH.sub.2).sub.vNH.sub.2;
--NH(CH.sub.2).sub.vSO.sub.3H; --NH(CH.sub.2).sub.vPO.sub.3H.sub.2;
--NH(CH.sub.2).sub.vNHC(NH)NH.sub.2; or
--NHCH(CO.sub.2H)(CH.sub.2).sub.v- CO.sub.2H; and
[0060] v is an integer from 1 to 20.
[0061] X.sub.4 and X.sub.5 are independently H; halogen; OH;
OCH.sub.3; CF.sub.3; NO.sub.2; NH.sub.2; amino substituted with
acyl, carbamate, alkyl or aryl sulfonates; COR" where R" is OH,
amino, alkoxy, aryloxy or heteroaryloxy.
[0062] Compounds of formula (IIA) have at least two chiral centers
and may exist in more than one diastereoisomeric form. The
invention includes within its scope all enantiomers, and
diastereosomers and the mixtures thereof.
[0063] The compounds of formula III have the following structure:
10
[0064] wherein
[0065] n is an integer from 1 to 3, with 1 being preferred;
[0066] R.sub.1 and R.sub.2 are together --(CH.sub.2).sub.m--, where
m is an integer from 4 to 8, with 4 being preferred;
--CH.sub.2CH(OH)(CH.sub.2- ).sub.2--;
CH.sub.2CH(F)(CH.sub.2).sub.2--; --(CH.sub.2).sub.2O(CH.sub.2).-
sub.2--; or --(CH.sub.2).sub.2CH.dbd.CHCH.sub.2--;
[0067] Ar is unsubstituted or mono- or di-substituted phenyl
wherein said substituents are selected from the group consisting of
halogen, OCH.sub.3, SO.sub.2CH.sub.3, CF.sub.3, amino, alkyl, and
3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl
methyl; or 9-fluorene;
[0068] X.sub.7 is --NHSO.sub.2CH.sub.3; --NHP(O)(OBn).sub.2;
--NHP(O)(OH).sub.2; --(CH.sub.2).sub.uNHSO.sub.2CH.sub.3;
--(CH.sub.2).sub.uNHC(S)NHCH(CO.sub.2H)(CH.sub.2).sub.uCO.sub.2H;
--CONHOH; or --(CH.sub.2).sub.uCONHOH; wherein u is an integer from
1 to 5
[0069] or X.sub.7 is 11
[0070] R.sub.6 is --H or -Ac
[0071] X.sub.8 is --CO.sub.2H; --NHSO.sub.2CH.sub.3;
--NHP(O)(OBn).sub.2; --NHP(O)(OH).sub.2;
[0072] --OP(O)(OBn).sub.2; or --OP(O)(OH).sub.2;
[0073] R.sub.7 is --NH(CH.sub.2).sub.vCO.sub.2H;
--NH(CH.sub.2).sub.vCH(NH- .sub.2)(CO.sub.2H);
--NHCH(CO.sub.2H)(CH.sub.2).sub.vNH.sub.2;
--NH(CH.sub.2).sub.vSO.sub.3H; --NH(CH.sub.2).sub.vPO.sub.3H.sub.2;
--NH(CH.sub.2).sub.vNHC(NH)NH.sub.2;
--NHCH(CO.sub.2H)(CH.sub.2).sub.vCO.- sub.2H; and
[0074] v is an integer from 1 to 20
[0075] The compounds of formula IIIA have the following structure:
12
[0076] wherein
[0077] n is an integer from 1 to 3, with 1 being preferred;
[0078] R.sub.1 and R.sub.2 are together --(CH.sub.2).sub.m--, where
m is an integer from 4 to 8, with 4 being preferred;
--CH.sub.2CH(OR)(CH.sub.2- ).sub.2--, wherein R is H, alkyl, acyl
or aroyl; CH.sub.2CH(F)(CH.sub.2).s- ub.2--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--; or --(CH.sub.2).sub.2CH.dbd-
.CHCH.sub.2;
[0079] Ar is unsubstituted or mono- or di-substituted phenyl;
wherein said substituents are selected from the group consisting of
halogen, OCH.sub.3, OH, SO.sub.2CH.sub.3, CF.sub.3, NH.sub.2,
alkyl, CN, unsubstituted and substituted sulfamoyl groups;
[0080] Ar may also be substituted with
--NH(CH.sub.2).sub.uCO.sub.2R';
--NH(CH.sub.2).sub.u(CH.dbd.CH).sub.u(CH.sub.2)CO.sub.2R';
--NHCO(CH.sub.2).sub.u(CH.dbd.CH).sub.u(CH.sub.2).sub.uCO.sub.2R;
--NHP(O)(OBn) 2; --NHP(O)(OR).sub.2;
--(CH.sub.2).sub.uNHSO.sub.2CH.sub.3- ;
--(CH.sub.2).sub.uNHC(S)NHCH(CO.sub.2R)(CH.sub.2).sub.uCO.sub.2R';
--CONHOH; or --(CH.sub.2).sub.uCONHOH;
[0081] wherein
[0082] u is an integer from 0 to 5;
[0083] R' is H or lower alkyl;
[0084] or Ar is 13
[0085] R.sub.6 is --H or -Ac
[0086] X.sub.8 is --CO.sub.2H; --NHSO.sub.2CH.sub.3;
--NHP(O)(OBn).sub.2; --NHP(O)(OH).sub.2; --OP(O)(OBn).sub.2; or
--OP(O)(OH).sub.2;
[0087] R.sub.7 is --NH(CH.sub.2).sub.vCO.sub.2H;
--NH(CH.sub.2).sub.vCH(NH- .sub.2)(CO.sub.2H);
--NHCH(CO.sub.2H)(CH.sub.2).sub.vNH.sub.2;
--NH(CH.sub.2).sub.vSO.sub.3H; --NH(CH.sub.2).sub.vPO.sub.3H.sub.2;
--NH(CH.sub.2).sub.vNHC(NH)NH.sub.2;
--NHCH(CO.sub.2H)(CH.sub.2).sub.vCO.- sub.2H; and
[0088] v is an integer from 1 to 20;
[0089] X.sub.7 is H; halogen; OH; OCH.sub.3; CF.sub.3; NO.sub.2;
NH.sub.2; amino substituted with acyl, carbamate, alkyl or aryl
sulfonates; COR" where R" is OH, amino, alkoxy, aryloxy or
heteroaryloxy.
[0090] Compounds of formula (IIIA) have at least one chiral center
and may exist in more than one diastereoisomeric form. The
invention includes within its scope all enantiomers, and
diastereosomers and the mixtures thereof.
[0091] The compounds of formula IIIB have the following structure:
14
[0092] wherein:
[0093] n is an integer from 1 to 3;
[0094] R.sub.1 and R.sub.2 are together alkylene of about 4 to
about 8 carbons, optionally substituted with a group R', where R'
is selected from --OH, halogen, --NR.sub.aR.sub.b, in which R.sub.a
and R.sub.b are independently selected from hydrogen,
--C(.dbd.O)R.sub.c, --SO.sub.2R.sub.d and
--C(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.e, in which R.sub.c and
R.sub.d are independently selected from alkyl, aryl and heteroaryl,
R.sub.e is hydrogen or alkyl and m is an integer from 1 to 3;
[0095] Ar is unsubstituted phenyl or mono-, di-, tri-, or
tetra-substituted phenyl, wherein said substituents are
independently selected from halogen; alkyl; alkoxy; aryloxy;
aralkyloxy; alkylene dioxide; --OH; --SO.sub.2R.sub.f in which
R.sub.f is alkyl or aryl; --CN; haloalkyl; --NR.sub.gR.sub.h, in
which R.sub.g and R.sub.h are independently selected from hydrogen,
alkyl, --C(.dbd.O)R.sub.f, --C(.dbd.O)--N(R.sub.e).sub.2,
--S(O).sub.2R.sub.f, and --(CH.sub.2).sub.y--CO.sub.2R.sub.e in
which y is an integer from 1 to 3; --S(O).sub.2N(R.sub.i)(R.sub.j),
in which R.sub.i and R.sub.j are each independently selected from
hydrogen, alkyl optionally substituted with --CO.sub.2R.sub.e, aryl
and aralkyl; or R.sub.i and R.sub.j together form
--(CH.sub.2).sub.2X(CH.sub.2).sub.2--, where X is a direct bond,
--CH.sub.2--, --NR.sub.e--, S or O;
[0096] R is hydrogen, halogen, --OH, alkoxy, or --NR.sub.kR.sub.l,
where R.sub.k and R.sub.l are independently selected from hydrogen
and alkyl.
[0097] Compounds of formula (IIIB) have at least one chiral center
and may exist in more than one diastereoisomeric form. The
invention includes within its scope all enantiomers, and
diastereosomers and the mixtures thereof.
[0098] The compounds of formula IIIB-i have the following
structure. 15
[0099] wherein:
[0100] x is an integer from 0 to 4;
[0101] R" is hydrogen, fluoro, --OH, --NHC(.dbd.O)R.sub.c,
--NHSO.sub.2R.sub.d and
--NHC(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.e, in which R.sub.c and
R.sub.d are independently selected from alkyl, aryl and heteroaryl,
R.sub.e is hydrogen or alkyl and m is an integer from 1 to 3
[0102] R.sub.3 is independently selected from halogen; alkyl;
alkoxy; aryloxy; aralkyloxy; alkylene dioxide; --OH;
--SO.sub.2R.sub.f in which R.sub.f is alkyl or aryl; --CN;
haloalkyl; --NR.sub.gR.sub.h, in which R.sub.g and R.sub.h are
independently selected from hydrogen, alkyl, --C(.dbd.O)R.sub.f,
--C(.dbd.O)--N(R.sub.e).sub.2, --S(O).sub.2R.sub.f in which R.sub.f
is alkyl or aryl, and --(CH.sub.2).sub.y--CO.sub.2R.sub.e in which
y is an integer from 1 to 3; --S(O).sub.2N(R.sub.i)(R.sub.j), in
which R.sub.i and R.sub.j are each independently selected from
hydrogen, alkyl optionally substituted with --CO.sub.2R.sub.e, aryl
and aralkyl; or R.sub.i and R.sub.j together form
--(CH.sub.2).sub.2X(CH.sub.2).sub.2--, where X is a direct bond,
--CH.sub.2--, --NR.sub.e--, S or O;
[0103] R is hydrogen, halogen, --OH, alkoxy, or --NR.sub.kR.sub.l,
where R.sub.k and R.sub.l are independently selected from hydrogen
and alkyl.
[0104] Compounds of formula (IIIB-i) have at least one chiral
center and may exist in more than one diastereoisomeric form. The
invention includes within its scope all enantiomers, and
diastereosomers and the mixtures thereof.
[0105] The compounds of formula IV have the following structure:
16
[0106] wherein
[0107] n is an integer from 1 to 3, with 1 being preferred;
[0108] R.sub.1 and R.sub.2 are together --(CH.sub.2).sub.m--, where
m is an integer from 4 to 8, with 4 being preferred;
--CH.sub.2CH(OH)(CH.sub.2- ).sub.2--;
CH.sub.2CH(F)(CH.sub.2).sub.2--; --(CH.sub.2).sub.2O(CH.sub.2).-
sub.2--; or --(CH.sub.2).sub.2CH.dbd.CHCH.sub.2--;
[0109] R.sub.3 and R.sub.4 are independently H; OCH.sub.3; alkyl;
or C--O(CH.sub.2).sub.2;
[0110] X.sub.9 represents 1 to 4 substituents selected from the
group consisting of -halogen; --CF.sub.3; --OCH.sub.3;
--SO.sub.2NH(CH.sub.2).s- ub.qCO.sub.2H;
--CONH(CH.sub.2).sub.qCO.sub.2H; --NH.sub.2; --NHSO.sub.2CH.sub.3;
--NHP(O)(OBn).sub.2; --NHP(O)(OH).sub.2; --SO.sub.2CH.sub.3;
--OP(O)(OBN).sub.2; --OP(O)(OH).sub.2; --CO.sub.2H;
--O(CH.sub.2).sub.qCO.sub.2H; --O(CH.sub.2).sub.qSO.sub.3H;
--O(CH.sub.2).sub.qOPO.sub.3H.sub.2; wherein q is 1 to 20;
[0111] or X.sub.9 is 17
[0112] wherein
[0113] t is an integer from 1 to 20
[0114] R.sub.5 is --H or -Ac
[0115] X.sub.6 is --CO.sub.2H; --NHSO.sub.2CH.sub.3;
--NHP(O)(OBn).sub.2; --NHP(O)(OH).sub.2; --OP(O)(OBn).sub.2; or
--OP(O)(OH).sub.2.
[0116] Compounds of formula (IV) have at least one chiral center
and may exist in more than one diastereoisomeric form. The
invention includes within its scope all enantiomers, and
diastereosomers and the mixtures thereof.
[0117] The compunds of formula IVA have the following structure:
18
[0118] wherein
[0119] n is an integer from 1 to 3, with 1 being preferred;
[0120] R.sub.1 and R.sub.2 are together --(CH.sub.2).sub.m--, where
m is an integer from 4 to 8, with 4 being preferred;
--CH.sub.2CH(OR)(CH.sub.2- ).sub.2--; wherein R is H, alkyl, acyl,
or aroyl; CH.sub.2CH(F)(CH.sub.2).- sub.2--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--; or --(CH.sub.2).sub.2CH.db-
d.CHCH.sub.2--;
[0121] R.sub.3 and R.sub.4 are independently H; OCH.sub.3; alkyl;
or --O(CH.sub.2).sub.2;
[0122] X.sub.9 represents 1 to 4 substituents selected from the
groups consisting of -halogen; --CF.sub.3; OH, --OCH.sub.3;
--SO.sub.2NH(CH.sub.2).sub.qCH.sub.3; --NH(CH.sub.2).sub.qCOR';
--NH(CH.sub.2).sub.q(CH.dbd.CH).sub.q(CH.sub.2).sub.qCO.sub.2R';
--NH(CH).sub.q(CH.ident.CH).sub.q(CH).sub.qCO.sub.2R;
--NHCO(CH.sub.2).sub.q(CH.dbd.CH).sub.q(CH.sub.2).sub.qCO.sub.2R;
and --NHCO(CH).sub.q(CH.dbd.CH).sub.q(CH).sub.qCO.sub.2R'
[0123] wherein
[0124] q is an integer from 0 to 20
[0125] R' is OH, lower alkyl, aryl ester or aryl amide.
[0126] Compounds of formula (IVA) have at least one chiral center
and may exist in more than one diastereoisomeric form. The
invention includes within its scope all enantiomers, and
diastereosomers and the mixtures thereof.
[0127] The meaning of the terms used in the specification and the
claims, unless otherwise denoted, are as follows.
[0128] The term "alkyl" as used herein alone or as part of another
group, denotes optionally substituted, straight and branched chain
saturated hydrocarbon groups, preferably having 1 to 12 carbons in
the normal chain, most preferably lower alkyl groups. Exemplary
unsubstituted alkyl groups include methyl, ethyl, propyl,
isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl,
4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl,
undecyl, dodecyl and the like. Exemplary substituents include one
or more of the following groups: halo, alkoxy, arylalkyloxy (e.g.,
benzyloxy), alkylthio, alkenyl, alkynyl, aryl, cycloalkyl,
cycloalkenyl, hydroxy, carboxyl (--COOH), amino, alkylamino,
dialkylamino, formyl, alkylcarbonyloxy, alkylcarbonyl, heterocyclo,
aryloxy, hydroxy or thiol (--SH).
[0129] The term "lower alkyl" as used herein denotes such
optionally substituted groups as described above for alkyl having 1
to 4 carbon atoms in the normal chain.
[0130] The terms "ar" or "aryl" as used herein or as part of
another group, denote optionally substituted, homocyclic aromatic
groups, preferably containing 1 or 2 rings and 6 to 12 ring
carbons. Exemplary unsubstituted groups include phenyl, biphenyl
and naphthyl. Exemplary substituents include one or more,
preferably three or fewer, nitro groups, alkyl groups as described
above, and/or one or more groups described above as alkyl
substituents. Preferred aryl groups are unsubstituted aryl and
hydroxyaryl.
[0131] The term "aralkyl" as used herein alone or as part of
another group, denotes an aryl-alkyl-group wherein aryl and alkyl
are as described previously. Exemplary aralkyl groups include
benzyl, phenethyl and naphthylmethyl.
[0132] The terms "heterocyclo" or "heterocyclic" as used herein
alone or as part of another group, denote optionally substituted
fully saturated or unsaturated, aromatic or non-aromatic cyclic
groups having at least one heteroatom in at least one ring,
preferably monocyclic or bicyclic groups having 5 or 6 atoms in
each ring. Aromatic heterocyclo or heterocyclic groups are also
referred to herein as "heteroaryl" groups. The heterocyclo group
may, for example, have 1 or 2 oxygen atoms, 1 or 2 sulfur atoms,
and/or 1 to 4 nitrogen atoms in the ring. Each heterocyclo group
may be bonded through any carbon or heteroatom off the ring system.
Preferred groups include those of the following formula, which may
be bonded through any atom of the ring system: 19
[0133] wherein r is 0 or 1 and T is --O--, --S--, --N--R.sup.8 or
--CH--R.sup.8 where R.sup.8 is hydrogen, alkyl, aryl or arylalkyl.
Exemplary heterocyclo groups include the following: thienyl, furyl,
pyrrolyl, pyridyl, imidazolyl, pyrrolidinyl, piperidinyl, azepinyl,
indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl,
benzoxazolyl, benzimidazolyl, morpholinyl, piperazinyl,
4-alkylpiperazinyl, 4-alkylpiperidinyl, 3-alkpyrrolidinyl,
oxazolyl, pyrazolyl, thiophenyl, pyridazinyl, thiazolyl, triazoyl,
pyrimidinyl, 1,4-dioxanyl, benzoxadiazolyl, and benzofurazanyl.
Exemplary substituents include one or more alkyl groups as
described above and/or one or more groups described above as alkyl
substituents.
[0134] The terms "halogen" or "halo" as used herein alone or as
part of another group, denote chlorine, bromine, fluorine and
iodine.
[0135] The term "acyl", as used herein alone or as part of another
group, denotes the moiety formed by removal of the hydroxyl group
from the group --COOH of an organic carboxylic acid. Exemplary
groups include alkylcarbonyl, arylcarbonyl, or carbocyclo- or
heterocyclocarbonyl. The term "acyloxy", as used herein alone or as
part of another group denotes an acyl group as described above
bonded through an oxygen linkage (--O--).
[0136] The term "alkoxy", as used herein, alone or as part of
another group, denotes an alkyl-O group wherein alkyl is as
described previously. Exemplary alkoxy groups include methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, pentoxy and heptoxy.
[0137] The term "aryloxy", as used herein, alone or as part of
another group, denotes an aryl-O group wherein aryl is as described
previously. Exemplary aryloxy groups include phenoxy and
naphthoxy.
[0138] The term "aralkyloxy", as used herein, alone or as part of
another group, denotes an aralkyl-O group wherein aralkyl is as
described previously. An exemplary aralkyloxy group is
benzyloxy.
[0139] The term "alkylene", as used herein, alone or as part of
another group, denotes a straight or branched bivalent hydrocarbon
chain group having from about 1 to 8 carbons. Exemplary alkylene
groups include methylene (--CH.sub.2--), ethylene
(--CH.sub.2CH.sub.2--), propylene (--CH.sub.2CH.sub.2CH.sub.2--)
and butylene (--CH.sub.2CH.sub.2CH.sub.2CH- .sub.2--).
[0140] The term "alkylene dioxide", as used herein, alone or as
part of another group, denotes a --O-alkylene-O-- group wherein
alkylene is as described previously. Exemplary alkylene dioxide
groups include methylene dioxide (--O--CH.sub.2--O--) and ethylene
dioxide (--O--CH.sub.2CH.sub.2-- -O--).
[0141] In the formulas described herein, it is intended that when
any symbol appears more than once in a particular formula or
substituent, its meaning in each instance is independent of the
other.
DETAILED DESCRIPTION OF THE INVENTION
[0142] Peripherally-acting .kappa. agonists can be prepared by the
attachment of polar groups to non-peptide .kappa. opioid receptor
selective agonists, such as the arylacetamides. In designing the
peripherally-acting ligands, the introduction of the polar groups
may result in either retention or enhancement of antinociceptive
potency and selectivity and also may increase the polarity of the
ligand sufficient to reduce or eliminate CNS penetration across the
blood-brain barrier (BBB). Thus, the identity and the positioning
of the polar group(s) are important.
[0143] Using the prototypic arylacetamide, U50,488, as an example,
the arylacetamide pharmacophore can be divided into three regions:
the aromatic region, the central region, and the amine region. All
three regions represent potential positions for the attachment of
polar groups. 20
[0144] Compounds of formula (I) of the present invention are made
as follows.
[0145] A series of novel compounds were made based on the class of
arylacetamides reported by Glaxo (J. Med. Chem. 1993, 36, 2075).
Specifcally, compound 1 can be deprotected to yield intermediate 2,
which can be derivatized by the attachment of a variety of polar
groups (Scheme 1). 21
[0146] The 3'-substituted series can be prepared via Scheme 2. The
reduction of the Schiff base intermediate formed during the
cyclization to 6 is expected to be stereoselective due to the
directing effect of the neighboring hydroxymethyl group. Both
intermediates 11 and 12 can be derivatized to confer peripheral
selectivity.
[0147] The 5'-substituted series can be prepared via Schemes 3 and
4. Starting from N-t-Boc-O-MEM-D-serine, the 5'-(S) series can be
prepared, and starting from from N-t-Boc-O-MEM-L-serine allows the
preparation of the 5'-(R) series. 22
[0148] wherein Ar, R.sub.1, R.sub.2, and n are defined in formula
I. 23
[0149] wherein Ar.sub.1, R.sub.1, R.sub.2 and n are as defined in
formula I. 24
[0150] wherein Ar.sub.1, R.sub.1, R.sub.2 and n are as defined in
formula I. 25
[0151] wherein Ar, R.sub.1, R.sub.2 and n are defined in formula
I.
[0152] Using Schemes 1-4 the following example compounds are
made.
[0153] Intermediate 3 can be treated with t-butyl bromoacetate and
deprotected to produce
{4-[1-(3,4-Dichlorophenyl)acetyl-2R-(1-pyrrolidiny-
l)-methyl]piperazinyl}acetic acid (26).
[0154] Intermediate 3 can be reacted with methane sulfonyl chloride
to produce
[1-(3,4-Dichlorophenyl)acetyl-4-methanesulfonyl-2R-(1-pyrrolidiny-
l)methyl]piperazine (27).
[0155] Intermediate 3 can be coupled to N-t-Boc-L-aspartic
acid-b-benzyl ester and deprotected to produce [4-S-Aspartic
acid-.alpha.-amido-1-(3,4--
dichlorophenyl)acetyl-2R-(1-pyrrolidinyl)methyl]piperazine
(28).
[0156] Intermediate 11 can be treated with t-butyl bromoacetate and
deprotected to produce Methyl-[2R-(O-2-acetic
acid)hydroxymethyl-4-(3,4-d-
ichlorophenyl)acetyl-3R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate
(29).
[0157] Intermediate 11 can be coupled to to N-t-Boc-L-aspartic
acid-b-benzyl ester and deprotected to produce
Methyl-[2R-(O-S-aspartic
acid-.alpha.-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-3R-(1-pyrr-
olidinyl)methyl]-1-piperazinecarboxylate (30).
[0158] Intermediate 12 can be treated with methanesulfonyl chloride
to produce
Methyl-[4-(3,4-dichlorophenyl)acetyl-2R-(N-methanesulfonamido)ami-
nomethyl-3R-(1-pyrrolidinyl)methyl)-1-piperazinecarboxylate
(31).
[0159] Intermediate 12 can be coupled to 2S-isothiocyanato-succinic
acid-dibenzyl ester and deprotected to yield
Methyl-{4-[3,4-dichloropheny-
l]acetyl-3R-[1-pyrrolidinyl]methyl-2R-[N-(succinic
acid-2S-thioureido)]ami- nomethyl}-1-piperazinecarboxylate
(32).
[0160] Intermediate 21 can be treated with t-butyl bromoacetate and
deprotected to produce Methyl-[2S-(O-2-acetic
acid)hydroxymethyl-4-(3,4-d-
ichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate
(33).
[0161] Intermediate 21 can be coupled to to N-t-Boc-L-aspartic
acid-b-benzyl ester and deprotected to produce
Methyl-[2S-(O-S-aspartic
acid-.alpha.-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrr-
olidinyl)methyl]-1-piperazinecarboxylate (34).
[0162] Intermediate 22 can be treated with methanesulfonyl chloride
to produce
Methyl-[4-(3,4-dichlorophenyl)acetyl-2S-(N-methanesulfonamido)ami-
nomethyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate
(35).
[0163] Intermediate 22 can be coupled to 2S-isothiocyanato-succinic
acid-dibenzyl ester and deprotected to yield
Methyl-{4-[3,4-dichloropheny-
l]acetyl-5R-[1-pyrrolidinyl]methyl-2S-[N-(succinic
acid-2S-thioureido)]ami- nomethyl}-1-piperazinecarboxylate
(36).
[0164] The 2R isomers of 33-34 and 35-36 can be prepared from
intermediates 24 and 25, respectively to produce
[0165] Methyl-[2R-(O-2-acetic
acid)hydroxymethyl-4-(3,4-dichlorophenyl)ace-
tyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (37).
[0166] Methyl-[2R-(O-S-aspartic
acid-a-acetyl)hydroxymethyl-4-(3,4-dichlor-
ophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate
(38).
[0167]
Methyl-[4-(3,4-dichlorophenyl)acetyl-2R-(N-methanesulfonamido)amino-
methyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (39).
[0168]
Methyl-{4-[3,4-dichlorophenyl]acetyl-5R-[1-pyrrolidinyl]methyl-2R-[-
N-(succinic
acid-2S-thioureido)]aminomethyl}-1-piperazinecarboxylate (40).
[0169] The corresponding structural formulas are shown hereunder.
2627282930
[0170] Compound of formula II of the present invention are made by
peripheralization by substitutions of the benzo portion of the
tetrahydronaphthyl ring of DuPont series of compounds with polar
groups. 31
[0171] Starting material or precursors of the starting material are
commercially available and thus allows regiospecific substitutions
of the tetrahydronaphthyl ring (Scheme 5). While
5-hydroxytetralone, 6-hydroxytetralone, 7-hydroxytetralone, and
7-aminotetralone derivatives are readily available,
5-aminotetralone could be prepared from 5-hydroxytetralone (J. Org.
Chem. 1972, 37, 3570).
[0172] The tetralone derivatives can be converted to
dihydronaphthyl derivatives and subjected to chemistry similar to
that employed in the preparation of U50,488 derivatives. The
resulting compounds are racemic mixtures that can be derivatized to
confer peripheral selectivity. If necessary, the final compounds or
one of the intermediates can be resolved to test both enantiomers.
32 33 34
[0173] wherein R.sub.1, R.sub.2, and n are as defined in formula
I.
[0174] Following the procedure shown in Schemes 5-7, the following
example compounds are prepared.
[0175] Intermediate (.+-.)-64 can be treated with t-butyl
bromoacetate and deprotected to produce
(.+-.)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,-
4-tetrahydro-5-(O-2-acetic
acid)-hydroxy-2-(1-pyrrolidinyl)naphthyl]acetam- ide (72).
[0176] Intermediate (.+-.)-65 can be treated with t-butyl
bromoacetate and deprotected to produce
(.+-.)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,-
4-tetrahydro-7-(O-2-acetic
acid)-hydroxy-2-(1-pyrrolidinyl)naphthyl]acetam- ide (73).
[0177] Intermediate (.+-.)-66 can be treated with methanesulfonyl
chloride to produce
(.+-.)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-
-7-(N-methanesulfonamido)-amino-2-(1-pyrrolidinyl)naphthyl]acetamide
(74).
[0178] Intermediate (.+-.)-67 can be treated with methanesulfonyl
chloride to produce
(.+-.)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-
-5-(N-methanesulfonamido)-amino-2-(1-pyrrolidinyl)naphthyl]acetamide
(75).
[0179] Intermediate (.+-.)-68 can be treated with glycine benzyl
ester and deprotected to produce
(.+-.)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,-
4-tetrahydro-5-(N-2-acetic
acid)-carboxamido-2-(1-pyrrolidinyl)naphthyl]ac- etamide (76).
[0180] Intermediate (.+-.)-69 can be treated with glycine benzyl
ester and deprotected to produce
(.+-.)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,-
4-tetrahydro-5-(N-2-acetic
acid)-sulfonamido-2-(1-pyrrolidinyl)naphthyl]ac- etamide (77).
[0181] Intermediate (.+-.)-70 can be treated with glycine benzyl
ester and deprotected to produce
(.+-.)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,-
4-tetrahydro-7-(N-2-acetic
acid)-carboxamido-2-(1-pyrrolidinyl)naphthyl]ac- etamide (78).
[0182] Intermediate (.+-.)-71 can be treated with glycine benzyl
ester and deprotected to produce
(.+-.)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,-
4-tetrahydro-7-(N-2-acetic
acid)-sulfonamido-2-(1-pyrrolidinyl)naphthyl]ac- etamide (79).
35
[0183] The compounds of formula III of the present invention are
prepared by substituting the central phenyl ring with polar groups.
36
[0184] wherein Ar, R.sub.1, R.sub.2, X.sub.7, and n are defined as
in formula III.
[0185] Compound 80 and analogues undergo a variety of
diazonium-involving reactions for the attachment of polar groups
(Scheme 7). 37
[0186] Using the procedure shown in Scheme 7, the following
compounds are made.
[0187] Intermediate 81 can be treated with dibenzyl phosphoryl
chloride followed by deprotection to produce
2-(3,4-dichlorophenyl)-N-methyl-N-{1--
3-(O-phosphoryl)hydroxyphenyl-2-(1-pyrrolidinyl)ethyl}acetamide
(87).
[0188] Intermediate 85 can be coupled to methanesulfonyl chloride
to produce
2-(3,4-dichlorophenyl)-N-methyl-N-{1-[3-(N-methanesulfonamido)ami-
nomethyl]phenyl-2-(1-pyrrolidinyl)ethyl}acetamide (88).
[0189] Intermediate 85 can be coupled to 2S-isothiocyanato succinic
acid and deprotected to produce
2-(3,4-dichlorophenyl)-N-methyl-N-{1-[3-(N-suc- cinic
acid-2S-thioureido)aminomethyl]phenyl-2-(1-pyrrolidinyl)ethyl}acetam-
ide (89).
[0190] Intermediate 80 can be treated with dibenzyl phosphoryl
chloride followed by deprotection to produce
2-(3,4-dichlorophenyl)-N-methyl-N-{1--
3-(N-phosphoramido)aminophenyl-2-(1-pyrrolidinyl)ethyl}acetamide
(90). 38
[0191] The compounds of formula IV may be prepared by Scheme 8.
39
[0192] wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are defined
in formulas III and IV.
[0193] The diamino intermediate 91 (J. Med. Chem. 1990, 33, 286)
can be coupled to different regioisomers of nitrophenylacetic acid,
which are all commercially available. Reduction of the nitro group
provides an amino group for the attachment of polar groups.
Alternatively, the amino intermediates 95-97 readily undergo
diazonium chemistry that converts the amino groups to carboxyl and
sulfonyl chloride groups. This allows the polar groups to be
attached via different linkers.
[0194] Following the procedure in Scheme 8, the following compounds
are made.
[0195] Intermediate 96 can be treated with methanesulfonyl chloride
to produce
(-)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyrrolidinyl)-1--
oxaspiro-[4,5]dec-8-yl]-3-(N-methanesulfonamido)aminophenylacetamide
(104).
[0196] Intermediate 98 can be coupled to glycine benzyl ester and
deprotected to yield
(-)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyr-
rolidinyl)-1-oxaspiro-[4,5]dec-8-yl]-3-(N-2-acetic
acid)sulfonamidophenyla- cetamide (105).
[0197] Intermediate 99 can be coupled to glycine benzyl ester and
deprotected to yield
(-)-(5.alpha.,7.alpha.,8.beta.)-N-methyl-N-[7-(1-pyr-
rolidinyl)-1-oxaspiro-[4,5]dec-8-yl]-3-(N-2-acetic
acid)carboxamidophenyla- cetamide (106). 40
[0198] Compounds of the above formulas may have one or more
asymmetric carbon atoms. Pure sterochemically isomeric forms of the
above compounds may be obtained, and diastereoisomers isolated by
physical separation methods, including, but not limited to
crystallization and chromatographic methods. Cis and trans
diasteriomeric racemates may be further resolved into their
isomers. If separated, active isomers may be identified by their
activity. Such purification is not, however, necessary for
preparation of the compositions or practice of the methods
herein.
[0199] As used herein, the compounds provided herein also include
pharmaceutically acceptable salts, acids and esters thereof,
stereoisomers, and also metabolites or prodrugs thereof that
possess activity as analgesics but do not cause substantial CNS
effects when administered or applied. Metabolites include any
compound that is produced upon administration of the compound and
metabolism thereof.
[0200] More detailed preparations of the compounds of the present
invention follow.
[0201] Compounds of Formula I
[0202] Preparatory for the compounds of formula I, the following
intermediates were prepared. 41
[0203] N-Benzyl-D-serine (1).sup.1: To a mixture of D-serine (25.0
g, 0.237 mol) and 200 mL anhydrous methanol was added sodium
cyanoborohydride (11.95 g, 0.190 mol), while maintaining the
temperature at 0.degree. C. with an ice bath. Then, benzaldehyde
(26.5 mL, 0.261 mol) was added to the reaction flask, dropwise, at
30.degree. C. The mixture was stirred for 60 Hr. at room
temperature. Then, the mixture was filtered and rinsed with
methanol (50 mL). The white solid was dried in a vacuum oven at
40.degree. C. and 10 mmHg over 2 nights: 24.5 g. The filtrate was
retained and the solvent was evaporated. This oil was passed
through a silica gel column (10% MeOH/CH.sub.2Cl.sub.2) and 3.4 g
of the desired compound was isolated. The total amount of the
product was 27.9 g (60.0% yield). .sup.1H NMR (DMSO-d.sub.6)
.delta. 3.25 (m, 1H, CH), 3.85 (m, 2H, CH.sub.2), 4.11 (d, 2H,
benzylic CH.sub.2), 7.45-7.53 (m, 5H, ArH).
[0204] Ref.
[0205] (1) Ohfune, Y.; Kurokawa, N.; Higuichi, N.; Saito, M.;
Hashimoto, M.; Tanaka, T. An efficient one-step reductive
N-monoalkyation of .alpha.-amino acids. Chemistry Letters. 1984,
441-444.
[0206] N-Benzyl-D-serine methyl ester (2): Hydrogen chloride (gas)
was bubbled into anhydrous methanol for 10 minutes. Then, the
solution was allowed to cool to room temperature. Then,
N-benzyl-D-serine (24.6 gm, 0.126 mol) was added to the reaction
flask and refluxed over night under dry nitrogen. Then, the solvent
was evaporated and dissolved in dichloromethane (200 mL), and
washed with a saturated solution of sodium bicarbonate. The
dichloromethane layer was dried with magnesium sulfate and the
solvent was evaporated. (23 gm, 87.2% yield). .sup.1H NMR
(CDCl.sub.3) .delta. 3.41 (d, 1H, CH), 3.52-3.80 (dd, 2H,
benzylic), 3.69 (s, 3H, OMe), 7.27 (s, 5H, ArH).
[0207]
N-[(1,1-Dimethylethoxy)carbonyl-D-Ser-(O-Bzl)-N-benzyl-D-Ser-OMe
(3): To a solution of N-boc-D-serine-(O-bzl)OH (15 g, 50.76 mmol)
in anhydryous dichloromethane (200 mL) was added HOBt (7.54 g, 55.8
mmol) at 0.degree. C. under dry nitrogen. Then, DCC (11.5 g, 55.7
mmol) in dichloromethane (100 mL) was added dropwise to the
reaction flask. Then, this mixture was stirred for 1 Hr. Then,
N-benzyl-D-serine-OMe (10 g, 47.8 mmol) in dichloromethane (100 mL)
was added dropwise to the reaction flask. Then, stirred for 4 days.
Then, filtered and rinsed with dichloromethane (100 ml). The white
precipitate was DCU and HOBt. The filtrate was evaporated and
re-dissolved in ethyl acetate (100 mL). Then, this was allowed to
precipitate, overnight--more DCU. This was filtered and rinsed with
ethyl acetate. Then, this was isolated on a silica gel column (20%
ethyl acetate/hexanes): an oil--17.3 g, 74.3% yield. .sup.1H NMR
(CDCl.sub.3) .delta. 1.43 (s, 9H, t-Bu), 3.54 (t, 1H, OH), 3.72 (s,
3H, OMe), 3.75 (dd, 2H, CH.sub.2) 3.79 (dd, 2H, CH.sub.2), 4.41 (d,
2H, CH.sub.2 benzylic), 4.43 (d, 2H, CH.sub.2 benzylic), 7.27-7.30
(m, 10H, ArH).
[0208]
(2R,5R)-2-((Benzyloxy)methyl)-5-(Hydroxymethyl)-4-(phenylmethyl)-3,-
6-piperazine dione (4).sup.2:
[0209] Into anhydrous chloroform (300 mL) was bubbled hydrogen
chloride (gas). Then, the dipeptide (3) (13.5 g, 27.7 mmol) in
chloroform (100 ml) was added to the reaction flask. The flask was
stoppered and stirred for 64 Hr. Then, a saturated solution (100
ml) of sodium bicarbonate was added and stirred vigorously for 48
Hr. The cyclization was completed at this point. The organic layer
was separated from the aqueous layer in a 1 L separatory funnel.
The product was isolated from a silica gel column, eluting with
dichloromethane-methanol-0.88 ammonia (96:2:2) to give (4) as an
amorphous solid (6.0 g, 61.1% yield). .sup.1H NMR (CDCl.sub.3)
.delta. 3.72-3.96 (m, 7H), 3.97-5.24 (dd, 2H, CH.sub.2 benzylic),
4.45 (dd, 2H, CH.sub.2 benzylic), 7.15-7.30 (m, 10H, ArH); MS (FAB)
m/e 355 (MH.sup.+).
[0210] Ref.
[0211] (2) Williams, T. M.; Ciccarone, T. M.; MacTough, S. C. and
et al. 2-Substituted piperazines as constrained amino acids. J.
Med. Chem. 1996, 39, 1345-1348.
[0212]
(2S,5S)-2-((Benzyloxy)methyl)-4-(phenylmethyl)-5-piperazinemethanol
(5): A suspension of lithium aluminum hydride (0.9 g, 23.7 mmol) in
anhydrous tetrahydrofuran (40 mL) was treated with a solution of
piperazinedione 4 (2.1 g, 5.92 mmol) in anhydrous tetrahydrofuran
(200 mL). The reaction mixture was heated at reflux for 24 Hr and
then, stirred at room temperature for 12 Hr. Water (10 ml) was
added followed by aqueous sodium hydroxide (1N, 10 mL) and water
(10 mL). The mixture was filtered, and the filtrate was evaporated
to give 5 (1.67 g, 86.4% yield) as a viscous oil. .sup.1H NMR
(CDCl.sub.3) .delta. 2.58 (dd, 2H, CH.sub.2), 2.61 (t, 1H, OH),
3.10 (dd, 2H, CH.sub.2), 3.25 (dd, 2H, CH.sub.2), 3.50 (dd, 2H,
CH.sub.2), 3.74 (s, 2H, CH.sub.2), 4.41 (dd, 2H, CH.sub.2
benzylic), 7.20-7.30 (m, 10H, ArH).
[0213] (2S,5S)-Methyl
2-[(Benzyloxy)methyl]-5-(hydroxymethyl)-4-(phenylmet-
hyl)-1-piperazine carboxylate (6).sup.3: A solution of 5 (1.67 g,
5.11 mmol.) in acetonitrile (20 mL) was treated with a solution of
methyl chloroformate (0.532 g, 5.63 mmol) in acetonitrile (10 mL)
at 0.degree. C. The mixture was stirred at ambient temperature for
30 min., and then aqueous sodium carbonate solution (15 mL) was
added. The organic solvent was removed, and the aqueous residue was
extracted with chloroform (3.times.10 mL). The combined organic
extracts were washed with aqueous sodium carbonate solution (10
mL), dried, and evaporated to give 6 (1.52 g, 77.3% yield) as an
oil. .sup.1H NMR (CDCl.sub.3) .delta. 2.54 (dd, 2H, CH.sub.2), 2.45
(t, 1H, OH), 2.72 (dd, 2H, CH.sub.2), 3.51 (dd, 2H, CH.sub.2), 3.67
(dd, 2H, CH.sub.2), 3.69 (s, 3H, OMe), 3.81 (dd, 2H, CH.sub.2),
4.44 (dd, 2H, CH.sub.2 benzylic), 7.17-7.31 (10H, ArH).
[0214] (2S,5S)-Methyl
2-[(Benzyloxy)methyl]-5-[(1-pyrrolidinyl)methyl]-4-(-
phenylmethyl)-1-piperazinecarboxylate (7).sup.3: A solution of
oxalyl chloride (0.545 mL, 6.24 mmol) in dichloromethane (10 mL) at
-65.degree. C. was treated with a solution of dimethyl sulfoxide
(1.14 mL, 16.0 mmol) in dichloromethane (5 ml) maintaining the
reaction temperature below -65.degree. C. The mixture was stirred
at -70.degree. C. for 10 min, and then a solution of the
piperazinemethanol (6: 2 g, 5.19 mmol) in dichloromethane (20 mL)
was added at such a rate that the reaction temperature was
maintained below -65.degree. C. The reaction mixture was stirred at
-65.degree. C. for 3 Hr, and a solution of N-methylmorpholine (1.42
mL, 12.91 mmol) in dichloromethane (5 mL) was added. The mixture
was stirred at -20.degree. C. for 45 min and then washed with
ice-cold hydrochloric acid (0.01 N. 100 mL and 50 mL), dried,
evaporated, and placed on a high vacuum pump overnight. The residue
was dissolved in methanol (10 mL) and was added to a solution of
pyrrolidine (0.91 mL, 10.94 mmol) in methanol (10 mL) at
-10.degree. C., which had been adjusted to pH 6.0 by the addition
of methanolic hydrogen chloride. Sodium cyanoborohydride (0.67 g,
10.66 mmol) and 4-.ANG. molecular sieves (0.66 g) were added, and
the mixture was stirred at ambient temperature for 18 Hr. The
mixture was filtered, and the filtrate was evaporated to dryness.
The residue was dissolved in aqueous sodium carbonate (1M, 25 mL)
and extracted with dichloromethane (2.times.50 mL). The product was
isolated from a silica gel column, eluting with
dichloromethane-methanol (98:2) to give (7: 1.0 g, 23.0% yield).
.sup.1H NMR (CDCl.sub.3) .delta. 1.75 (m, 4H, CH.sub.2CH.sub.2),
2.46 (m, 3H), 2.48 (m, 4H, CH.sub.2CH.sub.2), 2.55 (dd, 2H,
CH.sub.2), 2.70-2.85 (m, 3H), 3.41 (dd, 2H, CH.sub.2), 3.69 (s, 3H,
OMe), 4.10 (m, 1H), 4.20 (m, 1H), 4.41 (dd, 2H, CH.sub.2 benzylic),
7.10-7.31 (m, 10H, ArH), MS (FAB) m/e 438 (MH.sup.+).
[0215] (3) Naylor, A.; Judd, D. B.; Lloyd, J. E.; Scopes, D. I. C.;
Hayes, A. G.; Birch, P. J. A potent new class of k-Receptor
agonist: 4-subtituted
1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines. J. Med. Chem.
1993, 36, 2075-2083.
[0216] (2S,5S)-Methyl
2-(Hydroxymethyl)-5-[(1-pyrrolidinyl)methyl]-1-piper- azine
carboxylate (8): A solution of 7 (0.25 g, 0.571 mmol) in ethanol
(200 mL) was hydrogenated over 10% palladium on carbon (Degussa
type E101 NE/W) at 50 psi for 7 days. Then, filtered through celite
and filtrate was evaporated. (0.13 g, 0.5 mmol: 87% yield).
[0217] (2S,5S)-Methyl
4-[(3,4-Dichlorophenyl)acetyl]-2-(hydroxy)methyl-5-[-
(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (9): To a solution
of 1,1'-carbonyldiimiazole (0.20 g, 1.26 mmol) in dichloromethane
(10 mL) was added portionwise 3,4-dichlorophenylacetic acid (0.25
g, 1.26 mmol) and the resulting solution stirred under nitrogen for
1 Hr, at room temperature. A solution of 8 (0.13 g, 0.5 mmol) in
dichloromethane (10 mL) was added and the mixture at room
temperature for 18 Hr. The reaction mixture was washed with sodium
carbonate solution (2 N, 2.times.10 mL), dried, and evaporated to
give a viscous oil. This material was dissolved in a mixture of
tetrahydrofuran (5 mL) and water (5 mL) and treated with lithium
hydroxide (42 mg, 1.0 mmol). The reaction mixture was removed, and
the aqueous residue was extracted with dichloromethane (3.times.10
mL). The combined organic extracts were dried and evaporated to
give a colorless gum which was purified by flash column
chromatography on silica gel, eluting with ethyl acetate-methanol
(40:1) to give 9 (155 mg, 70%) as a colorless foam.
[0218] Utilizing the above-denoted intermediates, the following
compounds were prepared.
[0219] Chiral Compounds 42
EXAMPLE 1
(R)-4-(Phenylmethyl)-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)met-
hyl]piperazine hydrochloride [(R)-1 HCl]
[0220] The compound (R)-1 HCl was prepared following the literature
procedure.sup.3 in 54% yield; mp 168-170.degree. C.; .sup.1H NMR
(free base, 200 MHz, CDCl.sub.3) .delta. 1.65 (4H, m), 1.95-3.00
(6H, m), 3.10-3.80 (9H, m), 4.35 (1H, m), 4.70 (1H, m), 7.00 (1H,
m), 7.30 (7H, m); MS (FAB) 448 (M+H).sup.+; Anal. Calcd for
C.sub.24H.sub.29Cl.sub.2N.s- ub.30.2HCl.H.sub.2O: C, 53.64; H,
6.19; N, 7.82. Found: C, 53.69; H, 5.88; N, 7.49.
EXAMPLE 2
(R)-1-[(3,4-Dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperazine
hydrochloride [(R)-2HCl]
[0221] The compound was prepared by the catalytic hydrogenation of
(R)-1 HCl following the procedure described in the above reference.
The product was isolated as a free base as clear oil in 81% yield
and the dihydrochloride salt was prepared from 1M etherial HCl;
.sup.1H NMR (free base, 200 MHz, CDCl.sub.3) .delta. 1.67 (4H, m),
1.95-3.10 (6H, m), 3.10-3.80 (7H, m), 4.30 (1H, m), 4.65 (1H, m),
7.05 (1H, m), 7.35 (3H, m); MS (FAB) 356 (M+H).sup.+.
EXAMPLE 3
(R)-4-Methanesulfonyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)me-
thyl]-piperazine hydrochloride [(R)-3a HCl]
[0222] To the solution of (R)-2 (712 mg, 2 mmol in 10 ml
CH.sub.2Cl.sub.2), methanesulfonyl chloride (573 mg, 5 mmol) and
pyridine (1 ml) were added at 0.degree. C., stirred overnight at
that temperature, the solution was washed with aq. 5%
K.sub.2CO.sub.3 solution, extracted with dichloromethane, dried and
evaporated solvent to give crude oil. This material was purified by
flash column chromatography on silica gel, eluting with
dichloromethane-methanol-ammonia (100:5:1), to give the free base,
which was dissolved into 2 ml of dichloromethane and HCl (3 ml, 1 M
in Et.sub.2O) was added to afford a white salt (R)-3a HCl (600 mg,
69%): mp 130-132.degree. C.; .sup.1H NMR (free base, 200 MHz,
CDCl.sub.3) .delta. 1.61-1.85 (4H, m), 2.38-2.65 (6H, m), 2.72 (3H,
s), 2.80-3.06 (2H, m), 3.15-3.36 (1H, m), 3.50-3.96 (4H, m),
4.484.93 (1H, m), 7.00-7.10 (1H, m), 7.25-7.40 (2H, m); MS (FAB)
434 (M+H).sup.+; Anal. Calcd for
C.sub.18H.sub.25Cl.sub.2N.sub.3O.sub.3S.HCl.0.5 CH.sub.3OH.: C,
45.64; H, 5.59; N, 8.63. Found: C, 45.69; H, 5.58; N, 8.73.
EXAMPLE 4
(R)-4-t-Butyl-acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)met-
hyl]-piperazine [(R)-3b]
[0223] To the solution of (R)-2 (356 mg, 1 mmol in 10 ml acetone),
t-butyl bromoacetate (234 mg, 1.2 mmol) and K.sub.2CO.sub.3 (207
mg, 1.5 mmol) were added at 0.degree. C., stirred overnight at that
temperature, the solution was washed with aq. 5% K.sub.2CO.sub.3
solution, extracted with dichloromethane, dried and evaporated
solvent to give crude oil. This material was purified by flash
column chromatography on silica gel, eluting with
dichloromethane-methanol-ammonia (100:5:1), to give (R)-3b (329 mg,
70%): .sup.1H NMR (free base, 200 MHz, CDCl.sub.3) .delta. 1.36
(9H, s), 1.91-2.37 (7H, m), 2.65-3.13 (7H, m), 3.584.20 (6H, m),
5.00 (1H, m), 7.12-7.21 (2H, m), 7.40 (1H, m). The compound was
used directly into the following reaction.
EXAMPLE 5
(R)-4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazine-
acetic acid dihydrochloride [(R)-3c 2HCl]
[0224] Compound (R)-3b (329 mg, 0.7 mmol) was dissolved into 5 ml
THF/Et.sub.2O (1:1), and HCl (5 ml, 1 M in Et.sub.2O) was added,
kept 12 hrs to afford a white salt (R)-3c HCl (275 mg, 61%): mp
190.degree. C. (d). .sup.1H NMR (free base, 200 MHz, CDCl.sub.3)
.delta. 1.85-2.20 (4H, m), 2.95-4.41 (17H, m), 5.18-5.35 (1H, m),
7.30-7.45 (1H, m), 7.56-7.72 (2H, m); MS (FAB) 414 (M+H).sup.+;
Anal. Calcd for
C.sub.19H.sub.25Cl.sub.2N.sub.3O.sub.3.2HCl.0.5H.sub.2O.: C, 45.16;
H, 5.78; N, 8.32. Found: C, 44.91; H, 5.88; N, 8.56.
EXAMPLE 6
(R)-4-N-t-Boc-D-aspartic acid-.beta.-benzyl
ester-1-[(3,4-dichlorophenyl)a-
cetyl]-2-[(1-pyrrolidinyl)methyl]-piperazine [(R)-3d]
[0225] To the solution of N-t-Boc-D-aspartic acid-.beta.-benzyl
ester (646 mg, 2 mmol) and HOBt (270 mg, 2 mmol in 10 ml
CH.sub.2Cl.sub.2), DCC (413 mg, 2 mmol) was added at 0.degree. C.,
stirred 1 h at that temperature, (R)-2 (356 mg, 1 mmol in 10 ml
CH.sub.2Cl.sub.2) was added, stirred 24 hrs at room temperature,
the solution was washed with aq. 5% K.sub.2CO.sub.3 solution,
extracted with dichloromethane, dried and evaporated solvent to
give crude oil. This material was purified by flash column
chromatography on silica gel, eluting with dichloromethane-methano-
l-ammonia (100:1:1), to give (R)-3d (628 mg, 95%), .sup.1H NMR
(free base, 200 MHz, CDCl.sub.3) .delta. 1.35 (9H, s), 1.70-1.87
(4H, m), 2.32-3.16 (6H, m), 3.354.46 (6H, m), 4.80-5.68 (6H, m),
7.07-7.45 (8H, m). The compound was used directly into the reaction
below.
EXAMPLE 7
(R)-4-Aspartic
acid-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)meth-
yl]-piperazine dihydrochloride [(R)-3e 2HCl]
[0226] The compound (R)-3d was dissolved into 1 ml of HOAc, and HCl
(1 ml, 2N) was added, standing 20 min, then hydrogenated at 1 atm.,
10% Pd on carbon at room temperature for 1 h to afford a white salt
(R)-3e (430 mg, 91.5%): mp 168.degree. C. (d). .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.92-2.16 (4H, m), 2.75-5.28 (18H, m), 2.72
(3H, s), 7.31-7.52 (3H, m), 8.45-8.80 (3H, m); MS (FAB) 471
(M+H).sup.+; Anal. Calcd for
C.sub.21H.sub.28Cl.sub.2N.sub.4O.sub.4.2HCl: C, 46.34; H, 5.18; N,
10.29. Found: C, 45.52; H, 6.02; N, 9.73.
EXAMPLE 8
(R)-4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]-pip-
erazine hydrochloride [(R)-3f HCl]
[0227] The compound was prepared as reported in the literature (J.
Med. Chem. 1993, 36, 2075-2083) from (R)-2. the hydrochloride salt
was prepared from 1M etherial HCl to afford (R)-3f HCl in 88%
yield; mp 153-155.degree. C.; MS (FAB) 398 (M+H).sup.+. Anal. Calcd
for C.sub.19H.sub.25Cl.sub.2N.sub.3O.sub.2.HCl.H.sub.2O: C, 52.49;
H, 6.03; N, 9.66. Found: C, 50.40; H, 6.23; N, 9.28.
EXAMPLE 9
(R)-4-(Diethoxyphosphonate)-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrolidin-
yl)methyl]-piperazine hydrochloride [(R)-3g HCl]
[0228] To a solution of (R)-2 (0.178 g, 0.5 mmol) in 10 mL of
CH.sub.2Cl.sub.2 was added Et.sub.3N (0.101 g, 1.0 mmol) and
diethylchlorophosphonate (0.174 g, 1.0 mmol) under a nitrogen
atmosphere. The reaction mixture was stirred at room temperature
for 13 h and then poured over aqueous 10% K.sub.2CO.sub.3. The
organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4,
and evaporated to dryness under reduced pressure to give the
compound as a yellow oil. The oil was purified on a silica gel
column (solvent system: CH.sub.2Cl.sub.2:CH.sub.- 3OH:28%
NH.sub.4OH, 95:5:2) and converted to hydrochloride salt by usual
method to give (R)-3g HCl, 0.10 g (38%); mp 168-170.degree. C.;
.sup.1H NMR (free base, 200 MHz, CDCl.sub.3) .delta. 1.20 (6H, t,
J=7.0 Hz), 1.64 (4H, m), 2.30-2.70 (6H, m), 2.85-3.15 (1H, m),
3.45-3.80 (4H, m), 3.60 (2H, brs), 3.98 (4H, m), 4.35 (1H, m), 4.70
(1H, m), 7.00 (1H, m), 7.30 (2H, m); MS (FAB) 492, 494 (M+H).sup.+.
Anal. Calcd for
C.sub.21H.sub.32Cl.sub.2N.sub.3O.sub.4P.HCl.0.5H.sub.2O: C, 46.90;
H, 6.37; N, 7.81. Found: C, 46.66; H, 5.90; N, 8.16.
EXAMPLE 10
(R)-4-Trifluoroacetyl-1-(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)met-
hyl]-piperazine hydrochloride [(R)-3h HCl]
[0229] To a solution of (R)-2 (0.356 g, 1.0 mmol) in 10 mL of
CH.sub.2Cl.sub.2 was added Et.sub.3N (0.202 g, 2.0 mmol) and
trifluoroacetic anhydride (0.42 g, 2.0 mmol) in a nitrogen
atmosphere. The reaction mixture was stirred at room temperature
for 12 h and TLC showed staring material was still present, added
another equivalent of trifluoroacetic anhydride and stirring was
continued for additional 12 h. The reaction was worked up as above
and the hydrochloride salt was prepared as usual to give (R)-3h
HCl, 0.25 g (50%); mp 145-147.degree. C.; .sup.1H NMR (free base,
200 MHz, CDCl.sub.3) .delta. 1.60 (4H, m), 2.20-2.75 (6H, m), 3.10
(1H, m), 3.45-3.80 (4H, m), 4.00 (1H, J=14.0 Hz, d), 4.25 (1H, m),
4.45 (1H, J=14.0 Hz, d), 4.70 (1H, m), 7.00 (1H, m), 7.28 (2H, m);
MS (FAB) 452, 454 (M+H).sup.+. Anal. Calcd for
C.sub.19H.sub.22Cl.sub.2F.sub.3N.sub.3O.sub.2.HCl.0.5H.sub.2O: C,
45.85; H, 4.86; N, 8.44. Found: C, 46.26; H, 4.82; N, 8.33.
EXAMPLE 11
(R)-4-[(3,4-Dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazine-
carboxamide hydrochloride [(R)-3i HCl]
[0230] To a solution of (R)-2 (0.356 g, 1.0 mmol) in acetic acid
(0.186 g, 3.0 mmol) and water was added KOCN (0.244 g, 3.0 mmol)
and the reaction mixture was stirred at room temperature for 72 h.
An aqueous 10% K.sub.2CO.sub.3 was added to the reaction mixture to
bring the pH to near 12.0 and the product was extracted with
CH.sub.2Cl.sub.2, washed with saturated salt solution, dried over
anhydrous Na.sub.2SO.sub.4. The removal of solvent at reduced
oressure gave the crude product which was purified on a silica gel
column (solvent system: CH.sub.2Cl.sub.2:CH.sub.- 3OH:28%
NH.sub.4OH, 95:5:1) to give the desired product as a white solid.
The hydrochloride salt was prepared from 1M etheial HCl to give
(R)-3i HCl as a white solid, 0.15 g (31%); .sup.1H NMR (free base,
200 MHz, CDCl.sub.3) .delta. 1.65 (4H, m), 2.10-3.20 (6H, m),
3.40-3.70 (4H, m), 3.95 (2H, m), 4.20 (2H, J=14.0 Hz, d, m), 4.70
(1H, m), 5.35 (2H, bs), 7.00 (1H, m), 7.25 (2H, m); MS (FAB) 399,
401 (M+H).sup.+. Anal. Calcd for
C.sub.18H.sub.24Cl.sub.2N.sub.4O.sub.2.HCl.H.sub.2O.0.125
CH.sub.2Cl.sub.2: C, 46.88; H, 5.91; N, 12.06. Found: C, 46.66; H,
5.50; N, 11.97.
EXAMPLE 12
(R)-4-[(3,4-Dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazine-
carboxaldehyde hydrochloride [(R)-3j HCl]
[0231] To a solution of (R)-2 (0.356 g, 1.0 mmol) in 10 mL of
CH.sub.2Cl.sub.2 was added 1.0 mL of methylformate (excess) at
0.degree. C. under a nitrogen atmosphere. The reaction mixture was
stirred for 24 h and solvent was removed at reduced pressure to
give the crude product. The compound was purified on a silica gel
column (solvent system: CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH,
95:5:1) and converted to the hydrochloride salt, (R)-3j HCl, 0.10 g
(23%); mp 126.degree. C. (d); .sup.1H NMR (free base, 200 MHz,
CDCl.sub.3) .delta. 1.62 (4H, m), 2.10-3.20 (6H, m), 3.35-3.85 (5H,
m), 4.25 (3H, m), 4.60 (1H, m), 7.00 (1H, m), 7.26 (2H, m), 7.90
(1H, s); MS (FAB) 384, 386 (M+H).sup.+.
EXAMPLE 13
(R)-4-[(3,4-Dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazine-
-sulfonamide hydrochloride [(R)-3k HCl]
[0232] To a solution of (R)-2 (0.356 g, 1.0 mmol) in 5 mL of
p-dixane was added sulfamide.sup.4 (NH.sub.2SO.sub.2NH.sub.2, 0.96
g, 10 mmol) under a nitrogen atmosphere and the reaction mixture
was heated to reflux for 2 h. The reaction mixture was evaporated
to dryness under reduced pressure and the residue was redissolved
in CH.sub.2Cl.sub.2 and washed with aqueous 10% K.sub.2CO.sub.3,
saturated salt solution, and dried over anhydrous Na.sub.2SO.sub.4.
The removal of solvent resulted the free base of the product which
was purified on a silica gel column (solvent system:
CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH, 98:2:1). The
hydrochloride salt was prepared from 1M etherial HCl to give (R)-3k
HCl, 0.10 g (21%); mp 183-185.degree. C.; .sup.1H NMR (free base,
200 MHz, CDCl.sub.3) .delta. 1.68 (4H, m), 2.30-3.00 (6H, m),
3.15-4.00 (5H, m), 4.15-4.65 (3H, m), 4.85 (1H, m), 7.00 (1H, m),
7.31 (4H, m); MS (FAB) 435 (M+H).sup.+. Anal. Calcd for
C.sub.17H.sub.24Cl.sub.2N.sub.4O.sub.3S.HCl: C, 43.28; H, 5.34; N,
11.87. Found: C, 42.90; H, 5.35; N, 11.43.
[0233] Ref.
[0234] (4) Alker, D. et. al. J. Med. Chem. 1990, 33, 585.
EXAMPLE 14
(R)-4-(4-Methyphenylsulfonyl)-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-Pyrroli-
dinyl)methyl]-piperazine hydrochloride [(R)-3l HCl]
[0235] To a solution of (R)-2 (0.356 g, 1.0 mmol) in 5 mL of
CH.sub.2Cl.sub.2 was added p-toluenesulfonyl chloride (0.38 g, 2
mmol) followed by 0.5 mL of pyridine under a nitrogen atmosphere.
The reaction mixture was stirred at room temperature for 16 h and
then poured onto aqueous 10% K.sub.2CO.sub.3. The organic layer was
separated and dried over anhydrous Na.sub.2SO.sub.4. The removal of
solvent gave the product which was purified on a silica gel column
(solvent system: CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH,
98:2:1). The hydrochloride salt was prepared to give (R)-3l HCl,
0.15 g (27%); mp 240.degree. C. (d); .sup.1H NMR (free base, 200
MHz, CDCl.sub.3) .delta. 1.65 (4H, m), 1.95-3.00 (6H, m), 2.38 (3H,
s), 3.15-3.85 (5H, m), 4.45 (1H, m), 4.75 (1H, m), 6.95 (1H, m),
7.25 (4H, m), 7.50 (2H, J=8.0 Hz, d); MS (FAB) 510 (M+H).sup.+.
Anal. Calcd for C.sub.24H.sub.29Cl.sub.2N.sub.3O.sub.3S.HCl.-
0.25H.sub.2O: C, 52.32; H, 5.35; N, 7.63. Found: C, 52.23; H, 5.50;
N, 7.51.
[0236] Racemic Compounds
[0237] Racemic compounds were prepared as illustrated by the
following steps. 43
[0238] (R,S)-2-[(1-Pyrrolidinyl)methyl]piperazine hydrochloride
[(R,S)-4 HCl]
[0239] The compound was prepared following the literature
procedure.sup.1 and isolated as hydrochloride salt.
[0240] (R,S)-4-(R.dbd.SO.sub.2CH.sub.3, CO.sub.2CH.sub.3,
COCH.sub.3)-2-[(1-Pyrrolidinyl)methyl]piperazine hydrochloride
[(R,S)-5, 6, 7]
[0241] These compounds were also prepared according to the
procedures described in the literature.sup.1 and each of the
products were purified as free base before utilizing below.
EXAMPLE 15
(R,S)-4-Methanesulfonyl-1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl)-
methyl]-piperazine hydrochloride [(R,S)-8a HCl] (General
Procedure)
[0242] 1,1'-Carbonyldiimidazole (0.324 g, 2.0 mmol) was added to a
stirred solution of 3,4-dichlorophenylacetic acid (0.41 g, 2.0
mmol) in 10 mL of CH.sub.2Cl.sub.2 at room temperature under a
nitrogen atmosphere, and the resulting solution was continued
stirring for additional 1 h. The resulting solution was then added
to a stirred solution of (R,S)-5 (0.247 g, 1.0 mmol) in 10 mL of
CH.sub.2Cl.sub.2 at 0.degree. C. and the reaction mixture was
stirred for further 20 h. The reaction mixture was diluted with
CH.sub.2Cl.sub.2 and washed with aqueous 2M Na.sub.2CO.sub.3. The
organic layer was dried and evaporated to dryness and the product
was purified on a silica gel column (solvent system:
CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH, 98:2:1). The
hydrochloride salt was prepared by redissolving the compound in
CH.sub.2Cl.sub.2 and treating the solution with 1M etherial HCl to
give (R,S)-8a HCl as a white solid, 0.20 g (32%); NMR (see R-3a);
MS (FAB) 434 (M+H).sup.+; Anal. Calcd for
C.sub.18H.sub.25Cl.sub.2N.sub.3O.sub.3S.HCl.0.5H.sub.2O: C, 45.13;
H, 5.51; N, 8.77. Found: C, 45.46; H, 5.36; N. 8.71.
[0243] The following compounds were similarly prepared from
(R,S)-5, 6, and 7:
EXAMPLE 16
(R,S)-4-Methanesulfonyl-1-[(4-methylsulfonylphenyl)acetyl]-2-[(1-pyrrolidi-
nyl)-methyl]piperazine hydrochloride [(R,S)-8b HCl]
[0244] The compound was prepared from 4-methylsulfonylphenylacetic
acid and the hydrochloride salt was recrystallized from CH.sub.3OH
to give (R,S)-8b HCl in 60% yield; mp 185-188.degree. C.; .sup.1H
NMR (free base, 200 MHz, CDCl.sub.3) .delta. 1.65 (4H, m),
2.30-2.70 (6H, m), 2.80 (3H, s), 2.85-3.10 (3H, m), 3.00 (2H, m),
3.25 (1H, m), 3.50-3.95 (4H, m), 4.50 (1H, m), 4.80 (1H, m)), 7.40
(2H, J=7.5 Hz, d), 7.80 (2H, J=7.5 Hz, d); MS (FAB) 444
(M+H).sup.+; Anal. Calcd for C.sub.19H.sub.29N.sub.3O.su-
b.5S.sub.2.HCl: C, 47.54; H, 6.30; N, 8.75. Found: C, 46.03; H,
6.24; N, 8.80.
EXAMPLE 17
(R,S)-4-Methanesulfonyl-1-[(2-nitrophenyl)acetyl]-2-[(1-pyrrolidinyl)-meth-
yl]piperazine hydrochloride [(R,S)-8c HCl]
[0245] The compound was prepared from 2-nitrophenylacetic acid in
65% yield as hydrochloride salt; mp 253-255.degree. C.; .sup.1H NMR
(free base, 200 MHz, CDCl.sub.3) .delta. 1.70 (4H, m), 2.40-3.10
(6H, m), 2.75 (3H, s), 3.45 (1H, m), 3.70-4.00 (4H, m), 4.054.30
(2H, m), 4.50 (1H, m), 4.72 (1H, m), 7.45 (3H, m), 8.05 (1H, J=8.0
Hz, d); MS (FAB) 411 (M+H).sup.+; Anal. Calcd for
C.sub.18H.sub.26N.sub.4O.sub.5S.HCl: C, 48.37; H, 6.09; N, 12.54.
Found: C, 48.36; H, 5.66; N, 12.29.
EXAMPLE 18
(R,S)-4-Methanesulfonyl-1-[(4-trifluoromethylphenyl)acetyl]-2-[(1-pyrrolid-
inyl)-methyl]piperazine hydrochloride [(R,S)-8d HCl]
[0246] The compound was prepared as a hydrochloride salt from
4-trifluorometylphenylacetic acid in 82% yield; 182-185.degree. C.;
.sup.1H NMR (free base, 200 MHz, CDCl.sub.3) .delta. 1.65 (4H, m),
2.35-3.05 (6H, m), 2.71 (3H, s), 3.25 (1H, m), 3.50-3.95 (5H, m),
4.55 (1H, m), 4.85 (1H, m), 7.30 (2H, m), 7.50 (2H, J=7.8 Hz, d);
MS (FAB) 434 (M+H).sup.+; Anal. Calcd for
C.sub.19H.sub.26F.sub.3N.sub.3O.sub.3S.HCl.0- .5H.sub.2O: C, 47.65;
H, 5.89; N, 8.77. Found: C, 48.36; H, 5.80; N, 8.51.
EXAMPLE 19
(R,S)-4-Methanesulfonyl-1-[(3-indolylacetyl-2-[(1-pyrrolidinyl)-methyl]pip-
erazine hydrochloride [(R,S)-8e HCl]
[0247] The compound was prepared from 3-indoleacetic acid and
isolated as free base in 40% yield and converted to hydrochloride
salt; mp 219-221.degree. C.; .sup.1H NMR (free base, 200 MHz,
CDCl.sub.3) .delta. 1.65 (4H, m), 2.10-3.00 (6H, m), 2.55 (3H, S),
3.10-3.45 (2H, m), 3.45-3.90 (4H, m), 4.05 (1H, m), 4.55 (1H, m),
4.90 (1H, m), 7.05 (3H, m), 7.25 (1H, m), 7.50 (1H, m), 8.95 (1H,
bs); MS (FAB) 405 (M+H).sup.+; Anal. Calcd for
C.sub.20H.sub.28N.sub.4O.sub.3S.HCl.0.5H.sub.2O: C, 58.09; H, 7.07;
N, 13.55. Found: C, 58.37; H, 6.68; N, 13.30.
EXAMPLE 20
(R,S)-Methyl
4-[(4-methylsulfonylphenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl-
]-1-piperazinecarboxylate hydrochloride [(R,S)-9a HCl]
[0248] The compound was prepared from 4-methylsulfonylphenylacetic
acid and the hydrochloride was prepared from 1M etherial HCl to
give (R,S)-9a HCl in 46% yield; mp 225.degree. C.; .sup.1H NMR
(free base, 200 MHz, CDCl.sub.3) .delta. 1.60 (4H, m), 2.15-2.95
(6H, m), 2.98 (3H, s), 3.15 (2H, m), 3.35 (3H, m), 3.60 (3H, s),
3.95 (2H, m), 4.30 (1H, m), 4.72 (1H, m), 7.45 (2H, m), 7.75 (2H,
J=7.5 Hz, d); MS (FAB) 424 (M+H).sup.+; Anal. Calcd for
C.sub.20H.sub.29N.sub.3O.sub.5S.HCl.0.25H.sub.2O: C, 51.72; H,
6.62; N, 9.05. Found: C, 51.93; H, 6.47; N, 8.44.
EXAMPLE 21
(R,S)-Methyl
4-[(4-trifluoromethylphenyl)acetyl]-3-[(1-pyrrolidinyl)-methy-
l]-1-piperazinecarboxylate hydrochloride [(R,S)-9b HCl]
[0249] The compound was prepared as a hydrochloride salt from
4-trifluorometylphenylacetic acid to give (R,S)-9b HCl in 48%; mp
210.degree. C.; .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 1.50 (4H,
m), 1.95-2.30 (6H, m), 2.35-3.50 (4H, m), 3.65 (3H, S), 3.70-4.50
(5H, m), 7.45 (4H, m); MS (FAB) 414 (M+H).sup.+; Anal. Calcd for
C.sub.20H.sub.26F.sub.3N.sub.3O.sub.3.HCl.0.25H.sub.2O: C, 52.86;
H, 6.10; N, 9.25. Found: C, 53.03; H, 5.94; N, 8.94. 44
[0250] Another minor product (R,S)-11) was isolated as a
hydrochloride salt from this reaction in 10% yield; mp 190.degree.
C.; MS (FAB) 446 (M+H).sup.+.
EXAMPLE 22
(R,S)-Methyl
4-[(3-indolyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piperazin-
e-carboxylate hydrochloride [(R,S)-9c HCl]
[0251] The compound was prepared from 3-indoleacetic acid and the
hydrochloride salt was prepared to give (R,S)-9c HCl in 75% yield;
mp 143.degree. C.; .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 1.55
(4H, m), 1.90-2.52 (6H, m), 2.70-3.75 (9H, m), 3.35 (3H, S), 6.60
(2H, m), 6.85 (2H, m), 7.20 (1H, s), 7.65 (1H, brs); MS (FAB) 385
(M+H).sup.+.
EXAMPLE 23
(R,S)-Methyl
4-[(2-nitrophenyl)acetyl]-3-[(1-Pyrrolidinyl)-methyl]-1-piper-
azine-carboxylate hydrochloride [(R,S)-9d HCl]
[0252] The compound was prepared from 2-nitrophenyacetic acid and
hydrochloride was prepared from 1M etherial HCl to give (R,S)-9d
HCl in 42% yield; mp 228.degree. C.; .sup.1H NMR (free base, 200
MHz, CDCl.sub.3) .delta. 1.60 (4H, brs), 1.80-2.30 (4H, m), 2.70
(2H, m), 3.05 (2H, m), 3.60 (3H, s), 3.55-4.10 (4H, m), 4.35 (2H,
J=14.0 Hz, dd), 5.10 (1H, m), 7.50 (3H, m), 8.05 (1H, J=7.5 Hz, d);
MS (FAB) 391 (M+H).sup.+; Anal. Calcd for
C.sub.19H.sub.26N.sub.4O.sub.5.HCl: C, 53.46; H, 6.37; N, 13.12.
Found: C, 54.29; H, 6.38; N, 12.58.
EXAMPLE 24
(R,S)-Methyl
4-[(2-methoxyphenyl)acetyl]-3-[(1-pyrrolinyl)-methyl]-1-piper-
azine-carboxylate hydrochloride [(R,S)-9e HCl]
[0253] The compound was prepared as above from
2-methoxyphenylacetic acid to give (R,S)-9e HCl in 12% yield; mp
120.degree. C.; .sup.1H NMR (free base, 200 M, CDCl.sub.3) .delta.
1.65 (4H, m), 2.25-2.95 (6H, m), 3.10 (1H, m), 3.304.10 (5H, m),
3.60 (3H, s), 3.70 (3H, s), 4.40 (1H, m), 4.70 (1H, m), 6.84 (2H,
m), 7.15 (3H, m); MS (FAB) 376 (M+H).sup.+; Anal. Calcd for
C.sub.20H.sub.129N.sub.3O.sub.4.HCl.H.sub.2O: C, 55.87; H, 7.50; N,
9.77. Found: C, 55.78; H, 6.97; N, 9.42.
EXAMPLE 25
(R,S)-Methyl
4-[(2-aminophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1-piper-
azine-carboxylate dihydrochloride [(R,S)-9f 2HCl]
[0254] The compound was prepared by the hydrogenation of (R,S)-9e
HCl on 10% Pd/C following the procedure described in the
literature1. The compound, (R,S)-9f 2HCl, was isolated as
dihydrochloride in 84% yield; mp 195.degree. C. (d); .sup.1H NMR
(200 MHz, DMSO-d.sub.6) .delta. 2.00 (4H, m), 3.05-4.45 (16H, m),
3.75 (3H, s), 5.00 (1H, m), 7.45 (4H, brs); MS (FAB) 361
(M+H).sup.+; Anal. Calcd for C.sub.19H.sub.28N.sub.4O.sub.3.2HC-
l.H.sub.2O: C, 50.56; H, 7.15; N, 12.41. Found: C, 50.36; H, 7.26;
N, 12.05.
EXAMPLE 26
(R,S)-4-Acetyl-1-[(4-methylsulfonylphenyl)acetyl]-3-[(1-pyrrolidinyl)-meth-
yl]-piperazine hydrochloride [(R,S)-10a HCl]
[0255] The compound was prepared as above from
4-methylsulfonylphenylaceti- c acid and the hydrochloride salt was
prepared in usual fashion to give (R,S)-10a HCl in 45% yield; mp
145-147.degree. C.; .sup.1H NMR (200 MHz, DMSO-d.sub.6) .delta.
1.90 (4H, m), 2.17 (3H, s), 2.65-3.80 (6H, m). 3.32 (3H, s),
3.854.45 (8H, m), 5.05 (1H, m), 7.65 (2H, J=8.0 Hz, d), 7.95 (2H,
J=8.0 Hz, d); MS (FAB) 408 (M+H).sup.+.
EXAMPLE 27
(R,S)-4-Acetyl-1-(4-trifluoromethylphenyl)acetyl]-3-[(1-pyrrolidinyl)-meth-
yl]piperazinecarboxylate hydrochloride [(R,S)-10b HCl]
[0256] The compound was prepared from 4-trifluorometylphenylacetic
acid and isolated as hydrochloride salt, (R,S)-10b HCl, in 30%
yield; mp 110.degree. C.; .sup.1H NMR (200 MHz, DMSO-d.sub.6)
.delta. 2.00 (4H, m), 2.15 (3H, s), 2.70-3.25 (6H, m), 3.504.45
(8H, m), 5.05 (1H, m), 7.70 (4H, m); MS (FAB) 398 (M+H).sup.+.
EXAMPLE 28
(R,S)-4-Acetyl-1-[(2-trifluoromethylphenyl)acetyl]-3-[(1-pyrrolidinyl)-met-
hyl]piperazinecarboxylate hydrochloride [(R,S)-10c HCl]
[0257] The compound was prepared from 2-trifluorometylphenylacetic
acid and the hydrochloride salt was made from 1M etherial HCl to
give (R,S)-10c HCl in 57%; 220.degree. C. (d); .sup.1H NMR (free
base, 200 MHz, CDCl.sub.3) .delta. 1.65 (4H, m), 2.05 (3H, s),
2.25-3.25 (6H, m), 3.40-4.10 (6H, m), 4.50 (2H, m), 4.70 (1H, m),
7.30 (2H, m), 7.60 (2H, m); MS (FAB) 398 (M+H).sup.+.
EXAMPLE 29
(R,S)-4-Acetyl-1-[(3-nitrophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]pipera-
zine-carboxylate hydrochloride [(R,S)-10d HCl]
[0258] The compound was prepared from 3-nitrophenylacetic acid and
the hydrochloride salt, (R,S)-10d HCl was isolated as a white solid
in 69% yield; mp 143-145.degree. C.; .sup.1H NMR (free base, 200
MHz, CDCl.sub.3) .delta. 1.63 (4H, brs), 2.05 (3H, s), 2.20-2.80
(6H, m), 2.90-3.25 (2H, m), 3.50-3.90 (3H, m), 4.00 (1H, J=14.0 Hz,
d), 4.45 (2H, m), 4.65 (1H, m), 7.45 (2H, m), 8.00 (2H, m); MS
(FAB) 375 (M+H).sup.+; Anal. Calcd for
C.sub.19H.sub.26N.sub.4O.sub.4.HCl.H.sub.2O: C, 53.21; H, 6.81; N,
13.06. Found: C, 53.51; H, 6.13; N, 12.91.
EXAMPLE 30
(R,S)-4-Acetyl-1-[(2-nitrophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]pipera-
zine-carboxylate hydrochloride [(R,S)-10e HCl]
[0259] The compound was prepared as above from 2-nitrophenylacetic
acid to give (R,S)-10e HCl as white solid in 50% yield; mp
180.degree. C. (d); .sup.1H NMR (free base, 200 MHz, CDCl.sub.3)
.delta. 1.63 (4H, m), 2.04 (3H, s), 2.20-2.85 (6H, m), 2.98-3.35
(3H, m), 3.604.25 (4H, m), 4.60 (2H, m), 7.35 (3H, m), 8.00 (1H,
J=7.0 Hz, d); MS (FAB) 375 (M+H).sup.+; Anal. Calcd for
C.sub.19H.sub.26N.sub.4O.sub.4.HCl.0.5H.sub.2O: C, 55.54; H, 6.62;
N, 13.64. Found: C, 54.38; H, 6.35; N, 13.58.
EXAMPLE 31
(R,S)-4-Acetyl-1-[(4-nitrophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]pipera-
zine-carboxylate hydrochloride [(R,S)-10f HCl]
[0260] The compound was prepared from 2-nitrophenylacetic acid as
before to give (R,S)-10f HCl in 52% yield; 146-148.degree. C.;
.sup.1H NMR (free base, 200 MHz, CDCl.sub.3) .delta. 1.68 (4H, m),
2.07 (3H, s), 2.20-2.75 (6H, m), 3.40-3.90 (3H, m), 4.05 (1H,
J=13.5 Hz, d), 4.50 (2H, m), 7.35 (2H, J=8.0 Hz, d), 8.10 (2H,
J=8.0 Hz, d); MS (FAB) 375 (M+H).sup.+; Anal. Calcd for
C.sub.19H.sub.26N.sub.4O.sub.4.HCl.0.5H.sub.2O.0.125CH.su-
b.2Cl.sub.2: C, 53.36; 6.61; 13.01. Found: C, 53.16; H, 6.27; N,
13.36.
EXAMPLE 32
(R,S)-4-(Phenylmethyl)-1-[(4,5,-dichloro-2-nitrophenyl)acetyl]-2-[(1-pyrro-
lidinyl)methyl]piperazine dihydrochloride [(R,S)-12 2HCl]
[0261] The compound was prepared from
4-phenylmethyl-2[(1-pyrrolidinyl)met- hyl]piperazine (Ref. 1) and
4,5-dichloro-2-nitrophenylacetic acid following the method
described above to give (R,S)-12 2HCl in 63% yield; mp 235.degree.
C. (d); .sup.1H NMR (free base, 200 MHz, CDCl.sub.3) .delta. 1.66
(4H, m), 2.05-3.00 (8H, m), 3.45 (4H, m), 4.00 (5H, m), 4.60 (1H,
m), 7.35 (6H, m), 8.15 (1H, s); MS (FAB) 493 (M+H).sup.+; Anal.
Calcd for C.sub.24H.sub.29Cl.sub.2N.sub.4O.sub.3.2HCl: C, 50.99;
5.53; 9.91. Found: C, 50.55; H, 5.16; N, 9.44.
[0262] The preparation of compounds of formula IA (compounds 1a
through 1qq) follow according to Schemes A, B, C, D, E and F. 45 46
47 48 49 50
EXAMPLE 1a
Methyl-4-[-2-glycyl-4-(trifluoromethylphenyl)acetyl]-3-(R,S)-[(1-pyrrolidi-
nyl)-methyl]-1-piperazinecarboxylate
[0263]
Methyl-4-[(2-nitro-4-trifluoromethylphenyl)acetyl]-3-(R,S)-[(1-pyrr-
olidinyl)-methyl]-1-piperazinecarboxylate.sup.1 (Procedure A) (a):
To a solution of 2-nitro-4-trifluorophenylacetic acid (2.8 g, 11.2
mmol) in 30 mL of dry CH.sub.2Cl.sub.2 under a nitrogen atmosphere
was added HOBt (1.3 g., 9.6 mmol). The reaction mixture is stirred
at 0.degree. C. and added solid EDCI (2.25 g, 11.75 mmol). Then,
stirred for 30 minutes at 0.degree. C. A solution of
methyl-3-(R,S)-[(1-pyrrolidinyl)methyl]-1-pipe-
razinecarboxylate.sup.1 (2.0 g, 8.78 mmol) in 5 mL of dry
CH.sub.2Cl.sub.2 was added followed by DIEA (1.68 mL, 9.64 mmol).
The reaction mixture was stirred for 24 h while warming to room
temperature. The reaction mixture was then poured into water (50
mL) and stirred for 30 minutes. After dilution with
CH.sub.2Cl.sub.2, the organic layer was separated, washed with
saturated NaHCO.sub.3, salt solution, and water. Then, dried over
Mg.sub.2SO.sub.4. The compound was purified by flash column
chromatography on silica gel, eluting with
CH.sub.2Cl.sub.2:CH.sub.3OH: (98:2) to give the desired product as
a free base (3.15 g, 78% yield). Then, proceed on to the next step.
.sup.1H NMR (free base 200 MHz, CDCl.sub.3) .delta. 1.76 (4H, m),
2.65 (4H, m), 3.02 (2H, m), 3.74 (s, 3H), 4.21 (4H, m), 7.56 (dd,
J=2.4, 8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 8.4 (d, J=2.4 Hz, 1H);
MS (FAB) m/z 459.
[0264]
Methyl-4-[(2-amino-4-trifluoromethylphenyl)acetyl]-3-(R,S)-[(1pyrro-
lidinyl)-methyl]-1-piperazinecarboxylate hydrochloride (b):
Compound a (1.18 gm, 2.57 mmol) was dissolved in ethanol (50 mL)
and heated to 55.degree. C. Hydrazine hydrate (0.9 mL, 28.12 mmol)
and 1 scoop of Raney Nickel was added to the reaction flask. Stir
vigorously. Continue to add the Raney Nickel until all of the
hydrazine is consumed (when the bubbling has stopped). Cool to
30.degree. C. and filter through celite and wash with hot methanol.
(Do not allow the Raney nickel to become dry!). Evaporate the
solvent and generate an HCl salt (1.0 gm; 90.6%); m.p.
160-165.degree. C. .sup.1H NMR (free base 200 MHz, CDCl.sub.3)
.delta. 1.76 (4H, m), 2.5-3.1 (7H, m), 3.74 (3H, s), 4.15 (2H, m),
4.55 (2H, m), 6.90 (1H, J=2.4 Hz, d), 6.95 (1H, J=2.4, 8.0 Hz, dd),
7.15 (1H, J=8.0 Hz, d). MS (FAB) m/z 429. Anal. Calc. For
C.sub.20H.sub.27N.sub.4F.- sub.3O.sub.3.HCl.H.sub.2O: C, 49.69; H,
6.21; N, 11.60. Found: C, 49.57; H, 6.04; N, 11.32.
[0265] To a solution of bromoacetic acid (0.356 g, 2.56 mmol.) and
DIEA (1.0 mL, 5.74 mmol.) in CH.sub.3CN (15 mL) was added compound
b and heated to 55.degree. C. for 16 hr. Then, heated to 75.degree.
C. for 4 hr. The reaction was complete. Evaporate the solvent and
re-dissolve in ethanol (25.0 mL). Add 0.1 M Na.sub.2CO.sub.3 (20
mL) and filter and wash with boiling ethanol (15 mL). Evaporate the
filtrate and dissolve in isopropanol (10 mL). Add diethyl ether
(5.0 mL) until precipitate forms. Filtered. A white solid is
obtained (m.p. 165-170.degree. C.; 0.3 g, 24.8% yield). .sup.1H NMR
(free base 200 MHz, CDCl.sub.3) d 2.19 (4H, m), 2.95 (4H, m),
3.2-3.7 (4H, m), 3.74 (3H, s), 3.8-4.2 (4H, m), 4.7 (1H, m), 5.2
(1H, m), 6.86 (1H, J=2.4 Hz, d), 7.0 (2H, J=8.0 Hz, d). MS (FAB)
m/z 487. Anal. Calc. For C.sub.22H.sub.29N.sub.4F.sub.3O.sub.5.0.5
C.sub.2H.sub.6O. 0.5H.sub.2O: C, 53.28; H, 6.37; N, 10.81. Found:
C, 53.50; H, 6.25; N, 10.51.
EXAMPLE 1b
Methyl-4-[(2-[N,N-bis-methylsulfonamido]-4-trifluoromethyphenyl)acetyl]-3--
(R,S)-[(1-pyrrolidinyl)-methyl]-1-piperazinecarboxylate
dihydrochloride
[0266] To a solution of compound b (0.4 g, 0.933 mmol.) and
triethylamine (0.26 mL, 1.86 mmol.) in CH.sub.2Cl.sub.2(10.0 mL) at
0.degree. C. was added methanesulfonyl chloride (0.144 mL, 1.86
mmol.). The reaction was stirred for 16 hr. The reaction was
diluted with CH.sub.2Cl.sub.2(40.0 mL), washed with saturated
NaHCO.sub.3 solution and water. Then, dried over Mg.sub.2SO.sub.4.
Then, isolated on a silica gel column (solvent system:
CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH (98:2:2) to give the
desired product as a free base (0.4 g, 73%). Evaporate the solvent
and generate an HCl salt (0.14 gm; m.p. 155-160.degree. C.).
.sup.1H NMR (free base 200 MHz, CDCl.sub.3) .delta. 1.76 (4H, m),
2.75-3.31 (11H, m), 3.47 (3H, s), 3.50 (3H, s), 3.72 (3H, s),
3.8-4.3 (5H, m), 4.55 (1H, m), 4.95 (1H, m), 7.5-7.9 (3H, Ar). MS
(FAB) m/z 585. Anal. Calc. For
C.sub.22H.sub.31N.sub.4F.sub.3O.sub.7S.sub.2.2HCl: C, 42.54; H,
5.19; N, 9.02. Found: C, 42.58; H, 5.23; N, 8.91.
EXAMPLE 1c
Methyl-4-[(2-[N-methylsulfonamido]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)-
methyl]-1-piperazinecarboxylate hydrochloride
[0267]
Methyl-4-[(2-nitro-phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)methyl]--
1-piperazinecarboxylate (c): The compound was prepared from
2-nitro-phenylacetic acid following Procedure A and isolated on a
silica gel column (solvent system: CH.sub.2Cl.sub.2:CH.sub.3OH:28%
NH.sub.4OH (99:1:2) to give the desired product as a free base
(3.15 g, 78%). Then, proceed on to the next step. .sup.1H NMR (free
base 300 MHz, CDCl.sub.3) d 1.75 (4H, m), 2.53 (4H, m), 3.02 (2H,
m), 3.74 (s, 3H), 4.21 (4H, m), 7.4 (1H, ArH, m) 7.56 (1H, J=1.2
Hz, d), 7.61 (1H, J=1.2, 7.4 Hz, dd), 8.11 (1H, J=8.0 Hz, d).
[0268]
Methyl-4-[(2-amino-phenyl)acetyl]-3-(R,S)-[(1-pyrrolidinyl)methyl]--
1-piperazinecarboxylate (d): Then, compound c was dissolved in
ethanol (200 mL) and Pd/C (Degussa; 10%; 3.0 g) were added into a
Parr bottle (500 mL). Then, the bottle was attached to a Parr
Shaker Hydrogenator at 50 psi for 6 hr. The reaction was complete.
This was filtered through celite. Evaporate the solvent and proceed
on to the final step.
[0269] Then, to a solution of the above compound d (0.15 g, 0.33
mmol.) and triethylamine (0.10 mL, 0.66 mmol.) in CH.sub.2Cl.sub.2
(10.0 mL) at 0.degree. C. was added methanesulfonyl chloride (0.026
mL, 0.33 mmol.). The reaction was stirred for 16 hr. The reaction
was diluted with CH.sub.2Cl.sub.2 (20.0 mL), washed with saturated
NaHCO.sub.3 solution and water. Then, dried over Mg.sub.2SO.sub.4.
Then, isolated on a silica gel column (solvent system:
CH.sub.2Cl.sub.2: CH.sub.3OH:28% NOH (98:2:2) to give the desired
product as a free base (0.1 g, 68%). Evaporate the solvent and
generate an HCl salt (0.06 gm; m.p. 130-135.degree. C.). .sup.1H
NMR (free base 200 MHz, CDCl.sub.3) .delta. 1.75 (4H, m), 2.2 (1H,
m), 2.5-3.1 (6H, m), 3.01 (3H, s), 3.50 (2H, m), 3.73 (3H, s),
3.8-4.5 (5H, m), 5.02 (1H, m), 6.88-7.55 (3H, Ar). MS (FAB) m/z
439. Anal. Calc. For C.sub.20H.sub.30N.sub.4O.sub.5S.sub.2.HCl: C,
50.57; H, 6.58; N, 11.79. Found: C, 50.55; H, 6.64; N, 11.36.
EXAMPLE 1d
Methyl-4-[(2-[N,N-bis-methylsulfonamido]phenyl)acetyl]-3-(R,S)-[(1-pyrroli-
dinyl)methyl]-1-piperazinecarboxylate hydrochloride
[0270] To a solution of the compound d (0.70 g, 1.94 mmol.) and
triethylamine (0.44 mL, 3.19 mmol.) in CH.sub.2Cl.sub.2(10.0 mL) at
0.degree. C. was added methanesulfonyl chloride (0.247 mL, 3.19
mmol.). The reaction was stirred for 16 hr. The reaction was
diluted with CH.sub.2Cl.sub.2 (20.0 mL), washed with saturated
NaHCO.sub.3 solution and water. Then, dried over Mg.sub.2SO.sub.4.
Then, isolated on a silica gel column (solvent system:
CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH (98:2:2) to give the
desired product as a free base (0.7 g, 70%). Evaporate the solvent
and generate an HCl salt (0.75 g; m.p. 145-150.degree. C.). .sup.1H
NMR (free base 200 MHz, CDCl.sub.3) .delta. 1.76 (4H, m), 2.2 (1H,
m), 2.5-3.1 (6H, m), 3.44 (3H, s), 3.49 (3H, s), 3.71 (3H, s),
3.8-4.5 (5H, m), 4.50 (1H, m), 4.89 (1H, m), 7.23-7.75 (3H, Ar). MS
(FAB) m/z 517. Anal. Calc. For C.sub.21H.sub.32N.sub.4O.sub.7S.su-
b.2.HCl: C, 46.05; H, 6.22; N, 10.09. Found: C, 45.60; H, 6.01; N,
10.13.
EXAMPLE 1e
Methyl-4-[(2-[N-methylamino)sulfamyl]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidin-
yl)methyl]-1-piperazinecarboxylate hydrochloride
[0271] The compound Was prepared from (N-methylamino)sulfamyl
phenyl acetic acid (a mixture of the ortho and para isomer)
following Procedure A and isolated on a silica gel column [solvent
system: CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH (99:2:1):
R.sub.f=0.56] to give the desired product as a free base (0.70 g,
70%). Then, generate the HCl salt (m.p. 155-160.degree. C.; 0.31
g). .sup.1H NMR (free base 200 MHz, CDCl.sub.3) .delta. 1.75 (m,
4H), 2.53 (m, 4H), 2.66 (d, J=5.2 Hz, 3H), 2.82 (m, 3H), 3.25 (m,
1H), 3.72 (s, 3H), 3.84 (m, 2H), 4.15 (m, 2H), 4.50 (m, 1H), 4.85
(m, 1H), 7.45 (dd, J=4.0, 8.2 Hz, 2H) 7.79 (d, J=8.0 Hz, 1H), 7.83
(d, J=8.2 Hz, 1H); MS (FAB) m/z 439. Anal. Calc. For
C.sub.20H.sub.30N.sub.4O.sub.5S.HCl: C, 50.13; H, 6.61; N, 11.36.
Found: C, 50.57; H, 6.58; N, 11.79.
EXAMPLE 1f
Methyl-4-[-4-[N-methylamino)sulfamyl]phenyl)acetyl]-3-(R,S)-[(1-pyrrolidin-
yl)methyl]-1-piperazinecarboxylate hydrochloride
[0272] The compound was isolated from the above reaction on a
silica gel column [solvent system: CH.sub.2Cl.sub.2:CH.sub.3OH:28%
NH.sub.4OH (99:1:2): R.sub.f=0.62] to give the desired product as a
free base. Then, generate the HCl salt (m.p. 135-140.degree. C.;
6.0 mg). .sup.1H NMR (free base 200 MHz, CDCl.sub.3) .delta. 1.74
(m, 4H), 2.53 (m, 4H), 2.66 (d, J=5.2 Hz, 3H), 2.82 (m, 3H), 3.25
(m, 1H), 3.71 (s, 3H), 3.84 (m, 2H), 4.15 (m, 2H), 4.50 (m, 1H),
4.85 (m, 1H), 7.48 (m, 2H, ArH) 7.73 (m, 2H, ArH); MS (FAB) m/z
439. Anal. Calc. For C.sub.20H.sub.30N.sub.4O.sub.- 5S.HCl: C,
50.13; H, 6.61; N, 11.36. Found: C, 50.57; H, 6.58; N, 11.7.
EXAMPLE 1g
4-Trifluoroacetyl-1-[(trans-3-furanacyrlate]-2-(R,S)-(1-pyrrolidinyl)methy-
l]piperazine hydrochloride
[0273] 4-Trifluoroacetyl-2-(R,S)-(1-pyrrolidinyl)methyl piperazine
(e): To a solution of (R,S)2-(1-pyrrolidinyl)methyl]piperazine
hydrochloride (1.0 g, 3.58 mmol) and Et.sub.3N (0.5 mL, 3.58 mmol)
in 10 mL of CH.sub.2Cl.sub.2 was added trifluoroacetic anhydride
(0.5 mL, 3.58 mmol) at 0.degree. C. The reaction mixture is stirred
at 0.degree. C. for 5 h. The reaction mixture was evaporated under
reduced pressure (due to the water solubility of this compound
there was no aqueous work-up) and isolated on a silica gel column
(solvent system: CH.sub.2Cl.sub.2:CH.sub.- 3OH:28% NH.sub.4OH
(98:2:2) to give the desired product as a free base (0.18 g, 20%);
.sup.1H NMR (free base 200 MHz, CDCl.sub.3) d 1.76 (m, 4H),
2.25-3.15 (m, 10H), 3.26 (t, 2H), 3.88 (m, 1H), 4.39 (t, 1H).
[0274] To a solution of trans-3-furanacyrlic acid (0.10 g, 0.74
mmol) in 5 mL of dry CH.sub.2Cl.sub.2 under a nitrogen atmosphere
was added HOBt (0.10 g., 0.74 mmol). The reaction mixture is
stirred at 0.degree. C. and added solid EDCI (0.143 g, 0.75 mmol).
Then, stirred for 30 minutes at 0.degree. C. A solution of compound
e (0.18 g, 0.67 mmol) in 5 mL of dry CH.sub.2Cl.sub.2 was added
followed by DIEA (0.177 mL, 1.01 mmol). The reaction mixture was
stirred for 24 h while warming to room temperature. The reaction
mixture was then poured into water (50 mL) and stirred for 30
minutes. After dilution with CH.sub.2Cl.sub.2, the organic layer
was separated, washed with saturated NaHCO.sub.3, salt solution,
and water. Then, dried over Mg.sub.2SO.sub.4. The compound was
purified by flash column chromatography on silica gel, eluting with
CH.sub.2Cl.sub.2:CH.sub- .3OH:28% NH.sub.4OH (99:1:2) to give the
desired product as a free base (m.p. 144-145.degree. C.; 0.25 g,
95% yield). The hydrochloride salt was prepared from 1M etheral
HCl. (0.1 g) .sup.1H NMR (free base 200 MHz, CDCl.sub.3) .delta.
1.74 (m, 4H), 2.57 (m, 5H), 3.11 (m, 2H), 3.31 (m, 2H), 4.05 (m,
1H), 4.25 (m, 1H), 4.50 (m, 1H), 4.65 (m, 1H), 6.58 (d, J=3.3, 7.8
Hz, 2H), 7.44 (m, 1H), 7.64 (d, J=3.3 Hz, 2H); MS (FAB) m/z 386;
Anal. Calcd. For C.sub.18H.sub.22N.sub.3F.sub.3O.sub.3.HCl: C,
51.25; H, 5.50; N, 9.96. Found: C, 51.44; H, 5.57; N, 9.86.
EXAMPLE 1h
4-Trifluoroacetyl-1-[(-4-trifluoromethylphenyl)acetyl]-2-(R,S)-(1-pyrrolid-
inyl)methyl]piperazine hydrochloride
[0275] To a solution of 4-trifluoromethyl-phenyl acetic acid (0.08
g, 0.39 mmol) in CH.sub.2Cl.sub.2 (5.0 mL) was added 1,1'
carbonyldiimidazole (0.06 g, 0.39 mmol) under a nitrogen atmosphere
and stirred for 1 h. Cool to 0.degree. C. and compound e (0.1 g,
0.39 mmol) in CH.sub.2Cl.sub.2 (5.0 mL) was added. Then, stirred
for 16 h and the reaction mixture was then poured into a solution
of ice-cold saturated NaHCO.sub.3 and stirred for 30 minutes. After
dilution with CH.sub.2Cl.sub.2, the organic layer was separated,
washed with saturated salt solution, and dried over
Mg.sub.2SO.sub.4. The compound was purified by flash column
chromatography on silica gel, eluting with
CH.sub.2Cl.sub.2:CH.sub.3OH:28- % NH.sub.4OH (99:1:2) to give the
desired product as a free base (m.p. 140-145.degree. C.; 0.08 g,
47% yield). The hydrochloride salt was prepared from 1M etheral
HCl. (0.05 g) .sup.1H NMR (free base 200 MHz, CDCl.sub.3) .delta.
1.75 (m, 4H), 2.55 (m, 5H), 2.69-3.2 (m, 4H), 3.8 (m, 1H), 3.83 (m,
2H), 4.50 (m, 1H), 4.65 (m, 1H), 7.38 (d, J=7.7 Hz, 2H), 7.64 (d,
J=7.8 Hz, 2H); MS (FAB) m/z 452; Anal. Calcd. For
C.sub.20H.sub.23N.sub.3F.sub.3O.sub.2.HCl.0.3Et.sub.2O: C, 49.96;
H, 5.30; N, 8.24. Found: C, 49.62; H, 5.16; N, 7.84.
EXAMPLE 1i
Methyl-4-[(3,4-dichlorophenyl)acetyl]-3-(R,S)-[(4'-methylpiperazinecarboxy-
late)methyl]-1-piperazinecarboxylate hydrochloride
[0276] The compound was prepared by coupling of
3,4-dichlorophenylacetic acid with methyl-3
(R,S)-[(4'-methylpiperazinecarboxylate)methyl]-1-piper-
azinecarboxylate; mp: (HCl salt) 160-165.degree. C.; .sup.1H NMR
(free base, 200 MHz, CDCl.sub.3) .delta. 1.5-1.8 (2H, m), 2.2-3.2
(8H, m), 3.3-3.5 (5H, m), 3.6 (3H, s), 3.7 (3H, s), 3.94.5 (3H, m),
4.74.8 (1H, m), 7.1 (1H, m), 7.4 (2H, m); MS (FAB) 487 (M+H).sup.+;
Anal. Calcd. for C.sub.21H.sub.28Cl.sub.2N.sub.4O.sub.5.HCl.
H.sub.2O: C, 46.55; H, 5.77; N, 10.34. Found: C, 46.02; H, 5.93; N,
10.91.
EXAMPLE 1j
Methyl-4-[(4-a,a,a-trifluoromethylphenyl)acetyl]-3-(R,S)-[3-(S)-(4'-.alpha-
.,.alpha.,.alpha.-trifluoro
methylphenylacetate)-1-(pyrrolidinyl)methyl]-1-
-piperazinecarboxylate hydrochloride (1j)
[0277] The compound was prepared by coupling of
4-.alpha.,.alpha.,.alpha.-- trifluoromethylphenyl-acetic acid with
methyl-3-(R,S)-[3-(S)-hydroxy-1-(py-
rrolidinyl)methyl]-1-piperazine carboxylate; mp: (HCl salt)
98-100.degree. C.; .sup.1H NMR (free base, 200 MHz, CDCl.sub.3)
.delta. 1.6-3.1 (11H, m), 3.4-5.4 (12H, m), 7.1-7.7 (8H, m); MS
(FAB) 616 (M+H).sup.+; Anal. Calcd for
C.sub.29H.sub.31F.sub.6N.sub.3O.sub.5.HCl. H.sub.2O.0.25NH.sub.4Cl:
C, 50.97; H, 5.16; N, 6.66. Found: C, 50.45; H, 5.07; N, 6.67.
EXAMPLE 1k
Methyl-4-[(3,4-dichlorophenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemethyl-3'-
,4'-dichlorophenyl acetate)methyl]-1-piperazinecarboxylate
hydrochloride
[0278] The compound was prepared by coupling of
3,4-dichlorophenylacetic acid with
methyl-3-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperazine-
carboxylate; mp: (HCl salt) 77-80.degree. C.; .sup.1H NMR (free
base, 300 MHz, CDCl.sub.3) .delta. 1.3-2.0 (5H, m), 2.0-2.5 (4H,
m), 2.5-3.3 (5H, m), 3.7 (3H, s), 3.4-4.8 (3H, m), 3.8-4.9 (5H, m),
7.0 (2H, m), 7.3 (4H, m); MS (FAB) 632 (M+H).sup.+; Anal. Calcd for
C.sub.30H.sub.33F.sub.6N.su- b.3O.sub.4.
EXAMPLE 1l
Methyl-4-[(3,4-dichlorophenyl)acetyl]-3-(R)-[(2-(S)-pyrrolidinemethanol)me-
thyl]-1-piperazinecarboxylate hydrochloride
[0279] The compound was prepared by aq. LiOH hydrolization of 1k;
mp: (HCl salt)135-138.degree. C.; .sup.1H NMR (free base, 300 MHz,
CDCl.sub.3) .delta. 1.6-1.8 (4H, m), 3.7 (3H, s), 2.0-4.1 (15H, m),
4.3-4.8 (2H, m), 7.0 (1H, m), 7.3 (1H, m); MS (FAB) 444
(M+H).sup.+; Anal. Calcd. for
C.sub.20H.sub.27Cl.sub.2N.sub.3O.sub.4.HCl. H.sub.2O: C, 48.16; H,
6.06; N, 8.42. Found: C, 48.64; H, 6.05; N, 8.45.
EXAMPLE 1m
Methyl-4-[(2-nitro-4-.alpha.,.alpha.,.alpha.-trifluoromethylphenyl)acetyl]-
-3-(R,S)-[(2-(S)-pyrrolidine
methanol)methyl]-1-piperazinecarboxylate hydrochloride
[0280] The compound was prepared by aq. LiOH hydrolization of
methyl-4-[(2-nitro-4-.alpha.,.alpha.,.alpha.-trifluoromethylphenyl)acetyl-
]-3-(R,S)-[(2-(S)-pyrrolidine
methyl-2'-nitro-4'-.alpha.,.alpha.,.alpha.-t-
rifluoromethylphenyl)acetate)methyl]-1-piperazinecarboxylate; mp:
(HCl salt)136-140.degree. C.; .sup.1H NMR (free base, 300 MHz,
CDCl.sub.3) .delta. 1.6-1.9 (3H, m), 3.7 (3H, d), 2.1-3.6 (12H, m),
3.94.9 (6H, m), 7.4 (1H, d), 7.8 (1H, d), 8.3 (1H, s); MS (FAB) 489
(M+H).sup.+; Anal. Calcd. for
C.sub.21H.sub.27F.sub.3N.sub.3O.sub.6.HCl: C, 48.05; H, 5.38; N,
10.67. Found: C, 47.81; H, 5.27; N, 10.49.
EXAMPLE 1n
Methyl-4-[(4-methylsulphonylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemeth-
yl-4'-methylsulphonylphenylacetate)methyl]-1-piperazinecarboxylate
hydrochloride
[0281] The compound was prepared by coupling of
4-methylsulphonylphenylace- tic acid with
methyl-3-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]-1-piperaz-
inecarboxylate; mp: (HCl salt) 133-135.degree. C.; .sup.1H NMR
(free base, 300 MHz, CDCl.sub.3) .delta. 1.4-2.5 (5H, m), 3.0 (3H,
s), 2.6-3.3 (8H, m), 3.4-4.9 (15H, m), 7.4 (4H, m), 7.9 (4H, m); MS
(FAB) 650 (M+H).sup.+; Anal. Calcd. for
C.sub.30H.sub.39S.sub.2N.sub.3O.sub.9.HCl.0.75NH.sub.4Cl- : C,
49.61; H, 5.97; N, 7.23. Found: C, 50.07; H, 6.17; N, 7.26.
EXAMPLE 1o
Methyl-4-[(4-methylsulphonylphenyl)acetyl]-3-(R,S)-[(2-(S)-pyrrolidinemeth-
anol)methyl]-1-piperazinecarboxylate hydrochloride
[0282] The compound was prepared by aq. LiOH hydrolization of
compound 1n; mp: (HCl salt) 130-135.degree. C.; .sup.1H NMR (free
base, 300 MHz, CDCl.sub.3) .delta. 1.6-1.9 (4H, m), 2.1-2.5 (2H,
m), 2.5-3.4 (7H, m), 3.0 (3H, s), 3.44.2 (6H, m), 3.7 (3H, m),
4.2-5.0 (2H, m), 7.5 (2H, m), 7.9 (2H, m); MS (FAB) 454
(M+H).sub.t; Anal. Calcd. for
C.sub.21H.sub.31SN.sub.3O.sub.6.HCl.H.sub.2O: C, 49.65; H, 6.75; N,
8.27. Found: C, 50.19; H, 6.77; N, 8.26.
EXAMPLE 1p
Methyl-4-[(2-amino-4-.alpha.,.alpha.,.alpha.-trifluoromethylphenyl)acetyl]-
-3-(R,S)-[(2-(S)-pyrrolidine
methanol)methyl]-1-piperazinecarboxylate hydrochloride
[0283] The compound was prepared by Pd catalyzed hydrogenation of
compound 1m; mp: (HCl salt)140-143.degree. C.; .sup.1H NMR (free
base, 300 MHz, CDCl.sub.3) .delta. 1.7-3.3 (12H, m), 3.7 (3H, s),
3.34.3 (11H, m), 6.9 (2H, m), 7.1 (1H, m); MS (FAB) 459
(M+H).sup.+; Anal. Calcd. for
C.sub.21H.sub.29F.sub.3N.sub.4O.sub.4.2HCl.CH.sub.3OH: C, 46.90; H,
6.26; N, 9.94. Found: C, 46.96; H, 6.14; N, 9.93.
EXAMPLE 1q
Methyl-4-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-(3',4'-dichlorophenyl
acetate)-1-(pyrrolidinyl)methyl]-1-piperazinecarboxylate
hydrochloride
[0284] The compound was prepared by coupling of
3,4-dichlorophenylacetic acid with
methyl-3-(R,S)-[3-(S)-hydroxy-1-(pyrrolidinyl)methyl]-1-piperaz-
ine carboxylate; mp: (HCl salt) 125-128.degree. C.; .sup.1H NMR
(free base, 200 MHz, CDCl.sub.3) .delta. 1.9-3.1 (9H, m), 3.4-3.8
(8H, m), 4.04.2 (3H, m), 4.5-5.2 (3H, m), 7.1 (2H, m), 7.4 (4H, m);
MS (FAB) 618 (M+H).sup.+; Anal. Calcd for
C.sub.27H.sub.29Cl.sub.4N.sub.3O.sub.5.HCl: C, 49.60; H, 4.62; N,
6.43. Found: C, 49.39; H, 4.65; N, 6.44.
EXAMPLE 1r
4-Acetyl-1-[3-(N-methylsulfonamido)phenyl]acetyl-2-(R,S)-[(1-pyrrolidinyl)-
methyl]piperazine hydrochloride
[0285] The compound was prepared by methylsulphonylation of
4-acetyl-1-[3-amino)phenyl]acetyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperaz-
ine as clear oil, the dihydrochloride salt was prepared from 1M
etherial HCl; mp: (HCl salt)140.degree. C. (dec.); .sup.1H NMR
(free base, 200 MHz, CDCl.sub.3) .delta. 1.5-1.7 (4H, m), 1.8-3.1
(13H, m), 3.44.9 (9H, m), 6.5 (2H, m), 7.0 (2H, m); MS (FAB) 423
(M+H).sup.+. Anal. Calcd. for C.sub.20H.sub.30N.sub.4O.sub.4S.HCl.
NH.sub.4Cl: C, 46.87; H, 6.88; N, 13.67. Found: C, 44.83; H, 7.18;
N, 13.16.
EXAMPLE 1s
4-Acetyl-1-[(2-acetylamidophenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]p-
iperazine hydrochloride
[0286] The compound was prepared by acetylation of
4-acetyl-1-[(2-aminophe-
nyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine; mp: (HCl
salt)173.degree. C. (dec.); .sup.1H NMR (free base, 200 MHz,
CDCl.sub.3) .delta. 1.3-1.8 (6H, m), 2.0 (3H, s), 2.1 (3H, 3),
2.2-3.4 (8H, m), 3.64.8 (6H, m), 6.9-7.2 (3H, m), 7.8 (1H, m); MS
(FAB) 387 (M+H).sup.+; Anal. Calcd. for
C.sub.21H.sub.30N.sub.4O.sub.3.HCl.2H.sub.2O: C, 54.95; H, 7.69; N,
12.21. Found: C, 54.53; H, 6.91; N, 11.92.
EXAMPLE 1t
4-Acetyl-1-[(4-acetylamidophenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]p-
iperazine hydrochloride
[0287] The compound was prepared by acetylation of
4-acetyl-1-[(4-aminophe-
nyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine; mp: (HCl
salt)165.degree. C. (dec.); .sup.1H NMR (free base, 200 MHz,
CDCl.sub.3) .delta. 1.5-1.7 (5H, m), 1.9-2.1 (6H, m), 2.2-3.1 (8H,
m), 3.54.7 (6H, m), 7.0 (2H, m), 7.4 (2H, m); MS (FAB) 387
(M+H).sup.+; Anal. Calcd for C.sub.21H.sub.30O.sub.3N.sub.4.HCl.
H.sub.2O: C, 57.20; H, 7.54; N, 12.71. Found: C, 57.05; H, 7.31; N,
12.74.
EXAMPLE 1u
4-Acetyl-1-[(4-methylsulfonyl]phenyl)acetyl]-2-(R,S)-[3-(S)-(4'-methylsulf-
onyl phenyl acetate)-1-(Pyrrolidinyl)methyl]piperazine
hydrochloride
[0288] The compound was prepared by coupling of
4-methylsulfonylphenylacet- ic acid with
4-acetyl-2-(R,S)-[3-(S)-hydroxy-1-(pyrrolidinyl)methyl]pipera-
zine; mp: (HCl salt) 160-163.degree. C.; .sup.1H NMR (free base,
200 MHz, CDCl.sub.3) .delta. 1.7-2.2 (7H, m), 2.3-3.2 (12H, m), 3.0
(6H, s), 3.5-4.1 (8H, m), 4.4-5.2 (4H, m), 7.4 (4H, m), 7.8 (4H,
m); MS (FAB) 620 (M+H).sup.+; Anal. Calcd for
C.sub.29H.sub.37S.sub.2N.sub.3O.sub.8.HCl: C, 53.00; H, 5.98; N,
6.39. Found: C, 52.26; H, 6.00; N, 6.37.
EXAMPLE 1v
4-Acetyl-1-[(4-.alpha.,.alpha.,.alpha.-trifluoromethylphenyl)acetyl]-2-(R,-
S)-[3-(S)-(4'-.alpha.,.alpha.,.alpha.-trifluoro methylphenyl
acetate)-1-(Pyrrolidinyl)methyl]piperazine hydrochloride
[0289] The compound was prepared by coupling of
4-.alpha.,.alpha.,.alpha.-- trifluoromethyphenyl acetic acid with
4-acetyl-2-(R,S)-[3-(S)-hydroxy-1-(p-
yrrolidinyl)methyl]piperazine; mp: (HCl salt) 134-136.degree. C.;
.sup.1H NMR (free base, 200 MHz, CDCl.sub.3) .delta. 1.6-3.2 (15H,
m), 3.4-4.1 (5H, m), 4.3-5.2 (3H, m), 7.3 (4H, m), 7.5 (4H, m); MS
(FAB) 599 (M+H).sup.+; Anal. Calcd for
C.sub.29H.sub.31F.sub.6N.sub.3O.sub.4.HCl.0.- 5NH.sub.4Cl: C,
52.55; H, 5.17; N, 7.40. Found: C, 52.05; H, 5.56; N, 7.90.
EXAMPLE 1w
4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-(3',4'-dichlorophen-
yl acetate)-1-(pyrrolidinyl)methyl]piperazine hydrochloride
[0290] The compound was prepared by coupling of
3,4-dichlorophenylacetic acid with
4-acetyl-2-(R,S)-[3-(S)-hydroxy-1-(pyrrolidinyl)methyl]piperazi-
ne; mp: (HCl salt)122-125.degree. C.; .sup.1H NMR (free base, 200
MHz, CDCl.sub.3) .delta. 1.6-1.9 (3H, m), 2.1 (3H, s), 2.1-3.9
(14H, m), 4.0-5.3 (3H, m), 7.1 (2H, m), 7.4 (4H, m); MS (FAB) 602
(M+H).sup.+; Anal. Calcd for
C.sub.27H.sub.29Cl.sub.4N.sub.3O.sub.4.HCl: C, 50.84; H, 4.74; N,
6.59. Found: C, 49.33; H, 4.76; N, 6.85.
EXAMPLE 1x
4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidinemethyl--
3',4' dichlorophenylacetate)methyl]piperazine hydrochloride
[0291] The compound was prepared by coupling of
3,4-dichlorophenylacetic acid with
4-acetyl-2-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]piperazine; mp:
(HCl salt)107-110.degree. C.; .sup.1H NMR (free base, 300 MHz,
CDCl.sub.3) .delta. 1.5-2.0 (3H, m), 2.0-2.2 (3H, d), 2.2-3.3 (9H,
m), 3.54.1 (8H, m), 4.4-4.9 ((2H, m), 7.1 (2H, m), 7.4 (4H, m); MS
(FAB) 616 (M+H).sup.+; Anal. Calcd. for
C.sub.28H.sub.31Cl.sub.4N.sub.3O.sub.4.HCl. NH.sub.4Cl: C, 47.68;
H, 5.14; N, 7.94. Found: C, 47.80; H, 5.38; N, 9.05.
EXAMPLE 1y
4-Acetyl-1-[(4-trifluoromethylphenyl)acetyl]-2(R,S)-[2-(S)-pyrrolidinemeth-
yl-4'-trifluoromethylphenylacetate)methyl]piperazine
hydrochloride
[0292] The compound was prepared by coupling of
3,4-dichlorophenylacetic acid with
4-acetyl-2-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]piperazine; mp:
(HCl salt) 110-113.degree. C.; .sup.1H NMR (free base, 300 MHz,
CDCl.sub.3) .delta. 1.5-3.3 (12H, m), 2.1 (3H, s), 3.54.1 (9H, m),
4.34.9 (1H, m), 7.3 (4H, m), 7.5 (4H, m); MS (FAB) 614 (M+H).sup.+;
Anal. Calcd for
C.sub.30H.sub.33F.sub.6N.sub.3O.sub.4.HCl.0.5NH.sub.4Cl: C, 53.24;
H, 5.36; N, 7.24. Found: C, 53.86; H, 5.45; N, 6.91.
EXAMPLE 1z
4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidine
methanol)methyl]piperazine hydrochloride
[0293] The compound was prepared by aq. LiOH hydrolization of
compound 1x; mp: (HCl salt)123-125.degree. C.; .sup.1H NMR (free
base, 300 MHz, CDCl.sub.3) .delta. 1.6-2.0 (4H, m), 2.1 (3H, m),
2.2-3.4 (10H, m), 3.44.0 (5H, m), 4.4-5.0 (2H, m), 7.1 (2H, m), 7.4
(2H, m); MS (FAB) 428 (M+H).sup.+; Anal. Calcd. for
C.sub.20H.sub.27Cl.sub.2N.sub.3O.sub.3.HCl: C, 51.68; H, 6.07; N,
9.04. Found: C, 49.84; H, 6.08; N, 9.03.
EXAMPLE 1aa
4-Acetyl-1-[(4-methylsulphonylphenyl)acetyl]-2-(R,S)
[(2-(S)-pyrrolidinemethyl-4'-methylsulphonylphenylacetate)methyl]piperazi-
ne hydrochloride
[0294] The compound was prepared by coupling of
4-methylsulphonylphenylace- tic acid with
4-acetyl-2-(R,S)-[(2-(S)-pyrrolidinemethanol)methyl]piperazi- ne;
mp: (HCl salt)145-148.degree. C.; .sup.1H NMR (free base, 300 MHz,
CDCl.sub.3) .delta. 1.5-2.0 (3H, m), 2.1 (3H, m), 3.0 (6H, s),
2.5-3.3 (9H, m), 3.64.2 (9H, m), 4.5 (1H, m), 7.5 (4H, m), 7.9 (4H,
m); MS (FAB) 634 (M+H).sup.+; Anal. Calcd. for
C.sub.30H.sub.39S.sub.2N.sub.3O.sub.8.H- Cl.0.25NH.sub.4Cl: C,
52.71; H, 6.05; N, 6.66. Found: C, 52.02; H, 6.19; N, 6.59
EXAMPLE 1bb
4-Acetyl-1-[(4-methylsulphonylphenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidineme-
thanol)methyl]piperazine hydrochloride
[0295] The compound was prepared by aq. LiOH hydrolization of
compound 1aa; mp: (HCl salt) 138-140.degree. C.; .sup.1H NMR (free
base, 300 MHz, CDCl.sub.3) .delta. 1.6-2.0 (4H, m), 2.1 (3H, m),
2.2-3.0 (5H, m), 3.1 (3H, s), 3.14.0 (10H, m), 4.4-5.0 (2H, m), 7.5
(2H, m), 7.9 (2H, m); MS (FAB) 438 (M+H).sup.+; Anal. Calcd. for
C.sub.21H.sub.31SN.sub.3O.sub.5.H- Cl.H.sub.2O: C, 51.26; H, 6.96;
N, 8.54. Found: C, 50.36; H, 6.92; N, 8.90.
EXAMPLE 1cc
4-Acetyl-1-[(4-trifluoromethylphenyl)acetyl]-2-(R,S)-[(2-(S)-pyrrolidineme-
thanol)methyl]piperazine hydrochloride
[0296] The compound was prepared by aq. LiOH hydrolization of
compound 1y; mp: (HCl salt)123-125.degree. C.; .sup.1H NMR (free
base, 300 MHz, CDCl.sub.3) .delta. 1.6-2.2 (4H, m), 2.1 (3H, s),
2.2-4.0 (15H, m), 4.5-5.0 (2H, m), 7.4 (2H, m), 7.6 (2H, m); MS
(FAB) 428 (M+H).sup.+; Anal. Calcd for
C.sub.21H.sub.28F.sub.3N.sub.3O.sub.3.HCl.NH.sub.4Cl: C, 48.75; H,
6.43; N, 10.83. Found: C, 47.46; H, 6.04; N, 12.40.
EXAMPLE 1dd
4-Formyl-1-[(2-N-methylsulfamylphenyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)met-
hyl]piperazine hydrochloride
[0297] The compound was prepared by coupling of
2-(N-methylaminosulfonyl)p- henyl acetic acid with
4-formyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine- ; mp: (HCl
salt) 150.degree. C. (dec.); .sup.1H NMR (free base, 200 MHz,
CDCl.sub.3) .delta. 1.7 (4H, m), 2.2-3.2 (11H, m), 3.44.0 (4H, m),
4.2-5.4 (4H, m), 7.0 (1H, m), 7.4 (2H, m), 7.6 (1H,), 8.0 (1H, m);
MS (FAB) 409 (M+H).sup.+; Anal. Calcd for
C.sub.19H.sub.28O.sub.4N.sub.4S.HC- l.0.5NH.sub.4Cl: C, 48.38; H,
6.62; N, 13.36. Found: C, 48.08; H, 6.46; N, 13.33.
EXAMPLE 1ee
4-Carbonylimidazole-1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)-
methyl]piperazine hydrochloride
[0298] The compound was prepared by coupling of
1,1'-carbonyldiimidazole with
1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperaz-
ine; mp: (HCl salt) 148.degree. C. (dec.); .sup.1H NMR (free base,
200 MHz, CDCl.sub.3) .delta. 1.5-1.7 (4H, m), 2.1-2.5 (5H, m),
2.6-3.4 (4H, m), 3.5-4.8 (7H, m), 6.9-7.4 (4H, m), 8.0 (1H, m); MS
(FAB) 450 (M+H).sup.+; Anal. Calcd for
C.sub.21H.sub.25Cl.sub.2N.sub.5O.sub.2.2HCl. H.sub.2O: C, 46.60; H,
5.40; N, 12.94. Found: C, 45.41; H, 5.33; N, 12.73.
EXAMPLE 1ff
4-Allyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piper-
azine hydrochloride
[0299] The compound was prepared by coupling of allyl bromide with
1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(1-pyrrolidinyl)methyl]piperazine
in 81% yield; mp: (HCl salt)157-160.degree. C.; .sup.1H NMR (free
base, 200 MHz, CDCl.sub.3) .delta. 1.4-2.0(6H, m), 2.3-3.0 (6H, m),
3.1-3.8 (4H, m), 4.34.8 (1H, m), 4.9-5.1 (2H, m), 5.7-5.9 (1H, m),
7.0-7.3 (3H, m); MS (FAB) 396 (M+H).sup.+; Anal. Calcd for
C.sub.20H.sub.27Cl.sub.2N.s- ub.30.2HCl: C, 51.19; H, 6.23; N,
8.95. Found: C, 50.89; H, 6.42; N, 8.65.
EXAMPLE 1gg
4-Acetyl-1-[(2-pyridyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine
hydrochloride
[0300] The compound was prepared by coupling of 2-pyridylacetic
acid with 4-acetyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine; mp:
(HCl salt) 127-130.degree. C.; .sup.1H NMR (free base, 200 MHz,
CDCl.sub.3) .delta.1.4-1.7 (4H, m), 2.0 (3H, s), 2.2-3.2 (9H, m),
3.4-4.8 (6H, m), 6.8-7.5 (3H, m), 8.4 (1H, m); MS (FAB) 331
(M+H).sup.+; Anal. Calcd. for
C.sub.18H.sub.26N.sub.4O.sub.2.2HCl.0.5NH.sub.4Cl: C, 50.27; H,
7.03; N, 14.65. Found: C, 50.86; H, 6.47; N, 15.79.
EXAMPLE 1hh
4-Formyl-1-[(2-pyridyl)acetyl]-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine
hydrochloride
[0301] The compound was prepared by coupling of 2-pyridinylacetic
acid with 4-formyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine; mp:
(HCl salt) 125-128.degree. C.; .sup.1H NMR (free base, 200 MHz,
CDCl.sub.3) .delta. 1.5-1.7 (4H, m), 2.1-3.6 (10H, m), 3.7-4.9 (5H,
m), 6.9-7.3 (2H, m), 7.6 (1H, m), 8.0 (1H, m), 8.6 (1H, m); MS
(FAB) 317 (M+H).sup.+; Anal. Calcd. for
C.sub.17H.sub.24N.sub.4O.sub.2.2HCl.NH.sub.4Cl: C, 46.11; H, 6.83;
N, 15.82. Found: C, 46.37; H, 6.51; N, 16.35.
EXAMPLE 1ii
Methyl-4-[(3,4-dichlorophenyl)acetyl]-3-(S)-[(2-(S)-pyrrolidinemethanol)me-
thyl]-1-piperazinecarboxlate hydrochloride
[0302] The compound was prepared by aq. LiOH hydrolization of 1k;
mp: (HCl salt)137-140.degree. C.; .sup.1H NMR (free base, 300 MHz,
CDCl.sub.3) .delta. 1.5-2.0 (4H, m), 3.7 (3H, s), 2.1-3.7 (14H, m),
3.84.9 (3H, m), 7.1 (1H, m), 7.3 (2H, m); MS (FAB) 444 (M+H).sup.+;
Anal. Calcd. for
C.sub.20H.sub.27Cl.sub.2N.sub.3O.sub.4.HCl.0.5NH.sub.4Cl: C, 47.33;
H, 5.96; N, 9.66. Found: C, 47.55; H, 6.11; N, 9.39.
EXAMPLE 1jj
4-Methanesulfonyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-methanesul-
fonate-1-(pyrrolidinyl) methyl]piperazine hydrochloride
[0303] The compound was prepared from
1-[(3,4-dichlorophenyl)acetyl]-2-[(3-
-hydroxy-1-pyrrolidinyl)methyl]piperazine dihydrochloride.sup.1
(0.25 g, 0.56 mmol), methanesulfonyl chloride (0.43 mL, 5.56 mmol),
triethylamine (2.3 mL, 16.53 mmol) and CH.sub.2Cl.sub.2 (20 mL) at
0.degree. C. for 6 h. After dilution with saturated NaHCO.sub.3
solution (20 mL) and washed with water (20 mL). Then, dried over
MgSO.sub.4. The compound was purified by flash chromatography on
silica gel, eluting with CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH
(99:1:2) to give the desired product as a free base (0.28 g; 94%
yield) and a hydrochloride salt was generated (0.067 g; m.p.
130-132.degree. C.; .sup.1H NMR (free base, 300 MHz, CDCl.sub.3)
.delta. 2.10 (m, 1H), 2.29 (m, 1H), 2.59 (m, 4H), 2.89 (s. 3H),
3.01 (s, 3H), 3.2-3.5 (m, 2H), 3.60-3.9 (m, 4H), 4.90 (m, 1H), 5.15
(m, 1H), 7.12 (d, J=8.2 Hz, 1H), 7.43 (d, J=8.3 Hz, 2H); MS (FAB)
528 (M+H).sup.+; Anal. Calcd. for
C.sub.19H.sub.27Cl.sub.2N.sub.3O.sub.6S- .sub.2.HCl: C, 40.40; H,
5.00; N, 7.44. Found: C, 40.29; H, 5.07; N, 7.04.
EXAMPLE 1kk
4-Methylsulphonyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[3-(S)-(3',4'dich-
loro phenyl acetate)-1-(pyrrolidinyl)methyl]piperazine
hydrochloride
[0304] The compound was prepared by coupling of
3,4-dichlorophenylacetic acid with
4-methylsulphonyl-2-(R,S)-[3-(S)-(hydroxy)-1-(pyrrolidinyl)meth-
yl]piperazine; mp: (HCl salt)145-148.degree. C.; .sup.1H NMR
(freebase, 200 MHz, CDCl.sub.3) .delta. 1.5-1.9 (2H, m), 2.2-3.0
(7H, m), 2.7 (3H, s), 3.5-4.0 (8H, m), 4.9-5.2 (3H, m), 7.1 (2H,
m), 7.4 (4H, m); MS (FAB) 638 (M+H).sup.+; Anal. Calcd. for
C.sub.26H.sub.29Cl.sub.4N.sub.3O.sub.5S- .HCl.0.5NH.sub.4Cl: C,
44.52; H, 4.60; N, 7.00. Found: C, 45.66; H, 4.72; N, 7.61.
EXAMPLE 1ll
4-Methylsulphonyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R,S)-[(3-(S)-hydroxy-1-
-pyrrolidinyl) methyl]piperazine hydrochloride
[0305] The compound was prepared by aq. LiOH hydrolization of 1kk;
mp: (HCl salt) 150-153.degree. C.; .sup.1H NMR (free base, 200 MHz,
CDCl.sub.3) .delta. 1.5-2.3 (4H, m), 2.4-3.2 (7H, m), 2.8 (3H, s),
3.4-4.0 (5H, m), 4.5-5.2 (3H, m), 7.1 (1H, m), 7.4 (2H, m); MS
(FAB) 450 (M+H).sup.+; Anal. Calcd. For
C.sub.18H.sub.25Cl.sub.2N.sub.3O.sub.4S.HCl- .0.25NH.sub.4Cl: C,
43.22; H, 5.44; N, 9.10. Found: C, 43.23; H, 5.16; N, 9.8
EXAMPLE 1mm
4-Methylsulphonyl-1-[(4-.alpha.,.alpha.,.alpha.-triflouromethylphenyl)acet-
yl]-2-(R,S)-[3-(S)-(4'-.alpha.,.alpha.,.alpha.-triflouro
methylphenyl acetate)-1-(pyrrolidinyl) methyl]piperazine
hydrochloride
[0306] The compound was prepared by coupling of
4-(.alpha.,.alpha.,.alpha.- -triflouromethyl)phenyl acetic acid
with 4-methyl sulphonyl-2-(R,S)-[3-(S)- -hydroxy-1-(pyrrolidinyl)
methyl]piperazine; mp: (HCl salt) 120-123.degree. C.; .sup.1H NMR
(free base, 200 MHz, CDCl.sub.3) .delta. 1.8-2.2 (4H, m), 2.4-3.3
(8H, m), 2.7 (3H, s), 3.64.0 (6H, m), 4.8-5.2 (2H, m), 7.4 (4H, m),
7.6 (4H, m); MS (FAB) 636 (M+H).sup.+; Anal. Calcd. For
C.sub.28H.sub.31F.sub.6N.sub.3O.sub.5S. HCl: C, 50.04; H, 4.80; N,
6.25. Found: C, 50.34; H, 4.80; N, 6.09.
EXAMPLE 1nn
4-Methylsulphonyl-1-[(4-.alpha.,.alpha.,.alpha.-triflouromethylphenyl)acet-
yl]-2-(R,S)-[(3-(S)-hydroxy-1-pyrrolidinyl)methyl]piperazine
hydrochloride
[0307] The compound was prepared by aq. LiOH hydrolization of 1 mm;
mp: (HCl salt) 145.degree. C. (dec.); .sup.1H NMR (free base, 200
MHz, CDCl.sub.3) .delta. 1.5-2.1 (3H, m), 2.3-3.4 (9H, m), 2.8 (3H,
s), 3.74.0 (5H, m), 4.3-5.0 (2H, m), 7.4 (2H, m), 7.6 (2H, m); MS
(FAB) 450 (M+H).sup.+; Anal. Calcd. for
C.sub.19H.sub.26F.sub.3N.sub.3O.sub.4S. HCl: C, 46.96; H, 5.60; N,
8.65. Found: C, 46.45; H, 5.66; N, 8.69.
EXAMPLE 1oo
4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(S)-[(3'-(S)-hydroxy-1-pyrrolidi-
ne)methyl]piperazine hydrochloride
[0308] The compound was prepared by coupling of
3,4-dichlorophenylacetic acid with
4-acetyl-2-(R,S)-[(3'-(S)-hydroxypyrrolidine)methyl]piperazine.
Then, this racemic mixture was separated on a Chiralpak AD column
using 100% acetonitrile as the eluant. Then, from the 2-(S), 3'-(S)
enantiomer a HCl salt was generated (1.0 gm.); mp: (HCl
salt)130-135.degree. C.; [a].sup.20+25.560 (0.85%; w/v MeOH).
.sup.1H NMR (free base, 300 MHz, CDCl.sub.3) .delta. 1.74 (1H, m),
2.13 (3H, s), 2.2 (1H, m), 2.3-3.2 (10H, m), 3.45-3.71 (3H, m),
4.11 (1H, d) 4.21-4.74 (2H, m), 4.55 ((1H, m), 7.10 (1H, J=8.25 Hz,
d), 7.41 (2H, J=8.28 Hz, d); MS (FAB) 414 (M+H).sup.+; Anal. Calcd.
for C.sub.19H.sub.25Cl.sub.2N.sub.3O.sub.3.HCl.- 0.5H.sub.2O: C,
49.65; H, 5.77; N, 8.91. Found: C, 49.58; H, 5.65; N, 9.13.
EXAMPLE 1pp
4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(R)-[(3'-(R)-hydroxy-1-pyrrolidi-
ne)methyl]piperazine hydrochloride
[0309] The compound was prepared by coupling of
3,4-dichlorophenylacetic acid with
4-acetyl-2-(R,S)-[(3'-(R)hydroxy-1-pyrrolidine)methyl]piperazin- e.
Then, this racemic mixture was separated on a Chiralpak AD column
using 100% acetonitrile as the eluant. Then, from the 2-(R), 3'-(R)
enantiomer a HCl salt was generated (0.9 gm.); mp: (HCl
salt)130-135.degree. C.; [a].sup.20 -30.49.degree. (0.88%; w/v
MeOH). .sup.1H NMR (free base, 300 MHz, CDCl.sub.3) .delta. 1.74
(1H, m), 2.13 (3H, s), 2.2 (1H, m), 2.3-3.2 (10H, m), 3.45-3.71
(3H, m), 4.11 (1H, d) 4.21-4.74 (2H, m), 4.55 ((1H, m), 7.10 (1H,
J=8.25 Hz, d), 7.41 (2H, J=8.28 Hz, d); MS (FAB) 414 (M+H).sup.+;
Anal. Calcd. for C.sub.19H.sub.25Cl.sub.2N.sub.3O.sub.3.HCl: C,
50.62; H, 5.81; N, 9.32. Found: C, 49.94; H, 5.84; N, 8.97.
EXAMPLE 1qq
4-Acetyl-1-[(3,4-dichlorophenyl)acetyl]-2-(S)-[(3'-(R)-hydroxy-1-pyrrolidi-
ne)methyl]piperazine hydrochloride
[0310] The compound was prepared by coupling of
3,4-dichlorophenylacetic acid with
4-acetyl-2-(R,S)-[(3'-(R)-hydroxy-1-pyrrolidine)methyl]piperazi-
ne. Then, this racemic mixture was separated on a Chiralpak AD
column using 100% acetonitrile as the eluant. Then, from the 2-(S),
3'-(R) enantiomer a HCl salt was generated (1.05 gm); mp: (HCl
salt)130-135.degree. C.; [a].sup.20+28.80 (0.75%; w/v MeOH).
.sup.1H NMR (free base, 300 MHz, CDCl.sub.3) .delta. 1.74 (1H, m),
2.13 (3H, s), 2.2 (1H, m), 2.3-3.2 (10H, m), 3.45-3.71 (3H, m),
4.11 (1H, d) 4.21-4.74 (2H, m), 4.55 ((1H, m), 7.10 (1H, J=8.25 Hz,
d), 7.41 (2H, J=8.28 Hz, d); MS (FAB) 414 (M+H).sup.+; Anal. Calcd.
for C.sub.19H.sub.25Cl.sub.2N.sub.3O.- sub.3.HCl: C, 50.62; H,
5.81; N, 9.32. Found: C, 50.19; H, 5.86; N, 9.06.
[0311] Ref.
[0312] Naylor, A.; Judd, D. B.; Lloyd, J. E.; Scopes, D. I. C.;
Hayes, A. G.; Birch, P. J. J. Med. Chem. 1993, 36, 2075-2083 and
references cited in there.
[0313] U.S. Pat. No. 5,116,842; Naylor et al; 1992.
[0314] Compounds of Formula II
[0315] General procedure for DCC/pyr coupling. With stirring at
25.degree. C. under N.sub.2, DCC (2.06 eq) and CH.sub.2Cl.sub.2
were added to a mixture of the acid (2 eq) and pyridine (2.06 eq)
in CH.sub.2Cl.sub.2. After 1-2 min, a solution of the amine (1 eq)
in CH.sub.2Cl.sub.2 was added, and the mixture was stirred at
25.degree. C. under N.sub.2 overnight. The final concentration of
the mixture is around 0.1-0.3 mM with respect to the amine. Sat'd.
NaHCO.sub.3 (2 mL) was added to destroy excess active esters before
the mixture was filtered through celite, and the DCU was washed
with CH.sub.2Cl.sub.2. The filtrate was then partitioned between
sat'd NaHCO.sub.3 and CH.sub.2Cl.sub.2, which was dried
(Na.sub.2SO.sub.4), filtered through celite, and evaporated.
Toluene was added to azeotrope off pyridine before the crude
product was chromatographed and converted to the HCl salt.
[0316] Compounds having the following structures were prepared:
51
[0317] (.+-.)-1, X=--OMe
[0318] (.+-.)-2, X=--NO.sub.2
[0319] (.+-.)-3, X=--OMe, R.sub.1=--H,
R.sub.2=3,4-Cl.sub.2-phenyl
[0320] (.+-.)-4, X=--OH, R.sub.1=--H,
R.sub.2=3,4-Cl.sub.2-phenyl
[0321] (.+-.)-5, X=--OCH.sub.2CO.sub.2H, R.sub.1=--H,
R.sub.2=3,4-Cl.sub.2-phenyl
[0322] (.+-.)-6, X=--OMe, R.sub.1=R.sub.2=phenyl
[0323] (.+-.)-7, X=--OH, R.sub.1=R.sub.2=phenyl
[0324] (.+-.)-8, X=--NO.sub.2, R.sub.1=--H,
R.sub.2=2-NO.sub.2-4,5-Cl.sub.- 2-phenyl
[0325] (.+-.)-9, X=--NO.sub.2, R.sub.1=--H,
R.sub.2=3,4-Cl.sub.2-phenyl
[0326] (.+-.)-10, X=--NH.sub.2, R.sub.1=--H,
R.sub.2=3,4-Cl.sub.2-phenyl
[0327] (.+-.)-11, X=--NO.sub.2, R.sub.1=--H,
R.sub.2=4-methylsulfonylpheny- l
[0328] (.+-.)-12, X=--N(CH.sub.2CO.sub.2tBu).sub.2, R.sub.1=--H,
R.sub.2=3,4-Cl.sub.2-phenyl
[0329] (.+-.)-13, X=--N(CH.sub.2CO.sub.2H).sub.2, R.sub.1=--H,
R.sub.2=3,4-Cl.sub.2-phenyl
[0330] (.+-.)-14, X=--N(CH.sub.2CO.sub.2Et).sub.2, R.sub.1=--H,
R.sub.2=3,4-Cl.sub.2-phenyl
[0331] (.+-.)-15, X=--NHPO.sub.3Et.sub.2, R.sub.1=--H,
R.sub.2=3,4-Cl.sub.2-phenyl
[0332] (.+-.)-16, X=--N(CH.sub.2).sub.2PO.sub.3Et.sub.2,
R.sub.1=--H, R.sub.2=3,4-Cl.sub.2-phenyl
[0333] Intermediates (.+-.)-1 and (.+-.)-2 were prepared via
reported methods from the appropriate starting materials..sup.5
Compounds (.+-.)-3 and (.+-.)-4 are known compounds prepared via
reported methods..sup.5 Compounds (.+-.)-5 through (.+-.)-16 were
prepared by DCC coupling of either (.+-.)-1 or (.+-.)-2 to an
arylacetic acid followed by demethylation or reduction to allow
peripheralization.
[0334] Ref.
[0335] (5) Rajagopalan, P. et al. Bioorg. Med. Chem. Letters 1992,
2, 721-726. 52
[0336] Intermediates 17 and 18 were prepared via known methods from
6-methoxy-1-tetralone and 1-tetralone, respectively. Intermediates
17 and 18 were coupled to 3,4-dichlorophenylacetic acid to produce
(.+-.)-19 and (.+-.)-20. 53
[0337] Intermediates (.+-.)-21 and (.+-.)-23 were prepared via
similar chemistry from 1-benzosuberone and
(.+-.)-trans-2-bromo-1-indanol.1 Compounds (.+-.)-22, (.+-.)-25
(Niravoline),.sup.6 and (.+-.)-27 are known compounds prepared via
reported chemistry..sup.1 Compounds (.+-.)-24 through (.+-.)-29
were prepared by DCC coupling to the appropriate arylacetic
acid.
[0338] Ref.
[0339] (6) Bellissant, E. et al. J. Pharmacol. Exp. Ther. 1996,
278, 232-242.
[0340] Representative examples of formula II follow.
EXAMPLE 33
2-{7-[(.+-.)-trans-1-(N-3,4-dichlorophenylacetamido-N-methylamino)-2-(1-py-
rrolidinyl)-1,2,3,4-tetrahydronaphthoxy]}acetic acid ((.+-.)-5)
[0341] With stirring at 25.degree. C. under N.sub.2, t-butyl
bromoacetate (0.35 mL, 2.38 mmol) was added to a mixture of
(.+-.)-4 (0.688 g, 1.59 mmol) and K.sub.2CO.sub.3 (0.5 g, 3.6 mmol)
in DMF (8 mL), and the mixture was stirred at 25.degree. C. under
N.sub.2 overnight before the mixture was evaporated under high
vacuum. The residue was partitioned between sat'd NaHCO.sub.3 and
CH.sub.2Cl.sub.2 (2.times.100 mL), which was dried
(Na.sub.2SO.sub.4), filtered through celite, and evaporated. The
t-butyl ester intermediate was flash column chromatographed twice
eluting with CH.sub.2Cl.sub.2:2% NH.sub.3:2% MeOH and
CH.sub.2Cl.sub.2:2% NH.sub.3:1% MeOH, respectively. The t-butyl
ester was then deprotected in a mixture of THF (4 mL) and conc. HCl
(2 mL) with stirring at 25.degree. C. overnight and at 50.degree.
C. for 1 h before the mixture was evaporated. The residue was then
dissolved in a mixture of trifluoroacetic acid (2 mL), 4 N HCl (2
mL), and anisole (1 drop), and stirred at 25.degree. C. for 2.5
days before the mixture was evaporated. The oily residue was
triturated with Et.sub.2O and sonicated to yield (.+-.)-5.HCl
(0.259 g, 31%): m.p. (HCl salt) 138.degree. C. (dec); .sup.1H NMR
(HCl salt, DMSO-d.sub.6) .delta. 1.7-2.1 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.24.8 (complex, 13H, 6-CH.sub.2-- and
1-CH--), 2.79 (s, 3H, --NCH.sub.3), 5.98 (d, J=10.3 Hz, 1H,
--CH--), 6.40 (s, 1H, aromatic), 6.82 (m, 1H, aromatic), 7.12 (d,
J=8.2 Hz, 1H, aromatic), 7.39 (d, J=8.3 Hz, 1H, aromatic), 7.63 (m,
2H, aromatic). MS (FAB) m/z 491. Anal. (C, H,
N)C.sub.25H.sub.28N.sub.2O.sub.4Cl.sub.2HCl.
EXAMPLE 34
2,2-Diphenyl-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolidinyl)-7-methoxy-1,2,3,4-
-tetrahydronaphth-1-yl]acetamide ((.+-.)-6)
[0342] This compound was prepared via the general DCC/pyr coupling
method from (.+-.)-1 (1.453 g, 5.58 mmol), diphenylacetic acid
(2.369 g, 11.16 mmol), DCC (2.373 g, 11.50 mmol), and pyridine
(0.93 mL, 11.5 mmol). The product was flash column chromatographed
eluting with CH.sub.2Cl.sub.2:2% NH.sub.3:1% MeOH before it was
converted to the HCl salt with 1.0 M HCl in Et.sub.2O and
crystallized from MeOH-Et.sub.2O to yield (.+-.)-6.HCl (1.7 g,
63%): m.p. (HCl salt)>250.degree. C.; .sup.1H NMR (HCl salt,
DMSO-d.sub.6) .delta. 1.8-2.0 (br s, 4H, --CH.sub.2CH.sub.2--),
2.2-3.9 (complex, 9H, 4-CH.sub.2-- and 1-CH--), 2.79 (s, 3H,
--NCH.sub.3), 3.48 (s, 3H, --OCH.sub.3), 5.66 (s, 1H, --CH--), 6.1
(d, J=9.4 Hz, 1H, --CH--), 6.23 (s, 1H, aromatic), 6.77 (d of d,
J=2.4 Hz and 8.4 Hz, 1H, aromatic), 7.09 (d, J=8.5 Hz, 1H,
aromatic), 7.2-7.5 (complex, 10H, aromatic). MS (FAB) m/z 455.
Anal. (C, H, N) C.sub.30H.sub.34N.sub.2O.sub- .2.HCl.
EXAMPLE 35
2,2-Diphenyl-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolidinyl)-7-hydroxy-1,2,3,4-
-tetrahydronaphth-1-yl]acetamide ((.+-.)-7)
[0343] With stirring in dry ice-acetone under N.sub.2, 1.0 M
BBr.sub.3 in CH.sub.2Cl.sub.2 (19.7 mL) was added at a fast drop
rate to a solution of (.+-.)-6 (1.491 g, 3.28 mmol) in
CH.sub.2Cl.sub.2 (20 mL), and the mixture was allowed to slowly
warm to 25.degree. C. under N.sub.2 as the dry ice sublimed. After
6.5 h, the mixture was quenched with MeOH with ice-H.sub.2O cooling
and diluted with CH.sub.2Cl.sub.2 (50 mL). The mixture was
partitioned between sat'd NaHCO.sub.3 and CH.sub.2Cl.sub.2. Some
yellowish precipitate was extracted into CH.sub.2Cl.sub.2 by adding
some MeOH. The organic fraction was dried (Na.sub.2SO.sub.4),
filtered through celite, and evaporated. The product was flash
colum chromatographed eluting with CHCl.sub.3:2% NH.sub.3:2% MeOH
to yield (.+-.)-7 (0.426 g, 30%). Part of the free base was
converted to the HCl salt with 1.0 M HCl in Et.sub.2O: .sup.1H NMR
(free base, CDCl.sub.3) .delta. 1.5-1.8 (br s, 4H,
--CH.sub.2CH.sub.2--), 1.8-2.9 (complex, 9H, 4-CH.sub.2-- and
1-CH--), 2.55 (s, 3H, --NCH.sub.3), 5.21 (s, 1H, --CH--), 5.83 (d,
J=8.6 Hz, 1H, --CH--), 6.22 (s, 1H, aromatic), 6.46 (m, 1H,
aromatic), 6.78 (d, J=8.1 Hz, 1H, aromatic), 7-7.4 (complex, 10H,
aromatic). MS (FAB) m/z 441. Anal. (C, H,
N)C.sub.29H.sub.32N.sub.2O.sub.- 2.HCl.H.sub.2O.
EXAMPLE 36
2-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolidinyl)-
-7-nitro-1,2,3,4-tetrahydronaphth-1-yl]acetamide ((.+-.)-8)
[0344] This compound was prepared via the general DCC/pyr coupling
method from (.+-.)-2 (0.5790 g, 2.103 mmol),
2-nitro-4,5-dichlorophenylacetic acid (1.0512 g, 4.204 mmol), DCC
(0.8948 g, 4.34 mmol), and pyr (0.35 mL, 4.3 mmol). After stirring
at 25.degree. C. overnight, more 2-nitro-4,5-dichlorophenylacetic
acid (1.0510 g, 4.203 mmol), DCC (0.8946 g, 4.34 mmol), and
CH.sub.2Cl.sub.2 (10 mL) were added, and after 5 h, the reaction
was worked up according to the general procedure. The crude product
was purified by gravity column eluting with CH.sub.2Cl.sub.2:2%
NH.sub.3 before it was converted to the HCl salt with 1.0 M HCl in
Et.sub.2O and washed with hot MeOH to yield (.+-.)-8.HCl (0.4948 g,
43% yield): m.p. (HCl salt)>250.degree. C.; .sup.1H NMR (HCl
salt, DMSO-d.sub.6) .delta.1.8-2. (br s, 4H, --CH.sub.2CH.sub.2--),
2.24.6 (complex, 11H, 5-CH.sub.2-- and 1-CH--), 2.9 (s, 3H,
--NCH.sub.3), 6.1 (d, J=10.2 Hz, 1H, --CH--), 7.53 (d, J=8.5 Hz,
1H, aromatic), 7.89 (s, 1H, aromatic), 7.91 (s, 1H, aromatic), 8.12
(d of d, J=2.2 Hz and 8.5 Hz, 1H, aromatic), 8.4 (s, 1H, aromatic).
MS (FAB) m/z 507. Anal. (C, H,
N)C.sub.23H.sub.24N.sub.4O.sub.5Cl.sub.2.HCl.
EXAMPLE 37
2-(3,4-Dichlorophenyl)-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolidinyl)-7-nitro-
-1,2,3,4-tetrahydronaphth-1-yl]acetamide ((.+-.)-9)
[0345] This compound was prepared via the general DCC/pyr coupling
procedure from (.+-.)-2 (1.8173 g, 6.600 mmol),
3,4-dichlorophenylacetic acid (2.7066 g, 13.20 mmol), DCC (2.8057
g, 13.60 mmol), and pyr (1.10 mL, 13.6 mmol). The product was
purified by flash column eluting with CH.sub.2Cl.sub.2:2%
NH.sub.3:1% MeOH before it was converted to the HCl salt with
Et.sub.2O--HCl and washed with hot MeOH to yield (.+-.)-9.HCl (2.49
g, 76%): m.p. (HCl salt) 255-257.degree. C.; .sup.1H NMR (HCl salt,
DMSO-d.sub.6) 81.8-2 (br s, 4H, --CH.sub.2CH.sub.2--), 24.2
(complex, 11H, 5-CH.sub.2-- and 1-CH--), 2.83 (s, 3H, --NCH.sub.3),
6.1 (d, J=9.8 Hz, 1H, --CH--), 7.3-7.7 (complex, 5H, aromatic),
8.06 (d of d, J=2.4 Hz and 8.6 Hz, 1H, aromatic). MS (FAB) m/z 462.
Anal. (C, H, N)C.sub.23H.sub.25N.sub.3O.sub.3Cl.sub.2HCl.
EXAMPLE 38
2-(3,4-Dichlorophenyl)-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolidinyl)-7-amino-
-1,2,3,4-tetrahydronaphth-1-yl]acetamide ((.+-.)-10)
[0346] With stirring at 55.degree. C., Raney nickel (50% slurry in
H.sub.2O) was added in small portions to a mixture of
(.+-.)-9-(2.10 g, 4.54 mmol) and hydrazine hydrate (4 mL) in EtOH
(60 mL) until all hydrazine was decomposed in 30 min. The mixture
was filtered through celite, and the Raney nickel was washed with
hot MeOH (120 mL). The filtrate was evaporated and dried in vacuo
before the residue was partitioned between sat'd NaHCO.sub.3 and
CH.sub.2Cl.sub.2, which was dried (Na.sub.2SO.sub.4), filtered
through celite, and evaporated. The product was purified by gravity
column eluting with CHCl.sub.3:2% NH.sub.3:0.5% MeOH before it was
converted to the HCl salt with Et.sub.2O--HCl to yield
(.+-.)-10.HCl (0.3 g, 14%, unoptimized): m.p. (HCl
salt)>250.degree. C.; .sup.1H NMR (free base, CDCl.sub.3)
.delta. 1.64 (br s, 4H, --CH.sub.2CH.sub.2--), 1.9-3.8 (complex,
11H, 5-CH.sub.2-- and 1-CH--), 2.59 (s, 3H, --NCH.sub.3), 5.8 (d,
J=9.7 Hz, 1H, --CH--), 6.29 (s, 1H, aromatic), 6.43 (d, J=8 Hz, 1H,
aromatic), 6.8 (d, J=8 Hz, 1H, aromatic), 7.17 (d, J=8 Hz, 1H,
aromatic), 7.3 (m, 2H, aromatic). MS (FAB) m/z 432. Anal. (C, H,
N)C.sub.23H.sub.27N.sub.3OCl.su- b.2.2HCl.
EXAMPLE 39
2-(4-Methylsulfonylphenyl)-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolidinyl)-7-n-
itro-1,2,3,4-tetrahydronaphth-1-yl]acetamide ((.+-.)-11)
[0347] This compound was prepared via the general DCC/pyr coupling
procedure from (.+-.)-2 (0.3414 g, 1.240 mmol),
4-methylsulfonylphenylace- tic acid (0.5309 g, 2.478 mmol), DCC
(0.5288 g, 2.563 mmol), and pyr (0.21 mL, 2.55 mmol). After
stirring at 25.degree. C. overnight, more of
4-methylsulfonylphenylacetic acid (0.5307 g, 2.477 mmol), DCC
(1.1356 g, 5.504 mmol), and CH.sub.2Cl.sub.2 (13 mL) were added,
and the mixture was worked up according to the general procedure
after another night of stirring. The product was purified by
gravity column eluting with CHCl.sub.3:2% NH.sub.3:1% MeOH before
it was converted to the HCl salt with Et.sub.2O--HCl and washed
with hot MeOH to yield (.+-.)-11.HCl (0.4455 g, 76%): m.p. (HCl
salt) 284-285.degree. C.; .sup.1H NMR (HCl salt, DMSO-d.sub.6)
.delta. 1.96 (br s, 4H, --CH.sub.2CH.sub.2--), 2.14.3 (complex,
11H, 5-CH.sub.2-- and 1-CH--), 2.88 (s, 3H, --NCH.sub.3), 3.24 (s,
3H, --SO.sub.2CH.sub.3), 6.13 (d, J=10 Hz, 1H, --CH--), 7.51 (d,
J=8.8 Hz, 1H, aromatic), 7.68 (m, 3H, aromatic), 7.9 (d, J=8.7 Hz,
2H, aromatic), 8.08 (d of d, J=2.6 Hz and 8.5 Hz, 1H, aromatic). MS
(FAB) m/z 472. Anal. (C, H, N)C.sub.24H.sub.29N.sub.3O.sub.5S.HCl
0.25CH.sub.2Cl.sub.2.
EXAMPLE 40
2-(3,4-Dichlorophenyl)-N-methyl-N-{[.+-.]-trans-2-[1-pyrrolidinyl]-7-[N,N--
bis-(t-butoxycarbonylmethyl)-amino]-1,2,3,4-tetrahydronaphth-1-yl}acetamid-
e ((.+-.)-12)
[0348] With stirring in ice-H.sub.2O under N.sub.2, t-butyl
bromoacetate (0.34 mL, 2.32 mmol) was added dropwise to a mixture
of (.+-.)-10 (0.4014 g, 0.928 mmol) and NEt(iPr).sub.2 (0.81 mL,
4.64 mmol) in dry THF (10 mL). After 10 min, the mixture was
stirred at 25.degree. C. under N.sub.2 overnight before more
t-butyl bromoacetate (0.30 mL) was added at 25.degree. C. After
stirring overnight, more NEt(iPr).sub.2 (0.40 mL) and t-butyl
bromoacetate (0.30 mL) were added, and after one more night of
stirring, the mixture was partitioned between sat'd NaHCO.sub.3 and
CH.sub.2Cl.sub.2. The aqueous fraction was extracted with more
CH.sub.2Cl.sub.2, and the combined organic fraction was dried
(Na.sub.2SO.sub.4), filtered through celite, and evaporated. The
crude product was purified by gravity column eluting with
CH.sub.2Cl.sub.2:2% NH.sub.3:1% MeOH before part of the free base
was converted to the HCl salt with 1.0 M HCl in Et.sub.2O with
stirring in ice-H.sub.2O. The residue was sonicated in hexane to
yield (.+-.)-12.2HCl (0.1610 g, 25%, unoptimized): m.p. (HCl salt)
143.degree. C. (dec); .sup.1H NMR (free base, CDCl.sub.3) .delta.
1.39 (s, 9H, t-butyl), 1.43 (s, 9H, t-butyl), 1.65 (br s, 4H,
--CH.sub.2CH.sub.2--), 1.94.1 (complex, 15H, 7-CH.sub.2-- and
1-CH--), 2.58 (s, 3H, --NCH.sub.3), 5.8 (m, 1H, --CH--), 6.2-7.4
(complex, 6H, aromatic). MS (FAB) 660. Anal. (C, H,
N)C.sub.35H.sub.47N.sub.3O.sub.5Cl.sub.2.2HCl.0.5CH.sub.3CN.
EXAMPLE 41
2-(3,4-Dichlorophenyl)-N-methyl-N-{[.+-.]-trans-2-[1-pyrrolidinyl]-7-[N,N--
bis-(carboxymethyl)amino]-1,2,3,4-tetrahydronaphth-1-yl}acetamide
((.+-.)-13)
[0349] A solution of (.+-.)-12 (0.35 g, 0.5 mmol) in 1:1 AcOH and 3
N HCl (8 mL) with some anisole (2 drops) was stirred at 25.degree.
C. overnight before conc. HCl (0.5 mL) was added, and the mixture
was warmed to 40.degree. C. for 1 h. Then some anisole (4 drops)
was added, and the mixture was stirred at 25.degree. C. for 5 h
before it was evaporated. The residue was sequentially evaporated
from iPrOH and PhCH.sub.3 before it was sonicated with Et.sub.2O to
yield (.+-.)-13.HCl (0.2360 g, 81%): m.p. (HCl salt) 160.degree. C.
(dec); .sup.1H NMR (HCl salt, DMSO-d.sub.6) .delta. 1.93 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.24.3 (complex, 15H, 7-CH.sub.2-- and
1-CH--), 2.79 (s, 3H, --NCH.sub.3--), 5.93 (d, J=10.7 Hz, 1H,
--CH--), 6.37 (s, 1H, aromatic), 6.68 (d, J=8.8 Hz, 1H, aromatic),
7.00 (d, J=8.1 Hz, 1H, aromatic), 7.40 (d, J=8.1 Hz, 1H, aromatic),
7.63 (m, 2H, aromatic). MS (FAB) m/z 490 (M+1-CH.sub.2CO.sub.2H).
Anal. (C, H, N)C.sub.27H.sub.31N.sub.3O.sub.5Cl.- sub.2.1HCl.
EXAMPLE 42
2-(3,4-Dichlorophenyl)-N-methyl-N-{[1-trans-2-[1-pyrrolidinyl]-7-[N,N-bis--
(ethoxycarbonylmethyl)-amino]-1,2,3,4-tetrahydronaphth-1-yl}acetamide
((.+-.)-14)
[0350] With stirring in ice-H.sub.2O under N.sub.2, ethyl
bromoacetate (0.47 mL, 4.21 mmol) was added dropwise to a mixture
of (.+-.)-10 (0.3640 g, 0.842 mmol) and NEt(iPr).sub.2 (0.88 mL,
5.05 mmol) in dry THF (6 mL). After 10 min, the mixture was stirred
at 25.degree. C. under N.sub.2 overnight before it was partitioned
between sat'd NaHCO.sub.3 and CH.sub.2Cl.sub.2. The aqueous
fraction was extracted with more CH.sub.2Cl.sub.2, and the combined
organic fraction was dried (Na.sub.2SO.sub.4), filtered through
celite, and evaporated. The product was purified by gravity column
eluting with CH.sub.2Cl.sub.2:2% NH.sub.3:1% MeOH before it was
converted to the HCl salt with 1.0 M HCl in Et.sub.2O and washed
with Et.sub.2O to yield (.+-.)-14.HCl (0.27 g, 47%): m.p. (HCl
salt) 128.degree. C. (dec); .sup.1H NMR (HCl salt, DMSO-d.sub.6)
.delta. 1.2 (m, 6H, 2-CH.sub.3), 1.9 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.24.4 (complex, 19H, 9-CH.sub.2-- and
1-CH--), 2.78 (s, 3H, --NCH.sub.3), 5.9 (d, 1-10.3 Hz, 1H, --CH--),
6.14 (s, 1H, aromatic), 6.49 (d, J=8.2 Hz, 1H, aromatic), 6.91 (d,
J=8.3 Hz, 1H, aromatic), 7.39 (d, J=8.3 Hz, 1H, aromatic), 7.6 (m,
2H, aromatic). MS (FAB) m/z 605. Anal. (C, H,
N)C.sub.31H.sub.39N.sub.3O.sub.5Cl.sub.2.1.25-
HCl.0.3CH.sub.3CN.
EXAMPLE 43
2-(3,4-Dichlorophenyl)-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolidinyl)-7-(N-di-
ethylphosphoramidato-amino)-1,2,3,4-tetrahydronaphth-1-yl]acetamide
((.+-.)-15)
[0351] With stirring in ice-H.sub.2O under N.sub.2, diethyl
chlorophosphate (0.57 mL, 3.92 mmol) was added dropwise to a
mixture of (.+-.)-10 (0.3393 g, 0.785 mmol) and NEt(iPr).sub.2
(0.82 mL, 4.71 mmol) in dry THF (6 mL). After 10 min, the mixture
was stirred at 25.degree. C. under N.sub.2 overnight before the
mixture was evaporated and dried in vacuo. The residue was
partitioned between sat'd NaHCO.sub.3 and CH.sub.2Cl.sub.2. The
aqueous fraction was extracted with more CH.sub.2Cl.sub.2, and the
combined organic fraction was dried (Na.sub.2SO.sub.4), filtered
through celite, and evaporated. The product was purified by gravity
column eluting with CH.sub.2Cl.sub.2:2% NH.sub.3:1.5% MeOH before
it was converted to the HCl salt with 1.0 M HCl in Et.sub.2O and
sonicated in Et.sub.2O to yield (.+-.)-15.HCl (0.4205 g, 89%): m.p.
(HCl salt) 247-249.degree. C.; .sup.1H NMR (HCl salt, DMSO-d.sub.6)
.delta. 1.2 (m, 6H, 2-CH.sub.3), 1.95 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.24.1 (complex, 15H, 7-CH.sub.2-- and
1-CH--), 2.75 (s, 3H, --NCH.sub.3), 5.98 (d, J=10.3 Hz, 1H,
--CH--), 6.7 (s, 1H, aromatic), 6.9 (m, 1H, aromatic), 7.03 (d,
J=8.4 Hz, 1H, aromatic), 7.3 (d of d, J=2 Hz and 8.2 Hz, 1H,
aromatic), 7.6 (m, 2H, aromatic), 7.92 (d, J=9.7 Hz, --NHP). MS
(FAB) m/z 568. Anal. (C, H,
N)C.sub.27H.sub.36N.sub.3O.sub.4PCl.sub.2HCl 0.25H.sub.2O.
EXAMPLE 44
2-(34-Dichlorophenyl)-N-methyl-N-{[.+-.]-trans-2-[1-pyrrolidinyl]-7-[N-2-(-
diethylphosphoryl)ethyl-amino]-1,2,3,4-tetrahydronaphth-1-yl}acetamide
((.+-.)-16)
[0352] With stirring in ice-H.sub.2O under N.sub.2, diethyl
2-bromoethylphosphonate (0.8601 g, 3.52 mmol) was added to a
mixture of (.+-.)-10 (0.3042 g, 0.704 mmol) and NEt(iPr).sub.2
(0.74 mL, 4.2 mmol) in dry THF (4 mL). After 10 min, the mixture
was stirred at 25.degree. C. under N.sub.2 for 2.5 days before more
diethyl 2-bromoethylphosphonate (0.8546 g) and NEt(iPr).sub.2 (0.74
mL, 4.2 mmol) were added. After stirring for 14 more days, the
mixture was evaporated to dryness and dried in vacuo before the
residue was partitioned between sat'd NaHCO.sub.3 and
CH.sub.2Cl.sub.2. The aqueous fraction was extracted with more
CH.sub.2Cl.sub.2, and the combined organic fraction was dried
(Na.sub.2SO.sub.4), filtered through celite, and evaporated. The
product was purified by gravity column eluting with
CH.sub.2Cl.sub.2:2% NH.sub.3:1% MeOH and then by radial
chromatography eluting with CH.sub.2Cl.sub.2:2% NH.sub.3. The
product was converted to the HCl salt with 1.0 M HCl in Et.sub.2O
and solidified by evaporation from CH.sub.2Cl.sub.2 and sonication
with Et.sub.2O to yield (.+-.)-16.HCl (0.2466 g, 52%): m.p. (HCl
salt) 151.degree. C. (dec); .sup.1H NMR (HCl salt, DMSO-d.sub.6)
.delta. 1.24 (t, J=7 Hz, 6H, 2-CH.sub.3), 1.93 (br s, 4H,
--CH.sub.2CH.sub.2--), 24.3 (complex, 19H, 9-CH.sub.2-- and
1-CH--), 2.8 (s, 3H, --NCH.sub.3), 5.96 (d, J=10.2 Hz, 1H, --CH--),
6.69 (br s, 1H, aromatic), 6.87 (d, J=7.5 Hz, 1H, aromatic), 7.11
(d, J=8.1 Hz, 1H, aromatic), 7.43 (d, J=8.3 Hz, 1H, aromatic), 7.64
(m, 2H, aromatic). MS (FAB) m/z 596. Anal. (C, H, N)
C.sub.29H.sub.40N.sub.3O.sub.4PCl.sub.2.2H- Cl.
EXAMPLE 45
2-(3,4-Dichlorophenyl)-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolidinyl)-6-metho-
xy-7-(N-benzyl-N-methylaminosulfonyl)-1,2,3,4-tetrahydronaphth-1-yl]acetam-
ide ((.+-.)-19)
[0353] This compound was prepared via the general DCC/pyr coupling
procedure from (.+-.)-17 (0.6213 g, 1.40 mmol),
3,4-dichlorophenylacetic acid (0.5764 g, 2.81 mmol), DCC (0.5951 g,
2.88 mmol), and pyr (0.23 mL, 2.88 mmol). The product was gravity
column chromatographed eluting with CH.sub.2Cl.sub.2:2% NH.sub.3:1%
MeOH and further purified by radial chromatography eluting with
CH.sub.2Cl.sub.2:2% NH.sub.3. The product was converted to the HCl
salt with 1.0 M HCl in Et.sub.2O to yield (.+-.)-19.HCl (0.3 g,
32%): m.p. (HCl salt) 150.degree. C. (dec); .sup.1H NMR (HCl salt,
DMSO-d.sub.6) 1.91 (br s, 4H, --CH.sub.2CH.sub.2--), 2.2 4.1
(complex, 11H, 5-CH.sub.2-- and 1-CH--), 2.55 (s, 3H, --NCH.sub.3),
2.77 (s, 3H, --NCH.sub.3), 3.88 (s, 3H, --OCH.sub.3), 4.2 (s, 2H,
--CH.sub.2Ph), 6.0 (d, J=9.7 Hz, 1H, --CH--), 7.10 (s, 1H,
aromatic), 7.2-7.4 (complex, 7H, aromatic), 7.55 (m, 2H, aromatic).
MS (FAB) m/z 630. Anal. (C, H, N)
C.sub.32H.sub.37N.sub.3O.sub.4Cl.sub.2S.HCl.0.5H.sub- .2O.
EXAMPLE 46
2-(3,4-Dichlorophenyl)-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolidinyl)-7-(N-be-
nzyl-N-methylaminosulfonyl)-1,2,3,4-tetrahydronaphth-1-yl]acetamide
((.+-.)-20)
[0354] This compound was prepared via the general DCC/pyr coupling
procedure from (.+-.)-18 (0.4530 g, 1.095 mmol),
3,4-dichlorophenylacetic acid (0.4485 g, 2.19 mmol), DCC (0.4677 g,
2.27 mmol), and pyr (0.18 mL, 2.26 mmol). The product was purified
by flash column eluting with CH.sub.2Cl.sub.2:2% NH.sub.3 and then
by radial chromatography eluting with CH.sub.2Cl.sub.2:2% NH.sub.3.
The product was converted to the HCl salt with 1.0 M HCl in
Et.sub.2O and then washed with hot MeOH to yield (.+-.)-20.HCl
(0.33 g, 47%): m.p. (HCl salt) 251-254.degree. C.; .sup.1H NMR (HCl
salt, DMSO-d.sub.6) .delta. 1.97 (br s, 4H, --CH.sub.2CH.sub.2--),
2.3-4.2 (complex, 13H, 6-CH.sub.2-- and 1-CH--), 2.49 (s, 3H,
--NCH.sub.3), 2.90 (s, 3H, --NCH.sub.3), 6.17 (d, J=10.4 Hz, 1H,
--CH--), 7.2-7.8 (complex, 11H, aromatic). MS (FAB) m/z 600. Anal.
(C, H, N)C.sub.31H.sub.35N.sub.3SO.sub.3Cl.sub.2.HCl.
EXAMPLE 47
2-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolidinyl)-
-indan-1-yl]acetamide ((.+-.)-24)
[0355] This compound was prepared via the general DCC/pyr coupling
procedure from (.+-.)-23 (0.4265 g, 1.971 mmol),
2-nitro-4,5-dichlorophen- ylacetic acid (0.9859 g, 3.943 mmol), DCC
(0.8350 g, 4.047 mmol), and pyr (0.33 mL, 4.06 mmol). The crude
product was purified by silica gel column eluting with
CH.sub.2Cl.sub.2:2% NH.sub.3 before it was converted to the HCl
salt with 1.0 M HCl in Et.sub.2O and crystallized from MeOH to
yield (.+-.)-24.HCl (0.3630 g, 38%, first crop): m.p. (HCl salt)
284-287.degree. C.; .sup.1H NMR (HCl salt, DMSO-d.sub.6) .delta.
1.8-2.1 (br s, 4H, --CH.sub.2CH.sub.2--), 2.84 (s, 3H,
--NCH.sub.3), 3-4.4 (complex, 9H, 4-CH.sub.2-- and 1-CH--), 6.37
(d, J=8 Hz, 1H, --CH--), 7.08 (br s, 1H, aromatic), 7.3 (m, 3H,
aromatic), 7.92 (s, 1H, aromatic), 8.41 (s, 1H, aromatic). MS (FAB)
m/z 448. Anal. (C, H, N)
C.sub.22H.sub.23N.sub.3O.sub.3Cl.sub.2.HCl.
EXAMPLE 48
2-(2-Nitro-4-trifluoromethylphenyl)-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolid-
inyl)-indan-1-yl]acetamide ((.+-.)-26)
[0356] This compound was prepared via the general DCC/pyr coupling
procedure from (.+-.)-23 (0.3229 g, 1.492 mmol),
2-nitro-4-trifluoromethy- lphenylacetic acid (0.5579 g, 2.24 mmol),
DCC (0.5512 g, 2.67 mmol), and pyr (0.19 mL, 2.31 mmol). The crude
product was gravity column chromatographed eluting with
CH.sub.2Cl.sub.2:2% NH.sub.3 before it was converted to the HCl
salt with 1.0 M HCl in Et.sub.2O and crystallized from
MeOH-Et.sub.2O to yield (.+-.)-26.HCl (0.3643 g, 50%): m.p. (HCl
salt) 249-250.degree. C.; .sup.1H NMR (HCl salt, DMSO-d.sub.6)
.delta. 1.8-2.1 (br s, 4H, --CH.sub.2CH.sub.2--), 2.89 (s, 3H,
--NCH.sub.3), 34.6 (complex, 9H, 4-CH.sub.2-- and 1-CH--), 6.40 (d,
J=8.1 Hz, 1H, --CH--), 7.1 (br s, 1H, aromatic), 7.3 (m, 3H,
aromatic), 7.83 (d, J=8.1 Hz, 1H, aromatic), 8.17 (d, J=7.8 Hz, 1H,
aromatic), 8.41 (s, 1H, aromatic). MS (FAB) m/z 448. Anal. (C, H,
N) C.sub.23H.sub.24N.sub.3O.sub.3F.sub.3.HCl.
EXAMPLE 49
2,2-Diphenyl-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolidinyl)-indan-1-yl]acetam-
ide ((.+-.)-28)
[0357] This compound was prepared via the general DCC/pyr coupling
procedure from (.+-.)-23 (0.2615 g, 1.209 mmol), diphenylacetic
acid (0.5123 g, 2.41 mmol), DCC (0.5138 g, 2.49 mmol), and pyr
(0.20 mL, 2.5 mmol). The crude product was purified by gravity
column eluting with CH.sub.2Cl.sub.2:2% NH.sub.3 before it was
converted to the HCl salt with 1.0 M HCl in Et.sub.2O and
crystallized from MeOH to yield (.+-.)-28.HCl (0.3815 g, 71%): m.p.
(HCl salt)>300.degree. C.; .sup.1H NMR (HCl salt, DMSO-d.sub.6;
the cis-trans rotamers are observed in about 3.6 to 1 ratio. Only
peaks for the major rotamer are reported.) .delta.1.88 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.75 (s, 3H, --NCH.sub.3), 34.2 (complex,
7H, 3-CH.sub.2-- and 1-CH--), 5.61 (s, 1H, --CH--), 6.5 (d, J=8 Hz,
1H, --CH--), 6.88 (d, J=6.5 Hz, 1H, aromatic), 7.1-7.4 (complex,
13H, aromatic). MS (FAB) m/z 411. Anal. (C, H, N)
C.sub.28H.sub.30N.sub.2O.HCl- .0.75H.sub.2O.
EXAMPLE 50
2-(4-Methylsulfonylphenyl)-N-methyl-N-[(.+-.)-trans-2-(1-pyrrolidinyl)-ind-
an-1-yl]acetamide ((.+-.)-29)
[0358] This compound was prepared via the general DCC/pyr coupling
procedure from (.+-.)-23 (0.3271 g, 1.51 mmol),
4-methylsulfonylphenylace- tic acid (0.6464 g, 3.017 mmol), DCC
(0.6438, 3.12 mmol), and pyr (0.25 mL, 3.1 mmol). The product was
purified by gravity column eluting with CH.sub.2Cl.sub.2:2%
NH.sub.3 before it was converted to the HCl salt with 1.0 M HCl in
Et.sub.2O and crystallized from MeOH-Et.sub.2O to yield
(.+-.)-29.HCl (0.5295 g, 78%): m.p. (HCl salt) 246-248.degree. C.;
.sup.1H NMR (HCl salt, DMSO-d.sub.6) .delta. 1.8-2 (br s, 4H,
--CH.sub.2Cl.sub.2--), 2.81 (s, 3H, --NCH.sub.3), 2.94.2 (complex,
9H, 4-CH.sub.2-- and 1-CH--), 3.21 (s, 3H, --SO.sub.2CH.sub.3), 6.4
(d, J=8.1 Hz, 1H, aromatic), 7 (m, 1H, aromatic), 7.3 (m, 3H,
aromatic), 7.58 (d, J=8.1 Hz, 2H, aromatic), 7.9 (d, J=7.8 Hz, 2H,
aromatic). MS (FAB) m/z 413. Anal. (C, H,
N)C.sub.23H.sub.28N.sub.2SO.sub.3.HCl.0.25H.sub.2O.
[0359] The preparation of a compound of Formula IIA is shown in
Example 2a.
EXAMPLE 2a
(Z)-(.+-.)-trans-[(7-Amino-2-(3,4-dichlorophenyl)-N-methyl-2-(1-pyrrolidin-
yl)-1,2,3,4-tetrahydronaphth-1-yl)acetamido]4-oxo-butenoic acid
[0360] 54
[0361] To a solution of 7-amino compound (1).sup.1 (0.266 g, 0.614
mmol) in anhydrous THF (4.5 mL) under a nitrogen atmosphere was
added a solution of maleic anhydride (0.0602 g, 0.614 mmol) in
anhydrous TH (0.53 mL). The reaction mixture was stirrred at toom
temperatature for 20 h and the resulting solid was filtered, washed
with THF and ether, and dried in vacuo. The solid was then
suspended in hot waer, filtered, and dried to give 2, 0.267 g
(82%); mp 221-223.degree. C.; MS (FAB) 530 (M+1); .sup.1H NMR (200
MHz, DMSO-d.sub.6) .delta. 1.50-1.93 (m, 2H), 2.00-3.10 (m, 9H),
2.66 (s, 3H), 3.83 (m, 2H), 5.80 (m, 1H), 6.22 (m, 2H), 7.10 (d,
J=7.5 Hz, 1H), 7.26 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.5
Hz, 1H), 7.55-7.65 (m, 2H). Anal. (C, H, N)
C.sub.27H.sub.29N.sub.3O.sub.4Cl.sub.2- .0.5H.sub.2O.
[0362] Ref.
[0363] 1. U.S. Pat. No. 5,744,458
[0364] Compounds of Formula III
[0365] Compounds having the following structrues were prepared.
55
[0366] Compounds 1-5 were prepared by the method described in
Chang, A.-C. Ph.D. Thesis, University of Minnesota-Twin Cities,
1995. 56
[0367] Compounds 9-19 were prepared from the appropriate arylacetic
acids via DCC/pyr coupling, followed by reduction, deprotection,
and/or derivatization via known chemistry. Intermediate 8 was
prepared via the method described in Chang, A.-C. Ph.D. Thesis,
University of Minnesota-Twin Cities, 1995. 57
[0368] Intermediate 20 was prepared via minor modifications of
known methods..sup.7,8 Compounds 23 (EMD60400) and 24 (EMD61753)
are known compounds that were synthesized in-house via minor
modifications of reported methods..sup.9 Compounds 21, 22 and 25-27
were prepared by DCC coupling, following by reduction where
applicable.
[0369] Ref.
[0370] (7) Costello, G. F. et al. J. Med. Chem. 1991, 34,
181-189.
[0371] (8) Naylor, A. et al. J. Med. Chem. 1994, 37, 2138-2144.
[0372] (9) Gottschlich, R. et al. Bioorg. Med. Chem. Letters 1994,
4, 677-682.
EXAMPLE 51
2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-[N-(S-aspartic
acid-a-amide-S-aspartic
acid-a-amido)-3-aminophenyl]-2-[1-pyrrolidinyl]et- hyl}acetamide
(6)
[0373] With stirring in ice-H.sub.2O under N.sub.2,
1,3-dicyclohexylcarbodiimide (DCC, 0.353 g, 1.711 mmol) and dry
CH.sub.2Cl.sub.2 (2 mL) were added to a mixture of 5-t-butyl ester
(0.311 g, 0.538 mmol), N-Boc-L-aspartic acid-b-t-butyl ester (0.495
g, 1.711 mmol), and 1-hydroxybenzotriazole (HOBT, 0.232 g, 1.717
mmol) in dry CH.sub.2Cl.sub.2 (8 mL). After 5 min, the mixture was
stirred at 25.degree. C. under N.sub.2 overnight before H.sub.2O (1
mL) was added, and the mixture was filtered through celite. The
1,3-dicyclohexylurea (DCU) was washed with CH.sub.2Cl.sub.2 (18
mL). The filtrate was partitioned between sat'd NaHCO.sub.3 and
CH.sub.2Cl.sub.2, which was dried (Na.sub.2SO.sub.4), filtered
through celite, and evaporated. After flash column chromatography
eluting with CH.sub.2Cl.sub.2:2% NH.sub.3:2% MeOH, the protected
intermediate (0.411 g, 90%) was dissolved in 3N HCl (4 mL), AcOH (4
mL) with anisole (2 drops), and stirred at 25.degree. C. overnight.
The mixture was then evaporated to dryness, and evaporation from
iPrOH then yielded ADL-01-0010-7: .sup.1H NMR (HCl salt,
DMSO-d.sub.6) .delta. 2.0 (br s, 4H, --CH.sub.2CH.sub.2--), 2.9 (s,
3H, --NCH.sub.3), 6.1 (br m, 1H, --CH--). MS (FAB) m/z 636. Anal.
(C, H, N)
C.sub.29H.sub.35N.sub.5O.sub.7Cl.sub.2.1.5HCl.0.25iPrOH.
EXAMPLE 52
2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-[N-(bis-methylsulfonamido)-3-ami-
nophenyl]-2-[1-pyrrolidinyl]ethyl]acetamide (7)
[0374] With stirring at 25.degree. C., a solution of
methanesulfonyl chloride (MsCl, 0.25 mL, 3.2 mmol) in dry
CH.sub.2Cl.sub.2 (0.75 mL) was added to a mixture of ADL-01-0007-3
(0.225 g, 0.554 mmol) and Et.sub.3N (1 mL, 7 mmol) in dry
CH.sub.2Cl.sub.2 (4 mL), and the mixture was stirred at 25.degree.
C. fitted with a drying tube. After 5 h, more CH.sub.2Cl.sub.2 (6
mL), MsCl (0.5 mL), and Et.sub.3N (2 mL) were added, and the
mixture was stirred at 25.degree. C. overnight before it was
partitioned between CH.sub.2Cl.sub.2 (50 mL) and sat'd NaHCO.sub.3.
The aqueous fraction was extracted with more CH.sub.2Cl.sub.2 (25
mL), and the combined organic fraction was dried
(Na.sub.2SO.sub.4), filtered through celite, and evaporated.
Acetonitrile was used to azeotrope off Et.sub.3N before the product
was gravity column chromatographed twice eluting with
CH.sub.2Cl.sub.2:2% NH.sub.3:2% MeOH. The pure product was then
treated with 1.0 M HCl in Et.sub.2O to yield 7HCl (0.131 g, 39%,
unoptimized): m.p. (HCl salt) 145.degree. C. (dec); .sup.1H NMR
(free base, CDCl.sub.3) .delta. 1.7 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.4-3.8 (complex, 8H, 4-CH.sub.2--), 2.7 (s,
3H, --NCH.sub.3), 3.37 (s, 6H, 2-SO.sub.2CH.sub.3), 6.1 (m, 1H,
--CH--), 7.1-7.4 (complex, 7H, aromatic). MS (FAB) m/z 562. Anal.
(C, H, N)C.sub.23H.sub.29N.sub.3O.sub.-
5S.sub.2Cl.sub.2.HCl.0.75H.sub.2O.
EXAMPLE 53
2-(2-Nitrophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)eth-
yl]acetamide (10)
[0375] This compound was prepared via the general DCC/pyr coupling
procedure from 8 (1.4886 g, 5.97 mmol), 2-nitrophenylacetic acid
(2.1619 g, 11.93 mmol), DCC (2.5402 g, 12.31 mmol), and pyridine
(1.00 mL, 12.36 mmol). The crude product was converted to the HCl
salt with Et.sub.2O--HCl without chromatography and crystallized
from MeOH-Et.sub.2O. The first crop was recrystallized again from
MeOH-Et.sub.2O to yield 10.HCl (1.3663 g, 51%): m.p. (HCl salt)
258-259.degree. C.; .sup.1H NMR (HCl salt, DMSO-d.sub.6) .delta.
1.97 (br s, 4H, --CH.sub.2CH.sub.2--), 2.91 (s, 3H, --NCH.sub.3),
3.114.45 (complex, 8H, 4-CHR.sub.2--), 6.17 (m, 1H, --CH--),
7.51-8.25 (complex, 8H, aromatic). MS (FAB) m/z 413. Anal. (C, H,
N) C.sub.21H.sub.24N.sub.4O- .sub.5.HCl.0.25H.sub.2O.
EXAMPLE 54
2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-(3-aminophenyl)-2-(1-pyrrolidinyl)eth-
yl]acetamide (9)
[0376] With stirring at 55.degree. C., Raney nickel was added in
small quantities to a mixture of 10 (0.9857 g, 2.3899 mmol) and
hydrazine hydrate (55%, 2 mL) in EtOH (30 mL) until gas evolution
stopped in about 10 min. The mixture was then filtered through
celite, and the Raney nickel was washed with hot MeOH (100 mL). The
filtrate was evaporated and dried in vacuo before the residue was
partitioned between sat'd NaHCO.sub.3 and CH.sub.2Cl.sub.2, which
was dried (Na.sub.2SO.sub.4), filtered through celite, and
evaporated. The product was gravity column chromatographed eluting
with CHCl.sub.3:2% NH.sub.3:2% MeOH before it was converted to the
HCl salt with Et.sub.2O--HCl to yield 9.3HCl (0.3159 g, 29%,
unoptimized): m.p. (HCl salt) 219-222.degree. C.; .sup.1H NMR (HCl
salt, DMSO-d.sub.6) .delta. 1.98 (br s, 4H, --CH.sub.2CH.sub.2--),
2.87 (s, 3H, --NCH.sub.3), 3.2-4.3 (complex, 8H, 4-CH.sub.2--), 6.1
(m, 1H, --CH--), 7.11-7.45 (complex, 8H, aromatic). MS (FAB) m/z
353. Anal. (C, H, N)
C.sub.21H.sub.28N.sub.4O.3HCl.0.25H.sub.2O.
EXAMPLE 55
2-(N-Diethyl
phosphoramidate-2-aminophenyl)-N-methyl-N-[(1S)-1-(N-diethyl
phosphoramidate-3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide
(11)
[0377] With stirring in ice-H.sub.2O under N.sub.2, diethyl
chlorophosphate (0.53 mL, 3.67 mmol) was added to a mixture of 9
(0.2394 g, 0.6792 mmol) and NEt(iPr).sub.2 (0.77 mL, 4.40 mmol) in
dry THF (5 mL). After 10 min, the mixture was stirred at 25.degree.
C. under N.sub.2 for 3.5 days before it was diluted with
CH.sub.2Cl.sub.2, evaporated, and dried in vacuo. The residue was
partitioned between sat'd NaHCO.sub.3 and CH.sub.2Cl.sub.2. The
aqueous fraction was extracted with more CH.sub.2Cl.sub.2, and the
combined organic fraction was dried (Na.sub.2SO.sub.4), filtered
through celite, and evaporated. The product was chromatographed
eluting with CH.sub.2Cl.sub.2:2% NH.sub.3:2% MeOH before it was
converted to the HCl salt with 1.0 M HCl in Et.sub.2O and
crystallized from iPrOH-Et.sub.2O to yield 11.HCl (0.2364 g, 53%):
m.p. (HCl salt) 184-186.degree. C.; .sup.1H NMR (HCl salt,
DMSO-d.sub.6) .delta. 1.2 (m, 12H, 4-CH.sub.3), 1.96 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.81 (s, 3H, --NCH.sub.3), 34 (complex, 16H,
8-CH.sub.2--), 6.05 (m, 1H, --CH--), 6.7-7.3 (complex, 9H, aromatic
and 1 NH), 8.08 (d, J=9.4 Hz, 1H, NHP). MS (FAB) m/z 625. Anal. (C,
H, N) C.sub.29H.sub.46N.sub.4O.sub.7P.s- ub.2.HCl.
EXAMPLE 56
2-(N-Bis-sulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-(N-bis-sulfonamido--
3-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide (12)
[0378] With stirring at 0.degree. C. under N.sub.2, MsCl (0.61 mL,
7.87 mmol) was added to a mixture of 9 (0.2774 g, 0.787 mmol) and
Et.sub.3N (2.2 mL, 15.7 mmol) in CH.sub.2Cl.sub.2 (8 mL). After
10-15 min, the mixture was stirred at 25.degree. C. under N.sub.2
overnight before the mixture was partitioned between sat'd
NaHCO.sub.3 and CH.sub.2Cl.sub.2. The aqueous fraction was
extracted with more CH.sub.2Cl.sub.2, and the combined organic
fraction was dried (Na.sub.2SO.sub.4), filtered through celite, and
evaporated. Acetonitrile was added to azeotrope off Et.sub.3N. The
product was flash-column chromatographed eluting with
CH.sub.2Cl.sub.2: 2% NH.sub.3 before it was converted to the HCl
salt with 1.0 M HCl in Et.sub.2O to yield 12.HCl (0.3564 g, 65%):
m.p. (HCl salt) 180.degree. C.; .sup.1H NMR (HCl salt,
DMSO-d.sub.6) .delta. 2.0 (br s, 4H, --CH.sub.2CH.sub.2--), 2.76
(s, 3H, --NCH.sub.3), 34.3 (complex, 8H, 4-CH.sub.2--), 3.53 (s,
12H, 4-SO.sub.2CH.sub.3), 6.25 (m, 1H, --CH--), 7.3-7.6 (complex,
8H, aromatic). MS (FAB) m/z 665. Anal. (C, H, N)
C.sub.25H.sub.36N.sub.4O.sub.9S.sub.4.HCl.MeOH.
EXAMPLE 57
2-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyr-
rolidinyl)ethyl]acetamide (13)
[0379] This compound was prepared via the general DCC/pyr coupling
procedure from 8 (0.3690 g, 1.4801 mmol),
2-nitro-4,5-dichlorophenylaceti- c acid (0.7301 g, 2.920 mmol), DCC
(0.6213 g, 3.01 mmol), and pyridine (0.24 mL, 3.01 mmol). The crude
product was converted to the HCl salt with Et.sub.2O--HCl without
chromatography and crystallized from MeOH to yield 13.HCl (0.3232
g, 42%): m.p. (HCl salt) 165.degree. C. (dec); .sup.1H NMR (HCl
salt, DMSO-d.sub.6) .delta. 2.0 (br s, 4H, --CH.sub.2CH.sub.2--),
2.93 (s, 3H, --NCH.sub.3), 3.14.3 (complex, 6H, 3-CH.sub.2--), 4.4
(s, 2H, benzylic methylene), 6.2 (m, 1H, --CH--), 7.7-7.8 (m, 2H,
aromatic), 7.9 (s, 1H, aromatic), 8.14 (s, 1H, aromatic), 8.27 (d,
J=7.7 Hz, 1H, aromatic), 8.43 (s, 1H, aromatic). MS (FAB) m/z 481.
Anal. (C, H, N)
C.sub.21H.sub.22N.sub.4O.sub.5Cl.sub.2.HCl.0.5MeOH.
EXAMPLE 58
2-(4-Methylsulfonylphenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrroli-
dinyl)ethyl]acetamide (14)
[0380] This compound was prepared via the general DCC/pyr coupling
procedure from 8 (0.5138 g, 2.061 mmol),
4-methylsulfonylphenylacetic acid (0.8825 g, 4.119 mmol), DCC
(0.8771 g, 4.251 mmol), and pyridine (0.34 mL, 4.245 mmol). The
crude product was gravity column chromatographed eluting with
CHCl.sub.3:2% NH.sub.3 before it was converted to the HCl salt with
1.0 M HCl in Et.sub.2O and crystallized from MeOH to yield 14.HCl
(0.4695 g, 47%): m.p. (HCl salt) 276-277.degree. C.; .sup.1H NMR
(HCl salt, DMSO-d.sub.6) .delta. 2.0 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.92 (s, 3H, --NCH.sub.3), 3.2 (s, 3H,
--SO.sub.2CH.sub.3), 3.2-4.3 (complex, 8H, 4-CH.sub.2--), 6.25 (m,
1H, --CH--), 7.61 (d, J=7.2 Hz, 2H, aromatic), 7.75 (m, 2H,
aromatic), 7.89 (d, J=7 Hz, 2H, aromatic), 8.12 (s, 1H, aromatic),
8.25 (m, 1H, aromatic). MS (FAB) m/z 446. Anal. (C, H, N)
C.sub.22H.sub.27N.sub.3O.sub- .5S.HCl.
EXAMPLE 59
2-(N-Butyloxycarbonyl-4-aminophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2--
(1-pyrrolidinyl)ethyl]acetamide (18)
[0381] This compound was prepared via the general DCC/pyr coupling
method from 8 (1.9948 g, 8.001 mmol), N-Boc-4-aminophenylacetic
acid (3.0589 g, 12.173 mmol), DCC (2.6602 g, 12.89 mmol), and
pyridine (1.04 mL, 12.9 mmol). The crude product was gravity column
chromatographed eluting with CH.sub.2Cl.sub.2: 2% NH.sub.3:1% MeOH
before it was converted to the HCl salt with 1.0 M HCl in Et.sub.2O
and crystallized from MeOH to yield 18.HCl (0.4891 g, 12%, first
crop): m.p. (HCl salt) 170.degree. C. (dec); .sup.1H NMR (HCl salt,
DMSO-d.sub.6) .delta. 1.49 (s, 9H, t-butyl), 2.01 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.83 (s, 3H, --NCH.sub.3), 3.1-4.15
(complex, 8H, 4-CH.sub.2--), 6.27 (m, 1H, --CH--), 7.17 (d, J=8 Hz,
2H, aromatic), 7.39 (d, J=8 Hz, 2H, aromatic), 7.7 (m, 2H,
aromatic), 8.09 (s, 1H, aromatic), 8.23 (d, J=6 Hz, 1H, aromatic),
9.3 (s, 1H, --NHBoc). MS (FAB) 483. Anal. (C, H, N)
C.sub.26H.sub.34N.sub.4O.sub.5.HCl.0.25H.su- b.2O.
EXAMPLE 60
2-(4-Aminophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrrolidinyl)eth-
yl]acetamide (15)
[0382] The product from Example 59 (2.9211 g, 6.053 mmol) and
anisole (2 drops) were mixed in AcOH (10 mL) and 4N HCl (10 mL) and
stirred at 25.degree. C. overnight, fitted with a drying tube. The
mixture was adjusted to pH 13 with 1N NaOH with stirring in
ice-H.sub.2O and then extracted with CH.sub.2Cl.sub.2 (2.times.70
mL). The combined organic fraction was dried (Na.sub.2SO.sub.4),
filtered through celite, and evaporated. The product was gravity
column chromatographed eluting with CHCl.sub.3:2% NH.sub.3 before
it was converted to the HCl salt with Et.sub.2O--HCl to yield
15.HCl (0.5531 g, 22%, unoptimized): m.p. (HCl salt) 200.degree. C.
(dec); .sup.1H NMR (HCl salt, DMSO-d.sub.6) .delta. 1.98 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.86 (s, 3H, --NCH.sub.3), 3.24.3 (complex,
8H, 4-CH.sub.2--), 6.25 (m, 1H, --CH--), 7.16 (d, J=7.4 Hz, 2H,
aromatic), 7.33 (d, J=7.5 Hz, 2H, aromatic), 7.7 (m, 2H, aromatic),
8.08 (s, 1H, aromatic), 8.23 (m, 1H, aromatic). MS (FAB) m/z 383.
Anal. (C, H, N) C.sub.21H.sub.26N.sub.4O.sub.32HCl
0.75H.sub.2O.
EXAMPLE 61
2-(N-Bis-sulfonamido-4-aminophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(-
1-pyrrolidinyl)ethyl]acetamide (16)
[0383] With stirring in ice-H.sub.2O under N.sub.2, a solution of
MsCl (1.56 mL, 20.17 mmol) in CH.sub.2Cl.sub.2 (6 mL) was added
dropwise over 2-3 min to a mixture of 15 (1.5430 g, 4.0344 mmol)
and Et.sub.3N (5.6 mL, 40 mmol) in CH.sub.2Cl.sub.2 (24 mL). After
10 min, the mixture was stirred at 25.degree. C. under N.sub.2
overnight before the mixture was partitioned between
CH.sub.2Cl.sub.2 and sat'd NaHCO.sub.3. The aqueous fraction was
extracted with more CH.sub.2Cl.sub.2, and the combined organic
fraction was dried (Na.sub.2SO.sub.4), filtered through celite, and
evaporated. Acetonitrile was added to azeotrope off Et.sub.3N
before the crude product was flash column chromatographed eluting
with CH.sub.2Cl.sub.2:2% NH.sub.3. The product was converted to the
HCl salt with 1.0 M HCl in Et.sub.2O and washed with hot MeOH to
yield 16.HCl (1.3091 g, 56%, first crop): m.p. (HCl salt)
257-259.degree. C.; .sup.1H NMR (HCl salt, DMSO-d.sub.6) .delta.
1.99 (br s, 4H, --CH.sub.2CH.sub.2--), 2.87 (s, 3H, --NCH.sub.3),
3.154.3 (complex, 8H, 4-CH.sub.2--), 3.51 (s, 6H,
2-SO.sub.2CH.sub.3), 6.25 (m, 1H, --CH--), 7.4 (m, 4H, aromatic),
7.7 (m, 2H, aromatic), 8.1 (s, 1H, aromatic), 8.21 (m, 1H,
aromatic). MS (FAB) m/z 539. Anal. (C, H, N)
C.sub.23H.sub.30N.sub.4O.sub.7S.sub.2.HCl.0.5CH.sub.2Cl.sub.2.
EXAMPLE 62
2-(N-Bis-sulfonamido-4-aminophenyl)-N-methyl-N-[(1S)-1-(3-aminophenyl)-2-(-
1-pyrrolidinyl)ethyl]acetamide (17)
[0384] This compound was prepared from 16 (1.0729 g, 1.992 mmol),
Raney nickel, and hydrazine hydrate (2 mL) in EtOH (30 mL). The
conditions were similar to those used for the preparation of 9. The
product was gravity column chromatographed eluting with
CH.sub.2Cl.sub.2:2% NH.sub.3, and the pure fractions were converted
to the HCl salt with 1.0 M HCl in Et.sub.2O to yield 17.HCl (0.1194
g, 11%, unoptimized): m.p. (HCl salt) 252-255.degree. C.; .sup.1H
NMR (HCl salt, DMSO-d.sub.6) .delta. 2.0 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.86 (s, 3H, --NCH.sub.3), 3.14.2 (complex,
8H, 4-CH.sub.2--), 3.54 (s, 6H, 2-SO.sub.2CH.sub.3), 6.1 (m, 1H,
--CH--), 6.8-7.5 (complex, 8H, aromatic). MS (FAB) m/z 509. Anal.
(C, H, N) C.sub.23H.sub.32N.sub.4O.sub.5S.sub.2.1.75HCl.
EXAMPLE 63
2-(N-Bis-sulfonamido-4-aminophenyl)-N-methyl-N-[(1S)-1-(N-diethyl
phosphoramidate-3 aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide
(19)
[0385] With stirring in ice-H.sub.2O under N.sub.2, diethyl
chlorophosphate (0.84 mL, 5.81 mmol) was added to a mixture of 17
(0.7383 g, 1.4514 mmol) and NEt(iPr).sub.2 (1.5 mL, 8.7 mmol) in
dry THF (15 mL). After 10 min, the mixture was stirred at
25.degree. C. under N.sub.2 overnight before more THF (15 mL),
NEt(iPr).sub.2 (0.76 mL), and diethyl chlorophosphate (0.42 mL)
were sequentially added. After 3 h, the mixture was quenched with
H.sub.2O, diluted with CH.sub.2Cl.sub.2, evaporated, and dried in
vacuo. The residue was partitioned between CH.sub.2Cl.sub.2 and
sat'd NaHCO.sub.3. The aqueous fraction was extracted with more
CH.sub.2Cl.sub.2, and the combined organic fraction was dried
(Na.sub.2SO.sub.4), filtered through celite, and evaporated. The
crude product was flash column chromatographed eluting with
CH.sub.2Cl.sub.2:2% NH.sub.3:1.5% MeOH before it was converted to
the HCl salt with 1.0 M HCl in Et.sub.2O and crystallized from MeOH
to yield 19.HCl (0.3274 g, 33%): m.p. (HCl salt) 245-247.degree.
C.; .sup.1H NMR (HCl salt, DMSO-d.sub.6) .delta. 1.193 (t, J=7 Hz,
6H, 2-CH.sub.3), 1.95 (br s, 4H, --CH.sub.2CH.sub.2--), 2.81 (s,
3H, --NCH.sub.3), 3.14.1 (complex, 12H, 6-CH.sub.2--), 3.52 (s, 6H,
2-SO.sub.2CH.sub.3), 6.1 (m, 1H, --CH--), 6.79 (d, J=7.3 Hz, 1H,
aromatic), 6.91 (s, 1H, aromatic), 6.99 (d, J=7.7 Hz, 1H,
aromatic), 7.23 (t, J=7.8 Hz, 1H, aromatic), 7.36 (d, J=8.3 Hz, 2H,
aromatic), 7.44 (d, J=8.6 Hz, 2H, aromatic), 8.09 (d, J=9.4 Hz, 1H,
--NHP). MS (FAB) m/z 645. Anal. (C, H, N)
C.sub.27H.sub.41N.sub.4O.sub.8S- .sub.2P.HCl.
EXAMPLE 64
2-(2-Nitrophenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidin-
yl)]ethyl}acetamide (21)
[0386] With stirring at 25.degree. C. under N.sub.2, DCC (0.160 g,
0.79 mmol) was added to a mixture of 2-nitrophenylacetic acid
(0.140 g, 0.79 mmol) and pyridine (0.064 mL, 0.79 mmol) in
CH.sub.2Cl.sub.2 (1.5 mL). After 3 min, a solution of 20 (0.160 g,
0.72 mmol) in CH.sub.2Cl.sub.2 (1.5 mL) was added, followed by
NEt(iPr).sub.2 (0.375 mL, 2.15 mmol). The mixture was stirred at
25.degree. C. under N.sub.2 overnight before sat'd NaHCO.sub.3 was
added, and the mixture was filtered through celite. The DCU was
washed with a little CH.sub.2Cl.sub.2, and the filtrate was
partitioned between sat'd NaHCO.sub.3 and CH.sub.2Cl.sub.2, which
was dried (MgSO.sub.4), filtered through celite, and evaporated.
Toluene was added to azeotrope off pyridine. The product was flash
column chromatographed eluting with CHCl.sub.3:2% NH.sub.3:2% MeOH
before it was converted to the HCl salt with 1.0 M HCl in Et.sub.2O
and crystallized from MeOH to yield 21.HCl (0.14 g, 47%): m.p. (HCl
salt) 226-227.degree. C.; .sup.1H NM (HCl salt, DMSO-d.sub.6)
.delta. 1.8-2.4 (m, 2H, --CH.sub.2), 2.86 (s, 3H, --NCH.sub.3),
34.5 (complex, 8H, 4-CH.sub.2--), 5.5 (m, 1H, --CHOH), 6.1 (m, 1H,
--CH--), 73-7.8 (complex, 8H, aromatic), 8.11 (d, J=8 Hz, 1H,
aromatic). MS (FAB) m/z 384. Anal. (C, H,
N)C.sub.21H.sub.25N.sub.3O.sub.4.HCl.0.5H.sub.2O.
EXAMPLE 65
2-(2-Nitro-4,5-dichlorophenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-hydr-
oxypyrrolidinyl)]ethyl}acetamide (22)
[0387] This compound was prepared from 20 (0.2 g, 0.91 mmol),
2-nitro-4,5-dichlorophenylacetic acid (0.45 g, 1.8 mmol), DCC (0.37
g, 1.8 mmol), NEt(iPr).sub.2 (0.48 mL, 2.7 mmol), and pyridine
(0.15 mL, 1.8 mmol). The conditions are similar to those for the
preparation of 21. The product was column chromatographed eluting
with CH.sub.2Cl.sub.2:2% NH.sub.3:1% MeOH before it was converted
to the HCl salt with 1.0 M HCl in Et.sub.2O and crystallized from
iPrOH to yield 22.HCl (0.060 g, 14%): m.p. (HCl salt)
231-233.degree. C. (dec); .sup.1H NMR (HCl salt, DMSO-d.sub.6)
.delta. 1.8-2.4 (m, 2H, --CH.sub.2--), 2.85 (s, 3H, --NCH.sub.3),
3.14.5 (complex, 8H, 4-CH.sub.2--), 5.5 (m, 1H, --CHOH), 6.1 (m,
1H, --CH--), 7.2-7.5 (m, 5H, aromatic), 7.88 (s, 1H, aromatic),
8.42 (s, 1H, aromatic). MS (FAB) m/z 452. Anal. (C, H,
N)C.sub.21H.sub.23N.sub.3O.sub.4Cl.sub.2.HCl.
EXAMPLE 66
2-(4-Methylsulfonylphenyl)-N-methyl-N-{[1S-1-phenyl-2-[1-(3S)-(3-hydroxypy-
rrolidinyl)]ethyl}acetamide (25)
[0388] This compound was prepared from 20 (0.2 g, 0.91 mmol),
4-methylsulfonylphenylacetic acid (0.41 g, 1.8 mmol), DCC (0.37 g,
1.8 mmol), pyridine (0.15 mL, 1.8 mmol), and NEt(iPr).sub.2 (0.48
mL, 2.7 mmol). The conditions are similar to those for the
preparation of 21. After stirring at 25.degree. C. overnight, more
pyridine (0.075 mL, 0.9 mmol) and DCC (0.18 g, 0.9 mmol) were
added, and the reaction was worked up the next day. The product was
purified by radial chromatography eluting with CH.sub.2Cl.sub.2:2%
NH.sub.3: 1% MeOH before it was converted to the HCl salt with 1.0
M HCl in Et.sub.2O and washed with hot iPrOH to yield 25.HCl (0.15
g, 36%): m.p. (HCl salt) 240-241.degree. C.; .sup.1H NMR (HCl salt,
DMSO-d.sub.6) .delta. 1.8-2.4 (m, 2H, --CH.sub.2--), 2.8 (d, 3H,
--NCH.sub.3 of cis and trans amide rotamers), 3.23 (s, 3H,
--SO.sub.2CH.sub.3), 3.1-4.5 (m, 8H, 4-CH.sub.2--), 5.5 (m, 1H,
--CHOH), 6.15 (m, 1H, --CH--), 7.2-7.5 (m, 5H, aromatic), 7.55 (m,
2H, aromatic), 7.85 (m, 2H, aromatic). MS (FAB) m/z 417. Anal. (C,
H, N)C.sub.22H.sub.28N.sub.2O.sub.4S.HCl.
EXAMPLE 67
2-(2-Nitro-4-trifluoromethylphenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-
-hydroxypyrrolidinyl)]ethyl}acetamide (26)
[0389] With stirring at 25.degree. C. under N.sub.2, DCC (0.39 g,
1.9 mmol) was added to a mixture of
2-nitro-4-trifluoromethylphenylacetic acid (0.47 g, 1.9 mmol) and
pyridine (0.15 mL, 1.9 mmol) in CH.sub.2Cl.sub.2 (10 mL). After 5
min, a solution of 20 (0.4 g, 1.8 mmol) in CH.sub.2Cl.sub.2 (5 mL)
was added. After 2 h, more DCC (0.1 g, 0.5 mmol) was added, and the
mixture was stirred at 25.degree. C. overnight before more
2-nitro-4-trifluoromethylphenylacetic acid (0.045 g, 0.18 mmol) and
DCC (0.1 g, 0.5 mmol) were added After 2 h, the reaction was worked
up as in the preparation of 21. The product was purified by radial
chromatography eluting with CH.sub.2Cl.sub.2:2% NH.sub.3 before it
was converted to the HCl salt with 1.0 M HCl in Et.sub.2O and
precipitated from CH.sub.2Cl.sub.2 to yield 26.HCl (0.050 g, 5.4%):
.sup.1H NMR (HCl salt, DMSO-d.sub.6) .delta. 1.8-2.4 (m, 2H,
--CH.sub.2--), 2.87 (s, 3H, --NCH.sub.3), 3.1-4.5 (complex, 8H,
4-CH.sub.2--), 5.5 (m, 1H, --CHOH), 6.1 (m, 1H, --CH--), 7.2-7.5
(m, 5H, aromatic), 7.82 (d, J=7.7 Hz, 1H, aromatic), 8.16 (d, J=8
Hz, 1H, aromatic), 8.42 (s, 1H, aromatic). MS (FAB) m/z 452. Anal.
(C, H, N)C.sub.22H.sub.24F.sub.3N.sub.3O.sub.4.HCl.0-
.5H.sub.2O.
EXAMPLE 68
2-(2-Amino-4-trifluoromethylphenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-(3-
-hydroxypyrrolidinyl)]ethyl}acetamide (27)
[0390] This compound was prepared from 26 (0.14 g, 0.31 mmol),
Raney nickel, and hydrazine hydrate (0.2 mL) in EtOH (14 mL). The
conditions were similar to those used for the preparation of 9. The
product was purified by radial chromatography eluting with
CHCl.sub.3:2% NH.sub.3:2% MeOH before it was converted to the HCl
salt with Et.sub.2O--HCl to yield 27.HCl (0.11 g, 77%): .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.8-2.2 (m, 2H, --CH.sub.2--), 2.88 (s, 3H,
--NCH.sub.3), 3.1-4.5 (complex, 9H, 4-CH.sub.2-- and 1-CHOH), 6.2
(m, 1H, --CH--), 6.8-7.5 (complex, 8H, aromatic). MS (FAB) m/z 423.
Anal. (C, H, N)C.sub.22H.sub.26N.sub.3O.sub.-
2F.sub.3.HCl.2.5H.sub.2O.
[0391] Compounds of Examples 69-91 were prepared from the
appropriate arylacetic acids/acid chlorides via EDCI/DIPEA or
DCC/pyridine couplings, followed by reduction, deprotection, and/or
derivatization via known chemistry. Intermediate A was prepared via
the method reported in J. Med. Chem., 34, 1991 pp. 181-189,
Costello, G. F. et al. 58
[0392] General Procedure for EDCI/DIPEA Coupling.
[0393] To a solution of acid (1.1 eq.) and 1-Hydroxybenzotriazole
hydrate (HOBT; 1.1 eq.) in dry CH.sub.2Cl in an ice-bath under
N.sub.2 was added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI; 1.1 eq.). The mixture was stirred for 30
minutes. A solution of the amine (1.0 eq.) in dry methlylene
chloride was added drop-wise followed by N,N-Diisopropylethyamine
(DIPEA; 1.5 eq.). The solution was allowed to stir at room
temperature overnight. The reaction was quenched with sat. sodium
bicarbonate and separated from methylene chloride. The organic
layer was dried (Na.sub.2SO.sub.4), filtered through Celite, and
evaporated. The crude product was chromatographed and converted to
the HCl salt.
EXAMPLE 69
2,2-Diphenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide
[0394] To a solution of Diphenylacetic acid (1.5 g; 7.3 mmol) and
pyridine (11.0 mL; 12.2 mmol) in 20 mL of dry methylene chloride at
25 degrees under N.sub.2 was added 1,3 dicyclohexylcarbodiimide,
DCC (2.0 g; 9.8 mmol). After 5 minutes, 28 (1.0 g; 4.9 mmol) in 20
mL of dry methlylene chloride was added and the mixture was stirred
overnight. TLC (95:5 methylene chloride:methanol with 2% ammonia)
indicated all of the starting material was consumed. The reaction
was quenched with sat. sodium bicarbonate and filtered through a
Celite plug. The plug was rinsed with methylene chloride and the
aqueous layer was extracted with methylene chloride. The combined
organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to give 2.2 g of a light brown solid. The
crude product was purified by flash chromatography using a stepwise
gradient of 2% to 8% MeOH:methylene chloride with 2% ammonia to
afford 1.7 g (88%) of pure product which was treated with 1.0M HCl
in diethyl ether to give 29 as the HCl salt. .sup.1H NMR (HCl salt,
DMSO-d.sub.6) .delta. 2.0(br s, 4H, --CH.sub.2CH.sub.2--), 2.7(s,
3H, --NCH.sub.3), 6.2(br m, 1H, --CH--), 7.1-7.5(complex, 15H,
aromatic). MS (FAB) m/z 398. Anal. (C, H, N)
C.sub.27H.sub.30N.sub.2O.HCl.0.75H.sub.2O.
EXAMPLE 70
N',N'-Diphenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]urea
[0395] To a 0 degree solution of 28 (500 mg; 2.4 mmol) and
triethylamine (731 mL; 5.2 mmol) in 10 mL of dry methylene chloride
under N.sub.2 was added a solution of Diphenylcarbamyl chloride
(629 mg; 2.7 mmol) in 5 mL of dry methylene chloride. The solution
was warmed to room temperature and stirred overnight. TLC (95:5
methylene chloride:methanol with 2% ammonia) indicated the starting
material was consumed. The reaction solution was concentrated to a
residue, which was pre-adsorbed onto silica and purified using a
stepwise gradient of 2% to 7% MeOH:methylene chloride with 2%
ammonia to afford 350 mg (36%) of pure product which was treated
with 1.0M HCl in diethyl ether to give 30 as the HCl salt. .sup.1H
NMR (HCl salt, DMSO-d.sub.6) .delta. 2.0 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.5(s, 3H, --NCH.sub.3), 5.8(br, m, 1H,
--CH--), 7.1-7.5(complex, 15H, aromatic). MS (FAB) m/z 399. Anal.
(C, H, N) C.sub.26H.sub.29N.sub.3O.HCl.0.5H.sub.2O.
EXAMPLE 71
2-(2-Nitrophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetam-
ide
[0396] This compound was prepared via the procedure described in
the preparation of 29 from 28 (0.6 g; 2.9 mmol),
2-nitrophenylacetic acid (0.8 g; 4.4 mmol), DCC (1.2 g; 5.8 mmol),
and pyridine (00.1 mL; 1.4 mmol). The crude product was purified by
flash chromatography using a stepwise gradient of 2% to 7%
MeOH:methylene chloride with 2% ammonia to afford 0.2 g (20%) of
pure product which was treated with 1.0M HCl in diethyl ether to
give 31 as the HCl salt. .sup.1H NMR(HCl salt, DMSO-d.sub.6) 2.0(br
s, 4H, --CH.sub.2CH.sub.2--), 2.9(s, 3H, --NCH.sub.3), 6.1(br, m,
1H, --CH--)7.3-8.1(complex, 9H, aromatic). MS (FAB) m/z 367. Anal.
(C, H, N) C.sub.21H.sub.25N.sub.3O.sub.3.HCl.
EXAMPLE 72
2-(2-Nitro-4.5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl-
)ethyl]acetamide
[0397] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (1.4 g; 6.9 mmol), 2-nitro
4,5-dichlorophenylacetic acid (1.9 g; 7.6 mmol), HOBT (1.0 g; 7.6
mmol), EDCI (1.4 g; 7.6 mmol), and pyridine (0.8 mL; 10.3 mmol).
The crude product was purified by flash chromatography using a
stepwise gradient of 2% to 5% MeOH:methylene chloride with 2%
ammonia to afford 2.0 g (60%) of pure product which was treated
with 1.0M HCl in diethyl ether to give 32 as the HCl salt. .sup.1H
NMR(HCl salt, DMSO-d.sub.6) .delta. 2.0 (br, s, 4H,
--CH.sub.2CH.sub.2--), 2.9 (s, 3H, --NCH.sub.3), 6.1 (br, m, 1H,
--CH--), 7.2-7.6 (complex, 5H, aromatic), 7.9 (s, 1H, aromatic),
8.4 (s, 1H, aromatic). MS (FAB) m/z 436. Anal. (C, H, N)
C.sub.21H.sub.23N.sub.3O.sub- .3Cl.sub.2.HCl.0.25H.sub.2O.
EXAMPLE 73
2-(4-Methylsulfonylphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)eth-
yl]acetamide
[0398] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (432 mg; 2. mmol),
4-Methylsulfonylphenylacetic acid (500 mg; 2.3 mmol), HOBT (341 mg;
2.5 mmol), EDCI (483 mg; 2.5 mmol), and DIPEA (0.550 mL; 3.1 mmol).
The crude product was purified by flash chromatography using a
stepwise gradient of 2% to 4% MeOH:methylene chloride with 2%
ammonia to afford 160 mg (19%) of pure product which was treated
with 1.0M HCl in diethyl ether to give 33 as the HCl salt. .sup.1H
NMR (HCl salt, DMSO-d.sub.6) .delta. 2.0 (br, s, 4H,
--CH.sub.2CH.sub.2--), 2.9 (s, 3H, --NCH.sub.3), 3.2 (s,
--SO.sub.2CH.sub.3), 6.1 (br, m, 1H, --CH--), 7.3-7.5 (complex, 5H,
aromatic), 7.6 (br, d, 2H, aromatic), 7.9 (br, d, 2H, aromatic). MS
(FAB) m/z 400. Anal. (C, H, N)
C.sub.22H.sub.28N.sub.2O.sub.3S.HCl.0.5H.sub.2O.
EXAMPLE 74
2-(2-Methoxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acet-
amide
[0399] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (500 mg; 2.4 mmol),
2-Methoxyphenylacetic acid (610 mg; 3.6 mmol), HOBT (495 mg; 3.6
mmol), EDCI (700 mg; 3.6 mmol), and DIPEA (0.850 mL; 4.8 mmol). The
crude product was purified by flash chromatography using a stepwise
gradient of 1% to 7% MeOH:methylene chloride with 2% ammonia to
afford 822 mg (96%) of pure product which was treated with 1.0M HCl
in diethyl ether to give 34 as the HCl salt. .sup.1H NMR (free
base, CDCl.sub.3) .delta. 1.8 (br, s, 4H, --CH.sub.2CH.sub.2--),
2.8 (s, 3H, --NCH.sub.3), 3.8 (s, 3H, OCH.sub.3), 6.1 (br, m, 1H,
--CH--), 6.8-7.4 (complex, 9H, aromatic). MS (FAB) m/z 352. Anal.
(C, H, N) C.sub.22H.sub.28N.sub.2O.sub.2.HCl.
EXAMPLE 75
2-(3-Indolyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide
[0400] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (500 mg; 2.4 mmol), Indole-3-acetic acid
(641 mg; 3.6 mmol), HOB (494 mg; 3.6 mmol), EDCI (700 mg; 3.6
mmol), and DIPEA (0.637 mL; 3.6 mmol). The crude product was
purified by flash chromatography using a stepwise gradient of 1% to
7% MeOH:methylene chloride to afford 761 mg (88%) of pure product
which was treated with 1.0M HCl in diethyl ether to give 35 as the
HCl salt. .sup.1H NMR (HCl salt, CD.sub.3OD) .delta. 2.1 (br, s,
4H, --CH.sub.2CH.sub.2--), 2.8 (s, 3H, --NCH.sub.3), 6.3 (br, m,
1H, --CH--), 7.1-7.7 (complex, 9H, aromatic). MS (FAB) m/z 361.
Anal. (C, H, N) C.sub.23H.sub.27N.sub.3O.HCl.1.0H.sub.2O.
EXAMPLE 76
2-(.alpha.,.alpha.,.alpha.-Trifluoro-p-tolyl)-N-methyl-N-[(1S)-1-phenyl-2--
(1-pyrrolidinyl)ethyl]acetamide
[0401] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (200 mg; 0.9 mmol),
(.alpha.,.alpha.,.alpha.-Trifluoro-- p-tolyl) acetic acid (239 mg;
1.1 mmol), HOBT (157 mg; 1.1 mmol), EDCI (223 mg; 1.1 mmol), and
DIPEA (0.203 mL; 1.1 mmol). The crude product was purified by flash
chromatography using a stepwise gradient of 1% to 2% MeOH:methylene
chloride to afford 354 mg (93%) of pure product which was treated
with 11.0M HCl in diethyl ether to give 36 as the HCl salt. .sup.1H
NMR (HCl salt, CDCl.sub.3) .delta. 1.8 (br, s, 4H,
--CH.sub.2CH.sub.2--), 3.0 (s, 3H, NCH.sub.3), 6.4 (br, m, 1H, CH),
7.2-7.6 (complex, 9H, aromatic). MS (FAB) m/z 390. Anal. (C, H, N)
C.sub.22H.sub.25N.sub.2OF.sub.3.HCl.
EXAMPLE 77
2-(2-Nitro-.alpha.,.alpha.,.alpha.-Trifluro-4-tolyl)-N-methyl-N-[(1S)-1-ph-
enyl-2-(1-pyrrolidinyl)ethyl]acetamide
[0402] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (500 mg; 2.4 mmol),
(2-Nitro-.alpha.,.alpha.,.alpha.-tr- ifluro-4-tolyl) acetic acid
(728 mg; 2.9 mmol), OBT (395 mg; 2.9 mmol), EDCI (559 mg; 2.9
mmol), and DIPEA (0.510 mL; 2.9 mmol). The crude product was
purified by flash chromatography using a stepwise gradient of 2% to
10% MeOH:methylene chloride to afford 786 mg (74%) of pure product
which was treated with 1.0M HCl in diethyl ether to give 37 as the
HCl salt. .sup.1H NMR (HCl salt, CDCl.sub.3) d 2.0 (br, s, 4H,
--CH.sub.2CH.sub.2), 2.9 (s, 3H, --NCH.sub.3), 6.3 (br, m, 1H, CH),
7.1-7.5 (complex, 4H, aromatic), 7.8-7.9 (br, m, 2H, aromatic),
8.3-8.4 (br, s, 2H, aromatic). MS (FAB) m/z 435. Anal. (C, H, N)
C.sub.22H.sub.24N.sub.3O.sub.3F.sub.3.HCl.
EXAMPLE 78
2-(1-[4-Chlorobenzoyl)-5-methoxy-2-methyl
indole)-N-[(1S)-1-phenyl-2-(1-py- rrolidinyl)ethyl]acetamide
[0403] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (100 mg; 0.4 mmol),
(1-[p-chlorobenzoyl)-5-methoxy-2-me- thyl indole-3-acetic acid (189
mg; 0.5 mmol), HOBT (73 mg; 0.5 mmol), EDCI (101 mg; 0.5 mmol), and
DIPEA (128 mL; 0.7 mmol). The crude product was purified by flash
chromatography using a stepwise gradient of 2% to 5% MeOH:methylene
chloride to afford 200 mg (79%) of pure product which was treated
with 1.0M HCl in diethyl ether to give 38 as the HCl salt. .sup.1H
NMR (HCl salt, CDCl.sub.3) .delta. 1.6-1.8 (br, m, 4H,
--CH.sub.2CH.sub.2--), 2.3 (b, s, 3H, --CH.sub.3), 2.9 (br, s,
--NCH.sub.3), 3.8 (br, s, 3H, --OCH.sub.3), 6.7 (br, m, 1H, --CH),
7.1-7.6 (complex, 12H, aromatic). MS (FAB) m/z 509. Anal. (C, H, N)
C.sub.32H.sub.35N.sub.3O.sub.3Cl.HCl.
EXAMPLE 79
2-(4-Nitrophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetam-
ide
[0404] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (1.5 g; 7.3 mmol), 4-Nitrophenylacetic
acid (2.0 g; 11.0 mmol), HOBT (1.4 g; 11.0 mmol), EDCI (2.1 g; 11.0
mmol), and DIPEA (2.5 mL; 14.6 mmol). The crude product was
purified by flash chromatography using a stepwise gradient of 1% to
5% MeOH:methylene chloride to afford 2.5 g (93%) of pure product
which was treated with 11.0M HCl in diethyl ether to give 39 as the
HCl salt. .sup.1H NMR (HCl salt, CDCl.sub.3) .delta. 1.6 (br, m,
4H, --CH.sub.2CH.sub.2--), 2.8 (br, s, 3H, --NCH.sub.3), 6.4 (br,
m, 1H, --CH), 7.1-7.5 (complex, 7H, aromatic), 8.0 (br, d, 2h,
aromatic). MS (FAB) m/z 367. Anal. (C, H, N)
C.sub.21H.sub.25N.sub.3O.sub.3.HCl.
EXAMPLE 80
2-(3-Nitrophenyl)-N-methyl-N-[(1S)-1-Phenyl-2-(1-pyrrolidinyl)ethyl]acetam-
ide
[0405] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (1.5 g; 7.3 mmol), 3-Nitrophenylacetic
acid (2.0 g; 11.0 mmol), HOBT (1.4 g; 11.0 mmol), EDCI (2.1 g; 11.0
mmol), and DIPEA (2.5 mL; 14.6 mmol). The crude product was
purified by flash chromatography using a stepwise gradient of 1% to
5% MeOH:methylene chloride with 2% ammonia to afford 2.6 g (100%)
of pure product which was treated with 1.0M HCl in diethyl ether to
give 40 as the HCl salt. .sup.1H NMR (HCl salt, CDCl.sub.3) .delta.
2.0 (br, m, 4H, --CH.sub.2CH.sub.2--), 2.9 (br, s, 3H,
--NCH.sub.3), 6.3 (br, m, 1H, --CH), 7.2-7.6 (complex, 6H,
aromatic), 7.8 (br, d, 1H, aromatic), 8.1-8.2 (complex, 2H,
aromatic). MS (FAB) m/z 367. Anal. (C, H, N)
C.sub.21H.sub.25N.sub.3O.sub.3.HCl.0.5H.sub.2O.
EXAMPLE 81
2-(2-Pyridyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide
[0406] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (350 mg; 1.7 mmol), 2-Pyridylacetic acid
hydrochloride (326 mg; 1.8 mmol), HOBT (253 mg; 1.8 mmol), EDCI
(360 mg; 1.8 mmol) and DIPEA (0.644 mL; 3.7 mmol). The crude
product was purified by flash chromatography using a stepwise
gradient of 2% to 5% MeOH:methylene chloride with 2% ammonia to
afford 400 mg (72%) of pure product which was treated with 1.0M HCl
in diethyl ether to give 41 as the HCl salt. .sup.1H NMR (free
base, CDCl.sub.3) .delta. 1.7-1.9 (br, m, 4H, --CH.sub.2CH.sub.2),
2.8 (br, s, 3H, --NCH.sub.3), 6.0-6.2 (br, m, 1H, --CH), 7.1-7.8
(complex, 8H, aromatic), 8.5 (br, d, 1H, aromatic). MS (FAB) m/z
323. Anal. (C, H, N) C.sub.20H.sub.25N.sub.3O.2HCl.0.5H.sub.2O.
EXAMPLE 82
2-(3-Pyridyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide
[0407] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (120 mg; 0.5 mmol), 3-Pyridylacetic acid
hydrochloride (110 mg; 0.6 mmol), HOBT (85 mg; 0.6 mmol), EDCI (120
mg; 0.6 mmol), and DIPEA (0.280 mL; 1.5 mmol). The crude product
was purified by flash chromatography using a stepwise gradient of
1% to 6% MeOH:methylene chloride with 2% ammonia to afford 142 mg
(76%) of pure product which was treated with 11.0M HCl in diethyl
ether to give 42 as the HCl salt. .sup.1H NMR (HCl salt,
CDCl.sub.3) .delta.2.1 (br, m, 4H, --CH.sub.2CH.sub.2--), 2.9 (br,
s, 3H, --NCH.sub.3), 6.2-6.3 (br, m, 1H, --CH), 7.2-7.3 (complex,
5H, aromatic), 7.8-7.9 (br, t, 1H, aromatic), 8.6-8.9 (complex, 3H,
aromatic). MS (FAB) m/z 323. Anal. (C, H, N)
C.sub.20H.sub.25N.sub.3O.2HCl.1.25H.sub.2O.
EXAMPLE 83
2-((.+-.)-6-Methoxy-a-methyl-2-napthalene)-N-[(1S)-1-phenyl-2-(1-pyrrolidi-
nyl)ethyl]acetamide
[0408] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (200 mg; 0.9 mmol),
(.+-.)-6-Methoxy-.alpha.-methyl-2-n- aphaleneacetic acid (217 mg;
1.0 mmol), HOBT (142 mg; 1.0 mmol), EDCI (201 mg; 1.0 mmol), and
DIPEA (0.256 mL; 1.4 mmol). The crude product was purified by flash
chromatography using a stepwise gradient of 1% to 2% MeOH:methylene
chloride with 2% ammonia to afford 130 mg (33%) of pure product
which was treated with 1.0M HCl in diethyl ether to give 43 as the
HCl salt. .sup.1H NMR (HCl salt, CDCl.sub.3) .delta. 1.4 (d, 3H,
--CH.sub.3), 2.9 (br, s, --NCH.sub.3), 3.9 (s, --OCH.sub.3), 5.5
(br, m, 1H, --CH), 7.0-7.7 (complex, 11H, aromatic). MS (FAB) m/z
416. Anal. (C, H, N) C.sub.27H.sub.32N.sub.2O.sub.2.HCl.
0.25H.sub.2O.
EXAMPLE 84
2-(.alpha.,.alpha.,.alpha.-Trifluoro-3-tolyl)-N-methyl-N-[(1S)-1-phenyl-2--
(1-pyrrolidinyl)ethyl]acetamide
[0409] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (200 mg; 0.9 mmol),
(.alpha.,.alpha.,.alpha.-Trifluoro-- m-tolyl) acetic acid (214 mg;
1.0 mmol), HOBT (142 mg; 1.0 mmol), EDCI (201 mg; 1.0 mmol), and
DIPEA (0.256 mL; 1.4 mmol). The crude product was purified by flash
chromatography using a stepwise gradient of 2% to 6% MeOH:methylene
chloride to afford 250 mg (67%) of pure product which was treated
with 1.0M HCl in diethyl ether to give 44 as the HCl salt. .sup.1H
NMR (HCl salt, CDCl.sub.3) .delta. 2.0 (br, m, 4H,
--CH.sub.2CH.sub.2--), 2.9 (br, s, 3H, --NCH.sub.3), 6.4 (br, m,
1H), 7.1-7.7 (complex, 9H, aromatic). MS (FAB) m/z 390. Anal. (C,
H, N) C.sub.22H.sub.25N.sub.2OF.sub.3.HCl.
EXAMPLE 85
2-(4-Pyridyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide
[0410] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (120 mg; 0.5 mmol), 4-Pyridylacetic acid
hydrochloride (150 mg; 0.8 mmol), HOBT (117 mg; 0.8 mmol), EDCI
(166 mg; 0.8 mmol), and DIPEA (0.202 mL; 1.1 mmol). The crude
product was purified by flash chromatography using a stepwise
gradient of 2% to 5% MeOH:methylene chloride to afford 172 mg (92%)
of pure product which was treated with 1.0M HCl in diethyl ether to
give 45 as the HCl salt. .sup.1H NMR (HCl salt, CDCl.sub.3) .delta.
2.1 (br, m, 4H, --CH.sub.2CH.sub.2--), 2.9 (br, s, --NCH.sub.3),
6.3 (br, m, --CH), 7.2-7.3 (complex, 5H, aromatic), 7.8 (br, s, 2H,
aromatic), 8.6 (br, s, 2H, aromatic). MS (FAB) m/z 323. Anal. (C,
H, N) C.sub.20H.sub.25N.sub.3O.1.5HCl.0.5H.sub.2O.
EXAMPLE 86
2-(.alpha.,.alpha.,.alpha.-Trifluoro-2-tolyl)-N-methyl-N-[(1S)-1-phenyl-2--
(1-pyrrolidinyl)ethyl]acetamide
[0411] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (200 mg; 0.9 mmol),
(.alpha.,.alpha.,.alpha.-Trifluoro-- o-tolyl)acetic acid (239 mg;
1.1 mmol), HOBT (157 mg; 1.1 mmol), EDCI (223 mg; 1.1 mmol), and
DIPEA (0.203 mL; 1.1 mmol). The crude product was purified by flash
chromatography using a stepwise gradient of 1% to 4% MeOH:methylene
chloride with 2% ammonia to afford 339 mg (82%) of pure product
which was treated with 1.0M HCl in diethyl ether to give 46 as the
HCl salt. .sup.1H NMR (HCl salt, CDCl.sub.3) .delta. 2.0 (br, m,
4H--CH.sub.2CH.sub.2--), 2.9 (br, s, --NCH.sub.3), 6.3 (br, m, 1H,
--CH), 7.1-7.7 (complex, 9H, aromatic). MS (FAB) m/z 390. Anal. (C,
H, N) C.sub.22H.sub.25N.sub.2OF.sub.3.HCl.
EXAMPLE 87
2-((S)-(.+-.)-4-Isobutyl-a-methylphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-py-
rrolidinyl)ethyl]acetamide
[0412] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (200 mg; 0.9 mmol),
(S)-(.+-.)-4-Isobutyl-.alpha.-methy- lphenylacetic acid (217 mg;
1.0 mmol), HOBT (142 mg; 1.0 mmol), EDCI (201 mg; 1.0 mmol), and
DIPEA (0.256 mL; 1.4 mmol). The crude product was purified by flash
chromatography using a stepwise gradient of 1% to 2% MeOH:methylene
chloride with 2% ammonia to afford 240 mg (66%) of pure product
which was treated with 1.0M HCl in diethyl ether to give 47 as the
HCl salt. .sup.1H NMR (HCl salt, CDCl.sub.3) .delta. 0.8 (d, 6H,
--(CH.sub.3).sub.2), 1.4 (d, 2H, --CH.sub.3), 2.0 (br, m,
--CH.sub.2CH.sub.2--), 2.3-2.4 (d, 2H, --CH.sub.2--), 2.9 (s, 3H,
--NCH.sub.3), 5.6 (br, m, 1H, --CH), 7.0 (br, q, 4H, aromatic), 7.3
(br, s, 5H, aromatic). MS (FAB) m/z 392. Anal. (C, H,
N)C.sub.26H.sub.36N.sub.- 2O.HCl.0.25H.sub.2O.
EXAMPLE 88
2-(3,4,5-Trimethoxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)eth-
yl]acetamide
[0413] This compound was prepared via the general EDCI/DIPEA
coupling procedure from 28 (250 mg; 1.2 mmol),
3,4,5-Trimethoxyphenylacetic acid (304 mg; 1.3 mmol), HOBT (181 mg;
1.3 mmol), EDCI (256 mg; 1.3 mmol), and DIPEA (0.318 mL; 1.8 mmol).
The crude product was purified by flash chromatography using a
stepwise gradient of 2% to 5% MeOH:methylene chloride with 2%
ammonia to afford 500 mg (100%) of pure product which was treated
with 1.0M HCl in diethyl ether to give 48 as the HCl salt. .sup.1H
NMR (free base, CDCl.sub.3) .delta. 1.7 (br, m, 4H,
--CH.sub.2CH.sub.2--), 2.7 (s, 3H, --NCH.sub.3), 3.8 (d, 9H,
--OCH.sub.3), 6.0-6.2 (br, m, 1H, --CH), 6.4 (s, 2H, aromatic),
7.1-7.3 (complex, 5H, aromatic). MS (FAB) m/z 412. Anal. (C, H, N)
C.sub.24H.sub.32N.sub.2O.sub.4.HCl.
EXAMPLE 89
2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetam-
ide
[0414] Raney-Nickel (50% slurry in water) was added to a mixture of
31 (2.30 g; 6.1 mmol), 2.2 mL (61.9 mmol) of hydrazine hydrate and
45 mL of abs. EtOH at 55 degrees to maintain a regular gas
evolution. After 45 min., TLC (95:5 methylene chloride:methanol w/
2% ammonia) indicated that all of the starting material was
consumed. The mixture was filtered through a Celite plug and rinsed
with copious amounts of hot methanol. The filtrates were combined
and concentrated in vacuo to afford 270 mg of a waxy solid. The
crude product was purified by flash chromatography using a stepwise
gradient of 1% to 8% methanol:methylene chloride with 2% ammonia to
afford 2.01 g (97%) of desired product. The pure product was
treated with 1.0M HCl in diethyl ether to yield 49 as the HCl salt.
.sup.1H NMR (HCl salt, DMSO-d.sub.6) .delta. 2.0 (br, m, 4H,
--CH.sub.2CH.sub.2--), 2.9 (s, 3H, --NCH.sub.3), 6.1 (br, m, 1H,
--CH), 7.2 (complex, 9H, aromatic). MS (FAB) m/z 321. Anal. (C, H,
N) C.sub.21H.sub.27N.sub.3O.2HCl.0.75H.sub.2O.
EXAMPLE 90
2-(2-N,N-Dimethylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-
-pyrrolidinyl)ethyl]acetamide
[0415] To a solution of 49 (400 mg; 1.1 mmol) in 50 ml of dry
methylene chloride was added 429 mL of triethylamine and MsCl (913
mL; 11.8 mmol) dissolved in 6 mL of dry methylene chloride. The
dark red solution was allowed to stir overnight. TLC (95:5
methylene chloride:methanol w/ 2% ammonia) indicates the starting
material is consumed. The reaction solution was quenched with sat.
sodium bicarbonate and the layers were separated. The aqueous layer
was extracted with methylene chloride and the combined organic
layers were dried over anh. sodium sulfate, filtered and the
solvent was concentrated in vacuo to give 700 mg of a dark brown
residue. The crude product was purified by flash chromatography
using a stepwise gradient of 2% to 7% methanol:methylene chloride
with 2% ammonia to afford 580 mg (97%) of desired product. The pure
product was treated with 1.0M HCl in diethyl ether to yield 50 as
the HCl salt. .sup.1H NMR (HCl salt, DMSO-d.sub.6) .delta. 2.0 (br,
m, 4H, --CH.sub.2CH.sub.2--), 2.7 (br, s, 3H, --NCH.sub.3), 3.5
(br, s, (--SO.sub.2CH.sub.3).sub.2), 6.2 (br, d, 1H, --CH), 7.2-7.5
(complex, 9H, aromatic). MS (FAB) m/z 493. Anal. (C, H, N)
C.sub.23H.sub.31N.sub.3O.sub.5S.sub.2.HCl.0.25H.sub.2O.
EXAMPLE 91
2-(N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrro-
lidinyl)ethyl]acetamide
[0416] To a solution of 50 (500 mg; 1.0 mmol) in 6 mL of 2:1
MeOH:THF was added 4.0 mL of 1.0M NaOH. The solution was stirred
for 20 min., after which TLC (95:5 methylene chloride:methanol w/
2% ammonia) indicates the reaction is complete. The reaction was
quenched with 10% HCl and washed with water and brine. The organic
layer was dried over anh. sodium sulfate, filtered and concentrated
in vacuo to give 381 mg of a brown solid. The crude product was
purified by flash chromatography using a stepwise gradient of 2% to
4% methanol:methylene chloride with 2% ammonia to afford 326 mg
(80%) of desired product. The pure product was treated with 1.0M
HCl in diethyl ether to yield 51 as the HCl salt. .sup.1H NMR (HCl
salt, CDCl.sub.3) .delta. 2.0 (br, m, 4H, --CH.sub.2CH.sub.2--),
2.9 (br, s, 3H, --NCH.sub.3), 3.0 (s, 3H, --SO.sub.2CH.sub.3), 6.3
(br, m, 1H, --CH), 7.0-7.2 (complex, 8H, aromatic), 7.5 (br, d, 1H,
aromatic). MS (FAB) m/z 415. Anal. (C, H, N)
C.sub.22H.sub.29N.sub.3O.sub.3S.HCl.0.25H.- sub.2O.
EXAMPLE 92
2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl-
)ethyl]acetamide
[0417] To a solution of 32 (495 mg; 1.0 mmol) in 25 mL of abs. EtOH
was added 50 mg of 10% Pd/C. The mixture was placed on a Parr
apparatus under 10 psi of hydrogen. After 1 h, TLC (95:5 methylene
chloride:methanol) indicates no starting material remains. The
mixture was filtered through a Celite plug and basified with aq.
ammonium hydroxide. The solvent was concentrated in vacuo to get a
residue which was dissolved in EtOAc and washed repeatedly with
water. The organic layer was dried over anh. sodium sulfate,
filtered and concentrated to give 200 mg of crude free base. The
crude product was treated with 1.0M HCl in diethyl ether and dried
in a vacuum oven at 80 degrees overnight to recover 120 mg (30%) of
52 as the HCl salt. .sup.1H NMR (HCl salt, CDCl.sub.3) .delta.
1.6-1.7 (br, m, 4H, --CH.sub.2CH.sub.2--), 2.7 (s, 3H,
--NCH.sub.3), 5.9-6.1 (br, m, 1H, --CH), 7.1-7.2 (complex, 7H,
aromatic). MS (FAB) m/z 406. Anal. (C, H, N)
C.sub.21H.sub.25N.sub.3OCl.sub.2.HCl.1.5H.sub.2O.
EXAMPLE 93
2-(N,N-Dimethysulfonamido-2-amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-p-
henyl-2-(1-pyrrolidinyl)ethyl]acetamide
[0418] Same procedure as 50 using 223 mg (0.54 mmol) of 52, 0.5 mL
(6.4 mmol) of MsCl, 2.0 mL (14.3 mmol) of triethylamine and 25 mL
of dry methylene chloride. The crude product was purified by flash
chromatography using a stepwise gradient of 1% to 3% MeOH:methylene
chloride to yield 150 mg (49%) of pure product which was treated
with 1.0M HCl in diethyl ether to give 53 as the HCl salt. .sup.1H
NMR (HCl salt, CDCl.sub.3) .delta. 2.0 (br, m, 4H,
--CH.sub.2CH.sub.2--), 2.8 (s, 3H, NCH.sub.3), 3.3 (d, 6H,
--(SO.sub.2CH.sub.3).sub.2), 6.2 (br, m, 1H, --CH), 7.0-7.1
(complex, 2H, aromatic), 7.3 (complex, 5H, aromatic). MS (FAB) m/z
562. Anal. (C, H, N) C.sub.23H.sub.29N.sub.3O.sub.5S.sub.2Cl.su-
b.2. HCl. 0.5H.sub.2O.
EXAMPLE 94
2-(2-Amino,.alpha.,.alpha.,.alpha.-Trifluoro-4-toly)-N-methyl-N-[(1S)-1-ph-
enyl-2-(1-pyrrolidinyl)ethyl]acetamide
[0419] Same procedure as 49 using 710 mg (1.6 mmol) of 37, 0.5 mL
(16.3 mmol) of hydrazine hydrate in 50 mL of EtOH. The recovered
product, 650 mg (98% crude recovery) was not purified any further.
A small amount of the desired product was treated with 1.0M HCl in
diethyl ether to form 54 as the HCl salt. .sup.1H NMR (HCl salt,
CDCl.sub.3) .delta. 2.0 (br, m, 4H, --CH.sub.2CH.sub.2--), 2.9.
(br, s, 3H, --NCH.sub.3), 6.3 (br, m, 1H, --CH), 7.2-7.5 (complex,
8H, aromatic). MS (FAB) m/z 405. Anal. (C, H, N)
C.sub.22H.sub.26N.sub.3OF.sub.3 1.5 HCl.
EXAMPLE 95
2-(2-N,N-Dimethylsulfonamido-2-amino-.alpha.,.alpha.,.alpha.-trifluoro-4-t-
olyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide
[0420] Same procedure as 50 using 100 mg (0.24 mmol) of 54, 0.2 mL
(2.4 mmol) of MsCl, 0.8 mL (6.3 mmol) of triethylamine and 13 mL of
dry methylene chloride. The crude product was purified by flash
chromatography using a stepwise gradient of 1% to 5% MeOH:methylene
chloride to yield 110 mg (80%) of desired product. A small amount
of compound was treated with 1.0M HCl in diethyl ether to give 55
as the HCl salt. .sup.1H NMR (HCl salt, CDCl.sub.3) .delta. 2.0
(br, m, 4H, --CH.sub.2CH.sub.2--), 2.9 (s, 3H, --NCH.sub.3), 3.3
(d, 6H, --(SO.sub.2CH.sub.3).sub.2), 6.3 (br, m, 1H, --CH), 7.1-8.0
(complex, 8H, aromatic). MS (FAB) m/z 497. Anal. (C, H, N)
C.sub.24H.sub.30N.sub.3OF.su- b.3S.sub.2.HCl.0.5H.sub.2O.
EXAMPLE 96
2-(N-Methylsulfonamido-2-amino-.alpha.,.alpha.,.alpha.-trifluro-4-tolyl)-N-
-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide
[0421] Same procedure as 51 using 51 mg (0.1 mmol) of 55, 30 mL of
1.0M NaOH and 1.9 mL of 2:1 MeOH:THF. The crude product was
purified by flash chromatography using a stepwise gradient of 1% to
5% MeOH:methylene chloride with 2% ammonia to yield 27 mg (63%) of
pure product which was treated with 1.0 M HCl in diethyl ether to
form 56 as the HCl salt. .sup.1H NMR (HCl salt, CDCl.sub.3) .delta.
2.0 (br, m, 4H, --CH.sub.2CH.sub.2--), 2.9 (br, s, 3H,
--NCH.sub.3), 3.1 (br, s, 3H, --SO.sub.2CH.sub.3), 7.1-7.3
(complex, 8H, aromatic). MS (FAB) m/z 483. Anal. (C, H, N)
C.sub.23H.sub.28N.sub.3O.sub.3SF.sub.3.HCl.0.25H.sub.2O.
EXAMPLE 97
2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetam-
ide
[0422] Same procedure as 49 using 2.6 g (7.1 mmol) of 40, 2.5 mL
(80.2 mmol) of hydrazine hydrate in 70 mL of EtOH. The recovered
product, 1.8 g was purified by flash chromatography using a
stepwise gradient of 1% to 9% MeOH:methylene chloride with 2%
ammonia to yield 1.1 g (47%) of pure product which was treated with
1.0 M HCl in diethyl ether to give 57 as the HCl salt. .sup.1H NMR
(free base, CDCl.sub.3) .delta. 1.7-1.9 (br, m, 4H,
--CH.sub.2CH.sub.2--), 2.7 (s, 3H, --NCH.sub.3), 6.1 (br, m, 1H,
--CH), 6.5-6.8 (complex, 3H, aromatic), 7.0 (m, 2H, aromatic), 7.3
(complex, 4H, aromatic). MS (FAB) m/z 337. Anal. (C, H, N)
C.sub.21H.sub.27N.sub.3O.2HCl.0.5H.sub.2O.
EXAMPLE 98
2-(4-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetam-
ide
[0423] Same procedure as 49 using 2.3 g (6.3 mmol) of 39, 2.4 mL
(75.4 mmol) of hydrazine hydrate in 70 mL of EtOH. The recovered
product, 1.7 g was purified by flash chromatography using a
stepwise gradient of 2% to 3% MeOH:methylene chloride with 2%
ammonia to yield 1.53 g (73%) of pure product. A small amount of
compound was treated with 1.0 M HCl in diethyl ether to give 58 as
the HCl salt. .sup.1H NMR (free base, CDCl.sub.3) .delta. 1.8 (br,
m, 4H, --CH.sub.2CH.sub.2--), 2.7 (s, 3H, --NCH.sub.3), 6.1 (br, m,
1H, --CH), 6.7 (m, 2H, aromatic), 7.0 (d, 2H, aromatic), 7.3
(complex, 5H, aromatic). MS (FAB) m/z 337. Anal. (C, H, N)
C.sub.21H.sub.27N.sub.3O.2HCl.0.75H.sub.2O.
EXAMPLE 99
2-(N,N-Dimethylsulfonamido-3-aminophenyl-N-meth
yl-N-[(1S)-1-phenyl-2-(1-p- yrrolidinyl)ethyl]-acetamide
[0424] Same procedure as 50 using 500 mg (1.5 mmol) of 57, 1.1 mL
(14.8 mmol) of MsCl, 3.0 mL (22.2 mmol) of triethylamine and 8.0 mL
of dry methylene chloride. The crude product was purified by flash
chromatography using a stepwise gradient of 1% to 4% MeOH:methylene
chloride with 2% ammonia to yield 308 mg (42%) of pure product. A
small amount of compound was treated with 1.0 M HCl in diethyl
ether to give 59 as the HCl salt. .sup.1H NMR (free base,
CDCl.sub.3) .delta. 1.8 (br, m, 4H, --CH.sub.2CH.sub.2--), 2.8 (s,
3H, --NCH.sub.3), 3.4 (s, 6H, (--SO.sub.2CH.sub.3).sub.2), 6.1 (br,
m, 1H, --CH), 7.0-7.5 (complex, 9H, aromatic). MS (FAB) m/z 493.
Anal. (C, H, N) C.sub.23H.sub.31N.sub.3O.sub- .5S.sub.2.HCl
EXAMPLE 100
(2-(N,N-Dimethylsulfonamido-4-aminophenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-p-
yrrolidinyl)ethyl]acetamide)
[0425] Same procedure as 50 using 400 mg (1.2 mmol) of 58, 0.55 mL
(7.1 mmol) of MsCl, 1.6 mL (11.8 mmol) of triethylamine and 12.0 mL
of dry methylene chloride. The crude product was purified by flash
chromatography using a stepwise gradient of 2% to 5% MeOH:methylene
chloride with 2% ammonia to yield 395 mg (68%) of pure product. The
compound was treated with 1.0 M HCl in diethyl ether to give 60 as
the HCl salt. .sup.1H NMR (free base, CDCl.sub.3) .delta. 1.8 (br,
m, 4H, --CH.sub.2CH.sub.2--), 2.8 (s, 3H, --NCH.sub.3), 3.4 (s, 6H,
(--SO.sub.2CH.sub.3).sub.2), 6.1 (br, m, 1H, --CH), 7.0-7.5
(complex, 9H, aromatic). MS (FAB) m/z 493. Anal. (C, H, N)
C.sub.23H.sub.31N.sub.3O.sub- .5S.sub.2.HCl.0.25H.sub.2O.
EXAMPLE 101
2-(2-Hydroxyphenyl)-N-methyl-N-methyl-N-[(1S)-1-phenyl-2-(1-Pyrrolidinyl)e-
thyl]acetamide
[0426] To a solution of 34 (700 mg; 1.8 mmol) in 10 mL of dry
methylene chloride @ 78.degree. C. was added 10.8 mL (10.8 mmol;
1.0M solution of BBr.sub.3 in methylene chloride) over 15 minutes.
The reaction mixture was allowed to warm to room temperature and
stir overnight. TLC (95:5 methylene chloride: MeOH w/ 2% ammonia)
indicated no starting material remained. The reactionn was quenched
with the addition of MeOH at 0 degrees. After 30 minutes, 3N HCl
was added and the mixture was stirred for 30 minutes (white
precipitate seen). The mixture was made neutral with sat.
bicarbonate and extracted with methylene chloride (3.times.100
MmL). The organic layer was dried over anh. sodium sulfate,
filtered and concentrated in vacuo to give 610 mg of crude product.
The crude product was purified by flash chromatography using a
stepwise gradient of 2% to 3% MeOH:methylene chloride to yield 500
mg (82%) of pure product. The product was treated with 1.0 M HCl in
diethyl ether to give 61 as the HCl salt. .sup.1H NMR (free base,
CDCl.sub.3) .delta.1.7 (br, m, 4H, --CH.sub.2CH.sub.2--), 2.9 (s,
3H, --NCH.sub.3), 6.1 (br, m, 1H, --CH), 6.8-7.4 (complex, 9H,
aromatic). MS (FAB) m/z 338. Anal. (C, H, N)
C.sub.21H.sub.26N.sub.2O.sub.2.HCl.0.5H.sub.2O.
EXAMPLE 102
N-Methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)ethyl]-3,4,5-t-
rimethoxyphenylacetamide HCl
[0427] To a solution of 3,4,5-trimethoxyphenylaetic acid (1.0 g,
4.43 mmol) in 10 mL of CH.sub.2Cl.sub.2 under a nitrogen atmosphere
was added pyridine (0.12 g, 1.5 mmol) and N,N-diisopropylethylamine
(Hunig's Base) (0.57 g, 4.43 mmol). The reaction mixture was cooled
to 0.degree. C. and DCC (1.37 g, 6.65 mmol) was added in one
portion. The reaction mixture was stirrred at this temperature and
a solution of the diaminel (0.65 g, 3.0 mmol) in 10 mL of
CH.sub.2Cl.sub.2 was added and the stirring was continued while
warming to room temperature for 20 h. The reaction mixture was
poured onto an aqueous saturated solutoin of NaHCO.sub.3 and the
mixture was stirred for 30 min. The organic layer was separated and
dried over anhydrous Na.sub.2SO.sub.4. After removal of the
solvent, the product was purifed on a silica gel column [solvent
system: CHCl.sub.3:CH.sub.3OH:28% NH.sub.4OH (98:2:2)]. The free
base was converted to the hydrochloride salt from 1M etherial HCl
and recrystallized form CH.sub.2Cl.sub.2:Et.sub.2O (1:1) to give a
HCl 0.64 g (46%) as light pink solid; mp 230-232.degree. C.;
.sup.1H-NMR (200 MHz, CDCl.sub.3) .delta. 2.20 (m, 4H), 2.85 (s,
3H), 3.004.30 (m, 5H), 3.70 (ms, 9H), 4.50 (m, 2H), 5.30 (d, J=15.0
Hz, 1H), 6.50 (m, 3H), 7.28 (m, 5H). Anal. Calcd for
C.sub.24H.sub.32N.sub.2O.sub.5.HCl.0.25H.sub.2O: C, 61.40; H, 7.19;
N, 5.97. Found: C, 61.36; H, 6.84; 8.96; N, 5.91.
[0428] The structure of the compound is shown hereunder. 59
[0429] The preparation of compounds 3a through 3ddd of formula MA
follow according to Schemes G, H, I, J, K, L, M, and N. 60 61 62 63
6465 66 6768 69
EXAMPLE 3a
2-(2-N-Methylsulfonamido-4,5-dichlorophenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-
-pyrrolidinyl)ethyl]acetamide hydrochloride
[0430]
2-(N,N-Dimethylsulfonamido-2-amino-4,5-dichlorophenyl)-N-methyl-N-[-
(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide (for preparation
see U.S. Pat. No. 5,688,955) 130 mg; 0.22 mmol was treated with 0.2
mL of 10 M NaOH in 3.0 mL of 2:1 MeOH:THF as described in the
preparation of 3rr. The crude product was purified by flash
chromatography using a stepwise gradient of 2% to 4% MeOH:methylene
chloride with 2% ammonia to give 100 mg (95%) of desired product
which was treated with 1.0 M HCl to aford 3a as a tan solid. Mp
140-142.degree. C.; .sup.1H NMR (HCl salt, DMSO-d.sub.6) .delta.
2.0 (br s, 4H, --CH.sub.2CH.sub.2--), 2.8 (s, 3H, NCH.sub.3), 3.1
(s, 3H, SO.sub.2CH.sub.3), 3.6-3.8 (m, 2H), 4.04.3 (q, 2H), 6.0-6.2
(dd, 1H), 7.2-7.6 (complex, 5H, aromatic), 7.7-7.9 (d, 2H), 9.5 (s,
NH). MS (FAB) m/z 483. Anal. (C, H, N) Calcd. for
C.sub.22H.sub.29N.sub.3O.sub.3Cl.sub.2S.HCl 0.25H.sub.2O: C, 50.73;
H, 5.42; N, 8.07. Found: C, 49.32; H, 5.52; N, 7.58.
EXAMPLE 3b
N-[(4-Trifluoromethylphenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-pyrrolidinyl)]-
ethyl}acetamido]glycine hydrochloride
[0431] To a stirred solution of bromoacetic acid (0.75 g, 5.42
mmol) in anhydrous CH.sub.3CN (20 mL) was added
N,N-diisopropylethylamine (1.41 g, 11.0 mmol) under a nitrogen
atmosphere. After addition of
2-(2-Amino-4-trifluoromethylphenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-pyrrol-
idinyl)]ethyl}acetamide.sup.1 (2.0 g, 4.93 mmol) in anhydrous
CH.sub.3CN (10 mL) to the reaction mixture, it was heated to
70.degree. C. for 6 days. TLC [solvent system:
CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH (95:5:2)] of the
reaction mixture showed that still some starting material was
present. The reaction mixture was cooled to room temperature and
solvent was evaporated to dryness. The residue was partioned
between CH.sub.2Cl.sub.2 and water, organic layer was separated,
dried over anhydrous Na.sub.2SO.sub.4, and evaporated to dryness to
give the crude mixture. The residue was crystallized from acetone
and acetonitrile (1:1) to give the desired compound as a white
solid 0.6 g which was still contaminated with minor amounts of the
starting material.
[0432] The product 3b was finally purified on Chromatotran
(precoated silica plate) using solvent acetone:water (9:1) and
recrystallized from acetonitrile to give the product as a white
solid, 0.35 g (15%); mp 228-230.degree. C. (d); MS (FAB) 464 (M+1);
.sup.1H NMR (200 MHz, DMSO-d.sub.6) .delta. 2.16 (m, 4H), 2.88 (s,
3H), 3.474.00 (m, 9H), 4.50 (m, 1H), 4.95 (m, 1H), 6.34 (d, J=9.0
Hz. 1H), 6.82 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 7.18 (d, J=7.7 Hz,
1H), 7.55 (m, 5H). Anal. Calcd. for
C.sub.24H.sub.28F.sub.3N.sub.3O.sub.3.0.25H.sub.2O: C, 61.59; H,
6.14; N, 8.98. Found: C, 61.54; H, 6.10; N, 9.36.
[0433] Ref.
[0434] U.S. Pat. No. 5,688,955 (1997).
EXAMPLE 3c
2-(3,4-Dichlorophenyl)-N-methyl-N-[(1R,S)-1-(3-sulfamidophenyl)-2-(1-pyrro-
lidinyl)ethyl]acetamide hydrochloride
[0435] A solution of compound 1.sup.1 (203 mg, 0.5 mmol) and
sulfamide (480 mg, 5 mmol) in dioxane (15 ml) was refluxed for 4
hours in oil bath. After removal of dioxane, the residue was
partitioned between NaOH (1N, 50 ml) and CHCl.sub.3 (50 ml). The
aqueous layer was extracted with CHCl.sub.3 (2.times.25 ml), and
the combined extract was washed with brine, dried
(Na.sub.2SO.sub.4). Silica column chromatography of crude material
gave a pure product that was converted to hydrochloric acid salt
with HCl/ether (164 mg, 64%). Mp: 198-200.degree. C. Spectral data:
.sup.1H NMR (DMSO-d.sub.6) 1.97 (m, 4H), 2.80 (s, 3H), 3.12 (m,
2H), 3.52-3.66 (m, 3H), 3.72 (d, J=16.5 Hz, 1H), 4.014.10 (m, 2H),
6.04 (d, J=11.0 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.99 (s, 1H), 7.17
(m, 1H), 7.29 (m, 1H), 7.55 (d, J=4.5 Hz, 1H), 9.10 (s, 1H). Fab MS
(MH.sup.+): 485. Anal. Calcd For
C.sub.21H.sub.26N.sub.4O.sub.3Cl.sub.2S.HCl: C, 48.33; H, 5.21; N,
10.74. Found: C, 48.31; H, 5.21; N, 10.59.
EXAMPLE 3d
2-(4-Trifluoromethylphenyl)-N-methyl-N-{[1S]-1-[3-[(methylsulfonyl)amino]p-
henyl]-2-[1-pyrrolidinyl]ethyl}acetamide hydrochloride
[0436] 4-Trifluormethylphenyl acetic acid was condensed with
(1S)-1-[2-(methylamino)-2-(3-nitrophenyl)-ethyl]pyrrolidine
following the methods described in the literature.sup.1 to give the
intermediate, 3-nitro-derivative in 95% yield, .sup.1H NMR (200
MHz, CDCl.sub.3) .delta. 1.68 (m, 4H), 2.35-3.30 (m, 6H), 2.71 (s,
3H), 3.85 (m, 2H), 6.20 (m, 1H), 7.49 (m, 7H), 8.10 (s, 1H). The
nitro group was reduced again following the method described in
literature (Raney Ni/hydrazine hydrate) to corresponding 3-amino
derivative in nearly quantitative yield.
[0437] To a solution of the above 3-amino compound (2.9 g, 7.15
mmol) in CH.sub.2Cl.sub.2 (30 mL) was added triethyl amine (3.62 g,
35.76 mmol) and the reaction mixture was cooled to in an ice-bath.
Methane sulfonyl chloride (2.46 g, 21.45 mmol) was added dropwise
in 15 min and the ice-bath was removed. The reaction mixture was
stirred at room temperature for 72 h. The reaction mixture was
quenched with addition of water, organic layer was separated,
washed with water, saturated NaHCO.sub.3, saturated salt solution,
and dried over anhydrous Na.sub.2SO.sub.4. Removal of solvent gave
3-N-(bis-methylsulfonamide) derivative as a foam which was used
directly into the following reaction.
[0438] The above compound (4.0 g, 7.12 mmol) was dissolved in
CH.sub.3OH:THF (2:1, 32 mL) and stirred at room temperature. Sodium
hydroxide (10 M aqueous solution) (1.29 g, 32.26 mmol) was added
and stirred at room temperature for 20 min [TLC, solvent system:
CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH (95:5:2)]. Reaction
mixture was neutralized with the addition of 1N HCl and evaporated
to dryness under reduced pressure. The residue was redissolved in
ethyl acetate, washed with saturated NaHCO.sub.3, saturated salt
solution, and dried over anhydrous Na.sub.2SO.sub.4. Removal of the
solvent under reduced pressure gave a yellow foam which was
purified on a silica gel column [solvent system:
CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH (95:5:2)]. The
hydrochloride salt was prepared from 1M etherial HCl and
recrystallized from 2-propano:ether (1:1) to give 3d as a cream
colored solid in 45% yield; mp 173-175.degree. C.; .sup.1H NMR (200
MHz, CDCl.sub.3) .delta. 1.65 (m, 4H), 2.30-3.15 (m, 6H), 2.67 (s,
3H), 2.86 (s, 3H), 3.80 (m, 2H), 6.05 (m, 1H), 7.00-7.25 (m, 4H),
7.35 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H). Anal. Calcd. for
C.sub.23H.sub.28F.sub.3- N.sub.3O.sub.3S.HCl.0.5H.sub.2O: C, 55.22;
H, 5.72; N, 7.94. Found: C, 52.17; H, 5.61; N, 7.96.
EXAMPLE 3e
2-(4-Methanesulfonylphenyl)-N-methyl-N-{[1S]-1-[3-[(methylsulfo-
nyl)amino]phenyl]-2-[1-pyrrolidinyl]ethyl}acetamide
methanesulfonate
[0439] The compound was prepared from 4-methylsulfonylphenyl acetic
acid following the procedure described for 3d. The methane sulfonic
acid salt was recrystallized from CH.sub.2Cl.sub.2:ether to give 3e
as a beige colored solid in 32% yield; mp 140-142.degree. C.;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.00 (m, 4H), 2.40 (s,
3H), 2.78 (s, 3H), 2.97 (s, 3H), 3.20 (s, 3H), 3.404.10 (m, 6H),
3.94 (d, J=5.5 Hz, 2H), 6.10 (m, 1H), 7.00 (d, J=5.8 Hz, 1H), 7.15
(s, 1H), 7.20 (t, J=6.0 Hz, 1H), 7.35 (t, J=5.5 Hz, 1H), 7.50 (d,
J=12.5 Hz, 2H), 7.85 (d, J=12.0 Hz, 2H). Anal. Calcd. for
C.sub.23H.sub.31N.sub.3O.sub.5S.sub.2.CH.sub.3SO.sub.3H.
2.0H.sub.2O: C, 46.06; H, 6.28; N, 6.71. Found: C, 45.99; H, 6.03;
N, 6.55.
EXAMPLE 3f
2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-[3-[(methylsulfonyl)amino]phenyl-
]-2-[1-pyrrolidinyl]ethyl}acetamide hydrochloride
[0440]
2-(3,4-Dichlorophenyl)-N-methyl-N-([1S]-1-[3-(bis-methylsulfonyl)am-
ino]phenyl]-2-[1-pyrrolidinyl]ethyl}acetamide.sup.1 (1.8 g, 3.2
mmol) was dissolved in CH.sub.3OH:THF (2:1, 90 mL) and added 10 M
NaOH solution (0.58 g, 14.5 mmol). The reaction was followed by TLC
[solvent system: CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH
(95:5:2)] and worked up as described in case of 3d to give the
crude product as a foam. The compound was purified on a silica gel
column [solvent system: CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH
(95:5:2)] and the hydrochloride salt was prepared from 1M etherial
HCl. Recrystallization of the salt from CH.sub.2Cl.sub.2:ether
(1:1) gave 3f as a beige colored solid, 0.57 g (35%); mp
240-242.degree. C. Anal. Calcd. for
C.sub.22H.sub.27Cl.sub.2N.sub.3O.sub.3S.HCl.0.25H.sub.2O: C, 50.29;
H, 5.47; N, 8.00. Found: C, 50.63; H, 5.26; N, 7.66
EXAMPLE 3g
2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-[3-(diethyl
Phosphoryl)amino]phenyl)-2-(1-pyrrolidinyl)ethyl]acetamide
hydrochloride
[0441] 2-(3,4-Dichlorophenyl)-N-methyl-N-{[1
S]-1-(3-aminophenyl)-2-[1-pyr- rolidinyl]ethyl}-acetamide.sup.1
(0.411 g, 1.011 mmol) was dissolved in anhydrous THF (8 mL) and
cooled in an ice-bath under a nitrogen atmosphere.
Diisopropylethylamine (1.06 mL, 6.07 mmol) was added followed
diethyl chlorophosphate (0.58 mL, 4.045 mmol). The reaction mixture
was stirred at room temperature for 48 h, quenched with the
addition of water, and evaporated to dryness. The residue was
partitioned between CH.sub.2Cl.sub.2 and saturated NaHCO.sub.3
solution. The organic layer was separated, dried over anhydrous
sodium sulphate, and evaoparted under reduced pressure to give the
crude product. The compound was purified on a silica gel column
[solvent system: CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH
(99:1:2)] and converted to the hydrochloride salt from 1M etherial
HCl to give 3g, 0.44 g (81%); mp 140-142.degree. C.; .sup.1H NMR
(200 MHz, DMSO-d.sub.6) .delta. 1.18 (t, J=8.0 Hz, 3H), 1.95 (m,
4H), 2.77 (s, 3H), 3.004.20 (m, 12H), 6.05 (m, 1H), 6.75 (d, J=8.0
Hz, 1H), 6.88 (s, 1H), 7.00 (d, J=7.5 Hz, 1H), 7.25 (m, 2H), 7.53
(m, 2H), 8.05 (d, J=8.6 Hz, 1H). Anal. Calcd. for
C.sub.25H.sub.34Cl.sub.2N.sub.3O.sub.- 4P.HCl.0.5H.sub.2O: C,
51.07; H, 6.17; N, 7.15. Found: C, 50.91; H, 5.93; N, 6.97.
EXAMPLE 3h
[0442]
2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-[3-[(4-oxo-butenoate)]ami-
no]phenyl)-2-(1-pyrrolidinyl)ethyl]acetamide
[0443]
2-(3,4-Dichlorophenyl)-N-methyl-N-{[1S]-1-(3-aminophenyl)-2-[1-pyrr-
olidinyl]ethyl}-acetamide.sup.1 (0.0.347 g, 0.855 mmol) was
dissolved in anhydrous THF (8 mL) under a nitrogen atmosphere and
added a solution of maleic anhydride (0.084 g, 0.855 mmol) in
anhydrous THF (1 mL) at room temperature. The reaction mixture was
stirred at this temperature for 24 h and the resulting solid was
filtered, washed with THF and ether. The solid was dried under
vacuum to give 3h, (0.274 g, 63%); mp 174-176.degree. C.; MS 504
(m/z); .sup.1H NMR (200 MHz, DMSO-d.sub.6) .delta. 1.79 (m, 4H),
2.72 (s, 3H), 2.85-3.85 (m, 6H), 5.95 (m, 1H), 6.10 (m, 1H), 6.25
(m, 1H), 6.95 (d, J=8.0 Hz, 1H), 7.28 (m, 2H), 7.55 (m, 4H). Anal.
Calcd. for C.sub.25H.sub.27Cl.sub.2N.sub.3O.sub.4.0.25H.sub.2O- :
C, 59.00; H, 5.45; N, 8.26. Found: C, 58.69; H, 5.18; N, 8.01.
EXAMPLE 3i
2-(3,4-Dichlorophenyl)-N-methyl-N-{(1S)-1-[3-(3-(((iso-butoxycarbonyl)-met-
hyl)aminocarbonyl)propionamido)phenyl]-2-(1-pyrrolidinyl)ethyl}acetamide
hydrochloride
[0444] A solution of compound 1 (222 mg, 0.546 mmol) in
CH.sub.2CL.sub.2 (10 ml) at 0.degree. C. was treated with succinic
anhydride (82 mg, 0.819 mmol). The mixture was allowed to warm up
to room temperature and stirred for 18 hours. The solvent was
removed by rotary evaporation and the residue was recrystallized
from ethyl acetate and hexane (249 mg, 89%).
[0445] A mixture of the above compound (246 mg, 0.486 mmol),
1-hydroxybenzotriazole monohydrate (98 mg, 0.729 mmol), and
p-toluenesulfonic acid salt of 2-methylpropyl glycine (221 mg,
0.729 mmol) in THF (5 ml) was treated with Et.sub.3N (0.102 ml,
0.729 mmol), followed by dicyclohexylcarbodiimide (150 mg, 0.729
mmol) in THF (2 ml). The mixture was stirred at room temperature
for 48 hours, cooled in ice bath, and filtered. The filtrate was
concentrated, dissolved in ethyl acetate, and the solution was
washed with aqueous NaHCO.sub.3 (saturated), water, brine, dried
(Na.sub.2SO.sub.4). After concentration, the residue was allowed to
pass through a silica column eluted with 2% MeOH in
CH.sub.2Cl.sub.2 (2% ammonia). 216 mg of the desired product was
obtained (72%) and part of the product was converted to the
hydrochloric acid salt (compound 3i, 67 mg). Mp: 85.degree. C.
(decomposed). Spectral data: .sup.1H NMR (DMSO-d.sub.6) .delta.
0.86 (d, J=6.7 Hz, 6H), 1.84 (m, 1H), 1.97 (m, 4H), 2.40-2.50 (m,
4H), 2.77 (s, 3H), 3.14 (m, 1H), 3.47-3.70 (m, 3H), 3.75-3.83 (m,
5H), 3.984.14 (m, 2H), 6.06 (d, J=10.0 Hz, 1H), 6.93 (d, J=7.7 Hz,
1H), 7.30 (m, 2H), 7.50-7.57 (m, 4H), 8.37 (bs, 1H). Fab MS
(MH.sup.+): 485. Anal. Calcd for C.sub.31H.sub.40N.sub.4-
5Cl.sub.2.HCl.1.2H.sub.2O: C, 54.94; H, 6.46; N, 8.27. Found: C,
54.94; H, 6.43; N, 8.28.
EXAMPLE 3j
2-(3,4-Dichlorophenyl)-N-methyl-N-{(1R,S)-1-[3-(3-(((hydroxycarbonyl)-meth-
yl)aminocarbonyl)propionamido)phenyl]-2-(1-pyrrolidinyl)ethyl}acetamide
hydrochloride
[0446] A solution of compound 3i (144 mg, 0.233 mmol) in ethanol (3
ml) and water (1 ml) was cooled in ice bath and treated with NaOH
(1N, 0.7 ml) slowly. After stirring at room temperature for 1 hour,
the solution was adjusted to pH=5 with 6N HCl. The mixture was
stirred for 2 hours and then concentrated. The residue was
separated by reversed phase TLC plate to give the final product
(114 mg, 80%). Mp: 158.degree. C. (decomposed). Spectral data:
.sup.1H NMR (DMSO-d.sub.6) .delta. 1.65 (bs, 4H), 2.40-2.64 (m,
4H), 2.70 (s, 3H), 3.11 (m, 2H), 3.33 (m, 2H), 3.71 (m, 3H), 3.86
(d, J=16.0 Hz, 1H), 5.81 (dd, J=9.9, 4.9 Hz, 1H), 6.94 (d, J=8.1
Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.48-7.56 (m, 4H), 8.17 (bs, 1H),
9.95 (s, 1H). Fab MS (MH.sup.+): 563. Anal. Calcd for
C.sub.27H.sub.32N.sub.4O.sub.5Cl.sub.2.HCl.0.75H.sub.2O: C, 52.79;
H, 5.68; N, 9.12. Found: C, 52.83; H, 5.92; N, 9.10.
EXAMPLE 3k
2-[(2-N-Phenylsulfonamido)-phenyl)]-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrroli-
dinyl)ethyl]acetamide methane sulfonate
[0447]
2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl-
]acetamide (for preparation see U.S. Pat. No. 5,688,955) 1.2 g
(3.55 mmol) was stirred in 30 mL of dry CH.sub.2Cl.sub.2 at
0.degree. C. Triethylamine (0.5 mL; 3.55 mmol) and benzenesulfonyl
chloride (0.45 mL; 3.55 mmol) in 10 mL of dry CH.sub.2Cl.sub.2 were
added. After the addition the reaction solution was allowed to warm
to room temperature and stirred overnight. TLC (90:10 methylene
chloride:methanol w/ 2% ammonia) indicated the reaction was
incomplete. 0.22 mL (1.7 mmol) of the chloride and 0.25 mL (1.7
mmol) of the base were added at 0.degree. C. The solution was
stirred for 24 h at room temperature before it was complete. The
reaction was quenched with sat. sodium bicarbonate and the layers
were separated. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give 1.9
g of crude product which was purified by flash chromatography using
a stepwise gradient of 2% to 7% MeOH:methylene chloride w/ 2%
ammonia to yield 1.2 g of bis-alkylated product which was
hydrolyzed using the same preparation as 3rr to afford 900 mg (53%)
of desired product which was treated with 1.0 eq. of
methanesulfonic acid to give 3k as a tan solid. mp 205-207.degree.
C.; .sup.1H NMR (mesylate salt, CDCl.sub.3) .delta. 1.8 (br m, 1H),
2.1 (br d, 2H), 2.2 (br t, 2H), 2.8 (s, 3H, NCH.sub.3), 3.1 (t,
1H), 4.0-4.3 (d, 2H), 6.2 (dd, 1H), 7.0 (d, 2H), 7.1 (m, 2H), 7.30
(complex, 5H, aromatic), 7.4 (d, 1H), 7.5 (d, 1H), 7.9 (d, 2H), 9.0
(s, 1H), 10.3(br, NH). MS (FAB) m/z 477. Anal. (C, H, N) Calcd. for
C.sub.27H.sub.31N.sub.3O.sub.3S CH.sub.3SO.sub.3H: C, 58.62; H,
6.15; N, 7.32. Found: C, 58.66; H, 6.20; N, 7.27.
[0448] General procedure for the preparation of N-methyl sulfamoyl
derivatives of phenyl acetic acids 70
[0449] To a stirred ice-cold chlorosulfonic acid (43.82 g, 0.376
mol) under anhydrous condition was added dropwise methyl
phenylacetate (6.23 g, 0.042 mol). When addition was completed, the
reaction mixture was then stirred at room temperature and the
progress of the reaction was monitored by TLC [solvent:
hexane:ethyl acetate (4:1)] [In this case the reaction was over in
30 min and however depending upon the substitution (X=H) of the
aromatic ring, reaction may take from 12 to 72 h at room
temperature]. Reaction mixture was then carefully poured on
ice-water and the product was extracted with ether several times.
The combined etherial solution was washed with water, saturated
salt solution, and dried over anhydrous sodium sulfate. Removal of
ether under reduced pressure resulted in a mixture of 2- and
4-chlorosulfonyl compounds (63-85% yields) (chlorosulfonation was
also depended upon the directing effects of the X group) which were
used directly into next reaction.
[0450] To a stirred solution of methyl amine (19.5 ml, 2 M in THF,
0.039 mol) at 0.degree. C. under a nitrogen atmosphere was added a
solution of above chlorosulfonyl derivative (3.25 g, 0.013 mo) in
anhydrous THF (10 mL). Reaction mixture was stirred 15 min at this
temperature and 1-4 h at room temperature by this time TLC
[solvent: hexane:ethyl acetate (4:1)] showed no starting material
was present. The solvent was removed under reduced pressure and the
residue was partioned between ethyl acetate and water. The organic
layer was separated washed with saturated salt solution, dried over
anhydrous sodium sulfate, and evaporated to dryness to give methyl
sulfonamide derivative (90-96% yield). In most cases this product
was pure enough to proceed to next step, otherwise purified on a
silica gel column before the hydrolysis of the ester.
[0451] The methyl sulfonamide ester (3.0 g, 12.34 mmol) was
suspended in 3N aqueous HCl and heated to reflux with stirring for
24 h. The solvent was removed under reduced pressure and the
residue was re-dissolved in CH.sub.2Cl.sub.2, filtered, and
concentrated to a small volume. Addition of either ether or hexane
gave compound A in 80-95% yield and these acids were used in the
condensation reactions.
EXAMPLE 3l
2-[3-(N-Methylsulfamoyl)-4-chlorophenyl]-N-methyl-N-{[1S]-1-phenyl-2-[1-py-
rrolidinyl]ethyl}acetamide hydrochloride
[0452] To a solution of 3-(N-methylsulfamoyl)-4-chlorophenyl acetic
acid (prepared from 4-chlorophenyl acetic acid, 1.58 g, 6.0 mmol)
in anhydrous CH.sub.2Cl.sub.2 (20 mL) under a nitrogen atmosphere
was add N-hydroxybezotriazole (0.81 g, 6.0 mmol). Reaction mixture
was stirred at room temperature for 15 min then cooled in an
ice-bath and added 1-(3-diethylaminoprpyl)-3-ethylcarbodiimide
hydrochloride (1.165 g, 6.0 mmol). Stirring was continued at
ice-bath temperature for 30 min then added a solution of
(1S)-1-[(2-methylamino-2-phenyl)ethyl]pyrrolidine.sup- .1 (1.02 g,
5.0 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 mL) followed by
N,N-diisopropylethylamine (0.79 g, 6.1 mmol). Reaction mixture was
continued stirring for 48 h [TLC, solvent system:
CH.sub.2Cl.sub.2:CH.sub- .3OH:28% NH.sub.4OH (95:5:2)]. After
addition of more CH.sub.2Cl.sub.2, the organic phase was washed
with water, saturated sodium bicarbonate solution, saturated salt
solution, and dried over anhydrous sodium sulfate. Removal of the
solvent under reduced pressure gave the crude product which was
coverted to the hydrochloride salt from 1M etherial HCl. The salt
was re-crystallized from 2-prppanol to give 31 as off-white solid,
1.52 g (62%); 285-287.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 2.01 (m, 4H), 2.50 (d, J=4.5 Hz, 3H), 2.87
(s, 3H), 3.17 (m, 2H), 3.64 (m, 3H), 3.90 (d, J=10.0 Hz, 1H), 4.14
(d, J=10.5 Hz, 2H), 6.20 (m, 1H), 7.28-7.45 (m, 4H), 7.55-7.65 (m,
3H), 7.90 (d, J=3.5 Hz, 1H). Anal. Calcd. for
C.sub.22H.sub.28ClN.sub.3O.sub.3S.HCl.0.75H.sub- .2O: C, 52.85; H,
6.15; N, 8.40. Found: C, 52.84; H, 5.89; N, 8.40.
EXAMPLE 3m
2-(3-Sulfamoyl-4-chlorophenyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-pyrrolidinyl-
]ethyl}acetamide methanesulfonate
[0453] Prepared from 3-sulfonamido-4-chlorophenyl acetic acid
following the above procedure and the free base was converted to
methanesulfonic acid salt. Recrystallization from 2-propanol gave
3m as a white solid in 51% yield; mp 220-222.degree. C.; MS (FAB)
436 (M+1); .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.00 (m,
4H), 2.36 (s, 3H), 2.76 (s, 3H), 3.20 (m, 2H), 3.50-3.80 (m, 4H),
3.94 (bs, 2H), 6.15 (m, 1H), 7.25 (d, J=6.0 Hz, 1H), 7.30-7.65 (m,
6H), 7.88 (d, J=2.5 Hz, 1H). Anal. Calcd. for
C.sub.21H.sub.26ClN.sub.3O.sub.3S.CH.sub.3SO.sub.3H: C, 49.66; H,
5.68; N, 7.90. Found: C, 49.69; H, 5.63; N, 7.78.
EXAMPLE 3n
2-(3-Sulfamoyl-4-chlorophenyl)-N-methyl-N-{[1S]-1-[3-[(methylsulfonyl)amin-
o]phenyl]-2-[1-pyrrolidinyl]ethyl}acetamide methanesulfonate
[0454]
(S)-1-[2-(Methylamino)-2-(3-nitrophenyl)ethyl]pyrrolidine.sup.1 was
condensed with 3-sulfonamido-4-chlorophenyl acetic acid following
the general procedure described in 83% yield. The catalytic
reduction of the 3-nitro group was done with PtO.sub.2 to give the
3-amino intermediate. Bis-mesylation of the 3-amino group followed
by selective removal one of the mesyl group as described for 3d
resulted in the desired compound in 28% yield. Methanesulfonic acid
salt was prepared in 71% yied to give 3n; mp 170-173.degree. C.; MS
(FAB) 543 (M+1); .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.98
(m, 4H), 2.35 (s, 3H), 2.44 (d, J=5.0 Hz, 3H), 2.77 (s, 3H), 2.98
(s, 3H), 3.10-4.15 (m, 6H), 3.90 (d, J=8.0 Hz, 2H), 6.20 (m, 1H),
7.00-7.75 (m, 6H), 7.90 (d, J=2.0 Hz, 1H). Anal. Calcd. for
C.sub.23H.sub.31ClN.sub.4O.sub.5S.sub.2.CH.sub.3SO.sub.3H.0.5H.sub.2O:
C, 44.47; H, 5.60; N, 8.64. Found: C, 44.26; H, 5.53; N, 8.45.
EXAMPLE 3o
2-[3-(N-Methylsulfamoyl)-4-fluorophenyl]-N-methyl-N-{[1S]-1-phenyl-2-[1-py-
rrolidinyl]ethyl}acetamide hydrochloride
[0455] Prepared from 3-methylsulfonamido-4-fluorophenyl acetic acid
following the above procedure to give 3o as a white solid in 85%
yield; mp 278-280.degree. C.; .sup.1H NMR (free base, 200 MHz,
CDCl.sub.3) .delta. 1.73 (m, 4H), 2.61 (bs, 3H), 2.68 (s, 3H),
2.90-3.20 (m, 2H), 3.55-3.90 (m, 3H), 4.75 (b, 1H), 6.05 (m, 1H),
7.05-7.60 (m, 7H), 7.72 (bd, 1H). Anal. Calcd. for
C.sub.22H.sub.28FN.sub.3O.sub.3S.HCl: C, 56.22; H, 6.22; N, 8.94.
Found: C, 56.22; H, 6.24; N, 8.86.
EXAMPLE 3p AND 3r
2-[2&4-(N-Methylsulfamoyl)-phenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-pyrrolid-
inyl)ethyl]acetamide hydrochloride
[0456] Compounds 3p and 3r were prepared using the general
EDCI/DIPEA coupling procedure of
(1S)-N-methyl-2-pyrrolidino-1-phenethylamine (1.3 g; 6.34 mmol), a
mixture of 2 and 4 substituted reversed sulfamides acids (1.6 g;
6.98 mmol), HOBT (943 mg; 6.9 mmol), EDCI (1.33 g; 6.98 mmol) and
DIPEA (1.32 mL; 7.60 mmol). After 24 hours, TLC (95:5 methylene
chloride:methanol with 2% ammonia) indicates the reaction is
complete. After the standard work-up, the crude product was
purified using a stepwise gradient of 2% to 10% MeOH:methylene
chloride with 2% ammonia to afford 1.6 g of a mixture of the 2 and
4 substituted sulfamide products. The mixture was separated using a
stepwise gradient of 1% to 2% MeOH:methylene chloride with 2%
ammonia on a chromatotran to afford 14 mg (0.5%) of the
2-substituted compound 3p and 20 mg (0.7%) of the 4-substituted
compound 3r, which were converted to the HCl salt with 1.0 M HCl in
diethyl ether. .sup.1H NMR (HCl salt, CDCL.sub.3) .delta. 1.7(br s,
4H, --CH.sub.2CH.sub.2--), 2.4-2.6 (m, 2H), 2.6 (d, 3H,
NHCH.sub.3), 2.8 (s, 3H, NCH.sub.3), 3.0-3.3 (t, 2H), 3.8 (d, 2H),
6.0-6.2 (dd, 1H), 7.2-7.4 (complex, 5H, aromatic), 7.5-7.7 (m, 2H),
7.8 (s, 2H). MS (FAB) m/z 415.
EXAMPLE 3q
3-(N-Methylsulfamoyl)-phenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)e-
thyl]acetamide hydrochloride
[0457] Compound 3q was prepared using the HOBT/EDCI coupling
procedure described in U.S. Pat. No. 5,885,955 with
3-SO.sub.2NHCH.sub.3 phenyl acetic acid (A) 2.23 g; 9.73 mmol,
(1S)-N-methyl-2-pyrrolidino-1-phenethy- lamine (1.90 g; 9.26 mmol),
HOBT (1.31 g; 9.73 mmol), EDCI (1.85 g; 9.73 mmol) and DIPEA (3.38
mL; 19.46 mmol). The crude product was purified by flash
chromatography using a stepwise gradient of 2% to 8% MeOH:methylene
chloride with 2% ammonia to give 1.40 g (40%) of desired product
which was treated with 1.0 M HCl in diethyl ether to afford 3q as
the HCl salt. mp>250.degree. C. (dec.); .sup.1H NMR (HCl salt,
CDCl.sub.3 with 3 drops of CD.sub.3OD) .delta. 2.0-2.2 (br, 4H,
--CH.sub.2CH.sub.2--), 2.6 (s, 3H, NHCH.sub.3), 2.8 (s, 3H,
NCH.sub.3), 3.4-3.5 (d, 2H), 6.3-6.4 (dd, 1H), 7.2 (d, 2H), 7.3-7.4
(complex, 5H, aromatic), 7.5 (t, 1H), 7.6 (d, 1H), 7.7 (d, 1H), 7.8
(s, 1H). MS (FAB) m/z 415. Anal. (C, H, N) Calcd. for
C.sub.22H.sub.29N.sub.3O.sub.3S.HCl: C, 58.46; H, 6.69; N, 9.30.
Found C, 59.34; H, 6.62; N, 9.19.
EXAMPLE 3s
2-[N-Methylsulfamoyl)-4-bromo-phenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-pyrro-
lidinyl]ethyl acetamide hydochloride
[0458] Compound 3s was prepared using the HOBT/EDCI coupling
procedure described in U.S. Pat. No. 5,885,955 using
2-SO.sub.2NHCH.sub.3, 4-bromorphenyl acetic acid (2.3 g; 7.40
mmol), (1S)-N-methyl-2-pyrrolidin- o-1-phenethylamine (1.4 g; 7.08
mmol), HOBT (1.0 g; 7.46 mmol), EDCI (1.4 g; 7.46 mmol) and DIPEA
(1.5 mL; 8.95 mmol). The crude product was purified by flash
chromatography using a stepwise gradient of 2% to 8% MeOH:methylene
chloride with 2% ammonia to give 500 mg (30%) of 3s as the desired
product which was treated with 1.0 M HCl in diethyl ether to afford
the HCl salt. mp>280.degree. C.; MS (FAB) m/z 494. Anal. (C, H,
N) Calcd. for C.sub.22H.sub.28N.sub.3O.sub.3S Br HCl 0.5H.sub.2O:
C, 49.77; H, 5.51; N, 7.91. Found: C, 48.86; H, 5.36; N, 7.67.
[0459] Ref.
[0460] 2. Gottschlich R. et. Al. BioOrg. Med. Chem. Lett., 4,
677-682 (1994)
EXAMPLE 3w
(Z)-4-[2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-Pyrr-
olidinyl]ethyl]acetamido]4-oxo-butanoic acid
[0461] To a solution of
2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1--
phenyl-2-(1-pyrrolidinyl)-ethyl]acetamide.sup.1 (0.86 g, 2.0 mmol)
in anhydrous THF under a nitrogen atmosphere was added succinic
anhydride (0.25 g, 2.5 mmol). The reaction mixture was stirred at
room temperature for 96 h and added excess of anhydrous ether. The
resulting solid was filtered off, washed with ether and dried to
give crude product. The compound was purified on a silica gel
column (acetone:water, 9:1). The desired compound was re-dissolved
in CH.sub.2Cl.sub.2, filtered, and concentrated to a small volume.
Addition of ether resulted the solid which was filtered, washed
with ether, and dried to give 3w (0.32 g, 30%); mp 168-170.degree.
C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.03 (m, 4H), 2.36
(m, 1H), 2.66 (m, 2H), 2.81 (s, 3H), 2.80-2.95 (m, 2H), 3.10 (m,
1H), 3.40 (d, J=14.0 Hz, 1H), 3.67 (d, J=14.5 Hz, 1H), 4.18 (t,
J=12.0 Hz, 1H), 6.40 (d, J=11.5 Hz, 1H), 7.20 (m, 3H), 7.45 (m,
3H), 8.00 (s, 1H). Anal. Calcd. for
C.sub.25H.sub.29Cl.sub.2N.sub.3O.sub.4S.su- b.2.0.5H.sub.2O: C,
58.26; H, 5.87; N, 8.15. Found: C, 58.08; H, 5.75; N, 7.96.
EXAMPLE 3x
(Z)-4-[2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrr-
olidinyl]-ethyl]acetamido]4-oxo-2-butenoic acid
[0462] To a solution of
2-(2-amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1--
phenyl-2-(1-pyrrolidinyl)-ethyl]acetamide.sup.1 (0.8 g, 1.85 mmol)
in anhydrous THF (10 mL) under a nitrogen atmosphere was added
maleic anhydride (0.181 g, 1.85 mmol) and the stirred at room
temperature for 4 days. After addition of anhydrous ether, the
resulting solid was sonicated and filtered. Recrystallization of
the solid from CH.sub.2Cl.sub.2:ether (1:1) gave 3x (0.51 g, 52%
yield); mp 158-160.degree. C. (d); .sup.1H NMR (200, MHz,
CDCl.sub.3) .delta. 2.00 (m, 4H), 2.72 (s, 3H), 2.75-3.20 (m, 2H),
3.35 (d, J=12.5 Hz, 1H), 3.85 (d, J=13.0 Hz, 1H), 3.904.20 (m, 2H),
6.10 (d, J=12.5 Hz, 1H), 6.25 (m, 2H), 7.15 (m, 3H), 7.44 (m, 3H),
8.00 (s, 1H). Anal. Calcd. for
C.sub.25H.sub.27Cl.sub.2N.sub.3O.sub.4.0.25H.sub.2O: C, 59.00; H,
5.45; N, 8.26. Found: C, 59.20; H, 5.57; N, 7.90.
EXAMPLE 3y
(E) Ethyl
4-[2-(2-amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[-
1-pyrrolidinyl]ethyl]acetamido]4-oxo-2-butenoate hydrochloride
[0463] To a solution of fumaric acid monoethyl ester (1.30 g, 9.02
mmol) in anhydrous CH.sub.2Cl.sub.2 (20 mL) under a nitrogen
atmosphere was added DCC (1.86 g, 9.03 mmol) followed by pyridine
(0.43 mL, 5.31 mmol). The reaction mixture was stirred at room
temperature for 30 min then added a solution of
2-(2-amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phe-
nyl-2-(1-pyrrolidinyl)-ethyl]acetamide.sup.1 (2.30 g, 5.31 mmol) in
anhydrous CH.sub.2Cl.sub.2 (10 mL). The reaction mixture was
stirred at this temperature for 72 h, filtered and evaporated to
dryness to give the crude product. The compound was purified on a
silica gel column [solvent system: CH.sub.2Cl.sub.2:CH.sub.3OH:28%
NH.sub.4OH (99:1:2)] to give the free base of the desired product.
The hydrochloride salt was prepared from 1M etherial HCl and
recrystallized from CH.sub.2Cl.sub.2:ether (1:1) to give 3y (2.0 g,
60%); mp 165-167.degree. C. (d); .sup.1H NMR (300, MHz, CDCl.sub.3)
.delta. 1.28 (t, J=7.0 Hz, 3H), 2.00-2.40 (m, 4H), 2.89 (s, 3H),
2.96 (m, 2H), 3.28 (m, 1H), 3.50 (m, 2H), 3.954.10 (m, 4H), 4.21
(q, J=7.1 Hz, 2H), 4.50 (d, J=15.0 Hz, 1H), 6.33 (d, J=10.0 Hz,
1H), 6.89 (d, J=15.0 Hz, 1H), 7.10-7.40 (m, 5H), 7.93 (d, J=15.3
Hz, 1H), 8.43 (s, 1H). Anal. Calcd. for
C.sub.27H.sub.31Cl.sub.2N.sub.3O.sub.4.HCl.H.sub.2O- : C, 55.25; H,
5.84; N, 7.16. Found: C, 55.63; H, 5.73; N, 6.94.
EXAMPLE 3z
(Z)-4-[2-(2-Amino-4-trifluoromethylphenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-
-pyrrolidinyl]-ethyl]acetamido]4-oxo-2-butenoic acid
[0464] The compound 3z was prepared from
2-(2-amino-4-trifluoromethylpheny-
l)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl]acetamide.sup.1
following the above in 40% yield; mp 153-155.degree. C. (d); MS
(FAB) 504 (M+1); .sup.1H NMR (200, MHz, DMSO-d.sub.6) .delta. 2.01
(m, 4H), 2.85 (s, 3H), 2.85-3.30 (m, 2H), 3.40 (d, J=14.5 Hz, 1H),
3.95 (d, J=14.0 Hz, 1H), 4.10 (m, 2H), 6.30 (m, 3H), 7.18 (m, 3H),
7.38 (m, 4H), 8.15 (s, 1H). Anal. Calcd. for
C.sub.26H.sub.28F.sub.3N.sub.3O.sub.4.0.75H.sub.2O: C, 60.40; H,
5.75; N, 8.13. Found: C, 60.07; H, 5.50; N, 7.91.
EXAMPLE 3aa
(Z)-4-[2-(2-Aminophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-(1-pyrrolidinyl]-eth-
yl]acetamido]4-oxo-2-butenoic acid hemimaleate
[0465] The compound 3aa was prepared from
2-(2-aminophenyl)-N-methyl-N-[(1-
S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl]acetamide.sup.1 following the
above in 93% yield; mp 149-1511C; Anal. Calcd. for
C.sub.25H.sub.29N.sub.3O.sub- .4.0.5C.sub.4H.sub.4O.sub.4.H.sub.2O:
C, 63.39; H, 6.50; N, 8.21. Found: C, 63.37; H, 6.20; N, 8.22.
EXAMPLE 3bb
2-(N,N-Bisacetic
acid-2-amino-.alpha.,.alpha.,.alpha.-trifluro-4-tolyl)-N--
methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide
hydrochloride
[0466]
2-(2-Amino,.alpha.,.alpha.,.alpha.-trifluoro-4-toly)-N-methyl-N-[(1-
S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]-acetamide (for the preparation
see U.S. Pat. No. 5,688,955) 2.0 g; 4.93 mmol was dissolved in 50
ml of dry THF at 0.degree. C. DIPEA (5.15 mL; 29.6 mmol) and
t-butyl bromoacetate (3.64 ml; 24.65 mmol) were added 15 minutes
apart. The reaction was allowed to warm to room temperature and
stirred for 4 days. TLC (95:5 methylene chloride:methanol with 2%
ammonia) indicated the reaction is incomplete. Added 1.67 mL (9.58
mmol) of DIPEA to the reaction. After 24 hours the reaction mixture
was concentrated to a residue. The residue was dissolved in
methylene chloride and washed with sat. sodium bicarbonate and
brine. The organic layer was dried (anh. Na.sub.2SO.sub.4),
filtered and concentrated in vacuo to give a yellow oil. The crude
product was purified by flash chromatography using a stepwise
gradient of 1% to 8% MeOH:methylene chloride with 2% ammonia to
afford 1.2 g (61%) of bis-alkylated material which was used in the
next step [.sup.1H NMR, (Free base, CDCl.sub.3) .delta. 1.4 (s, 9H,
t-butyl), 1.5 (s, 9H, t-butyl), 1.7-1.9 (m, 4H), 3.2 (s, 3H,
NCH.sub.3), 3.6-3.7 (dd, 4H), 4.3-4.8 (q, 4H), 5.7-5.9 (dd, 1H),
6.0 (d, 1H), 6.4 (d, 1H), 6.6 (s, 1H), 6.9-7.2 (m, 2H), 7.4
(complex, 3H, aromatic). MS (FAB) m/z 633. The bis-alkylated
compound (1.2 g; 1.89 mmol) was stirred in 33 mL of glacial acetic
acid with 4 drops of anisole. After 60 hours, the reaction was
concentrated in vacuo. The residue was dissolved in acetonitrile
and added drop-wise to a solution of 1.0 M HCl in diethyl ether.
The precipitate was collected by filtration and dried at 40.degree.
C. under vacuum to yield 960 mg (93%) of 3bb as a tan solid. mp
166-169.degree. C.; .sup.1H NMR (HCl salt, DMSO-d.sub.6) .delta.
1.6 (br s, 4H, --CH.sub.2CH.sub.2--), 2.9 (s, 3H, NCH.sub.3), 3.8
(q, 4H0, 4.1-4.3 (d, 2H), 4.74.9 (m, 3H), 6.6 (br d, 1H), 7.1 (s,
1H), 7.4 (d, 1H), 7.6 (d, 1H), 7.7-8.0 (complex, 5H, aromatic). MS
(FAB) m/z 521. Anal. (C, H, N) Calcd. for
C.sub.26H.sub.30N.sub.5O.sub.3F.sub.3.2HCl.H.sub.2O: C, 58.46; H,
6.69; N, 9.30. Found: C, 58.40; H, 6.65; N, 9.21.
EXAMPLE 3cc
3-(2-N-Methylsulfonamido)-phenyl]-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidi-
nyl)ethyl]acetamide hydrochloride
[0467] Compound 3cc was prepared using the same procedure as
described in the preparation of compound
(2-N-Methylsulonamido-2-aminophenyl)-N-methyl-
-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide (for the
preparation see U.S. Pat. No. 5,688,955). Compound
3-(N,N-Dimethylsulfonamido-2-amino-
phenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide
(1.0 g; 2.02 mmol), 10 mL of 10 M NaOH and 30 mL of 2:1 MeOH:THF.
The crude product was clean by TLC and .sup.1H NMR (760 mg; 90%).
The product was treated with 1.0 M HCl in diethyl ether to give 3cc
as the HCl salt; mp 155-160.degree. C. (dec.); .sup.1H NMR (Free
base, CDCl.sub.3) .delta. 1.7 (br s, 4H, --CH.sub.2CH.sub.2--), 2.5
(br d, 2H), 2.8 (s, 3H, NCH.sub.3), 2.9 (s, 3H, SO.sub.2CH.sub.3),
3.7 (d, 2H), 6.0-6.1 (dd, 1H), 7.0-7.4 (complex, 9H, aromatic). MS
(FAB) m/z 415. Anal. (C, H, N) Calc. for
C.sub.22H.sub.29N.sub.3O.sub.3S HCl: C, 58.46; H, 6.69; N, 9.30.
Found: C, 58.40; H, 6.65; N, 9.21.
EXAMPLE 3dd
2-(O-Butylacetate)-phenyl-N-methyl-N-[(1S)-1-phenyl-2-[1-pyrrolidinyl]ethy-
l acetamide hydrochloride
[0468]
2-(2-Hydroxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)eth-
yl]acetamide (for preparation see U.S. Pat. No. 5,688,955) 1.3 g;
(3.80 mmol) was dissolved in 10 mL of dry THF and added to a
0.degree. C. slurry of NaH (95%, 100 mg; 4.03 mmol) in dry THF. The
mixture was allowed to warm to room temperature for 30 minutes,
then cooled to 0.degree. C. Ethyl bromoacetate (0.44 mL; 4.03 mmol)
was added drop-wise over a few minutes. After 30 minutes, the
mixture was warmed to room temperature and stirred for 5 days. TLC
(95:5 methylene chloride:methanol with 2% ammonia) indicated the
reaction was complete. The reaction was quenched with sat. ammonium
chloride and concentrated in vacuo. The residue was dissolved in
methylene chloride and separated from water. The organic layer was
washed with brine, dried (anh. Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to give 1.61 g of crude product, which was
purified by flash chromatography using a stepwise gradient of 2% to
9% MeOH:methylene chloride with 2% ammonia to afford 1.0 g (70%) of
3dd as a desired product, which was treated with 1.0 M HCl in
diethyl ether to give the HCl salt. mp 184-187.degree. C.; .sup.1H
NMR (HCl salt, CDCl.sub.3) .delta. 1.2 (t, 3H), 1.7-1.9 (br s, 4H,
--CH.sub.2CH.sub.2--), 2.0 (br d, 2H), 2.2-2.5 (m, 2H), 2.8-3.0 (m,
2H), 3.0 (s, 3H, NCH.sub.3), 3.3-3.5 (t, 1H), 4.04.1 (m, 2H), 4.2
(q, 2H), 6.2-6.3 (dd, 1H), 6.8 (d, 1H), 6.9-7.1 (t, 1H), 7.2-7.5
(complex, 7H, aromatic). MS (FAB) m/z 424. Anal. (C, H, N) Calcd.
for C.sub.25H.sub.32N.sub.2O.sub.4.HCl.0.5H.sub.2O: C, 65.14; H,
7.22; N, 6.08. Found: C, 63.70; H, 7.00; N, 6.09.
EXAMPLE 3ee
2-[Phenoxy-acetyl]methylamino-(1-pyrrolidinyl)ethyl]acetamide]hydrochlorid-
e
[0469]
2-(2-Hydroxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)eth-
yl]acetamide (for the preparation see U.S. Pat. No. 5,688,955) 960
mg; 2.83 mmol was dissolved in 6.0 mL of dry THF and added to a
slurry of NaH (95%) 79 mg; 3.12 mmol in dry THF at 0.degree. C. The
mixture was allowed to warm to room temperature and stirred for 30
minutes, then cooled to 0.degree. C. when t-butyl bromoacetate
(0.42 ml; 2.83 mmol) in 2 mL of dry THF was added drop-wise. The
solution was allowed to warm to room temperature and stirred
overnight. TLC (95:5 methylene chloride:methanol w/ 2% ammonia)
indicated the reaction was complete. The reaction was quenched with
saturated ammonium chloride and concentrated in vacuo. The residue
was dissolved in methylene chloride and separated from water. The
organic layer was washed with brine, dried (anh. Na.sub.2SO.sub.4),
filtered, and evaporated to give a brown residue. The crude product
was purified by flash chromatography using a stepwise gradient of
1% to 8% MeOH:methylene chloride with 2% ammonia to afford 900 mg
(70%) of desired compound; .sup.1H NMR (Free base, CDCl.sub.3),
.delta. 1.4 (s, 9H, t-butyl), 2.7-2.9 (br s, 4H), 2.7 (s, 3H), 3.8
(s, 2H), 4.5 (s, 2H), 6.1-6.2 (dd, 1H), 6.7-6.8 (d, 2H), 6.9-7.0
(t, 3H), 7.1-7.4 (complex, 5H, aromatic), MS (FAB) m/z 452, which
was used in the next step by adding 4.0 mL of 4N HCl, 4 drops of
anisole and stirring overnight at room temperature. TLC indicated
the reaction was incomplete. The solution was heated to 50.degree.
C. for 24 hours. The reaction mixture was concentrated in vacuo and
the residue was azeotroped with toluene. The crude product was
dissolved in triturated with diethyl ether to give 730 mg (93%) of
3ee as the free acid; mp 105-108.degree. C.; .sup.1H NMR (HCl salt,
DMSO-d.sub.6) .delta. 1.9-2.4 (br s, 4H, --CH.sub.2CH.sub.2--), 2.9
(s, 3H, NCH.sub.3)3.84.1 (m, 3H), 4.5-4.7 (d, 2H), 6.2 (dd, 1H),
6.8 (d, 1H), 6.9 (t, 1H), 7.1-7.3 (complex, 7H, aromatic). MS (FAB)
m/z 396. Anal (C, H, N) Calc. for C.sub.23H.sub.28N.sub.2O.sub.4.
HCl 0.75H.sub.2O: C, 63.81; H, 6.75; N, 6.47. Found C, 61.87; H,
6.84; N, 6.19.
EXAMPLE 3ff
2-[4-Trifluoromethylphenyl]-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-3-hydroxy--
pyrrolidinyl]ethyl}acetamide hydrochloride
[0470] The compound 3ff was prepared from
N-methyl-N-[(1S)-1-phenyl-2-((3S-
)-3-hydroxypyrrolidine-1-yl)ethyl]-2-aminophenylacetamide.sup.2 and
4-trifluoromethylphenyl acetic acid in 54% yield; mp
217-219.degree. C. (d); .sup.1H NMR (free base, 200, MHz,
CDCl.sub.3) .delta. 1.88 (m, 2H), 2.35 (m, 3H), 2.85 (s, 3H),
2.50-3.35 (m, 4H), 3.98 (m, 2H), 4.10 (m, 1H), 6.00 (m, 1H), 7.30
(m, 5H), 7.55 (d, J=9.0 Hz, 2H), 7.77 (d, J=9.5 Hz, 2H). Anal.
Calcd. for C.sub.22H.sub.25F.sub.3N.sub.2O.sub.2.HCl: C, 59.66; H,
5.92; N, 6.32. Found: C, 59.45; H, 5.68; N, 5.98.
EXAMPLE 3gg
2-(2-Pyridyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-3-hydroxy-pyrrolidinyl]e-
thyl}acetamide dihydrochloride
[0471] The compound 3gg was prepared as above from 2-pyridyl acetic
acid in 38% yield; mp 180-182.degree. C. (d); .sup.1H NMR (free
base, 200, MHz, CDCl.sub.3) .delta. 1.78 (m, 2H), 2.10-2.65 (m,
3H), 2.75 (s, 3H), 2.88-3.20 (m, 4H), 3.95 (d, J=13.0 Hz, 1H), 4.10
(d, J=13.5 Hz, 1H), 4.20 (m, 1H), 6.05 (m, 1H), 7.20 (m, 7H), 7.60
(t, J=7.0 Hz, 1H), 8.35 (d, J=6.5 Hz, 1H). Anal. Calcd. for
C.sub.20H.sub.25N.sub.3O.sub.2.2HCl.0.25H- .sub.2O: C, 57.63; H,
6.65; N, 10.8. Found: C, 57.73; H, 6.79; N, 9.83.
EXAMPLE 3hh
2-(5-Bromo-3-pyridyl)-N-methyl-N-[(1S)-1-phenyl-2-pyrrolidinyl
ethyl]acetamide hydrochloride
[0472] Compound 3hh was prepared using the general EDCI/DIPEA
coupling procedure from U.S. Pat. No. 5,688,955 with,
(1S)-N-methyl-2-pyrrolidino-- 1-phenethylamine (200 mg; 0.98 mmol),
5-bromo-3-pyridylacetic acid (231 mg; 1.07 mmol), HOBT (145 mg;
1.07 mmol), EDCI (204 mg; 1.07 mmol), and DIPEA (0.26 mL; 1.47
mmol). The reaction solution was allowed to stir at room
temperature overnight. TLC (95:5 methylene chloride:methanol with
2% ammonia) indicated the reaction was complete. The reaction was
quenched with sat. sodium bicarbonate and the layers were
separated. The organic layer was washed with brine and dried (anh.
Na.sub.2SO.sub.4), filtered and evaporated. The crude product was
purified by flash chromatography using a stepwise gradient of 2% to
4% MeOH:methylene chloride with 2% ammonia to afford 337 mg (85%)
of pure product which was treated with 1.0 M HCl in diethyl ether
to give 3hh as the HCl salt; mp 228-230.degree. C.; .sup.1H NMR
(HCl salt, DMSO-d.sub.6) 82.0 (br s, 4H, --CH.sub.2CH.sub.2--), 2.8
(s, 3H, NCH.sub.3), 4.1-4.2 (br m, CH.sub.2), 6.1-6.2 (br d, 1H,
CH), 7.2-7.5 (complex, 5H, aromatic), 8.0-8.1 (br s, 1H, pyridyl),
8.5 (s, 1H, pyridyl), 8.6 (s, 1H, pyridyl); MS (FAB) m/z 401. Anal.
(C, H, N) Calcd. for C.sub.20H.sub.24N.sub.3OBr.HCl: C, 54.75; H,
5.74; N, 9.58. Found: C, 54.66; H, 5.71; N, 9.41.
EXAMPLE 3ii
2-(5-Bromo-3-pyridyl)-N-methyl-N-{[1S]-1-phenyl-2-[1-(3S)-3-hydroxy-pyrrol-
idinyl]ethyl}acetamide hydrochloride
[0473] The compound 3ii was prepared from 5-bromo-3-pyridyl acetic
acid following the procedures described above in 44% yield; mp
144-146.degree. C.; .sup.1H NMR (free base, 200, MHz, CDCl.sub.3)
.delta. 1.66 (m, 2H), 2.00-2.50 (m, 3H), 2.77 (s, 3H), 2.88-3.40
(m, 4H), 3.80 (d, J=13.0 Hz, 1H), 3.95 (d, J=13.5 Hz, 1H), 4.35 (m,
1H), 6.15 (m, 1H), 7.20 (m, 5H), 7.75 (s, 1H), 8.50 (s, 1H), 8.85
(s, 1H). Anal. Calcd. for
C.sub.20H.sub.24BrN.sub.3O.sub.2.HCl.0.25H.sub.2O: C, 51.79; H,
5.65; N, 9.06. Found: C, 51.96; H, 5.55; N, 8.76.
EXAMPLE 3jj
2-(9-Anthracenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}acetam-
ide hydrochloride
[0474] The compound 3jj was prepared from 9-anthracene carboxylic
acid as above in 34% yield; mp 273-275.degree. C.; .sup.1H NMR
(200, MHz, CDCl.sub.3) .delta. 2.00 (m, 4H), 2.67 (s, 3H), 3.00 (m,
1H), 3.45 (m, 1H), 3.88 (m, 1H), 4.40 (m, 2H), 5.80 (m, 1H), 7.43
(m, 8H), 7.88 (m, 5H), 8.38 (s, 1H). Anal. Calcd. for
C.sub.28H.sub.28N.sub.2O.HCl.0.25H.su- b.2O: C, 74.82; H, 6.61; N,
6.23. Found: C, 75.00; H, 6.60; N, 6.26.
EXAMPLE 3kk
2-(2-Carboxyphenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}acet-
amide hydrochloride
[0475] To a solution of
(S)-1-[(2-methylamino-2-phenyl)ethyl]pyrrolidine.s- up.1 (1.0 g,
5.21 mmol) in anhydrous THF (5 mL) under a nitrogen atmosphere was
added homophthalic anhydride (0.845 g, 5.21 mmol) and the reaction
mixture was stirred at room temperature for 4 days. The resulting
solid was filtered, washed with THF and HCl salt was prepared by
usual fashion to give 3kk (1.0 g, 50%); mp 230-232.degree. C. (d);
MS (FAB) 367 (M+1); .sup.1H NMR (200, MHz, DMSO-d.sub.6) 82.07 (m,
4H), 2.92 (s, 3H), 3.30-3.98 (m, 5H), 4.00 (d, J=14.0 Hz, 1H), 4.18
(m, 1H), 4.43 (d, J=14.0 Hz, 1H), 6.15 (m, 1H), 7.30-7.65 (m, 8H),
8.00 (d, J=8.0 Hz, 1H). Anal. Calcd. for
C.sub.22H.sub.26N.sub.2O.sub.3.HCl: C, 65.58; H, 6.75; N, 6.96; Cl,
8.81. Found: C, 65.52; H, 6.81; N, 7.04; Cl, 8.81.
EXAMPLE 3ll
[2-(2-Phenyl)-N-methyl-N-{[1S]-1-Phenyl-2-(1-pyrrolidinyl)ethyl}acetamido]-
2-oxo-glycine hydrochloride
[0476] To a suspension of 3ff was condensed with glycine t-butyl
ester hydrochloride following the general procedure to give the
intermediate in 55% yield. The t-butyl group was removed by 4N HCl
to give the desired product which was recrystallized from
acetonitrile to give 3ll in 93% yield; mp 235-236.degree. C.; MS
(FAB) 424 (M+1); .sup.1H NMR (200, MHz, DMSO-d.sub.6) .delta. 1.95
(m, 4H), 2.72 (s, 3H), 3.35-4.25 (m, 1H), 6.18 (m, 1H), 7.20-7.65
(m, 8H), 8.70 (m, 1H). Anal. Calcd. for
C.sub.24H.sub.29N.sub.3O.sub.4.HCl.0.75H.sub.2O: C, 60.88; H, 6.71;
N, 8.87. Found: C, 60.97; H, 6.65; N, 8.91.
EXAMPLE 3mm
Methyl
N-[2-(2-pheny)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}ac-
etamido]2-oxo-glycinate hydrochloride
[0477] To a solution of 3ff (0.50 g, 1.05 mmol) in anhydrous
methanol (50 mL) was added Dowex.RTM.50Wx4-400 (H.sup.+) resin (5.0
g, pre-washed with methanol). The reaction mixture was the stirred
with refluxing under a nitrogen atmosphere for 48 h. The resin was
removed by filtration washed with excess of hot methanol and the
combined mehanolic solution was evaporated to dryness. The residue
was redissolved in CH.sub.2Cl.sub.2 and concentrated to a small
volume and addition of anhydrous ether resulted the compound 3 mm
(0.12 g, 24%); mp 204-206.degree. C.; MS (FAB) 438 (M+1); .sup.1H
NMR (200, MHz, CDCl.sub.3), .delta. 1.85-2.45 (m, 6H), 2.75-3.25
(m, 2H), 2.92 (s, 3H), 3.75 (s, 3H), 3.804.25 (m, 7H), 6.25 (bs,
1H), 7.15-7.77 (m, 9H). Anal. Calcd. for
C.sub.25H.sub.31N.sub.3O.su- b.4.HCl.0.25H.sub.2O: C, 62.75; H,
6.85; N, 8.78. Found: C, 62.65; H, 6.87; N, 8.60.
EXAMPLE 3nn
2-(3,4-Dihydroxyphenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}-
acetamide hydrochloride
[0478] The compound was prepared from 3,4-dihydroxyphenyl acetic
acid in 12% yield; mp 227-229.degree. C. (d); .sup.1H NMR (300,
MHz, DMSO-d.sub.6) .delta. 1.90 (m, 4H), 2.70 (s, 3H), 3.05-3.20
(m, 2H), 3.35 (bs, 2H), 3.45-3.70 (m, 4H), 4.50 (m, 1H), 6.12 (m,
1H), 6.45 (d, J=8.1 Hz, 1H), 6.62 (m, 2H), 7.18 (d, J=7.5 Hz, 2H),
7.32 (m, 3H), 8.73 (bs, 1H), 8.83 (bs, 1H). Anal. Calcd. for
C.sub.21H.sub.26N.sub.2O.sub.3.HCl.0- .25H.sub.2O: C, 63.79; H,
7.01; N, 7.08. Found: C, 63.59; H, 6.89; N, 7.15.
EXAMPLE 3oo
2-(3,4-Dimethoxyphenyl)-N-methyl-N-{[1S]-1-phenyl-2-(1-pyrrolidinyl)ethyl}-
acetamide hydrochloride
[0479] The compound was prepared from 3,4-dimethoxyphenyl acetic
acid in 65% yield; mp; 240-242.degree. C.; .sup.1H NMR (300, MHz,
CDCl.sub.3) .delta. 2.00-2.35 (m, 4H), 2.85 (s, m, 5H), 3.26 (m,
1H), 3.18 (s, m, 7H), 4.05 (m, 4H), 6.36 (m, 1H), 6.81 (m, 2H),
6.93 (s, 1H), 7.19 (m, 2H), 7.36 (m, 3H). Anal. Calcd. for
C.sub.23H.sub.30N.sub.2O.sub.3.HCl: C,; H, 7.01; N, 7.08. Found: C,
63.59; H, 6.89; N, 7.15.
EXAMPLE 3pp
2-(2-Methanesulfonamidophenyl)-N-methyl-N-[(1S)-1-(3-methanesulfon-amidoph-
enyl)-2-(1-pyrrolidinyl)ethyl]acetamide Hydrochloride
[0480] (1)
2-(2-Nitrophenyl)-N-methyl-N-[(1S)-1-(3-nitrophenyl)-2-(1-pyrro-
lidinyl)-ethyl]acetamide
[0481] A solution of 2-nitrophenylacetic acid (1.99 g, 11.0 mmol)
and 1-hydroxybenzotriazole (1.49 g, 11.0 mmol) in CH.sub.2Cl.sub.2
(50 ml) was cooled in an ice bath. To this slurry was added EDCI,
and the solution turned brown clear after 30 minutes at room
temperature. A solution of
(2s)-1-[2-(methylamino)-2-(3-nitrophenyl)ethyl]pyrrolidine.su- p.1
(2.49 g, 10.0 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added, followed
by DIPEA. The solution was stirred in ice bath for 30 minutes and
then at room temperature for 18 hours. The reaction was quenched by
adding saturated aqueous NaHCO.sub.3 (20 ml) and stirred for 10
minutes. After separation, the organic layer was washed with water,
brine, dried (Na.sub.2SO.sub.4). The solvent was removed via rotary
evaporation and the brown residue was purified by silica column
chromatography [2% MeOH/CH.sub.2Cl.sub.2 (2% NH.sub.3)] to give the
product (2.4 g, 58%).
[0482] (2)
2-(2-Aminophenyl)-N-methyl-N-[(1R,S)-1-(3-aminophenyl)-2-(1-pyr-
rolidinyl)ethyl]acetamide
[0483] A suspension of above compound (475 mg, 1.15 mmol) and Raney
nickel (50% slurry in water) in ethanol (10 ml) was heated at
50.degree. C. and treated with a solution of hydrazine hydrate (360
ml, 11.5 mmol) in ethanol (2 ml). Upon addition of the reagent,
effervescent occurred. The mixture was then stirred at 50.degree.
C. for 0.5 h. After cooling, the mixture was filtered through a bed
of celite, and the catalyst was washed with hot methanol (10 ml).
The combined filtrate and washing was evaporated and dried in
vacuum (388 mg, 95%). .sup.1H NMR (DMSO-d.sub.6): .delta. 1.64 (bs,
4H), 2.40 (bs, 2H), 2.58 (m, 2H), 2.66 (s, 3H), 3.06-3.59 (m, 4H),
4.95 (s, 2H), 5.01 (s, 2H), 5.77 (dd, J=4.9, 11.4 Hz, 1H),
6.39-6.48 (m, 4H), 6.63 (d, J=7.6 Hz, 1H), 6.89-7.04 (m, 3H).
[0484] To a solution of the diamine (388 mg, 1.11 mmol) in
CH.sub.2Cl.sub.2 (10 ml) cooled in an ice bath was added pyridine
(540 ml, 6.67 mmol), followed by MsCl (190 ml, 2.45 mmol) in
CH.sub.2Cl.sub.2 (5 ml). The mixture was stirred at 0.degree. C.
for 0.5 h and then at room temperature for 18 hours. The solution
was washed with saturated aqueous NaHCO.sub.3 (2.times.50 ml),
brine, dried (Na.sub.2SO.sub.4). The solvent was removed by rotary
evaporation and the residue was purified by silica column
chromatography to give gummy foam after drying (383 mg, 68%) which
was then converted to the HCl salt form. mp: 160.degree. C. (d).
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.96 (bs, 4H), 2.77 (s, 3H),
2.97 (s, 3H), 2.98 (s, 3H), 3.14 (m, 2H), 3.57 (m, 3H), 3.974.10
(m, 3H), 6.12 (d, J=10.8 Hz, 1H), 7.03-7.37 (m, 8H), 9.10 (s, 1H),
9.81 (s, 1H). Fab MS (MH.sup.+): 509. Anal. Calcd. for
C.sub.23H.sub.33N.sub.4O.sub.5S.- sub.2Cl: C, 48.47; H, 6.43; N,
9.50. Found: C, 48.57; H, 6.07; N, 9.25.
EXAMPLE 3qq
2-(2-Iso-butyramidophenyl)-N-methyl-N-[(1S)-1-(3-isobutyramido-phenyl)-2-(-
1-pyrrolidinyl)ethyl]acetamide Methanesulfonic acid salt
[0485] To a solution of the diamine (132 mg, 0.376 mmol) in
CH.sub.2Cl.sub.2 (5 ml) cooled in an ice bath was added pyridine
(182 ml, 2.26 mmol), followed by isobutyryl chloride (119 ml, 1.14
mmol) in CH.sub.2Cl.sub.2 (5 ml). The mixture was stirred at
0.degree. C. for 0.5 h and then at room temperature for 18 hours.
The solution was washed with aqueous saturated NaHCO.sub.3
(2.times.25 ml), brine, dried (Na.sub.2SO.sub.4). TLC indicated
that the compound was contaminated by bis-acylated side product.
Thus, the solvent was removed by rotary evaporation and the residue
was dissolved in MeOH (2 ml), treated with a drop of NaOH (13 N),
and stirred at room temperature for 5 minutes. After neutralization
with HCl (6N), the solvent was evaporated, the residue was purified
by silica column chromatography to give a gummy foam after drying
which was then converted to methanesulfonic acid salt (178 mg,
76%). Mp: 143-145.degree. C.; .sup.1H NMR (DMSO-d.sub.6): .delta.
1.08 (m, 12H), 1.88 (m, 2H), 2.00 (m, 2H), 2.31 (s, 3H), 2.56 (m,
2H), 2.65 (s, 3H), 3.18 (m, 2H), 3.36-3.63 (m, 6H), 3.80 (d, J=16.2
Hz, 1H), 4.10 (m, 1H), 6.09 (d, J=10.8 Hz, 1H), 6.90 (d, J=7.6 Hz,
1H), 7.10-7.63 (m, 7H), 9.20 (bs, 1H), 9.41 (s, 1H), 9.92 (s, 1H).
Fab MS (MH.sup.+): 493. Anal. Calcd. for
C.sub.30H.sub.44N.sub.4O.sub.6S: C, 58.86; H, 7.67; N, 9.15. Found:
C, 58.77; H, 7.51; N, 8.98.
EXAMPLE 3rr
4-[4-N-Methylsulfonamido-phenyl]-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)-ethyl-
]acetamide hydrochloride
[0486]
4-(N,N-Dimethylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-
-2-(1-pyrrolidinyl)ethyl]acetamide (for preparation see U.S. Pat.
No. 5,688,955) 1.3 g; 2.63 mmol was dissolved in 60 mL of 2:1
MeOH:THF and 2.0 mL of 10 M NaOH was added. After 20 minutes, TLC
(95:5 methylene chloride:methanol with 2% ammonia) indicated the
reaction was complete. The reaction was neutralized with 10% HCl
and concentrated in vacuo. The residue was dissolved in methylene
chloride and washed with 10% sodium bicarbonate, brine and dried
(anh. Na.sub.2SO.sub.4). The organic layer was concentrated in
vacuo and the crude product was purified by flash chromatography
using a stepwise gradient of 2% to 8% MeOH:methylene chloride with
2% ammonia to give 300 mg (28%) of desired product, which was
treated with 1.0 M HCl in diethyl ether to afford 3rr as a tan
solid. mp>260.degree. C. (dec.); .sup.1H NMR (HCl salt,
DMSO-d.sub.6) .delta. 2.0 (br s, 4H, --CH.sub.2CH.sub.2--), 2.8 (s,
3H, NCH.sub.3), 3.0 (s, 3H, SO.sub.2CH.sub.3), 3.8-4.0 (m, 2H),
6.1-6.3 (dd, 1H), 7.1-7.5 (complex, 9H, aromatic), 9.7 (s, 1H). MS
(FAB) m/z 415. Anal. (C, H, N) Calcd. for
C.sub.22H.sub.29N.sub.3O.sub.3S.HCl.0.25H.sub.2O: C, 58.46; H,
6.69; N, 9.30. Found: C, 57.89; H, 6.64; N, 9.19.
EXAMPLE 3ss
2-(3,4-Dichlorocinnamyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-Pyrrolidinyl)-ethy-
l]acetamide hydrochloride
[0487] The compound was prepared from 3,4-dichlorocinnamic acid in
70% yield; mp 220-222.degree. C.; Anal. Calcd. for
C.sub.22H.sub.24Cl.sub.2N.- sub.2O.HCl: C, 60.08; H, 5.73; N, 6.37.
Found: C, 60.25; H, 5.81; N, 6.28.
EXAMPLE 3tt
2-(2-Nitrocinnamyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)
ethyl]acetamide hydrochloride
[0488] The compound was prepared from 2-nitrocinnamic acid in 46%
yield; mp 195-197.degree. C.; Anal. Calcd. for
C.sub.22H.sub.25N.sub.3O.sub.3.HC- l: C, 63.53; H, 6.30; N, 10.10.
Found: C, 63.25; H, 6.38; N, 10.08.
EXAMPLE 3uu
(R,S)-1-[2-(Methanesulfonylamino)phenyl-N-methylacetamido]-1-(3-methoxyphe-
nyl)-2-(1-pyrrolidino)-ethane, methanesulfonic acid salt
(R,S)-3-Methoxy-phenylglycine (5, Scheme M)
[0489] NaCN (12.2 g, 0.249 mol) was dissolved in 50 ml of water,
and to this solution was added ammonium chloride (13.3 g, 0.249
mol). When all had dissolved, a solution of m-anisaldehyde (33.8 g,
0.249 mol) in 50 ml of EtOH was added slowly. The mixture was
stirred at ambient temperature for 2-3 hours. TLC indicated no
starting material left. The mixture was taken up in water/toluene
(50 ml/50 ml). The organic layer was washed with water (50 ml),
extracted with 6N HCl (2.times.30 ml). To hydrolyze the amino
cyanide, the hydrochloric extract was refluxed for 4-5 hours. The
solution was cooled to room temperature and filtered from some
tarry material. The filtrate was cooled in ice bath and the
aminoacid salt was collected via filtration, washed with cold water
(20 ml), ether, dried at 60 degrees overnight to give 5 (14.5 g,
27%); NMR (DMSO-d.sub.6), .delta. 3.7 (3H, s), 4.29 (1H, s), 6.87
(1H, m), 6.96 (1H, d, J=7.6 Hz), 6.98 (1H, s), 7.26 (1H, t, J=8.0
Hz).
[0490] (R,S)-N-Methoxycarbonyl-2-(3-methoxyphenyl)glycine (6)
[0491] (R,S)-3-Methoxy-phenylglycine (5, 14.5 g, 66.7 mmol) was
dissolved in NaOH (1N, 233 ml, 233 mmol) and the solution was
cooled in ice bath for 15 minutes. To this solution was added
methyl chloroformate (7.73 ml, 100 mmol) dropwise. After the
addition was complete, the mixture was stirred at room temperature
for 2 hours. The pH was adjusted to 10 with 2N NaOH and the
stirring was continued for 1 hour. The solution was washed with
ether (2.times.100 ml), acidified with 6N HCl after addition of
EtOAc (100 ml). The aqueous layer was extracted with EtOAc (100
ml), and the combined organic extracts were washed with brine (100
ml), dried over (Na.sub.2SO.sub.4), concentrated to yellow syrup 6,
(14.4 g, 90%). NMR (CDCl.sub.3), .delta. 3.70 (3H, s), 3.82 (3H,
s), 5.35 (1H, d), 5.77 (1H, d), 6.87-7.01 (3H, m), 7.31 (1H,
t).
[0492] (R,S)-N-Methoxycarbonyl-2-(3-methoxyphenyl) glycine,
pyrrolidine (7)
[0493] (R,S)-N-Methoxycarbonyl-2-(3-methoxyphenyl) glycine (6, 14.4
g, 60.4 mmol) and HOBt (8.97 g, 66.4 mmol) were dissolved in THF
(150 ml) and cooled in ice bath. To this solution was added a
solution of DCC (12.4 g, 60.4 mmol) in THF (50 ml). After stirring
at room temperature for 2 hours, the mixture was cooled in ice
bath, and the resulting DCU was filtered, washed with cold THF. The
filtrate was treated with a solution of pyrrolidine (5.0 ml, 60.4
mmol) in dichloromethane (50 ml). The solution was stirred at room
temperature for 18 hours and concentrated. The residue was taken up
in EtOAc (250 ml), and the mixture was washed with NaHCO.sub.3
(saturated, 200 ml), water, brine, dried over Na.sub.2SO.sub.4,
concentrated to a pale solution (50 ml) which was stored in
refrigerator overnight. The more precipitated DCU was filtered off,
and the filtrate was dried to give a pale yellow oil 7, (12.8 g,
77%). NMR (CDCl.sub.3), .delta. 1.8 (4H, m), 3.4-3.6 (4H, m), 3.65
(3H, s), 3.8 (3H, s), 5.35 (1H, d), 6.8-7.0 (3H, m), 7.3 (1H,
m).
[0494] (R,S)-1-(3-Methoxyphenyl)-1-methylamino-2-(1-pyrrolidino)
ethane (8)
[0495] LiAlH.sub.4 (5.3 g, 140 mmol) was stirred in anhydrous THF
(200 mL) under N.sub.2 and a solution of
(R,S)-N-Methoxycarbonyl-2-(3-methoxypheny- l) glycine, pyrrolidine
(12.8 g, 46.6 mmol) in THF (100 ml) was added over 30 minutes at
10-15 degree. The mixture was stirred at room temperature for 0.5
hour then at 55 degree for 2 hours. After cooling in ice bath the
mixture was carefully quenched with excess saturated NaHCO.sub.3,
filtered. The filtrate was washed with brine, dried over
Na.sub.2SO.sub.4, and evaporated to 10.0 grams of colorless oil (8)
that was used in further reaction without purification.
[0496]
(R,S)-1-(2-Nitrophenyl-N-methylacetamido)-1-(3-methoxyphenyl)-2-(1--
pyrrolidino)-ethane (9)
[0497] A solution of 2-Nitrophenylacetic acid (1.99 g, 11.0 mmol),
HOBt (1.49 g, 11.0 mmol) in THF (50 ml) was cooled in ice bath and
treated with a solution of DCC (2.27 g, 11.0 mmol) in THF (5 ml).
The mixture was warmed up to room temperature and stirred for 2
hours. After cooling in ice bath the precipitated DCU was filtered,
and the filtrate was treated with a solution of
(R,S)-1-(3-Methoxyphenyl)-1-methylamino-2-(1-pyrrolidi- no) ethane
(8) in CH.sub.2Cl.sub.2 (10 ml). The solution was stirred in
N.sub.2 at room temperature for 18 hours and concentrated. The
residue was dissolved in EtOAc (100 ml), washed with saturated
NaHCO.sub.3, brine, dried (Na.sub.2SO.sub.4). Removal of the
solvent, followed by silica column chromatography yielded 3.0 grams
of the product (9). NMR (CDCl.sub.3), .delta. 1.74 (4H, bs), 2.52
(2H, bs), 2.67 (2H, bs), 2.77 (1H, m), 2.84 (3H, s), 3.10 (1H, m),
3.83 (3H, s), 4.024.31 (2H, m), 6.03 (1H, dd, J=6.0, 9.8 Hz),
6.80-6.94 (3H, m), 7.26 (1H, m), 7.39-7.46 (2H, m), 7.54-7.59 (1H,
m), 8.10 (1H, dd, J=1.2, 8.0 Hz).
[0498]
(R,S)-1-(2-Aminophenyl-N-methylacetamido)-1-(3-methoxyphenyl)-2-(1--
pyrrolidino)-ethane
[0499] A suspension of
(R,S)-1-(2-nitrophenyl-N-methylacetamido)-1-(3-meth-
oxyphenyl)-2-(1-pyrrolidino)-ethane (8) (1.3 g, 3.27 mmol) and
Raney Ni (1 spatula) in EtOH (20 ml) was stirred at 50 degree and
treated with a solution of hydrazine hydrate in EtOH (10 ml). After
effervescent stopped, the mixture was stirred at 55 degree for 0.5
hour, then cooled to room temperature, filtered through a bed of
celite, washed with hot MeOH (20 ml). The combined filtrate and
washing was concentrated, dried to yellow residue (1.2 g) of amino
compound that was used with further purification.
[0500] (R,S)-1-[2-(Methanesulfonylamino)
phenyl-N-methylacetamido]-1-(3-me-
thoxyphenyl)-2-(1-pyrrolidino)-ethane, methanesulfonic acid salt
(3uu)
[0501] To a solution of
(R,S)-1-(2-aminophenyl-N-methylacetamido)-1-(3-met-
hoxyphenyl)-2-(1-pyrrolidino)-ethane (1.2 g, 3.24 mmol) in
CH.sub.2Cl.sub.2 (20 ml) was added pyridine (0.79 ml, 9.72 mmol),
followed by a solution of MsCl (0.376 ml. 4.86 mmol). The mixture
was stirred at room temperature for 18 hours. The mixture was
washed with water (20 ml), brine, dried (Na.sub.2SO.sub.4). The
solution was concentrated, and the residue was purified via silica
column chromatography to give a yellowish oil (1.20 g, 83%). 251 mg
of the free base was converted to methane sulfonic acid salt, 3uu.
M p: 135.degree. C. (decomposed). NMR (DMSO-d.sub.6), .delta. 1.92
(2H, bs), 2.02 (2H, bs), 2.32 (3H, s), 2.72 (3H, s), 2.97 (3H, s),
3.19 (2H, m), 3.56-3.97 (8H, m), 4.034.12 (2H, m), 6.08 (1H, d,
J=12.0 Hz), 6.74 (1H, s), 6.81 (1H, dd, J=2.3, 8.0 Hz), 7.16-7.39
(5H, m), 9.07 (1H, s), 9.26 (1H, bs). MS (FAB) m/z 446. Anal. (C,
H, N)C.sub.23H.sub.31N.sub.3O.sub.4S.CH.sub.3-
SO.sub.3H.0.2H.sub.2O.
EXAMPLE 3vv
(R,S)-1-[2-(Methanesulfonylamino)phenyl-N-methylacetamido]-1-(3-hydroxyphe-
nyl)-2-(1-pyrrolidino)-ethane, methanesulfonic acid salt
[0502] A solution of
(R,S)-1-[2-(methanesulfonylamino)phenyl-N-methylaceta-
mido]-1-(3-methoxyphenyl)-2-(1-pyrrolidino)-ethane (3uu, 196 mg,
0.440 mmol) in CH.sub.2Cl.sub.2 (15 ml) was cooled to -70 degree
and treated with a solution of BBr.sub.3 (1.0 M in
CH.sub.2Cl.sub.2, 1.45 ml, 1.45 mmol) in CH.sub.2Cl.sub.2 (2 ml).
The mixture was stirred at -70 degree for 1 hour, then slowly
warmed up to room temperature overnight. The mixture was carefully
quenched at 0 degree with MeOH (5 ml) and the solution was
evaporated under reduced pressure. The residue was stirred in 10 ml
of anhydrous MeOH/Et.sub.2O (1/1) for 6 hours and filtered. The
white solid was taken up in CHCl.sub.3 (50 ml) and
NaHCO.sub.3/Na.sub.2CO.sub.3 (pH.about.10)(50 ml). The organic
layer was washed with brine, dried (Na.sub.2SO.sub.4). After
removal of the solvent, the residue was dissolved in MeOH (5 ml)
and treated with CH.sub.3SO.sub.3H (0.026 ml, 0.404 mmol). The
solvent was evaporated and the residue was sonicated in ether. The
precipitate was filtered, dried to give 3vv, (0.164 g, 84%). mp:
232-234.degree. C. NMR (DMSO-d.sub.6), .delta. 1.93 (2H, bs), 2.02
(2H, bs), 2.32 (3H, s), 2.70 (3H, s), 2.97 (3H, s), 3.16 (2H, bs),
3.40-3.80 (4H, m), 4.034.12 (2H, m), 6.04 (1H, d, J=9.6 Hz),
6.63-6.72 (3H, m), 7.14-7.39 (5H, m), 9.06 (1H, s), 9.21 (1H, bs),
9.56 (1H, s). MS (FAB) m/z 432. Anal. (C, H, N)
C.sub.22H.sub.29N.sub.3O.sub.4S.CH.sub.3SO.sub.3H.0.2H.sub.2O.
EXAMPLE 3ww
2-(3-Indolyl)-N-methyl-N-[(1S)-1-phenyl-2-[(3S)-1-pyrrolidin-3-ol]ethyl]-a-
cetamide hydrochloride
[0503] Compound 3ww was prepared from indole-3-acetic acid (477 mg;
2.72 mmol), DCC (1.12 g; 5.44 mmol), pyridine (0.440 mL; 5.44 mmol)
and S-(-)-3-pyrrolidinol (600 mg; 2.72 mmol, for preparation see EP
0398 720 A2) in 15 mL of dry methylene chloride. After stirring at
room temperature for 24 h, TLC (95:5 methylene chloride:methanol w/
2% ammonia) indicated the reaction was complete. The reaction was
quenched with sat. sodium bicarbonate and the layers were
separated. The organic layer was washed with brine, dried over
anhydrous sodium sulfate, filtered and conc. in vacuo to give 2.04
g of a viscous yellow oil which was purified by flash
chromatography using a stepwise gradient of 2% to 3%
methanol:methylene chloride with 2% ammonia to yield 700 mg (69%)
of desired compound which was converted to the hydrochloride salt
with HCl/ether to give 720 mg of 3ww. m.p. 142.degree. C. (dec.);
.sup.1H NMR (HCl salt, CDCl.sub.3, 300 MHz) .delta. 2.1 (br, m,
4H), 2.8 (s, 3H), 4.5 (m, 1H), 6.3 (br, m, 1H), 7.2 (br, m, 1H),
7.3 (complex, 4H, aromatic), 7.5-7.6 (d, 2H), 7.8 (d, 2H). Fab MS
(MH.sup.+): 377. Anal. Calcd for C.sub.23H.sub.27O.sub.2N.sub.3
HCl: C, 63.29; H, 7.04; N, 9.63. Found C, 63.15; H, 7.03; N,
9.57.
EXAMPLE 3xx
2-(2-N-Benzyl-2-N-methylsulfamoyl-3,4-dimethoxyphenyl)-N-methyl-N-[(1S)-1--
phenyl-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride
[0504] 71
[0505] Compound B was prepared from methyl 3,4-dimethoxyphenyl
acetate following the literature procedure [J. Het. Chem. 29, 1667
(1992)] and condensed with the diamine in usual fashion to give 3xx
in 60% yield; mp 188-190.degree. C.; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.88 (m, 4H), 2.64 (s, 3H), 2.85-3.25 (m, 4H),
2.91 (s, 3H), 3.90 (s, 3H), 3.944.28 (m, 2H), 3.95 (s, 3H),
4.30-4.60 (m, 4H), 6.48 (m, 1H), 7.15-7.40 (m, 1H), 7.55 (s, 1H).
Anal. Calcd. for C.sub.31H.sub.39N.sub.3- O.sub.5S HCl 0.5H.sub.2O:
C, 60.92; H, 6.76; N, 6.88. Found: C, 60.73; H, 6.99; N, 6.82.
EXAMPLE 3yy
2-(N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-[(1R)-1-phenyl-2-(1-Pyrro-
lidinyl)ethyl]acetamide methane sulfonate
[0506] Compound 3yy was prepared using the same synthetic scheme as
described in U.S. Pat. No. 5,688,955 using (R)-1-[2-methylamino-2
phenyl)ethyl]pyrolidine (for preparation see J. Med. Chem. 34, 1991
pp181. Costello, G. F. et. al m.p. 179-181) C: .sup.1H NMR
(Mesylate salt, CDCl.sub.3, 300 MHz) .delta. 2.0-2.2 (br, m, 4H),
2.8 (s, 3H), 3.0 (s, 3H), 3.6 (d, 2H), 6.2-6.3 (d, 1H), 7.1 (m,
3H), 7.2 (m, 1H), 7.3 (m, 3H), 7.7 (d, 2H). Fab MS (MH.sup.+): 415.
Anal. Calcd. for C.sub.23H.sub.33O.sub.6N.sub.3S.sub.2: C, 53.99;
H, 6.50; N, 8.21. Found C, 53.98; H, 6.41; N, 8.10.
EXAMPLE 3zz
(R,S)-1-(4-Trifluoromethylphenyl-N-methylacetamido)-1-(3-methoxyphenyl)-2--
(1-pyrrolidino)-ethane, methanesulfonic acid salt
[0507] The procedure is the same as that of 3uu. Yield: 74%. Mp.:
166-168.degree. C. .NMR (CDCl.sub.3), .delta.: 2.11 (2H, m),
2.16-2.32 (2H, m), 2.81 (3H, s), 2.85-2.98 (4H, m), 3.12-3.21 (1H,
m), 3.75 (3H, s), 3.83 (1H, m), 4.054.33 (4H, m), 6.30 (1H, dd,
J=2.6, 12.0 Hz), 6.67 (1H, d, J=1.8 Hz), 6.75 (1H, d, J=7.6 Hz),
6.87 (1H, dd, J=2.4, 8.3 Hz), 7.30 (1H, m), 7.45 (1H, d, J=8.1 Hz),
7.57 (1H, d, J=8.1 Hz). MS (FAB) m/z 421. Anal. (C, H,
N)C.sub.23H.sub.27N.sub.2O.sub.2F.sub.3.CH.sub.3SO.- sub.3H.
EXAMPLE 3aaa
(R,S)-1-(4-Trifluoromethylphenyl-N-methylacetamido)-1-(3-hydroxyphenyl)-2--
(1-pyrrolidino)-ethane, methanesulfonic acid salt
[0508] The procedure is the same as that of 3vv. Yield: 38.5%. Mp:
158-160.degree. C. NMR (CDCl.sub.3), .delta.: 2.01-2.14 (4H, m),
2.73 (3H, s), 2.82 (3H, s), 2.94 (2H, m), 3.30 (1H, m), 3.76 (1H,
m), 4.03-4.14 (4H, m), 6.20 (1H, dd, J=3.3, 11.0 Hz), 6.63 (1H, d,
J=7.9 Hz), 6.86 (1H, dd, J=1.8, 8.0 Hz), 7.06 (1H, s), 7.18 (1H, t,
J=8.0 Hz), 7.41 (2H, d, J=8.0 Hz), 7.56 (2H, d, J=8.0 Hz).). MS
(FAB) m/z 407. Anal. (C, H,
N)C.sub.22H.sub.25N.sub.2O.sub.2F.sub.3.1.1CH.sub.3SO.sub.3H.
EXAMPLE 3bbb
2-Fluorophenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]-acetamid-
e hydrochloride
[0509] Compound 3bbb was prepared using the same general EDCI/DIPEA
coupling procedure as described in U.S. Pat. No. 5,688,955 with
2-fluorophenylacetic acid (415 mg; 2.69 mmol), HOBT (363 mg; 2.69
mmol), EDCI (514 mg; 2.69 mmol), N,N-diisopropylethylamine (0.63
mL; 3.66 mmol), and (1S)
1-[(2-methylamino-2-phenyl)ethyl]pyrrolidine (500 mg; 2.44 mmol) in
10 mL of dry methylene chloride at room temperature. After 24 h,
TLC (95:5 methylene chloride:methanol w/ 2% ammonia) indicated the
reaction was complete. The reaction solution was quenched with sat.
sodium bicarbonate and the layers were separated. The organic layer
was washed with brine, dried over anh. sodium sulfate, filtered and
conc. in vacuo to give 900 mg of a dark brown oil which was
purified by flash chromatography using a stepwise gradient of 2% to
4% methanol:methylene chloride with 2% ammonia to yield 750 mg
(90%) of desired product which was converted to the hydrochloride
salt with HCl/ether to give 880 mg of 3bbb. m.p. 255.degree. C.
(dec.); .sup.1H NMR (HCl salt, CDCl.sub.3, 300 MHz) .delta. 2.0
(br, m, 4H), 2.1-2.2 (br, m, 2H), 2.9 (s, 3H), 3.8-4.0 (dd, 4H),
7.0-7.4 (complex, 9H, aromatic). Fab MS (MH.sup.+): 340. Anal.
Calcd. for C.sub.21H.sub.25ON.sub.2F.HCl: C, 66.97; H, 6.95; N,
7.43. Found C, 66.76; H, 6.90; N, 7.43.
EXAMPLE 3ccc
4-Fluorophenyl-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide
hydrochloride (3ccc)
[0510] Compound 3ccc was prepared using the same general EDCI/DIPEA
coupling procedure from U.S. Pat. No. 5,688,955 with
4-fluorophenylacetic acid (415 mg; 2.69 mmol), HOBT (363 mg; 2.69
mmol), EDCI (514 mg; 2.69 mmol), N,N-diisopropylethylamine (0.63
mL; 3.66 mmol) and (1S)
1-[(2-methylamino-2-phenyl)ethyl]pyrrolidine (500 mg; 2.44 mmol) in
10 mL of dry methylene chloride at room temperature. After 24 h,
TLC (95:5 methylene chloride:methanol w/ 2% ammonia) indicated the
reaction was complete. The reaction was quenched with sat. sodium
bicarbonate and the layers were separated. The organic layer was
washed with brine, dried over anh. sodium sulfate, filtered and
conc. in vacuo to give 900 mg of a dark brown oil which was
purified by flash chromatography using a stepwise gradient of 2% to
3% methanol:methylene chloride with 2% ammonia to yield 800 mg
(96%) of desired product which was converted to the hydrochloride
salt with HCl in ether to give 3ccc. m.p. >260.degree. C.
(dec.); .sup.1H NMR (HCl salt; CDCl.sub.3, 300 MHz) .delta. 2.0
(br, m, 4H), 2.1-2.2 (br, m, 2H), 2.9 (s, 3H), 3.8-4.0 (dd, 4H),
7.0-7.4 (complex, 9H, aromatic). Fab MS (MH.sup.+): 340. Anal Calcd
for C.sub.21H.sub.25ON.sub.2HCl: C, 66.82; H, 6.95; N, 7.43. Found
C, 66.81; H, 6.94; N, 7.48
EXAMPLE 3ddd
(E)-4-[2-(2-Amino-4,5-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl)-2-[1-pyrr-
olidinyl]ethyl]acetamido]4-oxo-2-butenoic acid hydrochloride
[0511] To a solution of 3y (1.4 g, 2.63 mmol) in THF:CH.sub.3OH
(1:1, 20 mL) at room temperature was added 1M LiOH aqueous solution
(5.3 mL, 5.26 mmol) and the reaction mixture was stirred for 8 h.
Progress of reaction was followed by TLC and reaction mixture was
acidified to pH 4.0 from 1N HCl. The solvent was removed under
reduced pressure. The residue was triturated with CH.sub.2Cl.sub.2
(3.times.45 mL). The combined organic layer was washed with sat.
salt solution which resulted in the precipitation of the compound.
The solid was filtered off, washed with a small amount of water,
anhydrous ether, and dried to give 3ddd 0, 0.85 g (59%); mp
205-207.degree. C. (d); .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.93 (m, 4H), 2.84 (s, 3H), 3.00-3.75 (m, 6H), 3.98 (d, J=15.0 Hz,
1H), 4.05 (m, 1H), 4.35 (d, J=16.5 Hz, 1H), 6.12 (m, 1H), 6.65 (d,
J=15.4 Hz, 1H), 7.25-7.38 (m, 5H), 7.55 (s, 1H), 7.79 (d, J=15.0
Hz, 1H), 8.31 (s, 1H). Anal. Calcd. for
C.sub.25H.sub.27Cl.sub.2N.sub.3O.sub.4HCl.- NaCl.1.5H.sub.2O: C,
47.94; H, 4.99; N, 6.71. Found: C, 47.98; H, 4.92; N, 6.57.
[0512] Compounds of Formula IV
[0513] Intermediates
[0514] The following intermediates were prepared. 72
[0515] (.+-.)-trans-2-Pyrrolidinyl-N-methylcyclohexylamine (3)
[0516] The racemic diamine (3) was prepared by a number of
procedure reported in the literature..sup.10,11 Alternatively, the
amine was also prepared from cyclohexene oxide (1) following the
procedure described in Scheme I and the literature in 70% overall
yield as brown oil. A sample was purified by the distillation (b.p.
75-82.degree. C./1.0 mm, lit..sup.2 b.p. 76-80.degree. C./1.2 mm);
.sup.1H-NMR (200 MHz, CDCl.sub.3) .delta. 1.04-1.36 (m, 4H),
1.49-1.89 (m, 8H), 2.18 (d, J=5.0 Hz, 1H), 2.52 (s, 3H), 2.56-2.70
(m, 4H), 2.80-2.93 (m, 1H), 7.75 (bs, 1H). The corresponding chiral
amine (3) could be prepared following the literature
procedures.
[0517] Ref.
[0518] (10) Szmuszkovicz, J.; Von Voigtlander, P. F. J. Med. Chem.
1982, 25, 1125-1126.
[0519] (11) DeCosata, B.; George, C.; Rothman, R. B.; Jacobson, A.
E.; Rice, K. E. FEBBS Lett. 1987, 223, 335-339.
[0520] (12) Freeman, J. P.; Michalson, E. T.; D'Andrea, S. V.;
Baczynskyj, L.; Von Voigtlander, P. F.; Lahti, R. A.; Smith, M. W.;
Lawson, C. F.; Scahill, T. A.; Mizsak, S. A.; Szmuszkovicz, J. J.
Med. Chem. 1991, 34, 1891-1896.
[0521] Synthesis of Arylacetamides 73
[0522] General procedure for the preparation of aryl acetamides
(.+-.) 5 HCl
[0523] To a stirred solution of aryl acetic acid (4) (1.5 mmol) in
20 mL of dry CH.sub.2Cl.sub.2 was added pyridine (0.5 mmol) at
065.degree. C. under a nitrogen atmosphere.
N,N'-Dicyclohexyl-carbodiimide (2.0 mmol) was added in one portion
and the reaction mixture was continued stirring for 30 min while
warming to room temperature. A solution of the (.+-.) 3 (1.0 mml)
in 10 mL of dry CH.sub.2Cl.sub.2 was added and the progress of the
reaction was monitored by TLC in solvent system corresponds to
CHCl.sub.3:CH.sub.3OH:28% NH.sub.4OH (93:5:2). After disappearance
of the diamine 3, the reaction mixture was quenched with saturated
NaHCO.sub.3 and stirring was continued for addition 15 min. The
precipitated N,N'-dicyclohexylurea (DCU) was removed by filtration
and the filter cake was washed with additional amounts of
CH.sub.2Cl.sub.2. The combined filtrate was evaporated to dryness
and the residue was purified either on a silica gel column or using
Chromatotran silica gel plattes form the from the solvent system
mentioned for each compound to give (.+-.) 5 as free base. The
hydrochloride salts were prepared from dissolving (.+-.) 5 in
minimum amount of CH.sub.2Cl.sub.2 and addition of 2.0 equivalents
of 1M etherial HCl. The solvents were removed under reduced
pressure and the HCl salts were recystallized from the solvents
indicated below. The yields given below are for overall steps.
EXAMPLE 103
(.+-.)-trans-2-Nitro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetam-
ide Hydrochloride [(.+-.) 5a HCl]
[0524] Prepared from 2-nitrophenylacetic acid [solvent for
purification--CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH (98:2:2)]:
yield 21% as a white solid (2-prppanol); mp 267-269.degree. C. (d);
.sup.1H NMR ((200 MHz, CDCl.sub.3) .delta. 1.00-1.44 (m, 2H),
1.60-2.35 (m, 8H), 2.85 (m, 1H), 3.15 (s, 3H), 3.18-3.35 (m, 4H),
3.40 (m, 1H), 3.85 (m, 1H), 4.33 (dd, J=10.0 Hz, 2H), 4.64 (m, 1H),
7.35 (m, 1H), 7.56 (m, 2H), 8.05 (d, J=7.8 Hz, 1H), 11.02 (bs, 1H).
Anal. Calcd for C.sub.19H.sub.27N.sub.3O.sub.3.HCl: C, 59.75; H,
7.39; Cl, 9.28; N, 11.00. Found: C, 59.98; H, 7.38; 8.96; N,
10.85.
EXAMPLE 104
(.+-.)-trans-2-Amino-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetam-
ide Hydrochloride [(.+-.) 5b HCl]
[0525] To a solution of (.+-.) 5a HCl (0.5 g, 1.31 nmol) in 30 mL
of CH.sub.3OH was added 10% Pd/C (100 mg) and hydrogenated at 50
PSI in a Parr Apparatus at ambient temperature for 3 h. The
catalyst was removed by filtration through a celite pad and washed
with hot CH.sub.3OH and the combined filtrate was evaporated to
dryness. The residue was recrystallized from 2-propanol to give
(.+-.) 5b HCl as a white solid, 0.45 g (95%); mp 213-215.degree.
C.; .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 1.05-1.40 (m, 2H),
1.65-2.25 (m, 8H), 3.10 (s, 3H), 2.90-3.25 (m, 4H), 3.50 (d,
J=12.0, 1H), 3.65 (m, 1H), 3.88 (m, 1H), 4.20 (d, J=12.5 Hz, 1H),
4.70 (m, 1H), 6.65 (m, 2H), 7.00 (m, 2H), 7.25 (bs, 2H). Anal.
Calcd for C.sub.19H.sub.29N.sub.3O.HCl.0.5H.sub.2O: C, 63.23; H,
8.66; N, 11.64. Found: C, 63.59; H, 8.76; N, 11.61.
EXAMPLE 105
(.+-.)-trans-2-Nitro-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl-
]-phenylacetamide Hydrochloride [(.+-.) 5c HCl]
[0526] The compound was prepared according to the literature method
(DeCosata, B.; Linda, B.; Rothman, R. B.; Jacobson, A. E.; Bykov,
V.; Pert, A.; Rice, K. E. FEBBS Lett. 1989, 249, 178-182); .sup.1H
NMR (200 MHz, CDCl.sub.3) .delta. 1.15-1.45 (m, 2H), 1.55-2.30 (m,
8H), 3.10 (s, 3H), 2.85-3.20 (m, 4H), 3.40 (m, 1H), 3.88 (m, 1H),
4.25 (d, J=14.5 Hz, 1H), 4.45 (d, J=15.0 Hz, 1H), 4.65 (m, 1H),
7.70 (s, 1H), 8.13 (s, 1H). Anal. Calcd for
C.sub.19H.sub.25Cl.sub.2N.sub.3O.sub.3.HCl: C, 50.62; H, 5.81; N,
9.32. Found: C, 50.61; H, 5.61; N, 9.20.
EXAMPLE 106
(.+-.)-trans-2-Amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl-
]-phenylacetamide Hydrochloride [(.+-.) 5d HCl]
[0527] Obtained from (.+-.) 5c HCl following the literature
procedure (DeCosata, B.; Linda, B.; Rothman, R. B.; Jacobson, A.
E.; Bykov, V.; Pert, A.; Rice, K. E. FEBBS Lett. 1989, 249,
178-182); .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 1.10-1.40 (m,
4H), 1.48-2.20 (m, 8H), 3.00 (s, 3H), 3.10-3.30 (m, 4H), 3.55 (d,
J=14.0 Hz, 1H), 3.85 (d, J=14.0 Hz, 1H), 4.50 (m, 1H), 6.75 (s,
1H), 7.08 (s, 1H). Anal. Calcd for
C.sub.19H.sub.27Cl.sub.2N.sub.3O.HCl.0.75H.sub.2O: C, 52.54; H,
6.84; N, 9.67. Found: C, 52.561; H, 6.63; N, 9.33.
EXAMPLE 107
(.+-.)-trans-2-Methanesulfonamido-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl-
]-phenylacetamide Hydrochloride [(.+-.) 5e HCl]
[0528] To a solution of free base of (.+-.) 5b (1.0 g, 3.2 mmol) in
40 mL of dry CH.sub.2Cl.sub.2 at 0.degree. C. under a nitrogen
atmosphere was added Et.sub.3N (1.86 g, 18.4 mmol). A solution of
methanesulfonyl chloride (1.14 g, 9.92 mmol) in 15 mL of dry
CH.sub.2Cl.sub.2 was added dropwise within 15 min. After 2 h at
room temperature TLC [solvent system: CHCl.sub.3:CH.sub.3OH:28%
NH.sub.4OH (93:5:2)] showed still staring material was present.
Additional amounts of Et.sub.3N (1.86 g) and methanesulfonyl
chloride (1.14 g) were added and stirring was continued for another
2 h by this time no starting material was present in the reaction
mixture. After the mixture was diluted with 40 mL CH.sub.2Cl.sub.2
of, it was washed with saturated NaHCO.sub.3, water, saturated salt
solution, and dried over anhydrous Na.sub.2SO.sub.4. Removal of
solvent under reduced pressure gave the bis-sulfoamide as a brown
foam which was used directly in the following hydrolysis.
[0529] To a solution of bis-sulfonamide (1.0 g, 2.12 mmol) in 60 mL
of CH.sub.3OH:THF (2:1) was added 10 M aqueous NaOH (0.96 mL, 9.6
mmol)..sup.13 The mixture was stirred at room temperature for 30
min and then acidified with 1N HCl. The solvent was evaporated
under reduced pressure and the residue was redissolved in
CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 layer was then washed with
5% NaHCO.sub.3, saturated salt solution, and dried over anhydrous
Na.sub.2SO.sub.4. Removal of solvent under reduced pressure
chromatography on a silica gel column [solvent system:
CH.sub.2Cl.sub.2:CH.sub.3OH:28% NHOH (95:5:2)] gave the
mono-sulfonamide (free base) as an oil; .sup.1H NMR (200 MHz,
CDCl.sub.3) .delta. 1.05-1.95 (m, 12H), 2.45-2.80 (m, 5H), 2.95 (s,
3H), 3.10 (s, 3H), 3.50 (d, J=13.8 Hz, 1H), 3.65 (m, 1H), 3.85 (d,
J=14.0 Hz, 1H), 4.45 (m, 1H), 7.05 (m, 1H), 7.15 (m, 2H), 7.45 (d,
J=8.5 Hz, 1H). The hydrochloride salt was prepared by dissolving
the free base in CH.sub.2Cl.sub.2 and adding 1.2 equivalents of 1M
etherial HCl and recrystallizing from 2-propanol to give (.+-.) 5e
HCl as beige colored solid, 0.37 g (38%); mp 229-231.degree. C.;
.sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 1.10-2.20 (m, 12H),
2.90-3.20 (m, 4H), 3.00 (s, 3H), 3.15 (s, 3H), 3.50 (m, 1H), 3.65
(d, J=13.5 Hz, 2H), 3.80 (m, 1H), 4.40 (m, 1H), 7.05-7.30 (m, 3H),
7.60 (d, J=8.0 Hz, 1H), 8.90 (bs, 1H). Anal. Calcd for
C.sub.20H.sub.31N.sub.3O.sub.3S.HCl.0.25H.sub.2O: C, 55.28; H,
7.54; N, 9.67. Found: C, 55.40; H, 7.39; N, 9.49.
[0530] Ref.
[0531] (13) Li, C.-S.; Black, W. C.; Chan, C.-C.; Ford-Huctchinson,
A. W.; Gauthier, J.-Y.; Gordon, R.; Guay, D; Kargman, S.; Lau, C.
K.; Mancini, J.; Ouimet, N.; Roy, P.; Vickers, P.; Wong. E.; Young,
R. N.; Zamboni, R.; Prasit, P. J. Med. Chem. 1995, 38,
4897-4905.
EXAMPLE 108
N-[2-(.+-.)-trans-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-phenylacetamid-
o]glycine Hydrochloride [(.+-.) 5f HCl]
[0532] To a stirred solution of (.+-.) 5b (free base, 1.0 g, 3.2
mmol) in 15 mL of dry DMF at room temperature under a nitrogen
atmosphere was added 95% NaH (0.083 g, 3.3 mmol). After stirring at
room temperature for 30 min, the turbid solution was added to a
stirred solution of tert-butyl bromoacetate (0.66 g, 3.4 mmol) in
10 mL of dry DMF. The reaction mixture was continued stirring for
72 h however TLC of the reaction mixture [solvent system:
CHCl.sub.3:CH.sub.3OH:28% NH.sub.4OH (93:5:2)] showed still
starting material was present. The solvent was removed under
reduced pressure and the residue was partioned between
CH.sub.2Cl.sub.2/water. The product was purified on a silica gel
column from CH.sub.2Cl.sub.2:CH.sub.3OH (9:1) and was recystallized
from CH.sub.2Cl.sub.2:Et.sub.2O (1:1) to give the corresponding
tert-butyl ester, 0.16 (12%); .sup.1H NMR (200 MHz, CDCl.sub.3)
.delta. 1.05-1.35 (m, 4H), 1.35 (s, 9H), 1.55-2.20 (m, 8H), 2.92
(b, 4H), 3.12 (s, 3H), 3.45 (m, 1H), 3.60 (d, J=14.0 Hz, 2H), 3.78
(bt, 2H), 3.95 (m, 1H), 5.75 (b, 1H), 6.38 (d, J=6.5 Hz, 1H), 6.60
(t, J=5.5 Hz, 1H), 7.00 (m, 2H). The staring material was also
recovered in 50% yield.
[0533] The tert-butyl ester (0.16 g, 0.372 mmol) was suspended in
10 mL of 4N aqueous HCl and added one drop of anisole and the
mixture was stirred at room temperature for 24 h. The solvent was
evaporated under reduced pressure and the residue was redissolved
in CH.sub.3CN and filtered. The filtrate was evaporated under
reduced pressure and the residue was recrystallized from
2-propanol:ether (1:1) to give (.+-.) 5f HCl as a white solid,
0.070 g (42%); mp 212-214.degree. C. (d); .sup.1H NMR (200 MHz,
DMSO-d.sub.6) .delta. 1.15-2.25 (m, 12H), 2.90 (m, 1H), 3.05 (s,
3H), 3.14-3.70 (m, 6H), 3.85 (bs, 2H), 4.55 (b, 1H), 6.37 (d, J=6.0
Hz, 1H), 6.55 (t, J=5.0 Hz, 1H), 6.95 (m, 2H), 9.80 (b, 1H). Anal.
Calcd for C.sub.21H.sub.31N.sub.3O.sub.3.HCl.H.sub.2O: C, 58.93; H,
8.00; N, 9.81. Found: C, 58.79; H, 7.64; N, 9.43.
EXAMPLE 109
(.+-.)-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-p-
henylacetamide Hydrochloride [(.+-.) 5g HCl]
[0534] To a solution of 4-trifluoromethylphenyl acetic acid (1.45
g, 7.08 mmol) in 10 mL of dry CH.sub.2Cl.sub.2 under a nitrogen
atmosphere was added 1-hydroxybenzotriazole hydrate (HOBT) (0.95 g,
7.08 mmol) and stirred. The reaction mixture was cooled to
0.fwdarw.5.degree. C. and added solid EDCI
([1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl])(1.35 g, 7.08
mmol) and stirrat this temperature for 30 min. A solution (.+-.) 3
(1.0 g, 5.48 mmol) in 10 mL of dry CH.sub.2Cl.sub.2 was added
followed by N,N-diisopropylethylamine (Hunig's Base) (0.915 g, 7.08
mmol). The reaction mixture was stirred for 24 h while warming to
the room temperature. The reaction mixture was then poured on to
excess of ice-cold saturated aqueous NaHCO.sub.3 solution and
stirred for 30 min. After dilution with CH.sub.2Cl.sub.2, the
organic was separated, washed with saturated salt solution, and
dried over anhydrous Na.sub.2SO.sub.4. Removal of solvent gave a
brown oil which was chromatogrphed on a silica gel column [solvent
system: CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH (99:1:2)] to
give the desired product as free base. The hydrochloride salt was
prepared from 1M etherial HCl and recrystallized from
CH.sub.2Cl.sub.2: Et.sub.2O (1:1) to give (.+-.) 5g HCl as a cream
colored solid, 0.68 g (30%); 213-215.degree. C.; .sup.1H NMR (200
MHz, CDCl.sub.3) .delta. 1.02-1.47 (m, 4H), 1.52-2.22 (m, 8H),
2.75-2.90 (m, 2H), 2.94 (s, 3H), 3.07 (m, 1H), 3.37 (m, 1H), 3.62
(d, J=15.0 Hz, 1H), 3.77 (m, 1H), 4.17 (d, J=15.0 Hz, 1H), 4.57 (m,
1H), 7.30 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H). Anal. Calcd
for C.sub.20H.sub.27F.sub.3N.sub- .2O.HCl.0.25H.sub.2O: C, 58.68;
H, 7.02; N, 6.84. Found: C, 58.68; H, 6.84; N, 6.69.
[0535] Nitration of 4-trifluorometylphenyl acetic acid:
[0536] General Procedure: 74
[0537] Preparation of 2-nitro-4-trifluoromethylphenyl acetic acid
[4, R=2-NO.sub.2(4-CF.sub.3)--C.sub.6H.sub.4CH.sub.2]
[0538] To a solution of 4-trifluoromethylphenyl acetic acid (2.5 g,
12.25 mmol) in 8 mL of glacial acetic acid at 0.degree. C. under an
anhydrous atmosphere was added 5 mL of fuming H.sub.2SO.sub.4 (11%
SO.sub.3) (caution!) followed by cautious addition of 90% HNO.sub.3
(3.5 mL, 73.14 mmol) within 10 min. The reaction mixture was then
stirred at room temperature for 2 h and poured into ice-water. The
resulting solid was filtered and washed with cold deionized water
to give the desired product after drying as off-white solid, 2.5 g
(82%); .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 4.02 (s, 2H), 7.41
(d, J=8.0 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 8.28 (s, 1H). The
product was used directly into the following reactions.
EXAMPLE 110
(.+-.)-trans-2-Nitro-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclo-
hexyl]-phenylacetamide Hydrochloride [(.+-.) 5h HCl]
[0539] Prepared from 2-nitro-4-trifluoromethylphenyl acetic acid
following the procedure described in Example II to give (.+-.) 5h
HCl as cream colored solid in 56% yield; mp 259-261.degree. C. (d);
.sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 1.10-1.42 (m, 4H),
1.51-2.25 (m, 8H), 2.95-3.25 (m, 3H), 3.14 (s, 3H), 3.40 (m, 1H),
3.90 (m, 1H), 4.35 (d, J=13.8 Hz, 1H), 4.55 (d, J=14.0 Hz, 1H),
4.60 (m, 1H), 7.80 (dd, J=7.8 Hz, 2H), 8.25 (s, 1H). Anal. Calcd
for C.sub.20H.sub.26F.sub.3N.sub.3O.sub.3.HCl.0.25H.- sub.2O: C,
52.86; H, 6.10; N, 9.25. Found: C, 52.85; H, 6.02; N, 9.13.
EXAMPLE 111
(.+-.)-trans-2-Amino-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclo-
hexyl]phenylacetamide Hydrochloride [(.+-.) 5i HCl]
[0540] To a solution of free base 4h (0.4 g, 0.97 mmol) in 20 mL of
absolute alcohol was added 2 ml of hydrazine hydrate and the
reaction mixture was stirred at 50.degree. C. under a nitrogen
atmosphere. Raney.RTM.nickel (50% slurry in water) was added slowly
and the progress of the reaction was monitored on TLC plate
[solvent system: CHCl.sub.3:CH.sub.3OH:28% NH.sub.4OH (99:1:2)]. If
needed more of the Raney.RTM.nickel was added to the reaction
mixture. When reaction was completed, excess of Raney.RTM.nickel
was introduced to decompose the hydrazine hydrate. The reaction
mixture was filtered through a celite pad and the pad was washed
with hot CH.sub.3OH. The filtrate was evaporated to dryness. The
residue was purified on a silica gel column [solvent system:
CHCl.sub.3:CH.sub.3OH:28% NH.sub.4OH (99:1:2)] and the
hydrochloride salt was prepared from 1M etherial HCl.
Recrystallization from CH.sub.2Cl.sub.2:Et.sub.2O (2:1) gave (.+-.)
5i HCl as a white solid, 0.2 g (48%); mp 248-250.degree. C. (d);
.sup.1H NMR (200 MHz, DMSO-d.sub.6) .delta. 1.15-2.18 (m, 12H),
3.00 (s, 3H), 3.154.10 (m, 7H), 4.50 (m, 1H), 6.80 (d, J=7.8 Hz,
1H), 6.92 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 10.0 (bs, 1H). Anal.
Calcd for C.sub.20H.sub.28F.sub.3N.sub.3O.HCl.0- .5H.sub.2O: C,
56.01; H, 7.05; N, 9.80. Found: C, 55.70; H, 7.03; N, 9.65.
EXAMPLE 112
(.+-.)-trans-2-Bismethanesulfonamido-4-trifluoromethyl-N-methyl-N-[2-(1-py-
rrolidinyl)cyclohexyl]-phenylacetamide Hydrochloride [(.+-.) 5j
HCl]
[0541] The compound was prepared from free base (.+-.) 5i (0.5 g,
1.30 mmol) following the procedure described in the first part of
the preparation of (.+-.) 5e. The bismethaneslfonamide was purified
on a silica gel column [solvent system:
CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH (96:2:2)] to give the
desired product as a foam. The hydrochloride salt was prepared from
1M etheial HCl and recrystallized from 2-propanol:Et.sub.2O (1:1)
to give (.+-.) 5j HCl as a beige colored solid, 0.23 g (30%); mp
224-226.degree. C. (d); .sup.1H NMR (200 MHz, CDCl.sub.3) .delta.
1.12-1.51 (m, 4H), 1.53-2.24 (m, 8H), 1.82-3.17 (m, 2H), 2.98 (s,
3H), 3.32-3.56 (m, 2H), 3.28 (s, 3H), 3.33 (s, 3H), 3.77 (m, 1H),
3.97 (d, J=14.0 Hz, 1H), 4.27 (d, J=14.0 Hz, 1H), 4.62 (m, 1H),
7.39 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 111).
Anal. Calcd for C.sub.22H.sub.32F.sub.3N.sub.3O.sub.5S.sub.2.HCl:
C, 45.87; H, 5.77; N, 7.29. Found: C, 45.53; H, 5.81; N, 7.00.
EXAMPLE 113
(.+-.)-trans-2-Methanesulfonamido-4-trifluoromethyl-N-methyl-N-[2-(1-pyrro-
lidinyl)cyclohexyl]-phenylacetamide Hydrochloride [(.+-.) 5k
HCl]
[0542] To a solution of (.+-.) 5j HCl (0.16 g, 0.23 mmol) in 9 mL
of CH.sub.3OH:THF (2:1) at room temperature was added 0.12 mL of
10M aqueous NaOH and the mixture was stirred for 30 min. The
reaction mixture was neutralized with 1N HCl and evaporated to
dryness. The residue was redissolved in CH.sub.2Cl.sub.2 and
basified with saturated aqueous solution of NaHCO.sub.3. The
organic layer was separated, washed with water, saturated salt
solution, and dried over anhydrous Na.sub.2SO.sub.4. Removal of
solvent under reduced pressure gave the product as a free base. The
hydrochloride salt was prepared from 1M etherial HCl and
recrystallized from CH.sub.2Cl.sub.2: Et.sub.2O (1:1) to give
(.+-.) 5k HCl as a beige colored solid, 0.085 g (61%);
209-211.degree. C. (d); .sup.1H NMR (200 MHz, CDCl.sub.3) .delta.
1.15-1.24 (m, 4H), 1.50-2.10 (m, 8H), 2.20 (m, 2H), 2.90-3.10 (m,
2H), 3.05 (s, 6H), 3.55 (m, 2H), 3.80 (m, 1H), 4.64 (m, 1H), 7.20
(dd, J=7.8 Hz, 2H), 7.88 (s, 1H), 9.00 (s, 1H). Anal. Calcd for
C.sub.21H.sub.30F.sub.3N.sub.3O.sub.3S.HCl.0.125H.sub.2O: C, 50.42;
H, 6.30; N, 8.40. Found: C, 50.62; H, 6.49; N, 8.00.
EXAMPLE 114
N-[2-(.+-.)-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohex-
yl]-phenylacetamido]glycine Hydrochloride [(.+-.) 5l HCl]
[0543] To a solution of free base (.+-.) 5i (0.767, 2.0 mmol) in 10
mL of anhydrous THF under a nitrogen atmosphere at 0.degree. C. was
added N,N-diisopropylethylamine (Hunig's Base) (1.55 g, 12.0 mmol).
The reaction mixture was stirred at 0.degree. C. for 15 min then
added bromoacetic acid t-butyl ester (1.95 g, 10.0 mmol) and the
reaction mixture was continued to stir while warming to room
temperature 72 h. The solvent was evaporated at reduced pressure
and the residue was partitioned between CH.sub.2Cl.sub.2 and water.
The organic layer was then washed with, saturated NaHCO.sub.3,
saturated salt solution, and dried over anhydrous Na.sub.2SO.sub.4.
Removal of solvent gave the crude product which was purified on a
silica gel column [solvent system: CHCl.sub.3:CH.sub.3OH:28%
NH.sub.4OH (96:2:2)] to give the intermediate t-butyl ester 0.477 g
(40%); .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 1.05-1.25 (m, 4H),
1.38-1.90 (m, 8H), 1.40 (s, 9H), 2.15-2.75 (m, 5H), 2.85 (s, 3H),
3.60 (m, 2H), 3.75 (d, J=4.0 Hz, 2H), 4.45 (m, 1H), 5.85 (m, 1H),
6.55 (s, 1H), 6.80 (d, J=7.5 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H).
[0544] The above t-butyl ester (0.47 g, 0.77 mmol) was suspended in
10 mL of aqueous 4N HCl and added 2-3 drops of anisole. The
reaction mixture was stirred at room temperature for 72 h and
filtered. The filtrate was evaporated to dryness, redissolved in
CH.sub.3CN, filtered again, and concentrated. Addition of the ether
gave the product which was filtered, washed with ether, and dried
to give (.+-.) 5l HCl as a beige colored solid, 0.17 g (41%); mp
178-180.degree. C. (d); MS (FAB) 442 (M+1); .sup.1H NMR (200 MHz,
CDCl.sub.3) .delta. 1.05-2.20 (m, 12H), 2.75 (s, 3H), 2.90-3.25 (m,
5H), 3.30-3.55 (m, 2H), 3.70-4.35 (m, 4H), 4.65 (m, 1H), 6.72 (s,
1H), 6.80 (m, 1H), 6.95 (d, J=7.7 Hz, 1H). Anal. Calcd for
C.sub.22H.sub.30F.sub.3N.sub.3O.sub.3.HCl.0.125Et.sub.2O: C, 55.47;
H, 6.67; N, 8.62. Found: C, 55.64; H, 7.06; N, 9.00.
EXAMPLE 115
(.+-.)-trans-3-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-p-
henylacetamide Hydrochloride [(.+-.) 5m HCl]
[0545] Following the Example II, (.+-.) 5m HCl was prepared from
3-trifluoromethylphenyl acetic acid in 67% yield as a cream colored
solid; mp 245-247.degree. C.; .sup.1H NMR (200 MHz, CDCl.sub.3)
.delta. 1.15-1.55 (m, 4H), 1.60-2.30 (m, 8H), 2.80-3.05 (m, 2H),
3.00 (s, 3H), 3.18 (m, 1H), 3.45 (m, 1H), 3.75 (d, J=15.0 Hz, 1H),
3.85 (m, 1H), 4.25 (d, J=14.8 Hz, 1H), 4.65 (m, 1H), 7.40 (m, 4H).
Anal. Calcd for C.sub.20H.sub.27F.sub.3N.sub.2O.HCl.0.25H.sub.2O:
C, 58.68; H, 7.02; N, 6.84. Found: C, 58.46; H, 7.17; N, 6.69.
[0546] Nitration of 3-trifluorometylphenyl acetic acid: 75
Preparation of 2-nitro-3-trifluoromethylphenyl acetic acid [4,
R=2-NO.sub.2(3-CF.sub.3)--C.sub.6H.sub.4CO.sub.2H] and Preparation
of 5-nitro-3-trifluoromethylphenyl acetic acid [4,
R=5-NO.sub.2(3-CF.sub.3)-- -C.sub.6H.sub.4CO.sub.2H]
[0547] The nitration of 3-trifluorophenylacetic acid as shown
earlier resulted into a 1:1 non-separable mixture of 2- and 5-nitro
compounds in 66% yield. The structural assignment of the compounds
were made on the basis of .sup.1H NMR spectrum. The mixture was
used in the condensation reaction.
EXAMPLE 116
(.+-.)-trans-5-Nitro-3-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclo-
hexyl]-phenylacetamide Hydrochloride [(.+-.) 5n HCl] and
(.+-.)-trans-2-Nitro-3-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cycl-
ohexyl]-phenylacetamide Hydrochloride [(.+-.) 5o HCl]
[0548] The compounds were prepared as shown in Example 109 and the
mixture of 2- and 5-nitrophenylacetic acids to give the mixture of
products. Initially the compounds were separated on a silica gel
column [solvent system: CHCl.sub.3:CH.sub.3OH:28% NH.sub.4OH
(96:2:2)] which resulted in the free base of the compounds as pure
mixture. The products were again purified on Chromatotran using a 4
mm silica gel plate [solvent system: CHCl.sub.3 containing 2%
NH.sub.4OH]. The first product was isolated and converted to the
hydrochloride salt and the salt was recrystallized from
2-propanol:ether (1:1) to give (.+-.) 5n HCl as a cream colored
solid in 10% yield; mp 236-238.degree. C.; .sup.1H NMR (200 MHz,
CDCl.sub.3) .delta. 1.15-1.55 (m, 4H), 1.65-2.30 (m, 8H), 2.85-3.20
(m, 3H), 3.10 (s, 3H), 3.40 (m, 1H), 3.70 (d, J=14.0 Hz, 1H), 3.85
(m, 1H), 4.60 (brd, 2H), 7.90 (s, 1H), 8.25 (s, 1H), 8.32 (s, 1H).
Anal. Calcd for C.sub.20H.sub.26F.sub.3N.sub.3O.sub.3.HCl: C,
53.39; H, 6.05; N, 9.34. Found: C, 53.28; H, 6.06; N, 9.36.
[0549] The second product, (.+-.) 5o HCl, was also isolated in 10%
yield after the recrystallization of the hydrochloride salt from
2-propanol:ether (1:1) as a white solid; mp 243-245.degree. C. (d);
.sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 1.10-1.50 (m, 4H),
1.55-2.20 (m, 8H), 2.90-3.20 (m, 3H), 3.10 (s, 3H), 3.44 (m, 1H),
3.65 (d, J=13.5 Hz, 1H), 3.90 (m, 1H), 4.65 (brd, 2H), 7.70 (s,
1H), 7.82 (s, 2H). Anal. Calcd for
C.sub.20H.sub.26F.sub.3N.sub.3O.sub.3.HCl.H.sub.2O: C, 51.34; H,
6.25; N, 8.98. Found: C, 51.69; H, 6.24; N, 8.89.
EXAMPLE 117
(.+-.)-trans-2-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-p-
henylacetamide Hydrochloride [(.+-.) 5p HCl]
[0550] The compound was prepared from 2-trfluoromethylphenylacetic
acid following the Example II. The hydrochloride salt was made from
1M etherial HCl and recrystallized from 2-propanol:ether (1:1) to
give (.+-.) 5p HCl in 20% yield as a white solid; mp
282-284.degree. C. (d); .sup.1H NMR (200 MHz, CDCl.sub.3) .delta.
1.20-1.50 (m, 4H), 1.55-2.30 (m, 8H), 3.85-3.04 (m, 2H), 3.08 (s,
3H), 3.10-3.27 (m, 1H), 3.40-3.60 (m, 1H), 3.90 (m, d, J=14.5 Hz,
2H), 4.26 (d, J=14.7 Hz, 1H), 4.63 (m, 1H), 7.26 (t, J=8.0 Hz, 1H),
7.45 (t, J=8.0 Hz, 1H), 7.60 (t, J=7.5 Hz, 2H). Anal. Calcd for
C.sub.20H.sub.27F.sub.3N.sub.2O.HCl: C, 59.33; H, 6.97; N, 6.92.
Found: C, 59.28; H, 6.73; N, 6.84.
[0551] Nitration of 2-trifluorometylphenyl acetic acid: 76
Preparation of 4-nitro-2-trifluoromethylphenyl acetic acid [4,
R=4-NO.sub.2(2-CF.sub.3)--C.sub.6H.sub.4CO.sub.2H]
[0552] The nitration of 2-trifluorophenylacetic acid as depicted in
Scheme III gave mostly the corresponding 4-nitro derivative and
only a trace amount of 6-nitro compound was detected in the proton
NMR; .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 3.90 (s, 2H), 7.55
(d, J=8.4 Hz, 1H), 8.35 (dd, J=2.4, 8.0 Hz, 1H), 8.50 (d, J=2.4 Hz,
1H). The compound was used directly into the following coupling
reaction.
EXAMPLE 118
(.+-.)-trans-4-Nitro-2-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclo-
hexyl]-phenylacetamide Hydrochloride [(.+-.) 5q HCl]
[0553] The compound was prepared following the coupling method
described in Example 109 from 4-nitro-2-trifluorophenylacetic acid.
The hydrochloride salt was prepared by known method and
recrystallized from 2-propanol:ether (1:1) to give (.+-.) 5q HCl as
a beige colored solid in 37% yield; mp 265-267.degree. C. (d);
.sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 1.15-1.45 (m, 4H),
1.50-2.30 (m, 8H), 2.85-3.20 (m, 3H), 3.05 (s, 3H), 3.45 (m, 1H),
3.90 (m, d, J=14.0 Hz, 2H), 4.60 (brd, 2H), 8.00 (d, J=8.0 Hz, 1H),
8.25 (dd, J=2.4, 8.0 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H). Anal. Calcd
for C.sub.20H.sub.26F.sub.3N.sub.3O.sub.3.HCl: C, 53.39; H, 6.05;
N, 9.34. Found: C, 53.29; H, 5.93; N, 9.17.
EXAMPLE 119
(.+-.)-trans-4-Amino-2-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclo-
hexyl]-phenylacetamide Hydrochloride [(.+-.) 5r 2HCl]
[0554] The compound was prepared from free base (.+-.) 5q following
the reduction procedure described for the preparation of (.+-.) 5h.
The free base was converted to di-hydrochloride from 1M etherial
HCl and recrystallized from CH.sub.2Cl.sub.2:CH.sub.3OH:Et.sub.2O
(6:3:1) to give (.+-.) 5r 2HCl as a White solid in 68% yield; mp
288-290.degree. C. (d); .sup.1H NMR (200 MHz, DMSO-d.sub.6) .delta.
1.10-2.20 (m, 12H), 2.98 (s, 3H), 3.00-3.30 (m, 4H), 3.50 (m, 1H),
3.80 (d, J=14.5 Hz, 1H), 4.20 (d, J=14.8 Hz, 1H), 4.50 (m, 1H),
7.50 (m, 3H). Anal. Calcd for C.sub.20H.sub.28F.sub.3N.sub.30.2HCl:
C, 52.64; H, 6.63; N, 9.21. Found: C, 52.67; H, 6.52; N, 9.06.
EXAMPLE 120
(.+-.)-trans-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]2,2-dphenylacetamide
Hydrochloride [(.+-.) 5s HCl]
[0555] The compound was prepared from diphenylacetic acid following
the general procedure for the preparation of aryl acetamides. The
hydrochloride salt was recrystallized from 2-propanol to give
(.+-.) 5s HCl as a white solid in 20% yield; mp 295-297.degree. C.
(d); .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 1.20-2.40 (m, 12H),
2.85-3.15 (m, 2H), 3.00 (s, 3H), 3.25-3.60 (m, 2H), 3.95 (m, 1H),
4.75 (m, 1H), 5.70 (s, 1H), 7.35 (m, 10H). Anal. Calcd for
C.sub.25H.sub.32N.sub.2O.HCl.0.25H.sub.2O: C, 71.92; H, 8.09; N,
6.71. Found: C, 72.25; H, 8.40; N, 6.52.
EXAMPLE 121
(.+-.)-trans-4-Methylsulfonyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phe-
nylacetamide Hydrochloride [(.+-.) 5t HCl]
[0556] The compound was prepared from 4-methylsulfonylphenylacetic
acid to the method of Example 109 and the hydrochloride salt was
recrystallized from CH.sub.2Cl.sub.2:ET.sub.2O (1:1) to give (.+-.)
5t HCl as a cream colored solid in 50% yield; mp 152-154.degree. C.
(d); .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 1.10-2.30 (m, 12H),
2.95 (s, 6H), 3.00-3.25 (m, 2H), 3.40 (m, 1H), 3.65 (d, J=14.5 Hz,
1H), 3.85 (m, 1H), 4.35 (d, J=14.0 Hz, 1H), 4.67 (m, 1H), 7.45 (d,
J=8.0 Hz, 2H), 7.80 (d, J=8.0 77
[0557] Hz, 2H). Anal. Calcd for
C.sub.20H.sub.30N.sub.2O.sub.3S.HCl.1.5H.s- ub.2O: C, 54.35; H,
7.75; N, 6.34. Found: C, 54.20; H, 7.38; N, 6.15.
[0558] Preparation of compounds 4a through 41 of formula IVA is
according to Scheme 0.
[0559] The chiral compounds were prepared from the enantiomeric
pure diamine B.
EXAMPLE 4a
(Z)-4-[2-((.+-.)-trans-2-Amino-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-
-cyclohexyl]phenylaetamido)]4-oxo-2-butenoic acid
[0560] To a solution of
(.+-.)-trans-2-amino-4,5-dichloroN-methyl-N-[2-(1--
pyrrolidinyl)cyclohexyl]-phenylacetamide3 (0.12 g, 0.312 mmol) in
anhydrous THF (2.5 mL) under a nitrogen atmosphere was added maleic
anhydride (0.03 g, 0.312 mmol). The reaction mixture was stirred at
room temperature for 3 days. The precipitated solid was filtered
off, washed with anhydrous THF, and dried to give 4a (0.088 g,
58%); mp 246-248.degree. C. (d); MS (FAB) 482 (M.sup.+). Anal.
Calcd. for C.sub.23H.sub.29Cl.sub.2N.sub.3O.sub.4.H.sub.2O: C,
55.20; H, 6.24; N, 8.40. Found: C, 55.32; H, 6.01; N, 8.09.
[0561] Ref.
[0562] 3. de Costa, B. R. et. al. FEBS Lett. 249, 178-182
(1989).
EXAMPLE 4b
(Z)-4-[2-((.+-.)-trans-2-Amino-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolid-
inyl)-cyclohexyl]-phenylaetamido)]4-oxo-2-butenoic acid
[0563] The compound 4b was prepared from
(.+-.)-trans-2-amino-4-trifluorom-
ethyl-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]phenylacetamide.sup.1
following the above procedure in 60% yield; mp 256-258.degree. C.;
.sup.1H NMR (300 MHz, DMSO-d) .delta. 1.15-2.18 (m, 12H), 3.01 (s,
3H), 3.15-4.10 (m, 7H), 4.50 (m, 1H), 5.95 (d, J=15.0 Hz, 1H), 6.35
(d, J=14.5 Hz, 1H), 7.37 (m, 2H), 8.16 (s, 1H). Anal. Calcd for
C.sub.24H.sub.30F.sub.3N.sub.3O.sub.4: C, 59.87; H, 6.28; N, 8.37.
Found: C, 59.64; H, 6.14; N, 8.57.
EXAMPLE 4c
(.+-.)-trans-2-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-pyridylacetamide
dihydrochloride
[0564] The compound 4c was prepared from 2-pyridyl acetic acid
hydrochloride and
(.+-.)-trans-2-pyrrolidinyl-N-methylcyclohexylamine.sup- .3
following the general procedure in 37% yield; mp 264-266.degree. C.
(d); .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.10-2.00 (m,
12H), 3.04 (s, 3H), 3.15-4.70 (m, 5H), 4.30 (d, J=16 Hz, 1), 4.55
(m, 1H), 4.67 (d, J=16.0 Hz, 1H), 7.82 (t, J=7.5 Hz, 1H), 8.10 (d,
J=7.8 Hz, 1H), 8.55 (t, J=7.5 Hz, 1H), 8.88 (d, J=7.0 Hz, 1H).
Anal. Calcd for C.sub.18H.sub.27N.sub.30.2HCl.0.25H.sub.2O: C,
57.07; H, 7.85; N, 11.09. Found: C, 57.04; H, 7.48; N, 10.69.
EXAMPLE 4d
(.+-.)-trans-3-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-5-bromo-pyridylac-
etamide hydrochloride
[0565] The compound 4d was prepared 5-bromo-3-pyridyl acetic acid
in 77% yield; mp 130-132.degree. C.; .sup.1H NMR (free base 200
MHz, CDCl.sub.3) .delta. 1.00-2.00 (m, 12H), 2.88 (s, 3H),
2.35-2.77 (m, 5H), 3.75 (m, 2H), 4.50 (m, 1H), 7.65 (bs, 1H), 8.30
(bs, 1H), 8.67(s, 1H). Anal. Calcd for
C.sub.18H.sub.26BrN.sub.3O.HCl: C, 51.87; H, 6.53; N, 10.08. Found:
C, 51.48; H, 6.11; N, 9.70.
EXAMPLE 4e
(.+-.)-trans-3,5-Di-Trifluoromethyl-N-methyl-N-[2-(1-Pyrrolidinyl)cyclohex-
yl]phenylacetamide hydrochloride
[0566] Prepared from 3,5-di-trifluoromethyl-phenyl acetic acid in
27% yield; mp 211-213.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 1.20-2.25 (m, 12H), 3.04 (s, 3H), 3.00-3.35 (m, 3H), 3.50
(m, 1H), 3.80 (d, J=15.0 Hz, 1H), 4.00 (m, 1H), 4.60 (m, 2H), 7.75
(s, 1H), 7.84 (s, 2H). Anal. Calcd for
C.sub.21H.sub.26F.sub.6N.sub.2O.HCl: C, 53.34; H, 5.75; N, 5.92.
Found: C, 53.14; H, 5.74; N, 5.76.
EXAMPLE 4f
(.+-.)-trans-3-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-(trans-3-furyl)ac-
etamide hydrochloride
[0567] The compound 4f was prepared from trans-3-furan acrylic acid
in 56% yield; mp 164-166.degree. C. (d); .sup.1H NMR (200 MHz,
CDCl.sub.3) .delta. 1.20-2.25 (m, 12H), 3.15(s, 3H), 2.75-3.95 (m,
4H), 4.70 (m, 2H), 6.57 (bs, 1H), 6.65 (d, J=15.0 Hz, 1H), 7.34 (s,
1H), 7.46 (d, J=15.2 Hz, 1H), 7.55 (s, 1H). Anal. Calcd for
C.sub.18H.sub.26N.sub.2O.sub.3.HCl.0.5- H.sub.2O: C, 62.15; H,
8.11; N, 8.05. Found: C, 61.94; H, 8.01; N, 7.91.
EXAMPLE 4g
(.+-.)-trans-2-Methoxy-3-methylsulfamoyl-N-methyl-N-[2-(1-Pyrrolidinyl)cyc-
lohexyl]phenylacetamide hydrochloride
[0568] The compound 4g was prepared from
2-methoxy-3-methylsulfamoyl-pheny- l acetic acid (prepared from
methyl 2-methoxy phenyl acetic acid by the procedure reported
earlier) in 45% yield; mp 168-170.degree. C.; .sup.1H NMR (200 MHz,
CDCl.sub.3) .delta. 1.15-2.20 (m, 12H), 2.52 (d, J=2.5 Hz, 3H),
2.76 (s, 3H), 2.40-2.70 (m, 4H), 3.58 (d, J=5.0 Hz, 1H), 3.79 (s,
3H), 3.84 (d, J=4.8 Hz, 1H), 4.75 (m, 2H), 6.84 (d, J=8.7 Hz, 1H),
7.65 (m, 2H). Anal. Calcd for
C.sub.21H.sub.33N.sub.3O.sub.4S.HCl.0.5H.sub.2O: C, 53.78; H, 7.52;
N, 8.96. Found: C, 53.80; H, 7.50; N, 8.90.
EXAMPLE 4h
(.+-.)-trans-3-N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]indoleacetamide
hydrochloride
[0569] Prepared from indole 3-acetic acid in 61% yield;
262-264.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.20-2.15 (m, 12H), 2.95 (s, 3H), 2.97-3.55 (m, 4H), 3.83 (s, 2H),
4.55 (m, 2H), 6.96 (t, J=7.5 Hz, 1H), 7.02 (t, J=7.0 Hz, 1H), 7.17
(s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H). Anal.
Calcd for C.sub.21H.sub.29N.sub.3O.0.9HCl: C, 67.75; H, 8.10; N,
11.29. Found: C, 67.78; H, 8.12; N, 11.22.
EXAMPLE 4i
(.+-.)-trans-4-Fluoro-3-methylsulfamoyl-N-methyl-N-[2-(1-pyrrolidinyl)cycl-
ohexyl]phenylacetamide hydrochloride
[0570] The compound 4i was prepared from
4-fluroro-3-methylsulfamoyl phenyl acetic acid in 48% yield; mp
265-267.degree. C.; .sup.1H NMR (200 MHz, DMSO-d.sub.6) .delta.
1.30-2.20 (m, 12H), 2.60 (s, 3H), 3.06 (s, 3H), 3.15-3.80 (m, 4H),
3.91 (d, J=15.0 Hz, 1H), 4.20 (d, J=15.5 Hz, 1H), 4.65 (m, 1H),
7.50 (t, J=8.0 Hz, 1H, 7.75 (m, 2H). Anal. Calcd for
C.sub.20H.sub.30FN.sub.3O.sub.3S.HCl.H.sub.2O: C, 51.55; H, 7.14;
N, 9.02. Found: C, 51.93; H, 6.81; N, 8.70.
EXAMPLE 4j
N-[1S.
2S-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl-
]-phenylacetamido]glycine Hydrochloride
[0571] 1S,
2S-trans-2-Nitro-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidiny-
l)cyclohexyl]-phenylacetamide hydrochloride
[0572] To a solution of (1S,
2S)-(.+-.)-trans-2-pyrrolidinyl-N-methylcyclo- hexylamine.sup.3
(1.9 g, 10.42 mmol) in anhydrous CH.sub.2Cl (25 mL) under a
nitrogen atmosphere was added 2-nitro-4-trifluorophenyl acetic
acid.sup.1 (3.9 g, 15.63 mmol) and pyridine (0.42 mL, 5.21 mmol).
The reaction mixture was cooled to 0.degree. C. and added DCC (4.3
g, 20.84 mmol) in one portion and stirred the mixture for 3.5 h.
The TLC [solvent system: CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH
(95:5:2)] showed no starting material was present. The DCU was
removed by filtration and the solvent was removed under reduced
pressure. The residue was partitioned between 10% citric acid (100
mL) and ether (100 mL). The ether layer was discarded and the
aqueous layer was washed with ether twice. The aqueous layer was
then made alkaline from 28% ammonia hydroxide and the product was
extracted with CH.sub.2Cl.sub.2. The organic layer was separated,
dried over anhydrous Na.sub.2SO.sub.4, and evaporated to dryness to
give the crude product. The hydrochloride salt was prepared from 1M
etherial HCl and recrystallized from 2-prppanol:ether (1:1) to give
the desired product, 4.2 g (97%); [.alpha.].sup.18.8.sub.589
-20.42.degree. (c 1.01, CH.sub.3OH); .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.20-2.35 (m, 12H), 298-3.28 (m, 4H), 3.20 (s,
3H), 3.45 (m, 1H), 3.98 (m, 1H), 4.45 (d, J=14.0 Hz, 1H), 4.70 (d,
J=14.5 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H),
8.34 (s, 1H). The compound was used directly into the following
reaction.
[0573]
1S,2S-trans-2-Amino-4-trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl-
)cyclohexyl]phenyl-acetamide hydrochloride
[0574] The above 2-nitro compound as hydrochloride salt (4.1 g,
9.09 mmol) was dissolved in methanol (30 mL), added PtO.sub.2 (0.4
g), and hydrogenated at room temperature at atmospheric pressure
for 1 h. The catalyst was filtered off, washed with hot methanol
and the combined filtrate was evaporated to dryness. The residue
was re-crystallized from ethyl acetate to give the 2-amino compound
as hydrochloride salt, 3.2 g (84%); [.alpha.].sup.18.6.sub.589
-6.48.degree. (free base, c 0.51, CH.sub.3OH); .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 1.25-2.35 (m, 12H), 3.00-3.30 (m, 4H),
3.15 (s, 3H), 3.45 (m, 1H), 3.97 (m, 1H), 4.35 (m, 1H), 4.80 (m,
1H), 6.90 (s, d, 2H), 7.05 (d, J=7.5 Hz, 1H). The free base of the
2-amino compound was used to prepare the target compound.
[0575] The 2-amino compound (free base, 2.8 g, 7.30 mmol) was
dissolved in anhydrous THF (20 mL) under a nitrogen atmosphere.
N,N-Diisopropylethylamine (1.88 g, 14.60 mmol) was added at room
temperature followed by t-butyl bromoacetate (2.14 g, 11.0 mmol)
and the reaction mixture was stirred at room temperature for 3
days. The TLC [solvent system: CH.sub.2Cl.sub.2:CH.sub.3OH:28% NOH
(95:5:2)] showed still starting material was pesent, the reaction
mixture was heated to 60-70.degree. C. (oil-bath temperature) for
48 h after the addition of N,N-diisopropylethylamine (1.88 g, 14.60
mmol) and by t-butyl bromoacetate (2.14 g, 11.0 mmol). The reaction
mixture was cooled to room temperature and the solvent was removed
under reduced pressure. The residue was then re-dissolved in
CH.sub.2Cl.sub.2, washed with water, 10% aqueous NaHCO.sub.3,
saturated salt solution, and dried over anhydrous Na.sub.2SO.sub.4.
Removal of solvent at reduced pressure resulted the crude product
which was purified on a silica gel column [solvent system:
CH.sub.2Cl.sub.2:CH.sub.3OH:28% NH.sub.4OH (98:2:2)] to the desired
t-butyl ester, 2.3 g (63%), as a foam; %);
[.alpha.].sup.19.5.sub.589 -9.50 (c 1.0, CH.sub.2Cl.sub.2); the
chiral purity (>90%) of the compound was checked on
ChiralPak.RTM. AD column; MS (FAB) 498 (M+1); .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.10-2.00 (m, s, 21H), 2.45-2.75 (m, 4H), 2.90
(s, 3H), 3.70 (m, 2H), 3.88 (m, 2H), 4.50 (m, 1H), 6.65 (s, 1H),
6.90 (d, J=7.0 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H).
[0576] The t-butyl ester (2.1 g, 4.22 mmol) was dissolved in acetic
acid (20 mL) and added 4N aqueous HCl (25 mL). After addition of 4
drops of p-anisole, the raction mixture was stirred at room
temperature for 4 days. The solvent was removed under reduced
pressure and the residue was re-dissolved in minimum amount of
acetonitrile and added excess of ether. The resulting solid was
filtered, washed with ether, and dried. Re-crystallization from
acetonitrile:ethylacetate (1:1) gave compound 4j (1.0 g, 50%); mp
176-178.degree. C; [.alpha.].sup.20.5.sub.589 +6.50 (c 0.5,
CH.sub.2Cl.sub.2); .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.10-2.05 (m, s, 12H), 2.70 (s, 3H), 2.98-3.30 (m, 4H), 3.404.15
(m, 6H), 6.65 (s, 1H), 6.82 (d, J=7.5 Hz, 1H), 7.10 (d, J=7.5 Hz,
1H). Anal. Calcd for C.sub.22H.sub.30FN.sub.3O.sub.3.HCl: C, 55.29;
H, 6.54; N, 8.79. Found: C, 55.61; H, 6.76; N, 8.97.
EXAMPLE 4k
N-[1R,2R-trans-4-Trifluoromethyl-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-
-phenylacetamido]glycine Hydrochloride
[0577] The compound was prepared from (1R,
2R)-(-)-trans-2-pyrrolidinyl-N-- methylcyclohexyl-amine.sup.3 (1.9
g, 10.42 mmol) following the above procedures in 36% yield;
[.alpha.].sup.20.5.sub.589 -7.40 (c 0.52, CH.sub.2Cl.sub.2). Anal.
Calcd for C.sub.22H.sub.30FN.sub.3O.sub.3.HCl.0.- 25 CH.sub.3CN: C,
55.35; H, 6.55; N, 9.32. Found: C, 55.78; H, 6.81; N, 9.24.
Compounds of Formula IIIB
[0578] The following is a description of compounds of formula
(IIIB) in accordance with an embodiment of the present invention.
In this regard, as noted above, in one aspect of the invention,
there are provided compounds of formula (IIIB) which have the
following structure: 78
[0579] wherein:
[0580] n is an integer from 1 to 3;
[0581] R.sub.1 and R.sub.2 are together alkylene of about 4 to
about 8 carbons, optionally substituted with a group R', where R'
is selected from --OH, halogen, --NR.sub.aR.sub.b, in which R.sub.a
and R.sub.b are independently selected from hydrogen,
--C(.dbd.O)R.sub.c, --SO.sub.2R.sub.d and
--C(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.e, in which R.sub.c and
R.sub.d are independently selected from alkyl, aryl and heteroaryl,
R.sub.e is hydrogen or alkyl and m is an integer from 1 to 3;
[0582] Ar is unsubstituted phenyl or mono-, di-, tri-, or
tetra-substituted phenyl, wherein said substituents are
independently selected from halogen; alkyl; alkoxy; aryloxy;
aralkyloxy; alkylene dioxide; --OH; --SO.sub.2R.sub.f in which
R.sub.f is alkyl or aryl; --CN; haloalkyl; --NR.sub.gR.sub.h, in
which R.sub.g and R.sub.h are independently selected from hydrogen,
alkyl, --C(.dbd.O)R.sub.f, --C(.dbd.O)--N(R.sub.e).sub.2,
--S(O).sub.2R.sub.f, and --(CH.sub.2).sub.y--CO.sub.2R.sub.e in
which y is an integer from 1 to 3; --S(O).sub.2N(R.sub.i)(R.sub.j),
in which R.sub.i and R.sub.j are each independently selected from
hydrogen, alkyl optionally substituted with --CO.sub.2R.sub.e, aryl
and aralkyl; or R.sub.i and R.sub.j together form
--(CH.sub.2).sub.2X(CH.sub.2).sub.2--, where X is a direct bond,
--CH.sub.2--, --NR.sub.e--, S or O;
[0583] R is hydrogen, halogen, --OH, alkoxy, or --NR.sub.kR.sub.l,
where R.sub.k and R.sub.l are independently selected from hydrogen
and alkyl.
[0584] In the compounds of formula (IIIB), R.sub.1 and R.sub.2 are
together alkylene of about 4 to about 8 carbons, optionally
substituted with a group R', where R' is selected from --OH,
halogen, --NR.sub.aR.sub.b, in which R.sub.a and R.sub.b are
independently selected from hydrogen, --C(.dbd.O)R.sub.c,
--SO.sub.2R.sub.d and --C(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.e,
in which R.sub.c and R.sub.d are independently selected from alkyl,
aryl and heteroaryl, R.sub.e is hydrogen or alkyl and m is an
integer from 1 to 3. Preferably, substituent group R' is in the S
configuration, and m is 1. Also in preferred embodiments, R.sub.1
and R.sub.2 are together unsubstituted alkylene of about 4 to about
6 carbons or alkylene of about 4 to about 6 carbons substituted
with --OH or alkoxy. In more preferred embodiments, R.sub.1 and
R.sub.2 are together --(CH.sub.2).sub.4-- or
--CH.sub.2CH(OH)(CH.sub.2).sub.2--.
[0585] In the compounds of formula (IIIB), Ar is mono-, di-, tri-,
or tetra-substituted phenyl, wherein said substituents are
independently selected from halogen; alkyl; alkoxy; aryloxy;
aralkyloxy; alkylene dioxide; --OH; --SO.sub.2R.sub.f in which
R.sub.f is alkyl or aryl; --CN; haloalkyl; --NR.sub.gR.sub.h, in
which R.sub.g and R.sub.h are independently selected from hydrogen,
alkyl, --C(.dbd.O)R.sub.f, --C(.dbd.O)--N(R.sub.e).sub.2,
--S(O).sub.2R.sub.f, and --(CH.sub.2).sub.y--CO.sub.2R.sub.e in
which y is an integer from 1 to 3; --S(O).sub.2N(R.sub.i)(R.sub.j),
in which R.sub.i and R.sub.j are each independently selected from
hydrogen, alkyl optionally substituted with --CO.sub.2R.sub.e, aryl
and aralkyl; or R.sub.i and R.sub.j together form
--(CH.sub.2).sub.2X(CH.sub.2).sub.2--, where X is a direct bond,
--CH.sub.2--, --NR.sub.e--, S or O. In preferred embodiments, Ar is
mono-, di-, tri-, or tetra-substituted phenyl, wherein said
substituents are independently selected from alkyl; alkoxy;
aralkyloxy; alkylene dioxide; --OH; haloalkyl; --NR.sub.gR.sub.h,
in which R.sub.g and R.sub.h are independently selected from
hydrogen, alkyl, and --S(O).sub.2R.sub.f;
--S(O).sub.2N(R.sub.i)(R.sub.j), where R.sub.i and R.sub.j are each
independently selected from hydrogen, alkyl optionally substituted
with --CO.sub.2R.sub.e, and aralkyl; or R.sub.i and R.sub.j
together form --(CH.sub.2).sub.2X(CH.sub.2).sub.2--, where X is a
direct bond, --NR.sub.e--, S or O. In more preferred embodiments,
Ar is mono-, di-, tri-, or tetra-substituted phenyl, wherein said
substituents are independently selected from lower alkyl;
--OCH.sub.3; --OCH.sub.2C.sub.6H.sub.5; --OCH.sub.2O; --OH;
--CF.sub.3; --N(SO.sub.2CH.sub.3).sub.2; --NHSO.sub.2CH.sub.3;
--SO.sub.2N(CH.sub.3).sub.2;
--SO.sub.2N(CH.sub.3)(CH.sub.2CO.sub.2H); --SO.sub.2NHCH.sub.3;
--SO.sub.2N(CH.sub.3)(CH.sub.2C.sub.6H.sub.5); 79
[0586] where X' is --N(CH.sub.3)-- or --O--.
[0587] In the compounds of formula (IIIB), n is an integer from 1
to 3. Preferably, n is 1.
[0588] In certain preferred embodiments, compounds of the present
invention have the structure of formula (IIIB), except that when n
is 1, R.sub.1 and R.sub.2 are unsubstituted alkylene of 4 carbons
(i.e., --(CH.sub.2).sub.4--), and R is H, then Ar is other than
2-aminophenyl, 3-aminophenyl, 4-aminophenyl,
2-amino-4,5-dichlorophenyl, 3,4-dichlorophenyl,
2-amino-4-trifluoromethyl, 2-N(SO.sub.2CH.sub.3).sub.- 2-phenyl,
3-N(SO.sub.2CH.sub.3).sub.2-phenyl, 4-N(SO.sub.2CH.sub.3).sub.2--
phenyl, 2-NHSO.sub.2CH.sub.3-phenyl, 3-NHSO.sub.2CH.sub.3-phenyl,
4-NHSO.sub.2CH.sub.3-phenyl,
2-N(SO.sub.2CH.sub.3).sub.2-4,5-dichlorophen- yl,
2-N(SO.sub.2CH.sub.3).sub.2-4-trifluoromethylphenyl,
2-NHSO.sub.2CH.sub.3-4-trifluoromethylphenyl,
4-SO.sub.2CH.sub.3-phenyl, 2-methoxyphenyl, 2-hydroxyphenyl,
2-trifluoromethylphenyl, 3-trifluoromethylphenyl,
4-trifluoromethylphenyl, 3,4,5-trimethoxyphenyl,
2-NHSO.sub.2CH.sub.3-4,5-dichlorophenyl,
2-NHCH.sub.2CO.sub.2H-4-trifluor- omethylphenyl,
2-NH(SO.sub.2C.sub.6H.sub.5)-phenyl,
3-SO.sub.2NHCH.sub.34-chlorophenyl,
3-SO.sub.2NH.sub.2-4-chlorophenyl,
3-SO.sub.2NHCH.sub.3-4-fluororophenyl, 4-SO.sub.2NHCH.sub.3-phenyl,
3-SO.sub.2NHCH.sub.3-phenyl, 2-SO.sub.2NHCH.sub.3-phenyl,
2-SO.sub.2NHCH.sub.34-bromophenyl,
2-methoxy-3-SO.sub.2NHCH.sub.3-phenyl,
4-methoxy-3-SO.sub.2NHCH.sub.3-phenol,
2-N(CH.sub.2CO.sub.2H).sub.2-4-tri- fluoromethylphenyl,
3,4-dihydroxyphenyl, 3,4-dimethoxyphenyl,
2-SO.sub.2N(CH.sub.3)CH.sub.2C.sub.6H.sub.5-4,5-dimethoxyphenyl,
2-fluorophenyl, or 4-fluorophenyl,
2-SO.sub.2NCH.sub.3--CH.sub.2CO.sub.2H- -3,4-olimethoxyphenol.
[0589] Also in certain preferred embodiments, compounds of the
present invention have the structure of formula (IIIB), except that
when n is 1, R.sub.1 and R.sub.2 are unsubstituted alkylene of 4
carbons, and R is NH.sub.2, then Ar is other than
3,4-dichlorophenyl, 2-aminophenyl or
4-N(SO.sub.2CH.sub.3).sub.2-phenyl.
[0590] In still other preferred embodiments, compounds of the
present invention have the structure of formula (IIIB), except that
when n is 1, R.sub.1 and R.sub.2 are
--CH.sub.2CH(OH)(CH.sub.2).sub.2--, and R is hydrogen, then Ar is
other than 2-amino-4-trifluoromethylphenyl, aminophenyl,
4-SO.sub.2CH.sub.3-phenyl, 3,4,5-trimethoxyphenyl,
2-SO.sub.2NHCH.sub.3-phenyl, trifluoromethylphenyl, methylphenyl,
halophenyl, methoxyphenyl, unsubstituted phenyl,
3-chloro-4-hydroxyphenyl- , 4-benzyloxyphenyl, hydroxyphenyl,
aminochlorophenyl, aminobromophenyl, acetamidophenyl,
methylsulfonylaminophenyl, formamidophenyl or
3-amino-4-methoxyphenyl.
[0591] Also in other preferred embodiments, compounds of the
invention have the strucuture of formula (m), except that when n is
1, R.sub.1 and R.sub.2 are --CH.sub.2CH(OH)(CH.sub.2).sub.2--, and
R is hydroxy or amino, then Ar is other than
trifluoromethylphenyl.
[0592] In yet other preferred embodiments, compounds of the present
invention have the structure of formula (IIIB), except that when n
is 1, R.sub.1 and R.sub.2 are unsubstituted alkylene of 4 carbons,
and R is OH or OCH.sub.3, then Ar is other than
2-NHSO.sub.2CH.sub.3-phenyl, 4-trifluoromethylphenyl, or
3,4-dichlorophenyl.
[0593] In preferred form, the compounds of formula (IIIB) have the
following formula (IIIB-i). 80
[0594] wherein:
[0595] x is an integer from 0 to 4;
[0596] R" is hydrogen, fluoro, --OH, --NHC(.dbd.O)R.sub.c,
--NHSO.sub.2R.sub.d and
--NHC(.dbd.O)(CH.sub.2).sub.mCO.sub.2R.sub.e, in which R.sub.c and
R.sub.d are independently selected from alkyl, aryl and heteroaryl,
R.sub.e is hydrogen or alkyl and m is an integer from 1 to 3
[0597] R.sub.3 is independently selected from halogen; alkyl;
alkoxy; aryloxy; aralkyloxy; alkylene dioxide; --OH;
--SO.sub.2R.sub.f in which R.sub.f is alkyl or aryl; --CN;
haloalkyl; --NR.sub.gR.sub.h, in which R.sub.g and R.sub.h are
independently selected from hydrogen, alkyl, --C(.dbd.O)R.sub.f,
--C(.dbd.O)--N(R.sub.e).sub.2, --S(O).sub.2R.sub.f in which R.sub.f
is alkyl or aryl, and --(CH.sub.2).sub.y--CO.sub.2R, in which y is
an integer from 1 to 3; --S(O).sub.2N(R.sub.i)(R.sub.j), in which
R.sub.i and R.sub.j are each independently selected from hydrogen,
alkyl optionally substituted with --CO.sub.2R.sub.e, aryl and
aralkyl; or R.sub.i and R.sub.j together form
--(CH.sub.2).sub.2X(CH.sub.2).sub.2--, where X is a direct bond,
--CH.sub.2--, --NR.sub.e--, S or O;
[0598] R is hydrogen, halogen, --OH, alkoxy, or --NR.sub.kR.sub.l,
where R.sub.k and R.sub.l are independently selected from hydrogen
and alkyl.
[0599] In the above formula (IIIB-i), R.sub.3 is independently
selected from halogen; alkyl; alkoxy; aryloxy; aralkyloxy; alkylene
dioxide; --OH; --SO.sub.2R.sub.f in which R.sub.f is alkyl or aryl;
--CN; haloalkyl; --NR.sub.gR.sub.h, in which R.sub.g and R.sub.h
are independently selected from hydrogen, alkyl,
--C(.dbd.O)R.sub.f, --C(.dbd.O)--N(R.sub.e).sub.2,
--S(O).sub.2R.sub.f in which R.sub.f is alkyl or aryl, and
--(CH.sub.2).sub.y--CO.sub.2R.sub.e in which y is an integer from 1
to 3; --S(O).sub.2N(R.sub.i)(R.sub.j), in which R.sub.i and R.sub.j
are each independently selected from hydrogen, alkyl optionally
substituted with --CO.sub.2R.sub.e, aryl and aralkyl; or R.sub.i
and R.sub.j together form --(CH.sub.2).sub.2X(CH.sub.2).sub.2--,
where X is a direct bond, --CH.sub.2--, --NR.sub.e--, S or O. In
preferred embodiments, R.sub.3 is independently selected from
alkyl; alkoxy; aralkyloxy; alkylene dioxide; --OH; haloalkyl;
--NR.sub.gR.sub.h, in which R.sub.g and R.sub.h are independently
selected from hydrogen, alkyl, and --S(O).sub.2R.sub.f;
--S(O).sub.2N(R.sub.i)(R.sub.j), in which R.sub.i and R.sub.j are
each independently selected from hydrogen, alkyl optionally
substituted with --CO.sub.2R.sub.e, and aralkyl; or R.sub.i and
R.sub.j together form --(CH.sub.2).sub.2X(CH.sub.2).sub.2--, where
X is a direct bond, --NR.sub.e--, S or O. In more preferred
embodiments, R.sub.3 is independently selected from lower alkyl;
--OCH.sub.3; --OCH.sub.2C.sub.6H.sub.5; --OCH.sub.2O--; --OH;
CF.sub.3; --N(SO.sub.2CH.sub.3).sub.2; --NHSO.sub.2CH.sub.3;
--SO.sub.2N(CH.sub.3).sub.2;
--SO.sub.2N(CH.sub.3)(CH.sub.2CO.sub.2H); --SO.sub.2NHCH.sub.3;
--SO.sub.2N(CH.sub.3)(CH.sub.2C.sub.6H.sub.5); 81
[0600] where X' is --N(CH.sub.3)-- or --O--.
[0601] Also in the above formula (IIIB-i), R is hydrogen, halogen,
--OH, alkoxy, or --NR.sub.kR.sub.l, where R.sub.k and R.sub.l are
independently selected from hydrogen and alkyl. In preferred
embodiments, R is hydrogen, halogen, --OH or alkoxy.
[0602] In the compounds of formula (IIIB-i), n is an integer from 1
to 3. Preferably, n is 1.
[0603] Also in the above formula (IIIB-i), R' is preferably in the
S configuration, and m is preferably 1.
[0604] In certain preferred embodiments, compounds of the present
invention have the structure of formula (IIIB-i), except that when
R and R" are H, then the phenyl ring and (R.sub.3).sub.x together
are other than 2-aminophenyl, 3-aminophenyl, 4-aminophenyl,
2-N(SO.sub.2CH.sub.3).s- ub.2-phenyl,
3-N(SO.sub.2CH.sub.3).sub.2-phenyl 4-N(SO.sub.2CH.sub.3).sub.-
2-phenyl, 2-NHSO.sub.2CH.sub.3-phenyl, 3-NHSO.sub.2CH.sub.3-phenyl,
4-NHSO.sub.2CH.sub.3-phenyl, 4-SO.sub.2CH.sub.3-phenyl,
2-methoxyphenyl, 2-hydroxyphenyl, 2-trifluoromethylphenyl,
3-trifluoromethylphenyl, 4-trifluoromethylphenyl,
3-SO.sub.2NHCH.sub.3-phenyl, 2-SO.sub.2NHCH.sub.3-phenyl,
4-SO.sub.2NHCH.sub.3-phenyl, 2-fluorophenyl, 4-fluorophenyl,
3,4-dichlorophenyl, 2-amino-4-trifluoromethyl,
2-N(SO.sub.2CH.sub.3).sub.2-4-trifluoromethylphenyl,
2-NHSO.sub.2CH.sub.34-trifluoromethylphenyl,
2-NHCH.sub.2CO.sub.2HA-trifl- uoromethylphenyl,
3-SO.sub.2NHCH.sub.3-4-chlorophenyl,
3-SO.sub.2NH.sub.2-4-chlorophenyl,
3-SO.sub.2NHCH.sub.3-4-fluororophenyl,
2-SO.sub.2NHCH.sub.3-4-bromophenyl,
2-methoxy-3-SO.sub.2NHCH.sub.3-phenyl- ,
4-methoxy-3-SO.sub.2NHCH.sub.3-phenol,
2-N(CH.sub.2CO.sub.2H).sub.2-4-tr- ifluoromethylphenyl,
3,4-dihydroxyphenyl, 3,4-dimethoxyphenyl,
2-amino-4,5-dichlorophenyl,
2-N(SO.sub.2CH.sub.3).sub.2-4,5-dichloropheny- l,
3,4,5-trimethoxyphenyl, 2-NHSO.sub.2CH.sub.3-4,5-dichlorophenyl, or
2-SO.sub.2N(CH.sub.3)CH.sub.2C.sub.6H.sub.5-4,5-dimethoxyphenyl,
2-SO.sub.2(CH.sub.3)--CH.sub.2CO.sub.2H-3,4-dimethoxyphenol.
[0605] In other certain preferred embodiments, compounds of the
present invention have the structure of formula (IIIB-i), except
that when R" is H and R is NH.sub.2, then the phenyl ring and
(R.sub.3).sub.x together are other than 3,4-dichlorophenyl,
2-aminophenyl or 4-N(SO.sub.2CH.sub.3).sub.2-phenyl.
[0606] In still other certain preferred embodiments, compounds of
the present invention have the structure of formula (IIIB-i),
except that when R" is OH and R is hydrogen, then the phenyl ring
and (R.sub.3).sub.x together are other than unsubstitued phenyl,
2-amino-4-trifluoromethylphe- nyl, aminophenyl,
4-SO.sub.2CH.sub.3-phenyl, 3,4,5-trimethoxyphenyl,
2-SO.sub.2NHCH.sub.3-phenyl, trifluoromethylphenyl, methylphenyl,
halophenyl, methoxyphenyl, 3-chloro-4-hydroxyphenyl,
4-benzyloxyphenyl, hydroxyphenyl, aminochlorophenyl,
aminobromophenyl, acetamidophenyl, methylsulfonylaminophenyl,
formamidophenyl or 3-amino-4-methoxyphenyl.
[0607] Also in other certain preferred embodiments, compounds of
the present invention have the structure of formula (IIIB-i),
except that when R" is OH and R is hydroxy or amino, then the
phenyl ring and (R.sub.3).sub.x together are other than
trifluoromethylphenyl.
[0608] In yet other certain preferred embodiments, compounds of the
present invention have the structure of formula (IIIB-i), except
that when when R" is H and R is OH or OCH.sub.3, then the phenyl
ring and (R.sub.3).sub.x together are other than
2-NHSO.sub.2CH.sub.3-phenyl, 4-trifluoromethylphenyl or
3,4-dichlorophenyl.
[0609] Preparatory for the compounds of formula IIIB and IIIB-i,
the following intermediates were prepared. 82
[0610] 4-Methoxy-5-nitrophenyl acetic acid (iii):
[0611] To a solution of 4-hydroxy-5-nitrophenyl acetic acid (20.0
g, 0.101 mol) in anhydrous methanol (500 mL) was added Dowex
50Wx4-400 (H.sup.+) resin, pre-washed with methanol. The suspension
was stirred with refluxing for 24 hr. The resin was filtered and
the filtrate was evaporated to dryness to give as a light yellow
oil; 21.3 g (99.3%). The ester was used directly in the following
reaction.
[0612] The above ester (21.3 g, 0.1 mol) was redissolved in
anhydrous acetone (250 mL) and anhydrous potassium carbonate (20.94
g, 0.14 mol) was added to the reaction mixture. The reaction
mixture was stirred at room temperature for 15 minutes followed by
slow addition of methyl iodide (20.1 g, 0.14 mol) and the stirring
was continued for an additional 48 h at room temperature. The
reaction mixture was filtered and the filtrate was evaporated to
dryness. The residue was portioned between CH.sub.2Cl.sub.2 and
water. The organic layer was separated and washed with water and
saturated salt solution, and was dried over anhydrous sodium
sulfate. Evaporation to dryness afforded (ii) as a yellow solid;
23.0 g (100%); .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 3.62 (s,
2H), 3.72 (s, 3H), 3.96 (s, 3H), 7.05 (d, J=8.5 Hz, 1H), 7.48 (m,
1H), 7.80 (d, J=2.2 Hz, 1H). The compound was used in next step
without any further purification.
[0613] A suspension of ester (ii) (23.0 g) in 4N HCl (300 mL) and
acetic acid (20 mL) was heated to reflux with stirring for 18 h.
The reaction mixture was cooled to room temperature and the
resulting solid was filtered, washed with water, and dried to give
the acid (iii) as a light yellow solid, 17.5 g (81%); .sup.1H NMR
(d.sub.6DMSO, 300 MHz) .delta. 3.63 (s, 2H), 3.89 (s, 3H), 7.28 (d,
J=8.5 Hz, 1H), 7.50 (m, 1H), 7.77 (d, J=2.0 Hz, 1). Acid (iii) was
sufficiently pure to use in the coupling reaction, discussed
infra.
[0614]
2-(4-Methoxy-5-nitrophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolid-
inyl)ethyl]-acetamide (va)
[0615] To a solution of acid (iii) (17.5 g, 85.78 mmol) in
anhydrous CH.sub.2Cl.sub.2 (175 mL) was added
1-hydroxybenzotriazole hydrate (11.58 g, 85.78 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI,
18.02 g, 94.36 mmol). After stirring the reaction mixture at room
temperature for 30 min, a solution of the diamine (iv-a) (16.00 g,
78.43 mmol) in anhydrous CH.sub.2Cl.sub.2 (60 mL) was added,
followed by N,N-diisopropylethylamine (10.43 g, 80.0 mmol). The
reaction mixture was stirred at room temperature for 72 h. The
reaction mixture was quenched with saturated sodium bicarbonate
solution and the organic layer was separated, washed with saturated
salt solution and dried over anhydrous sodium sulfate. The removal
of CH.sub.2Cl.sub.2 under reduced pressure gave crude compound
(v-a) as dark brown oil. The product (v-a) was purified on a silica
gel column to give a yellow syrup, 31 g (99%);
.sup.1HNMR(CDCl.sub.3, 300 MHz) .delta. 1.74 (m, 4H), 2.75 (s, 3H),
3.95 (s, 3H), 6.10 (m, 1H), 7.05-7.75 (m, 8H).
EXAMPLE 122
2-(3-N-Methylsulfonamido-3-amino-4-methoxyphenyl)-N-methyl-N-[(1S)-1-pheny-
l-2-(1-pyrrolidinyl)ethyl]acetamide methane sulfonate (1)
[0616] 83
[0617] To a solution of compound (v) (31.0 g, 78.0 mmol) in ethanol
(700 mL) at 50-60.degree. C. was added hydrazine hydrate (15 mL)
followed by Raney/Nickel slowly until all the starting material was
reduced, as shown by TLC. The reaction mixture was cooled to room
temperature and the catalyst was filtered off and washed thoroughly
with warm ethanol. The filtrate was evaporated to dryness to give
the amino compound, which was used directly in the following
reaction.
[0618] To a stirred solution of the amino compound (26.6 g, 72.45
mmol) in anhydrous CH.sub.2Cl.sub.2 (250 mL) was added pyridine
(12.1 g, 152.6 mmol) and the reaction mixture was cooled to
0-5.degree. C. in an ice-bath. A solution of methanesulfonyl
chloride (13.1 g, 114.4 mmol) in anhydrous CH.sub.2Cl.sub.2 (50 mL)
was added dropwise in 15 min with continued stirring. After the
completion of the addition, the ice-bath was removed and the
reaction mixture was stirred at room temperature for 60 h. The
reaction was quenched by the slow addition of saturated sodium
bicarbonate, and the organic layer was separated, washed with
water, saturated salt solution and dried over anhydrous sodium
sulfate. The removal of solvent gave the crude free base of
compound (1), which was purified on a silica gel column. The
methane sulfonic acid salt was prepared and recrystallized twice
from 2-propanol to give (1) as an off-white solid, 19.7 g (50%); mp
149-151.degree. C.; .sup.1H NMR (d.sub.6DMSO, 300 MHz) .delta. 2.01
(m, 4H), 2.38 (s, 3H), 2.73 (s, 3H), 2.93 (s, 3H), 3.17 (m, 2H),
3.81 (s, 3H), 6.15 (m, 1H), 7.00-7.34 (m, 8H), 8.90 (s, 1H); MS 446
(M+H).sup.+.
[0619] Intermediates for the compounds prepared in following
examples were prepared as depicted below. 84
[0620]
2-(4-Hydroxy-5-nitrophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolid-
inyl)ethyl]-acetamide (vi)
[0621] The diamine (iv-a) was condensed with
4-hydroxy-5-nitrophenyl acetic acid following the method described
for compound (v). The product (vi) was isolated as a hydrochloride
salt in 60% yield; .sup.1HNMR(CDCl.sub.3, 300 MHz) .delta.
2.00-2.40 (m, 4H), 2.93 (s, 3H), 3.65 (d, J=9.0 Hz, 1H), 4.05 (m,
4H), 4.38 (d, J=9.5 Hz, 1H), 6.40 (m, 1H), 7.05-7.50 (m, 6, H),
7.70 (d, J=5.5 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H). Intermediate
compound (vi) was then used in the preparation of intermediate
(vii).
[0622]
2-(4-Benzyloxy-5-nitrophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrol-
idinyl)ethyl]-acetamide (vii)
[0623] To a solution of compound (vi) (3.2 g, 7.62 mmol) in
anhydrous acetone (50 mL) was added anhydrous potassium carbonate
(4.22 g, 30.5 mmol). The mixture was stirred at room temperature
for 30 mins then added dropwise benzyl bromide (1.30 g, 7.62 mmol).
The stirring was continued for an additional 48 h and the reaction
mixture was filtered off. The cake was washed thoroughly with
acetone and the combined filtrate was evaporated to dryness. The
residue was redissolved in CH.sub.2Cl.sub.2 and the organic layer
was washed with water, saturated salt solution and dried over
anhydrous sodium sulfate. The removal of the solvent resulted in a
yellow foam, and the product was purified on a silica gel column to
give (vii) as a solid, 2.5 g (69%); MS 474 (M+H).sup.+.
[0624] Intermediate compound (vii) was then used to prepare
compounds 2 and 3 of the present invention, as depicted below.
85
EXAMPLE 123
2-(3-N-Methylsulfonamido-3-amino-4-benzyloxyphenyl)-N-methyl-N-[(1S)-1-phe-
nyl-2-(1-pyrrolidinyl)ethyl]acetamide (2)
[0625] Compound (viii) and compound (2) were prepared according to
the procedure described for (v). Compound (2) was isolated as a
hydrochloride salt in 95% yield (HCl salt); mp 219-221.degree. C.;
MS 522 (M+H).sup.+; .sup.1H NMR (d.sub.6DMSO, 300 MHz) .delta. 2.00
(m, 4H), 2.78 (s, 3H), 2.90 (s, 3H), 3.15 (m, 2H), 3.70 (m, 5H),
4.05 (m, 1H), 5.16 (s, 2H), 6.15 (m, 1H), 7.07-7.53 (m, 14H), 8.94
(s, 1H).
EXAMPLE 124
2-(3-N-Methylsulfonamido-3-amino-4-hydroxyphenyl)-N-methyl-N-[(1S)-1-pheny-
l-2-(1-pyrrolidinyl)ethyl]acetamide (3)
[0626] To a solution of compound (2) (2.4 g, 4.6 mmol) in ethanol
(150 mL) was added 10% Pd/C (0.25 g), and the resulting suspension
was hydrogenated at room temperature for 24 h. The catalyst was
removed by filtration and washed with hot methanol. The combined
filtrate was evaporated to dryness to give a solid, which was
recystallized from acetonitrile to give compound (3) as a white
solid, 1.6 g (72%) (HCl salt); mp 228-230.degree. C.; MS 432
(M+H).sup.+; .sup.1H NMR (d.sub.6DMSO, 300 MHz) .delta. 1.98 (m,
4H): 2.76 (s, 3H), 2.93 (s, 3H) 3.17 (m, 2H), 3.44-4.00 (m, 6H),
6.14 (m, 1H), 6.80-7.37 (m, 7H), 8.70 (s, 8H).
[0627] Employing similar chemistry, the following compounds of
formula IIIB were prepared.
EXAMPLE 125
2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S-
)-(3-hydroxypyrrolidinyl)ethyl]]acetamide
[0628] Prepared from diamine (iv-b) in 31% yield (HCl salt); mp
168-171.degree. C.; MS (FAB) 432 (MH).sup.+.
EXAMPLE 126
2-(2-N-Methylsulfonamido-2-amino-4-trifluoromethylphenyl)-N-methyl-N-[(1S)-
-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide
[0629] Prepared from diamine (iv-b) in 18% yield (HCl salt); mp
178-181.degree. C.; MS (FAB) 500 (MH).sup.+.
EXAMPLE 127
2-(3-N-Methylsulfonamido-3-amino-4-methoxyphenyl)-N-methyl-N-[(1S)-1-pheny-
l-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide
[0630] Prepared from diamine (iv-b) in 44% yield (HCl salt); mp
148-151.degree. C.; MS (FAB) 462 (MH).sup.+.
EXAMPLE 128
2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-1-(4-methoxyphenyl)-2-(-
1-pyrrolidinyl)ethyl]acetamide
[0631] Prepared from the diamine (iv-a) (R=4-OCH.sub.3) in 40%
yield (CH.sub.3SO.sub.3H salt); mp 170-172.degree. C.; MS 446
(M+H).sup.+; .sup.1H NMR (d.sub.6DMSO, 300 MHz) .delta. 1.90 (m,
4H), 2.34 (s, 3H), 2.70 (s, 3H), 2.98 (s, 3H), 3.20 (m, 2H), 3.60
(m, 4H), 3.75 (s, 3H), 4.07 (m, 2H), 6.10 (m, 1H), 6.93 (d, J=8.5
Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 7.29 (m, 4H), 9.06 (s, 1H).
EXAMPLE 129A
(R,S)-2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-1-(4-hydroxypheny-
l)-2-(1-pyrrolidinyl)ethyl]acetamide
[0632] To a solution of the compound prepared in Example 128 (1.07
g, 2.04 mmol) in CH.sub.2Cl.sub.2 (20 mL) at -70.degree. C. under a
nitrogen atmosphere was added dropwise a solution of BBr.sub.3 1M
in CH.sub.2Cl.sub.2 (7.95 mL, 7.93 mmol). The reaction mixture was
stirred for 1 additional hour and was slowly warmed to room
temperature. After stirring for 24 h, the reaction mixture was then
quenched with anhydrous methanol (10 mL). The solvent was removed
under reduced pressure, and the resulting residue was stirred in
methanol:ether (1:1) to give a solid. The solid was re-dissolved in
CH.sub.2Cl.sub.2 and basified to give the free base of the title
compound. The methane sulfonic acid salt was prepared to give the
title compound in 83% yield (CH.sub.3SO.sub.3H salt); mp
197-199.degree. C.; .sup.1H NMR (d.sub.6DMSO, 300 MHz, HBr Salt)
.delta. 1.93 (m, 4H), 2.70 (m, 3H), 2.98 (m, 3H), 3.16 (m, 2H),
3.60 (m, 4H), 3.73 (d, J=14.0 Hz, 1H), 4.05 (d, J=14.5 Hz, 1H),
6.02 (m, 2H), 6.74 (d, 8.0 Hz, 2H), 7.04 (d, J=8.3 Hz, 2H), 7.27
(m, 4H), 9.07 (s, 1H).
[0633] The preparation of the compound of Example 129B follows
according to the following Scheme P. 8687
[0634] Key: i. (tert)-Butyldimethylsilyl chloride, imidazole, DMF,
0.degree. C..fwdarw.25.degree. C., 2 h. ii. DCC, HOBt, pyrrolidine,
DCM, rt, 3 h. iii. LAH, THF, 0.degree. C..fwdarw.35.degree. C., 8
h. iv. DCC, HOBt, 2-nitrophenylacetic acid, DMF, rt, 3 h. v. 10% Pd
on C, EtOH, H.sub.2 gas, rt, 12 h. vi. CH.sub.3SO.sub.2Cl, DCM,
DIEA, 0.degree. C..fwdarw.25.degree. C., 2 h. vii. TBAF, THF, rt, 2
h.
EXAMPLE 129B
(S)-2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-1-(4-hydroxyphenyl)-
-2-(1-pyrrolidinyl)ethyl]acetamide
[0635] 88
[0636] Starting nitro phenyl derivative 1 (2.28 g; 4.58 mmol) was
dissolved in ethanol (100 mL). The reaction vessel was evacuated
under reduced pressure and purged with nitrogen. 10% Pd on C was
added to the reaction mixture. The mixture was evacuated under
reduced pressure and put over hydrogen via a balloon. The reaction
proceeded to completion after 4-6 h, following the disappearance of
the starting material by TLC (R.sub.f SM=0.5; R.sub.f Prod=0.48; 2%
MeOH in DCM). The reaction mixture was filtered through Celite, and
concentrated to give the product amine. Purification of the product
amine 2 by column chromatography afforded 1.14 g (2.4 mmol; 53%)
yield. 89
[0637] Starting amine 2 (1.0 g; 2.16 mmol) was dissolved in DCM.
DIEA (1.16 mL; 6.49 mmol) was added to the reaction vessel and the
mixture was cooled to 0.degree. C. with an ice bath. Mesyl chloride
(0.37 mL; 4.76 mmol) was added drop-wise to the mixture at
0.degree. C., after which the reaction mixture was allowed to warm
to ambient temperature. The reaction proceeded for 1 hour after
which the starting material disappeared by TLC (R.sub.f SM=0.6;
R.sub.f prod=0.8; 10% MeOH in DCM). The reaction was diluted with
ethylacetate, washed with water, brine, then dried over MgSO.sub.4.
The mixture was filtered and concentrated to yield product 3 (1.3
g; 2.08 mmol; 96%), which was used crude in the next step. 90
[0638] Amine 3 from the above reaction (1.3 g; 2.08 mmol) was
dissolved in THF (20 mL). A THF solution of TBAF (1M solution in
THF; 4.16 mL; 4.16 mmol) was added to the reaction mixture, and the
mixture was stirred at room temperature for 2 h monitoring the
disappearance of the starting material (R.sub.f SM=0.8; R.sub.f
prod=0.4; 10% MeOH in DCM). Phenol 129B was obtained after standard
work-up and purification by silica gel chromatography. LCMS:
M+H=432. Elemental analysis (CHN):
C.sub.22H.sub.29N.sub.3O.sub.4S.H.sub.2O (calc % C=58.78; % H=6.95;
% N=9.35; % S=7.13; found % C=58.55; % H=6.83; % N=8.94; %
S=7.27).
EXAMPLE 130
2-(3-N-Bis-methylsulfonamido-3-amino-4-hydroxyphenyl)-N-methyl-N-[(1S)-1-p-
henyl-2-(1-pyrrolidinyl)ethyl]acetamide
[0639] The title compound was prepared from
2-(2-amino-4-hydroxyphenyl)-N--
methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide and
methane sulfonyl chloride as described above in 83% yield. The
title compound was isolated as the methane sulfonic acid salt; mp
197-199.degree. C. (CH.sub.3SO.sub.3H salt); MS (FAB) 510
(M+H).sup.+; .sup.1H NMR (d.sub.6DMSO, 300 MHz) .delta. 2.05 (m,
4H), 2.36 (s, 3H), 2.75 (s, 3H), 3.05 (s, 3H), 3.51 (s, 3H), 6.15
(m, 1H), 7.35 (m, 5H), 9.5 (bs, 1H).
[0640] The following general chemistry was employed in the
preparation of sulfonyl chloride derivatives, as described in J.
Heterocyclic Chem., 29, 1667-1669 (1992), similar to methods
described hereinabove, in the preparation of compounds of formula
IIIB and IIIB-i, as prepared in Examples 131 to 147. 91
[0641] To a solution of the ester derivatives (ix) (10.3 mmol) and
acetic anhydride (30.7 mmol) in ethyl acetate (15.3 mL) was added,
dropwise, a solution of concentrated sulfuric acid (11.2 mmol) in
ethyl acetate (4.1 mL) at 0.degree. C. The reaction mixture was
stirred at room temperature for 3 h, after which a solution of
potassium acetate (11.2 mmol) in 95% ethanol was added and the
mixture was stirred for additional 30 min at room temperature. The
potassium salt (x) (90%) was isolated by filtration and used in the
next reaction.
[0642] A solution of thionyl chloride (8.74 mmol) and anhydrous DMF
(0.01 mL) was added to potassium salt (x) (1.6 mmol) under a
nitrogen atmosphere. The reaction mixture was stirred at 60.degree.
C. for 3.5 h and then poured into an ice water mixture and
extracted with CH.sub.2Cl.sub.2 (3.times.20 mL). The combined
organic extract was dried and evaporated to dryness to give (xi)
(81%). The material was used in the following reaction.
[0643] To a solution of 70 mmol of an appropriate amine
(N-benzylmethylamine in the presently exemplified chemistry) in
anhydrous THF (30 mL) at 0.degree. C. under a nitrogen atmosphere
was added dropwise a solution of (xi) (31.7 mmol) in anhydrous THF
(30 mL). After the addition was complete, the reaction mixture was
stirred at room temperature for 20 h. The resulting solid was
filtered off, the cake was washed with THF and the filtrate was
evaporated to dryness. The residue was portioned between
CH.sub.2Cl.sub.2 and water. The organic layer was separated, dried
over anhydrous sodium sulfate and evaporated to dryness to give
(xii) in 88% yield. The compound was used directly into the
hydrolysis reaction.
[0644] To a solution of (xii) (3 mmol) in tetrahydrofuran:methanol
(1:1, 5 mL) at 0-5.degree. C. was added 1M lithium hydroxide (6 mL)
and the reaction mixture was stirred at this temperature for 1 h
then at room temperature for 24 h. After neutralization of the
solution with concentrated HCl, the solvent was removed under
reduced pressure to give a white solid. The solid was filtered off,
washed with water and dried to give (xiii), (95%); .sup.1HNMR
(R.sub.1=R.sub.2=OCH.sub.3; CDCl.sub.3, 300 MHz) .delta. 2.61 (s,
3H), 3.87 (s, 3H), 3.90 (s, 3H), 4.08 (s, 2H), 4.27 (s, 2H), 6.85
(s, 1H), 7.31 (m, 5H), 7.49 (s, 1H).
[0645] The compounds of Examples 131 to 147 were prepared employing
the general procedure described for compound (v). Crude compounds
were purified on a silica gel column and isolated as salts either
from hydrochloric acid or methane sulfonic acid.
EXAMPLE 131
2-[2-(N-Benzyl-N-methylsulfamoyl)-4,5-methylenedioxyphenyl]-N-methyl-N-[(1-
S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide
[0646] Yield, 82% (CH.sub.3SO.sub.3H salt); mp 236-238.degree. C.;
.sup.1H NMR (d.sub.6DMSO, 300 MHz) .delta. 1.98 (m, 4H), 2.48 (s,
3H), 2.55 (s, 3H), 2.74 (s, 3H), 3.10-3.75 (m, 6H), 4.054.40 (m,
4H), 6.10 (m, 1H), 6.16 (bs, 2H), 7.05 (s, 1H), 7.35 (m, 11H), 9.30
(bs, 1H).
EXAMPLE 132
2-[2-(N-Dimethylsulfamoyl)-4,5-methylenedioxyphenyl]-N-methyl-N-[(1S)-1-ph-
enyl-2-[(1-pyrrolidinyl)ethyl]]acetamide
[0647] Yield, 48% (HCl salt); mp 269-271.degree. C.; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.96 (m, 4H), 2.25 (m, 2H), 2.69 (s,
6H), 2.92 (bs, 3H), 4.05 (m, 4H), 4.35 (q, J=10.0 Hz, 2H), 6.03 (d,
J=9.5 Hz, 2H), 6.35 (m, 1H), 7.27 (m, 7H).
EXAMPLE 133
2-[2-(N-Dimethylsulfamoyl)-4,5-methylenedioxyphenyl]-N-methyl-N-[(1S)-1-ph-
enyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide
[0648] Prepared from diamine (iv-b), yield, 41% (HCl salt);
mp>240.degree. C. (d); MS 491 (M+H).sup.+.
EXAMPLE 134
2-[2-(N-Pyrrolidinesulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phen-
yl-2-[(1-pyrrolidinyl)ethyl]]acetamide
[0649] Yield 67% (HCl salt); mp 240-242.degree. C.; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.70 (m, 4H), 2.00-2.45 (m, 4H), 2.94
(s, 3H), 3.25 (m, 5H), 3.90 (s, 3H), 3.99 (m, 6H), 4.15 (m, 2H),
4.30 (d, J=10.5 Hz, 1H), 4.50 (d, J=10.6 Hz, 1H), 6.38 (m, 1H),
7.25 (m, 3H), 7.34 (m, 3H), 7.48 (s, 1H).
EXAMPLE 135
2-[2-(N-Pyrrolidinesulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phen-
yl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide
[0650] Prepared from diamine (iv-b) in 49% yield (CH.sub.3SO.sub.3H
salt); mp>120.degree. C. (d); MS 532 (M+H).sup.+.
EXAMPLE 136
2-[2-(N-Dimethylsulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl--
2-[(1-pyrrolidinyl)ethyl]]acetamide
[0651] Yield, 55% (HCl salt); mp 246-248.degree. C.; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.00-2.40 (m, 4H), 2.69 (s, 3H), 2.94
(m, 4H), 3.25 (m, 1H), 3.90 (s, 3H), 4.00 (m, 6H), 4.34 (d, J=11.0
HZ, 1H), 4.41 (d, J=10.7 Hz, 1H), 6.35 (m, 1H), 7.20-7.40 (m, 6H),
7.45 (s, 1H).
EXAMPLE 137
2-[2-(N-Dimethylsulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl--
2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide
[0652] Prepared from diamine (iv-b) in 45% yield (HCl salt); mp
221-223.degree. C.; MS 474 (M+H).sup.+.
EXAMPLE 138
2-[2-[N-(4-Methylpiperazine)]sulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(-
1S)-1-phenyl-2-[1-(pyrrolidinyl)ethyl]]acetamide
[0653] Yield, 62% (di HCl salt); mp 255-257.degree. C. (d); .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. 2.00-2.38 (m, 4H), 2.77 (s, 3H),
2.95 (s, 3H), 3.05-3.28 (m, 4H), 3.30-3.48 (m, 2H), 3.55-3.80 (m,
4H), 3.95-4.15 (m, 10H), 4.20 (d, J=10.5 Hz, 1H), 4.30 (d, J=10.5
Hz, 1H), 6.40 (m, 1H), 7.27 (m, 2H), 7.35 (m, 2H), 7.46 (m,
3H).
EXAMPLE 139
2-[2-[N-(4-Methylpiperazine)]sulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(-
1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide
[0654] Prepared from diamine (iv-b) in 74% yield (di HCl salt); mp
168-171.degree. C.; MS 561 (M+H).sup.+.
EXAMPLE 140
2-[2-N-(Morpholinesulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-pheny-
l-2-[1-(pyrrolidinyl)ethyl]]acetamide
[0655] Yield 75% (HCl salt), mp 229-231.degree. C.; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.05-2.40 (m, 4H), 2.94 (m 6H), 3.08
(m, 4H), 3.25 (m, 1H), 3.68 (m, 4H), 3.90 (s, 3H), 3.97 (s, 3H),
4.15 (m, 2H), 4.37 (m, 2H), 6.38 (m, 1H), 7.25-7.39 (m, 6H), 7.52
(s, 1H).
EXAMPLE 141
2-[2-N-(Morpholinesulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-pheny-
l-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide
[0656] Prepared from diamine (iv-b) in 77% yield (HCl salt); mp
158-161.degree. C.; MS 548 (M+H).sup.+.
EXAMPLE 142
N-Methyl-[[2-(N-sulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl--
2-[1-(pyrrolidinyl)ethyl]]acetamido]glycine
[0657] The desired sulfamoyl phenyl acetic acid was prepared from
sulfonyl chloride (xi) (R.sup.1=R.sup.2=OCH.sub.3) and sarcosine
t-butyl ester followed by the hydrolysis of the methyl ester. The
acid was condensed with diamine (iv-a) and the cleavage of t-butyl
ester gave (21) in 80% overall yield (HCl salt); mp 231-233.degree.
C. (d); MS (FAB) 534 (MH).sup.+; .sup.1H NMR (d.sub.6DMSO, 300 MHz)
.delta. 2.05 (m, 4H), 2.77 (s, 3H), 2.81 (s, 3H), 3.504.35 (m,
17H), 6.15 (m, 1H), 7.25-7.55 (m, 7H).
EXAMPLE 143
2-[2-(N-Pyrrolidinesulfamoyl)-3,4,5-trimethoxyphenyl]-N-methyl-N-[(1S)-1-p-
henyl-2-[(1-pyrrolidinyl)ethyl]]acetamide
[0658] Yield, 62% (HCl salt); mp 225-227.degree. C.; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.80 (m, 4H), 2.50-2.80 (m, 8H), 2.75
(s, 7H), 3.90 (s, 6H), 4.00 (s, 3H), 4.20 (m, 2H), 6.50 (m, 1H),
7.20-7.44 (m, 6H).
EXAMPLE 144
2-[2-(N-t-Butylsulfamoyl)-3,4,5-trimethoxyphenyl]-N-methyl-N-[(1S)-1-pheny-
l-2-[(1-pyrrolidinyl)ethyl]]acetamide
[0659] Yield, 74% (HCl salt); mp 248-250.degree. C.; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.34 (s, 9H), 2.05-2,30 (m, 4H), 2.69
(s, 6H), 2.90 (m, 6H), 4.05 (m, 2H), 4.30 (d, J=9.5 HZ, 1H), 4.40
(d, J=9.6 Hz, 1H), 6.30 (m, 1H), 7.27 (m, 4H), 7.60 (m, 3H), 7.83
(s, 1H).
EXAMPLE 145
2-[2-(N-Methylsulfamoyl)-4-methoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1--
pyrrolidinyl)ethyl]]acetamide
[0660] Yield, 25% (CH.sub.3SO.sub.3H salt); mp 232-234.degree. C.;
.sup.1H NMR (d.sub.6DMSO, 300 MHz) .delta. 1.80-2.01 (m, 4H), 2.37
(s, 3H), 2.39 (s, 3H), 2.75 (s, 3H), 3.18 (m, 2H), 3.50-3.57 (m,
3H), 3.85 (m, 2H), 3.88 (s, 3H), 6.15 (m, 1H), 6.99 (m, 1H), 7.20
(m, 2H), 7.35 (m, 2H), 7.48 (m 1H), 7.68 (m, 1H).
EXAMPLE 146
2-[4-N-(Methylsulfamoyl)-phenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hy-
droxypyrrolidinyl)ethyl]]acetamide
[0661] The sulfamoyl acid was prepared from methyl phenyl acetate
as described above and condensed with diamine (iv-b) to give the
title compound in 42% yield (CH.sub.3SO.sub.3H salt); mp
201-203.degree. C.; .sup.1H NMR (d.sub.6DMSO, 300 MHz) .delta.
1.70-2.35 (m, 2H), 2.32 (s, 3H), 2.40 (d, J=5.0 Hz, 3H), 2.74 (s,
3H), 3.15-3.80 (m, 5H), 3.814.20 (m, 3H), 4.354.55 (m, 1H), 5.44
and 5.55 (m, 1H), 6.13 (m, 1H), 7.50-7.45 (m, 5H), 7.47 (d, J=8.1
Hz, 2H), 7.71 (d, J=8.2 Hz, 1H), 9.55 (bs, 1H), 9.87 (bs, 1H).
EXAMPLE 147
2-[2-(N-Methylsulfamoyl)-phenyl]-N-methyl-N-[1-(2-fluorophenyl-2-[(1-pyrro-
lidinyl)ethyl]]acetamide
[0662] Prepared from diamine (iv-a) (R=2-F) in 63% yield
(CH.sub.3SO.sub.3H salt); mp 232-234.degree. C.; .sup.1H NMR
(d.sub.6DMSO, 300 MHz) .delta. 1.80-2.50 (m, 4H), 2.33 (s, 3H),
2.41 (d, J=4.9 Hz), 2.76 (s, 3H), 3.22 (m, 2H), 3.50-3.80 (m, 3H),
3.88 (s, 2H), 4.23 (m, 2H), 6.28 (m, 2H), 7.20-7.35 (m 2H),
7.35-7.50 (4H), 7.71 (d, J=8.2 Hz, 2H), 9.33 (bs, 1H).
EXAMPLE 148
2-[2-(N-Benzyl-N-methylsulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1--
phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide
[0663] Yield, 46% (HCl salt); mp 188-189.degree. C.; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.15 (m, 4H), 2.56 (s, 3H), 2.92 (s,
3H), 3.25 (m, 1H), 3.90 (s, 3H), 4.04 (m, 10H), 4.50 (m, 2H), 6.38
(m, 1H), 7.26 (m, 11H), 7.50 (s, 1H).
[0664] In a composition aspect, the kappa agonist compounds of the
present invention are formulated into parenteral, local and topical
formulations.
[0665] The compositions are formulated as injectables, as oral and
rectal formulations for systemic administration, and for local and
topical administration as creams, aqueous or non-aqueous
suspension, lotions, emulsions, suspensions or emulsions containing
micronized particles, gels, foams aerosols, solids and other
suitable vehicles for application to the skin, eyes, lips and
mucosa, as suppositories or cream for vaginal administration, and
as combinations with bandages, patches, bioadhesives and dressings.
The compounds may be formulated in combination with other agents,
such as local anesthetics and other therapeutic agents. The other
agents may be mixed in the compositions are provided and
administered prior to, simultaneously with or subsequent to
administration of the compositions provided for the methods herein.
Such agents include, but are not limited to: antibiotics, including
cephalosporins, .beta.-lactams, tetracyclines, vancomycins, sulfas
and aminoglycosides; antivirals, including acylovir; and
antifungals including clotrimazole.
[0666] In a method aspect the present invention provides method to
treat hyperalgesia by applying an amount of a compound or
composition to a mammal to ameliorate or eliminate pain. Thus, the
method of the present invention comprises a method of treating pain
internally or externally present in the mammalian body including:
internal injuries, such as caused by accident or surgical
procedures; abnormal functioning of body organs; irritation
associated with inflammation following local infection, blisters,
boils, or acute skin injuries, such as abrasions, burns,
superficial cuts, surgical incisions, toothaches, contusions,
irritations, inflammatory skin conditions, including but not
limited to poison ivy, and allergic rashes and dermatitis and any
condition that yields a hyperalgesic pain state and other such
conditions.
[0667] Assessment of Anti-Hyperalgesic Activity
[0668] The pharmacological activity of the compounds of the present
invention may be assessed by several art-recognized in vitro and in
vivo models. Some of the typical models are described herein.
[0669] (a) In Vitro Binding Assay (Primary Screen).sup.14
[0670] The initial test of these compounds is
[.sup.3H]diprenorphine binding to the cloned human kappa receptor.
The compounds that inhibit binding by at least 80% at 1 .mu.M are
titrated and K.sub.i values are determined by Cheng-Prusoff
transformations of IC.sub.50 values. The IC.sub.50 value is the
concentration of inhibitor that inhibits binding of radiolabel by
50% and the K.sub.i value is the affinity of the inhibitor for the
receptor. Compounds are also tested against [.sup.3H]U69593
(agonist) binding to this receptor. No compound is known to inhibit
only agonist binding or antagonist binding. However, such a
compound may have a unique pharmacological profile as a result of
its specificity for one region of the receptor.
[0671] Initial specificity is determined by testing compounds using
[.sup.3H]diprenorphine binding to cloned human mu and delta
receptors at 10 .mu.M and titrating those compounds that inhibit
binding by at least 80%. Compounds that do not have K.sub.i values
at least 100-fold higher against mu and delta receptors may be more
likely to have additional side effects and are not pursued to
enable further evaluation of specific compounds.
[0672] Ref.
[0673] (14) Raynor et al., Mol. Pharmacol. 45, 330-334 (1994)
[0674] (b) In Vivo Evaluation of Formalin-Induced Nociception
[0675] Administration of formalin into the paw results in a
localized inflammation and a pain response that is moderate in
intensity and continuous in duration. Unlike many other assays of
nociception, the formalin assay measures tonic pain that is a
result of tissue injury, and therefore is a model which is more
relevant to clinical pain states in humans [see Tjolsen et al.
(1992) Pain 51: 5-17]. In the rat the response to formalin-induced
pain consists of spontaneous flinching behavior, characterized by
paw lifting and paw shaking, and a rapid vibration of the paw after
drawing it under the body. The flinching response can be reliably
quantitated and exhibits two peaks of activity which are indicative
of acute and tonic pain [Wheeler-Aceto and Cowan (1991)
Psychopharmacology 104: 35-44]. The early or acute phase lasts from
0-5 min post-formalin and is followed by a quiescent period lasting
approximately 15 min. The tonic phase occurs from 20-35 min
following formalin injection and is the interval where the number
of flinching responses is maximal. This model has been
characterized in several species [Tjolsen et al. (1992) Pain 51:
5-17] and is sensitive to the analgesic effects of opiates
administered by a variety of routes, including local administration
directly into the paw. In addition, the test is particularly
sensitive to the effects of .kappa. agonists [Wheeler-Aceto and
Cowan (1991) Psychopharmacology 104: 35-44].
[0676] Inflammation is induced by subcutaneous injection of 50
.mu.L of a 5% formalin solution into the dorsal surface of the
right hind paw of male Sprague-Dawley rats weighing 70-90 g.
Injections of drug are given into the dorsal surface of the paw
prior to formalin injection, and flinching behavior is quantitated
by counting the number of responses that occur during the tonic
phase of pain, lasting from 20-35 min after formalin injection.
Results are expressed as the mean percent antagonism of
formalin-induced flinching calculated for individual drug-treated,
formalin-injected rats using the following formula:
(mean formalin response-mean saline response)-individual
response.times.100
[0677] mean formalin response-mean saline response
[0678] The mean formalin response is the mean behavioral score of
vehicle-treated and formalin-injected rats. The mean saline
response is the pooled behavioral score from rats injected with 50
.mu.L of saline into the paw.
[0679] (d) Randall-Selitto Test
[0680] Numerous variations and exemplifications of this assay are
known to those of skill in this art [see, Randall et al. (1957)
Arch. Int. Pharmacodyn. 111: 409-419; see, also, e.g., U.S. Pat.
No. 5,434,292, U.S. Pat. No. 5,369,131, U.S. Pat. No. 5,345,943,
U.S. Pat. No. 5,242,944 and U.S. Pat. No. 5,109,135.
[0681] The pain threshold is measured in this method as the amount
of pressure in g required to induce a flight reaction (struggle)
when applied to the foot of an experimental animal exhibiting
hyperalgesia, typically an inflamed paw, compared to a control,
such as the same or equivalent animal in the absence of the
inflammation, and/or in the absence of a test compound. Incremental
pressure is applied to the paw with a wedge-shaped blunt piston
onto the dorsal surface of the hind paw by means of a paw pressure
analgesia meter. The pressure required to elicit paw withdrawal,
the paw pressure threshold (PPT), is determined.
[0682] Stein and coworkers [Stein et al. (1988) Pharmacol. Biochem.
Behav. 31: 445-451; Stein et al. (1989) J. Pharmacol. Exp. Ther.
248: 1269-1275] have developed a model of peripheral inflammation
and hyperalgesia in rats, which supports the role of opiates in
mediating peripheral analgesia. In this protocol, modified Freund's
adjuvant is used as the inflammatory stimulus, and the paw pressure
test is used to assess the response of the rat to a painful
pressure stimulus. The model is sensitive to opiate agonists of the
.mu., .delta. and .kappa. subtypes, which produce analgesia upon
administration [Antonijevic et al. (1995) J. Neurosci. 15: 165-172;
Stein et al. (1988) Neurosci. Lett. 84: 225-228; Stein et al.
(1989) J. Pharmacol. Exp. Ther. 248: 1269-1275]. Histological
verification of opiate receptor localization and density have
confirmed that peripheral opiate receptors are accessible on
primary afferent nerve fibers and are upregulated following
inflammation [Hassan et al. (1993) Neuroscience 55: 185-193;
Przewlocki et al. (1992) Neuroscience 48: 491-500].
[0683] Experiments are conducted in rats weighing 150-250 g at the
time of inoculation. Modified Freund's complete adjuvant (FCA) is
used as the inflammatory stimulus. Rats are administered an i.pl.
injection of the FCA suspension into the right hind foot.
Hyperalgesia and antinociception are evaluated using the paw
pressure test. The rat is gently restrained and incremental
pressure is applied to the paw with a wedge-shaped blunt piston
onto the dorsal surface of the hind paw by means of a paw pressure
analgesia meter. The pressure required to elicit paw withdrawal,
the paw pressure threshold (PPT), is determined. A cutoff pressure
of 250 g is used to avoid undue stress and pain to the animal.
Baseline responding is established by determining the average of
three consecutive trials separated by 10 sec. The same procedure is
conducted on the contralateral side and the sequence of sides is
alternated between animals to control for order effects. Typically
injections are not made in the contralateral (noninflamed) paw;
however, in selected cases drugs may be administered to the
contralateral paw to evaluate the potential for drug effects in the
absence of inflammation.
[0684] Analgesic activity is determined by expressing the increase
in PPT resulting from the effect of the drug as a percentage of
basal preinjection thresholds.
[0685] Hyperalgesia can also be produced by inflammatory stimuli
such as yeast or carrageenan, endogenous inflammatory mediators
such as bradykinin or prostaglandins, or other types of chemical
irritants [see Hargreaves and Joris (1993) APS Journal 2:
51-59].
[0686] (e) Acetic Acid-Induced Writhing
[0687] This test identifies novel agents which exhibit peripheral
analgesic activity against visceral or chemical pain [see Barber
and Gottschlich (1986) Med. Res. Rev. 12: 525-562; Ramabadran and
Bansinath (1986) Pharm. Res. 3: 263-270]. Injection of acetic acid
into the peritoneal cavity is used as the noxious stimulus, and the
number of writhing responses that occur in response to acetic acid
are counted in order to quantify the response to pain. Compounds
which possess analgesic activity reduce the number of writhing
responses that occur. Opiate agonists of the .mu. and .kappa.
subtype exhibit analgesic activity in this model [Barber and
Gottschlich (1986) Med. Res. Rev. 12: 525-562; Millan (1990) Trends
Pharmacol. Sci. 11: 70-76]. Novel compounds which demonstrate
potency and efficacy in this assay are potential drugs for the
treatment of various pathological conditions involving peripheral
pain.
[0688] The writhing assay is adapted from the procedure originally
described by Taber et al. [(1969) J. Pharmacol. Exp. Ther. 169:
29-38], using male CF-1 mice weighing 20-25 g. Animals are treated
with various doses of drugs prior to the administration of an i.p.
injection of 0.6% acetic acid solution. Mice are then placed into
observation chambers and the number of writhing responses, as
defined by a full hindlimb extension and retraction, are
recorded.
[0689] The mean number of writhing responses is calculated for
vehicle-treated control mice, and the percent inhibition (% I) of
writhing is calculated for each mouse that is treated with drug
using the following formula:
% I=100.times.(mean control writhing responses-individual test
responses)
[0690] mean control writhing responses
1TABLE I Compounds of Formula I 92 Late Phase Ki, nM Formalin
Compounds R Ar .sup.3H-Diprenorphin .sup.3H-U-69,593 A.sub.50 (mg);
i.paw GR 89696 CO.sub.2CH.sub.3 3,4-Cl.sub.2 0.095, 0.10 1.6, 1.5
0.35(0.20-0.62) (R) (R-1) Bn 3,4-Cl.sub.2 57, 38 9.3 53% @ 300
(R-2) H 3,4-Cl.sub.2 14, 17 1.5, 1.3 57% @ 300 (R-3a)
SO.sub.2CH.sub.3 3,4-Cl.sub.2 0.2, 1.3 0.19, 0.5 14 (5.6-29) (R-3b)
CH.sub.2CO.sub.2t-Bu 3,4-Cl.sub.2 30% @ 1 uM 75% @ 1 uM 75% I @ 1
.mu.M (R-3c) CH.sub.2CO.sub.2H 3,4-Cl.sub.2 62% @ 1 uM 23, 21 26% @
300 (R-3d) 93 3,4-Cl.sub.2 36% @ 1 uM 379, 249 Not tested. (R-3e)
94 3,4-Cl.sub.2 39% @ 1 uM 37, 28 22% A @ 300 (R-3f) COCH.sub.3
3,4-Cl.sub.2 4.2, 1.4 0.11, 0.14 95% @ 300 (R-3g) PO(OEt).sub.2
3,4-Cl.sub.2 99, 33 1.3, 1.4 54% @ 300 (R-3h) COCF.sub.3
3,4-Cl.sub.2 6.9, 1.8 0.26, 0.16 94% @ 300 (R-3i) CONH.sub.2
3,4-Cl.sub.2 56, 29 2.9 68% @ 300 (R-3j) CHO 3,4-Cl.sub.2 96% @ 1
uM 0.40 65% @ 300 (R-3l) SO.sub.2-Tol 3,4-Cl.sub.2 120 6.2 24% @
300 (R,S-8a) SO.sub.2CH.sub.3 3,4-Cl.sub.2 5.4, 4.0 0.37, 0.65 96%
@ 300 (R,S-8b) SO.sub.2CH.sub.3 p-SO.sub.2CH.sub.3 41% @ 1 uM 20,
31 Not tested (R,S-8c) SO.sub.2CH.sub.3 o-NO.sub.2 15% @ 1 uM 51% @
1 uM Not tested (R,S-8d) SO.sub.2CH.sub.3 p-CF.sub.3 16, 17 1.3,
1.9 97% @ 300 (R,S-8e) SO.sub.2CH.sub.3 3-indole 74% 5.3, 3.2 Not
tested (R,S-9a) CO.sub.2CH.sub.3 p-SO.sub.2CH.sub.3 11 0.37, 0.42
46% @ 300 (R,S-9b) CO.sub.2CH.sub.3 p-CF.sub.3 0.49 0.076, 0.13 98%
@ 300 (R,S-9c) CO.sub.2CH.sub.3 3-indole 3.0 0.27, 0.40 95% @ 300
(R,S-9d) CO.sub.2CH.sub.3 o-NO.sub.2 37 0.74, 0.73 93% @ 300
(R,S-9e) CO.sub.2CH.sub.3 o-OCH.sub.3 7.3 0.46, 1.3 98% @ 300
(R,S-9f) CO.sub.2CH.sub.3 o-NH.sub.2 4.6, 3.2 0.67, 0.41 97% @ 300
(R,S-10a) COCH.sub.3 p-SO.sub.2CH.sub.3 27% 2.3 6% @ 300 (R,S-10b)
COCH.sub.3 p-CF.sub.3 26, 24 2.y0 89% @ 300 (R,S-10c) COCH.sub.3
o-CF.sub.3 45% @ 1 uM 16 Not tested (R,S-10d) COCH.sub.3 m-NO.sub.2
94% @ 1 uM 0.72 Not tested (R,S-10e) COCH.sub.3 o-NO.sub.2 541 24
Not tested (R,S-10f) COCH.sub.3 p-NO.sub.2 59% @ 1 uM 2.4 Not
tested (R.S-11) Bn p-CF.sub.3 2.2, 2.4 0.39, 0.57 92% @ 300
[0691]
2TABLE IA Compounds of Formula IA 95 Formalin (% A @ 300 nM) Ki(nM)
i. paw or R Ar R' R" n X (.sup.3H)-Diprenorphin A.sub.50 mg/kg s.c.
1a CO.sub.2CH.sub.3 96 H H 1 CH.sub.2 248 Not tested 1b
CO.sub.2CH.sub.3 97 H H 1 CH.sub.2 7 Not tested 1c CO.sub.2CH.sub.3
98 H H 1 CH.sub.2 65% @ 1 mM 69% @ 300 1d CO.sub.2CH.sub.3 99 H H 1
CH.sub.2 7.6 77% @ 300 1e CO.sub.2CH.sub.3 100 H H 1 CH.sub.2 14
55% @ 300 1f CO.sub.2CH.sub.3 101 H H 1 CH.sub.2 53.5 Not tested 1g
COCF.sub.3 102 H H 1 CH.sub.2 5% @ 1 mM Not tested 1h COCF.sub.3
103 H H 1 CH.sub.2 50 100% @ 300 1i CO.sub.2CH.sub.3 104 H
CO.sub.2CH.sub.3 2 N 12% @ 1 mM Not tested 1j CO.sub.2CH.sub.3 105
H 106 1 CH 13 Not tested 1k CO.sub.2CH.sub.3 107 108 H 1 CH 51.5
95% @ 300 1l (R, S) CO.sub.2CH.sub.3 109 110 H 1 CH 3.5 1.7 1m
CO.sub.2CH.sub.3 111 112 H 1 CH 49.5 1.7 1n CO.sub.2CH.sub.3 113
114 H 1 CH 12% @ 1 mM Not tested 1o CO.sub.2CH.sub.3 115 116 H 1 CH
133 41% @ 300 1p CO.sub.2CH.sub.3 117 118 H 1 CH 11 Not tested 1q
CO.sub.2CH.sub.3 H 119 1 CH 5.2 98% @ 300 1r COCH.sub.3 120 H H 1
CH 43% @ 1 mM Not tested 1s COCH.sub.3 121 H H 1 CH 53% @ 1 mM Not
tested 1t COCH.sub.3 122 H H 1 CH 1% @ 1 mM Not tested 1u
COCH.sub.3 123 H 124 1 CH 1780 Not tested 1v COCH.sub.3 125 H 126 1
CH 4.3 70% @ 300 1w COCH.sub.3 127 H 128 1 CH 1156 60% @ 300 1x
COCH.sub.3 129 130 H 1 CH 36% @ 1 mM Not tested 1y COCH.sub.3 131
132 H 1 CH 45% @ 1 mM Not tested 1z COCH.sub.3 133 134 H 1 CH 102
71% @ 300 1aa COCH.sub.3 135 136 H 1 CH % @ 1 mM Not tested 1bb
COCH.sub.3 137 138 H 1 CH 11% @ 1 mM 46% @ 300 1cc COCH.sub.3 139
140 H 1 CH 22% @ 1 mM 10% @ 300 1dd CHO 141 H H 1 CH 13% @ 1 mM Not
tested 1ee 142 143 H H 1 CH 58.9 1.0 1ff allyl 144 H H 1 CH 0.58
98% @ 300 1gg COCH.sub.3 145 H H 1 CH 27% @ 1 mM Not tested 1hh CHO
146 H H 1 CH 0% @ 1 mM Not tested 1ii (S, S) CO.sub.2CH.sub.3 147
148 H 1 CH 21.5 60% @ 300 1jj SO.sub.2CH.sub.3 149 H 150 1 CH 11.5
49% @ 300 1kk SO.sub.2CH.sub.3 151 H 152 1 CH 5.1 52% @ 300 1ll
SO.sub.2CH.sub.3 153 H 154 1 CH 2.86 52% @ 300 1mm SO.sub.2CH.sub.3
155 H 156 1 CH 287 Not tested 1nn SO.sub.2CH.sub.3 157 H 158 1 CH
2.33 7.1
[0692]
3TABLE II Compounds of Formula II 159 K.sub.i (nM) K.sub.i (nM) k k
Late Phase [.sup.3H] (mg) Formalin Compounds R, n R' Diprenorphin
[.sup.3H]U69,593 A.sub.50 (mg) II-1 7-OCH.sub.3, n = 1 160 4.7 0.8
44% A @ 300 II-2 7-OCH.sub.3, n = 1 161 142 20 124 II-3 7-OH, n = 1
162 0.6 0.18 7 II-4 7-OH, n = 1 163 549 432 Not tested II-5
7-OCH.sub.2CO.sub.2H, n = 1 164 40 7 39% @ 300 II-6 7-NO.sub.2, n =
1 165 2.8 0.8 65 II-7 7-NO.sub.2, n = 1 166 57% @ 1 mM 12.8 40% A @
300 II-8 7-NO.sub.2, n = 1 167 9.6 0.7 891 II-9 7-NH.sub.2, n = 1
168 2.2 0.35 19 II-10 7-N(CH.sub.2CO.sub.2Et).sub.2, n = 1 169 4.6
0.68 37% A @ 300 II-11 7-N(CH.sub.2CO.sub.2tBu)- .sub.2, n = 1 170
7.4 2.8 nM 155 II-12 7-N(CH.sub.2CO.sub.2H).sub.2, n = 1 171 3.8
0.68 232 II-13 7-NH(CH.sub.2).sub.2PO.sub.3Et.sub.2, n = 1 172 6.2
2.2 Not tested II-14 7-NHPO.sub.3Et.sub.2, n = 1 173 2.4 0.6 34
II-15 7-SO.sub.2NCH.sub.3Bn, n = 1 6-OMe 174 48 8.0 Not tested
II-16 7-SO.sub.2NCH.sub.3Bn, n = 1 175 200 40 Not tested II-17 --H,
n = 2 176 8.4 2.8 21% A @ 300 II-18 R.dbd.H, n = 0 177 12 2.0 80% @
300 II-19 R.dbd.H, n = 0 178 46% @ 1 mM 29 Not tested II-20
R.dbd.H, n = 0 179 29% @ 1 mM 146 Not tested II-21 R.dbd.H, n = 0
180 5.7 0.74 Not tested II-22 R.dbd.H, n = 0 181 75% @ 1 mM 9 Not
tested II-23 (.+-.)- Niravoline R.dbd.H, n = 0 182 13 1.8 92% @
300
[0693]
4TABLE IIA Compound of Formula IIA K.sub.i (nM) [.sup.3H] Late
Phase Compound Structure Diprenorphin .kappa. Formalin II-24 (2a)
183 28.0 69% @ 300 .mu.g
[0694]
5TABLE III Compounds of Formula III K.sub.i (nM) K.sub.i (nM) Late
Phase k k Formalin Compounds X R R' [.sup.3H]Diprenorphin
[.sup.3H]U69.593 A.sub.50 (mg) III-1 --H --NO.sub.2(3-5%
p-NO.sub.2) 184 0.65 0.25 16 III-2 --H --H 185 2.9, 9.0 0.7, 1.0 29
III-3 --OH R.dbd.H 186 0.61 0.085 15 III-4 --H --H 187 0.2 0.1 5.3
III-5 --OH R.dbd.H 188 0.09 0.07 2.7 mg/ms (i-paw) 0.18 mg/kg (sc)
III-6 --H --H 189 0.20 0.26 27 III-7 --OH R.dbd.H 190 0.16 0.11 97%
@ 300 III-8 --H --H 191 0.28 0.08 95% @ 300 III-9 --H --H 192 24% @
1 mM 1.35 Not tested III-10 --H --NO.sub.2 193 35 3.2 Not tested
III-11 --H --NO.sub.2 194 0.3 0.07 Not tested III-12 --H --NO.sub.2
195 31 1.5 Not tested III-13 --H --NO.sub.2 196 76% @ 1 mM 6.4 Not
tested III-14 --H --NO.sub.2 197 25% @ 1 mM 79% @ 1 mM Not tested
III-15 --H --NO.sub.2 198 19% @ 1 mM 168 Not tested III-16 --H
2,3-Br.sub.24-NH.sub.2 199 9.4 4.25 306 III-17 --H --NH.sub.2 200
0.14 0.04 0.4 III-18 --H --H 201 8.15 1.45 65 III-19 --H --H 202 13
0.85 58% @ 300 III-20 --H --H 203 22 1.8 52% @ 300 III-21 --H --H
204 0.10 0.055 7 III-22 --H --H 205 0.09 0.10 0.02 mg/Kg(s.c)
III-23 --OH R.dbd.H 206 0.18 0.12 0.02 mg/kg sc III-24 --H
--NH.sub.2 207 20 2.6 81% @ 300 III-25 (EMD 60400) --OH R.dbd.H 208
0.8 0.175 33 III-26 --H --NH.sub.2 209 61% @ 1 mM 43 Not tested
III-27 --H --NH-a-D-Asp 210 3.65 1.05 72 III-28 --H --NH-a-L-Asp
211 1.9 0.5 9.1 III-29 --H --NH-a-L-(Asp).sub.2 212 2.0 0.67 14
III-30 --H --NH-b-L-Asp 213 2.3 0.7 47 III-31 --H --NH-g-D-Glu 214
62 III-32 --H --N(SO.sub.2Me).sub.2 215 6.45 1.2 58 III-33 --H --H
216 57% @ 1 mM 6.4, 8.9 17 III-34 --H --H 217 54, 40 6.8, 3.5 mg/Kg
(s.c.) III-35 --H --H 218 0.38, 0.45 0.01, 0.09 28 III-36 --H --H
219 0.83, 0.49 0.29, 0.43 Not tested III-37 --H --H 220 2.2, 3.8
0.64, 0.38 Not tested III-38 --H --H 221 63% at 1 mM 10.8 91% @ 300
III-39 --H --H 222 198 32 Not tested III-40 --H
--N(SO.sub.2Me).sub.2 223 7% @ 1 mM 58% @ 1 mM Not tested III-41 --
--NHPO.sub.3Et.sub.2 224 33 48 Not tested III-42 --H
--NHPO.sub.3Et.sub.2 225 56% @ 1 mM 76 Not tested III-43 (EMD
61753) --OH R.dbd.H 226 0.52 0.34 59 mg/ms (i-paw) 28 mg/kg (sc)
III-44 --H --H 227 25, 18 4.8, 3.0 67 III-45 --H --H 228 55, 42, 60
7.7, 15 174 III-46 --H --H 229 0.2, 0.17 0.21, 1.7 27 III-47 --OH
R.dbd.H 230 0.23 0.16 Not tested III-48 --H --H 231 5.4, 3.7 0.36,
0.39 39 III-49 --H --H 232 0.43, 0.88 0.33, 0.38 29 III-50 --H --H
233 0.94, 0.28 0.5, 0.07, 0.06 13 III-51 --H --H 234 0.12, 0.013
0.050, 0.060 0.009 mg/Kg(s.c.) III-52 --H --H 235 0.30 0.12 97% @
300 III-53 --H --H 236 1.3 0.18 98% @ 300 III-54 --H --H 237 22, 13
3.3, 1.3 90% A @ 300 III-55 --H --H 238 65% @ 1 mM 98% @ 1 mM 43% @
300 III-56 --H --H 239 52 4.8 51% @ 300 III-57 --H --H 240 5.4, 4.9
2.2. 1.2 Not tested III-58 --H --H 241 75% at 1 mM 9.0 32% @ 300
III-59 --H --H 242 19 2.2 40% @ 300 III-60 --H --H 243 100% @ 1 mM
91% @ 1 mM 94% @ 300 III-61 --OH R.dbd.H 244 1.06 0.36 Not
tested
[0695]
6TABLE IIIA Compounds of Formula IIIA 245 K.sub.i (nM) [.sup.3H]-
Late Phase Diprenorphin Formalin Compound X R R' .kappa. A.sub.50
(mg/kg) 3a --H --H 246 1.0 1.8 3b --H --H 247 464.0 Not tested 3c
--H --NHSO.sub.2NH.sub.2 248 0.12 0.27 3d --H --NHSO.sub.2Me 249
0.28 16.0 3e --H --NHSO.sub.2Me 250 3.2 71% @ 300 3f --H
--NHSO.sub.2Me 251 0.18 8.9 3g --H --NHPO.sub.3Et.sub.2 252 0.12
4.4 3h --H --NH-maleic acid 253 1.80 59% @ 10 3i --H
--NH--C.sub.10H.sub.16O.sub.4N.sub.2 254 0.14 23% @ 300 3j --H
--NH--C.sub.6H.sub.8O.sub.3N 2.3 38% @ 300 3k --H --H 255 18.0 Not
tested 3l --H --H 256 3.8 73% @ 300 3m --H --H 257 5.1 65% @ 300 3n
--H --NHSO.sub.2CH.sub.3 258 7.3 73% @ 300 3o --H --H 259 30.5 59%
@ 300 3p --H --H 260 9.7 84% @ 300 3q --H --H 261 3.2 Not tested 3r
--H --H 262 7.3 10.0 3s --H --H 263 86% @ 300 3t --OH --H 264 4.2
65% @ 300 3u --H --H 265 1.0 48% @ 300 3v --OH --H 266 46.0 36% @
300 3w --H --H 267 2.5 90% @ 300 3y --H --H 268 0.35 Not tested 3z
--H --H 269 1.7 98% @ 300 3aa --H --H 270 5279.0 Not tested 3bb --H
--H 271 438.0 Not tested 3cc --H --H 272 3.1 52% @ 30 3dd --H --H
273 3.8 65% @ 300 3ee --H --H 274 26.0 34% @ 300 3ff --OH --H 275
0.17 97% @ 300 3gg --OH --H 276 5.2 1.4 3hh --H --H 277 0.56 0.11
3ii --OH --H 278 0.44 88% @ 300 3jj --H --H 279 50% @ 1 .mu.M Not
tested 3kk --H --H 280 53% @ 1 .mu.M 23% @ 300 3ll --H --H 281 68%
@ 1 .mu.M 77% @ 300 3mm --H --H 282 16.4 53% @ 300 3nn --H --H 283
8.8 Not tested 3oo --H --H 284 2.8 Not tested 3pp --H
--NHSO.sub.2CH.sub.3 285 4.6 Not tested 3qq --H
--NHCOCH(CH.sub.3).sub.2 286 21.0 Not tested 3rr --H --H 287 0.44
2.9 3ss --H --H 288 361.5 Not tested 3tt --H --H 289 164.0 Not
tested 3uu --H --OCH.sub.3 290 17.5 Not tested 3vv --H --OH 291
19.5 Not tested 3ww --OH --H 292 1.28 Not tested 3xx --H --H 293
0.83 Not tested 3yy --H --H (R-isomer) 294 0% @ 1 .mu.M Not tested
3zz --H --OCH.sub.3 295 0.64 Not tested 3aaa --H --OH 296 0.59 Not
tested 3bbb --H --H 297 4.45 Not tested 3ccc --H --H 298 1.1 Not
tested 3ddd --H --H 299 Not tested
[0696]
7TABLE IIIB Compounds of Formula IIIB and IIIB-i 300 K.sub.i(nM)
Late Phase [.sup.3H]- Formalin Example Diprenorphin (i. paw) No. R
R" Ar .kappa. A.sub.50(.mu.g/kg) 130 H H 301 1.3 46% @ 300 131 H H
302 0.22 -- 132 H H 303 0.25 100% @ 300 133 H OH 304 0.64 98% @ 300
134 H H 305 0.26 99% @ 300 135 H OH 306 0.66 -- 136 H H 307 0.44
97% @ 300 137 H OH 308 0.83 -- 138 H H 309 1.3 80% @ 300 139 H OH
310 4.2 -- 140 H H 311 0.56 -- 141 H OH 312 1.3 98% @ 300 142 H H
313 13 -- 143 H H 314 2.1 98% @ 300 144 H H 315 0.17 -- 122 H H 316
0.80 85% @ 300 145 H H 317 20.5 83% @ 300 123 H H 318 23.6 87% @
300 124 H H 319 5.6 77% @ 300 125 H OH 320 5.3 81% @ 300 126 H OH
321 0.61 93% @ 300 127 H OH 322 0.82 94% @ 300 128 (racemic)
4-OCH.sub.3 H 323 110 56% @ 300 129A (racemic) 4-OH H 324 59 46% @
300 129B (S-isomer) 4-OH H 325 75 >46% @ 300 146 H OH 326 1 52%
@ 300 147 (racemic) 2-F H 327 10 56% @ 300 148 H H 328 0.83 --
[0697]
8TABLE IV Compounds of Formula IV 5a-t 329 Late Phase K.sub.i(nM)
K.sub.i(nM) Formalin Compounds R diprenorphine U-69593 A.sub.50(mg)
U-50488 330 4.3 0.6 Not tested (5a) 331 596 100 Not tested (5b) 332
1031 433 Not tested (5c) 333 6.7 1.4 3.5 (5d) 334 10.6 1.7 72.0
(5e) 335 3185 675 Not tested (5f) 336 14% @ 1 .mu.M 866 Not tested
(5g) 337 77% @ 1 .mu.M 3.75 59% @ 300 .mu.g (5h) 338 59% @ 1 .mu.M
13.4 58% @ 300 .mu.g (5i) 339 43% @ 1 .mu.M 5.4 73% @ 300 .mu.g
(5j) 340 13% @ 1 .mu.M 48% @1 .mu.M Not tested (5k) 341 16% @ 1
.mu.M 216.0 Not tested (5l) 342 43.5 2.35 4.7 (5m) 343 192.5 11.25
6.2 (5n) 344 61% @ 1 .mu.M 10.85 70% @ 300 .mu.g (5o) 345 5.65 1.4
86% @ 300 .mu.g (5p) 346 53% @ 1 .mu.M 25.0 Not tested (5r) 347 50%
@ 1 .mu.M 21.0 Not tested (5s) 348 1171 330 Not tested (5t) 349 40%
@ 1 mM 96 Not tested
[0698]
9TABLE IVA Compounds of Formula IVA 5 350 Formalin (% A @ 300 .mu.g
i-paw K.sub.i(nM) or Compounds R [.sup.3H]-Diprenorphin
A.sub.50(mg/kg s.c.) 4a 351 77.0 26% @ 300 4b 352 22% @ 1 .mu.M Not
tested 4c 353 7% @ 1 .mu.M NT 4d 354 340.5 Not tested 4f 355 0% @ 1
.mu.M Not tested 4g 356 294.0 Not tested 4h 357 164.0 56% @ 300 4i
358 31% @ 1 .mu.M Not tested 4j (1S,2S) 359 10.30 91% @ 300 4k (1R,
2R) 360 28% @ 1 .mu.M 80% @ 300
FORMULATIONS OF THE PRESENT INVENTION
[0699] Effective concentrations of one or more of the compounds of
the present invention or pharmaceutically acceptable derivatives
thereof are mixed with a suitable pharmaceutical carrier or vehicle
for systemic, topical or local administration. Compounds are
included in an amount effective for reducing the hyperalgesic state
or other symptoms for which treatment is contemplated. The
concentration of active compound in the composition will depend on
absorption, inactivation, excretion rates of the active compound,
the dosage schedule, and amount administered as well as other
factors known to those of skill in the art. For topical and local
administration, the dosages are higher, typically at least about 5
to 10 fold, than the amount delivered when administered
systemically orally.
[0700] The compounds of the present invention possess analgesic
activity and can be used for the relief of pain without loss of
consciousness. For example, compounds can be used to treat muscle
spasm, arthritis and other musculoskeletal conditions, e.g.,
bursitis, relieve mild to moderate postoperative and postpartum
pain, dysmenorrhea and pain of traumatic origin.
[0701] Additionally, the compounds of the present invention can be
administered for the treatment of severe pain, e.g., pain
associated with adenocarcinoma, amputation of a limb, and third
degree burns over a major portion of the body in animals and
humans.
[0702] Selected compounds of the present invention have activity as
narcotic antagonists. They can be used to counteract or prevent
excessive central nervous system depression and respiratory
depression resulting from the administration of morphine or other
morphine-like drugs, e.g., hydromorphone, oxymorphone, methadone
and meperidine. The compounds are also capable of inducing an
abstinence syndrome in narcotic addicted subjects, i.e., induce
withdrawal effects for diagnostic purposes.
[0703] The dosage of the compound of Formulas I, IA, II, IIA, III,
IIIA, IIIB, IIIB-i, IV, and IVA for analgesic purposes is from
about 0.001 to about 20 mg/kg body weight of the patient. The
compounds of Formulas I, IA, II, IIA, III, IIIA, IIIB, IIIB-i, IV,
and IVA are conveniently prepared in 5, 10, 25, 50, 75, 100 and 200
mg dosage units for administration for 1 to 4 times a day.
Preferred unit dosages are from 0.05 to 10 mg/kg body weight of the
patient.
[0704] The compounds are administered orally, parenterally,
rectally and topically.
[0705] Pharmaceutical carriers or vehicles suitable for
administration of the compounds and for the methods provided herein
include any such carriers known to those skilled in the art to be
suitable for the particular mode of administration. In addition,
the compounds may be formulated as the sole pharmaceutically active
ingredient in the composition or may be combined with other active
ingredients.
[0706] a) Systemic Formulations
[0707] The formulations of the present invention are provided for
administration to humans and animals in unit dosage forms, such as
tablets, capsules, pills, powders, granules, sterile parenteral
solutions or suspensions, and oral solutions or suspensions, and
oil-water emulsions containing suitable quantities of a compound of
Formulas I, IA, II, IIA, III, IIIA, IIIB, IIIB-i, IV, and IVA or
pharmacologically acceptable salts thereof.
[0708] Pharmaceutical dosage unit forms are prepared to provide
from about 0.05 mg to about 500 mg and preferably from about 1.0 to
about 200 mg of the essential active ingredient or a combination of
essential ingredients per dosage unit form.
[0709] Oral pharmaceutical dosage forms are either solid or liquid.
The solid dosage forms are tablets, capsules, granules, and bulk
powders. Types of oral tablets include compressed, chewable
lozenges and tablets which may be enteric-coated, sugar-coated or
film-coated. Capsules may be hard or soft gelatin capsules, while
granules and powders may be provided in non-effervescent or
effervescent form with the combination of other ingredients known
to those skilled in the art.
[0710] Pharmaceutically acceptable carriers utilized in tablets are
binders, lubricants, diluents, disintegrating agents, coloring
agents, flavoring agents, and wetting agents. Enteric-coated
tablets, due to their enteric-coating, resist the action of stomach
acid and dissolve or disintegrate in the neutral or alkaline
intestines. Sugar-coated tablets are compressed tablets to which
different layers of pharmaceutically acceptable substances have
been applied. Film-coated tablets are compressed tablets which have
been coated with a water soluble polymers. Multiple compressed
tablets are compressed tablets made by more than one compression
cycle utilizing the pharmaceutically acceptable substances
previously mentioned. Coloring agents may also be used in the above
dosage forms. Flavoring and sweetening agents are used in
compressed tablets, sugar-coated, multiple compressed and chewable
tablets. Flavoring and sweetening agents are especially useful in
the formation of chewable tablets and lozenges.
[0711] Examples of binders include glucose solution, acacia
mucilage, gelatin solution, sucrose and starch paste. Lubricants
include talc, starch, magnesium or calcium stearate, lycopodium and
stearic acid. Diluents include, for example, lactose, sucrose,
starch, kaolin, salt, mannitol and dicalcium phosphate.
Disintegrating agents include corn starch, potato starch,
bentonite, methylcellulose, agar and carboxymethylcellulose.
Coloring agents include, for example, any of the approved certified
water soluble FD and C dyes, mixtures thereof, and water insoluble
FD and C dyes suspended on alumia hydrate. Sweetening agents
include sucrose, lactose, mannitol and artificial sweetening agents
such as sodium cyclamate and saccharin, and any number of spray
dried flavors. Flavoring agents include natural flavors extracted
from plants such as fruits and synthetic blends of compounds which
produce a pleasant sensation. Wetting agents include propylene
glycol monostearate, sorbitan monooleate, diethylene glycol
monolaurate and polyoxyethylene laural ether. Enteric-coatings
include fatty acids, fats, waxes, shellac, ammoniated shellac and
cellulose acetate phthalates. Film coatings include
hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene
glycol 4000 and cellulose acetate phthalate.
[0712] Liquid oral dosage forms include aqueous solutions,
emulsions, suspensions, solutions and/or suspensions reconstituted
from non-effervescent granules and effervescent preparations
reconstituted from effervescent granules. Aqueous solutions
include, for example, elixirs and syrups. Emulsions are either
oil-in water or water-in-oil.
[0713] Elixirs are clear, sweetened, hydroalcoholic preparations.
Pharmaceutically acceptable carriers used in elixirs include
solvents. Syrups are concentrated aqueous solutions of a sugar, for
example, sucrose, and may contain a preservative. An emulsion is a
two-phase system in which one liquid is dispersed in the form of
small globules throughout another liquid. Pharmaceutically
acceptable carriers used in emulsions are non-aqueous liquids,
emulsifying agents and preservatives. Suspensions use
pharmaceutically acceptable suspending agents and preservatives.
Pharmaceutically acceptable substances used in non-effervescent
granules, to be reconstituted into a liquid oral dosage form,
include diluents, sweeteners and wetting agents. Pharmaceutically
acceptable substance used in effervescent granules, to be
reconstituted into a liquid oral dosage form, include organic acids
and a source of carbon dioxide. Coloring and flavoring agents are
used in all of the above dosage forms.
[0714] Solvents include glycerin, sorbitol, ethyl alcohol and
syrup. Examples of preservatives include glycerin, methyl and
propylparaben, benzoic acid, sodium benzoate and alcohol. Examples
of non-aqueous liquids utilized in emulsions include mineral oil
and cottonseed oil. Examples of emulsifying agents include gelatin,
acacia, tragacanth, bentonite, and surfactants such as
polyoxyethylene sorbitan monooleate. Suspending agents include
sodium carboxymethylcellulose, pectin, tragacanth, Veegum and
acacia. Diluents include lactose and sucrose. Sweetening agents
include sucrose, syrups, glycerin and artificial sweetening agents
such as sodium cyclamate and saccharin. Wetting agents include
propylene glycol monostearate, sorbitan monooleate, diethylene
glycol monolaurate and polyoxyethylene lauryl ether. Organic acids
include citric and tartaric acid. Sources of carbon dioxide include
sodium bicarbonate and sodium carbonate. Coloring agents include
any of the approved certified water soluble FD and C dyes, and
mixtures thereof. Flavoring agents include natural flavors
extracted from plants such fruits, and synthetic blends of
compounds which produce a pleasant taste sensation.
[0715] Parenteral administration of the formulations of the present
invention includes intravenous, subcutaneous and intramuscular
administrations.
[0716] Preparations for parenteral administration include sterile
solutions ready for injection, sterile dry soluble products ready
to be combined with a solvent just prior to use, including
hypodermic tablets, sterile suspensions ready for injection,
sterile dry insoluble products ready to be combined with a vehicle
just prior to use and sterile emulsions. The solutions may be
either aqueous or nonaqueous.
[0717] Pharmaceutically acceptable carriers used in parenteral
preparations include aqueous vehicles, nonaqueous vehicles,
antimicrobial agents, isotonic agents, buffers, antioxidants, local
anesthetics, suspending and dispersing agents, emulsifying agents,
sequestering or chelating agents and other pharmaceutically
acceptable substances.
[0718] Examples of aqueous vehicles include Sodium Chloride
Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile
Water Injection, Dextrose and Lactated Ringers Injection.
Nonaqueous parenteral vehicles include fixed oils of vegetable
origin, cottonseed oil, corn oil, sesame oil and peanut oil.
Antimicrobial agents in bacteriostatic or fungistatic
concentrations must be added to parenteral preparations packaged in
multiple-dose containers which include phenols or cresols,
mercurials, benzyl alcohol, chlorobutanol, methyl and propyl
p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and
benzethonium chloride. Isotonic agents include sodium chloride and
dextrose. Buffers include phosphate and citrate. Antioxidants
include sodium bisulfate. Local anesthetics include procaine
hydrochloride. Suspending and dispersing agents include sodium
carboxymethylcelluose, hydroxypropyl methylcellulose and
polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80
(Tween 80). A sequestering or chelating agent of metal ions include
EDTA. Pharmaceutical carriers also include ethyl alcohol,
polyethylene glycol and propylene glycol for water miscible
vehicles and sodium hydroxide, hydrochloric acid, citric acid or
lactic acid for pH adjustment.
[0719] The concentration of the pharmaceutically active compound is
adjusted so that an injection provides an effective amount to
produce the desired pharmacological effect. The exact dose depends
on the age, weight and condition of the patient or animal as is
known in the art.
[0720] The unit-dose parenteral preparations are packaged in an
ampoule or a syringe with a needle.
[0721] All preparations for parenteral administration must be
sterile, as is known and practiced in the art.
[0722] Illustratively, intravenous or intraarterial infusion of a
sterile aqueous solution containing an active compound is an
effective mode of administration. Another embodiment is a sterile
aqueous or oily solution or suspension containing an active
material injected as necessary to produce the desired
pharmacological effect.
[0723] Pharmaceutical dosage forms for rectal administration are
rectal suppositories, capsules and tablets for systemic effect.
[0724] Rectal suppositories are used herein mean solid bodies for
insertion into the rectum which melt or soften at body temperature
releasing one or more pharmacologically or therapeutically active
ingredients.
[0725] Pharmaceutically acceptable substances utilized in rectal
suppositories are bases or vehicles and agents to raise the melting
point.
[0726] Examples of bases include cocoa butter (theobroma oil),
glycerin-gelatin, carbowax, (polyoxyethylene glycol) and
appropriate mixtures of mono-, di- and triglycerides of fatty
acids. Combinations of the various bases may be used. Agents to
raise the melting point of suppositories include spermaceti and
wax. Rectal suppositories may be prepared either by the compressed
method or by molding. The typical weight of a rectal suppository is
about 2 to 3 gm.
[0727] Tablets and capsules for rectal administration are
manufactured using the same pharmaceutically acceptable substance
and by the same methods as for formulations for oral
administration.
[0728] The pharmaceutically therapeutically active compounds of
Formulas I, II, III and IV are administered orally, parenterally or
rectally in unit-dosage forms or multiple-dosage forms. Unit-dose
forms as used herein refers to physically discrete units suitable
for human and animal subjects and packaged individually as is known
in the art. Each unit-dose contains a predetermined quantity of the
therapeutically active compound sufficient to produce the desired
therapeutic effect, in association with the required pharmaceutical
carrier, vehicle or diluent. Examples of unit-dose forms include
ampoules and syringes individually packaged tablet or capsule.
Unit-dose forms may be administered in fractions or multiples
thereof. A multiple-dose form is a plurality of identical
unit-dosage forms packaged in a single container to be administered
in segregated unit-dose form. Examples of multiple-dose forms
include vials, bottles of tablets or capsules or bottles of pint or
gallons. Hence, multiple dose form is a multiple of unit-doses
which are not segregated in packaging.
[0729] Compounds of the present invention in formulations may be
included with other active compounds to obtain desired combinations
of properties. Other active compounds with known pharmacological
properties include analgesics such as aspirin, phenacetin
acetaminophen, propoxyphene, pentazocine, codeine, meperidine,
oxycodone, mefenamic acid, and ibuprofen; muscle relaxants such as
methocarbamol, orphenadrine, carisoprodol, meprobamate,
chlorphenesin carbamate, diazepam, chlordiazepoxide and
chlorzoxazone; analeptics such as caffeine, methylphenidate and
pentylenetetrazol; corticosteroids such as methylprednisolone,
prednisone, prednisolone and dexamethasone; antihistamines such as
chlorpheniramine, cyproheptadine, promethazine and pyrilamine.
[0730] b) Local and Topical Formulations
[0731] Typically a therapeutically effective dosage is formulated
to contain a concentration of at least about 0.1% w/w up to about
50% w/w or more, preferably more than 1% w/w of the active compound
to the treated tissue. The active ingredient may be administered at
once, or may be divided into a number of smaller doses to be
administered at intervals of time. It is understood that the
precise dosage and duration of treatment is a function of the
tissue being treated and may be determined empirically using known
testing protocols or by extrapolation from in vivo or in vitro test
data. It is to be noted that concentrations and dosage values may
also vary with the age of the individual treated. It is to be
further understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the formulations, and that the
concentration ranges set forth herein are exemplary only and are
not intended to limit the scope or practice of the claimed
formulations.
[0732] The compound may be suspended in micronized or other
suitable form or may be derivatized to produce a more soluble
active product or to produce a prodrug. The form of the resulting
mixture depends upon a number of factors, including the intended
mode of administration and the solubility of the compound in the
selected carrier or vehicle. The effective concentration is
sufficient for ameliorating the hyperalgesic or other condition and
may be empirically determined.
[0733] Compounds are typically included at concentrations 0.001%
w/w or greater than 1% w/w up to 50% w/w or higher. The
concentration is generally greater than the concentration for
systemic administration of the compound. Preferable concentrations
are in the range of 0.01% w/w to about 25% w/w, more preferably 1%
w/w to 25% w/w, yet more preferably greater than about 1% w/w to
about 10% w/w, and most preferably greater than 1% w/w up to about
5% w/w. Aqueous suspensions and formulations contain 1% w/w or
more.
[0734] The resulting mixture may be a solution, suspension,
emulsions or the like and are formulated as creams, gels,
ointments, emulsions, solutions, elixirs, lotions, suspensions,
tinctures, pastes, foams, aerosols, irrigations, sprays,
suppositories, bandages, or any other formulations suitable for
topical or local administration.
[0735] The route of administration herein is topical or local
administration, and compositions are formulated in a manner
suitable for each route of administration. Preferred modes of
administration include topical application to the skin, eyes or
mucosa, and local application to the joints, such as by
intra-articular injection. Thus, typical vehicles are those
suitable for pharmaceutical or cosmetic application to body
surfaces or for local injection.
[0736] Pharmaceutical and cosmetic carriers or vehicles suitable
for administration of the compounds provided herein include any
such carriers known to those skilled in the art to be suitable for
the particular mode of administration. In addition, the compounds
may be formulated as the sole pharmaceutically active ingredient in
the composition or may be combined with other active ingredients.
The active compound is included in the carrier in an amount
sufficient to exert a therapeutically useful effect in the absence
of serious toxic effects on the treated individual. The effective
concentration may be determined empirically by testing the
compounds using in vitro and in vivo systems, including the animal
models described herein.
[0737] For topical administration, the compounds may be formulated
in compositions in the form of gels, creams, lotions, solids,
solutions or suspensions, or aerosols. Compositions for treating
human skin are formulated for topical application with an
anti-hyperalgesic effective amount of one or more of the compounds
selected as described herein, in an effective concentration range
[by weight], between about 0.1% and 80%, preferably 0.1 to 50%,
more preferably greater than about 1% up to about 50% or more in a
cream, ointment, lotion, gel, solution or solid base or vehicle
known in the art to be non-toxic and dermatologically acceptable or
suitable for application to the mucosa. Aqueous suspensions are
preferably formulated at concentrations greater than about 1% w/w,
more preferably 2% w/w.
[0738] To formulate a composition, the weight fraction of compound
is dissolved, suspended, dispersed or otherwise mixed in a selected
vehicle at an effective concentration such that the hyperalgesic
condition is relieved or ameliorated. Generally, emollient or
lubricating vehicles that help hydrate the skin are more preferred
than volatile vehicles, such as ethanol, that dry the skin.
Examples of suitable bases or vehicles for preparing compositions
for use with human skin are petrolatum, petrolatum plus volatile
silicones, lanolin, cold cream [USP], and hydrophilic ointment
[USP].
[0739] The choice of an acceptable vehicle is largely determined by
the mode of application and tissue to be treated. Suitable
pharmaceutically and dermatologically acceptable vehicles for
topical application include those suited for use include lotions,
creams, solutions, gels, tapes and the like. Generally, the vehicle
is either organic in nature or an aqueous emulsion and capable of
having the selected compound or compounds, which may be micronized,
dispersed, suspended or dissolved therein. The vehicle may include
pharmaceutically-acceptable emollients, skin penetration enhancers,
coloring agents, fragrances, emulsifiers, thickening agents, and
solvents.
[0740] For local internal administration, such as intra-articular
administration, the compounds are preferably formulated as a
suspension in an aqueous-based medium, such as isotonically
buffered saline or are combined with a biocompatible support or
bioadhesive intended for internal administration.
[0741] Lotions
[0742] The lotions contain an effective concentration of one or
more of the compounds. The effective concatenation is preferably
effective to deliver an anti-hyperalgesic amount, typically at a
concentration of between about 0.1-50% w/w or more of one or more
of the compounds provided herein. The lotions also contain from 1%
to 50% w/w, preferably from 3% to 15% w/w of an emollient and the
balance water, a suitable buffer, a C.sub.2 or C.sub.3 alcohol, or
a mixture of water of the buffer and the alcohol. Any emollients
known to those of skill in the art as suitable for application to
human skin may be used. These include, but are not limited to, the
following:
[0743] (a) Hydrocarbon oils and waxed, including mineral oil,
petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax,
polyethylene, and perhydrosqualene.
[0744] (b) Silicone oils, including dimethylpolysiloxanes,
methylphenylpolysiloxanes, water-soluble and alcohol-soluble
silicone-glycol copolymers.
[0745] (c) Triglyceride fats and oils, including those derived from
vegetable, animal and marine sources. Examples include, but are not
limited to, castor oil, safflower oil, cotton seed oil, corn oil,
olive oil, cod liver oil, almond oil, avocado oil, palm oil, sesame
oil and soybean oil.
[0746] (d) Acetoglyceride esters, such as acetylated
monoglycerides.
[0747] (e) Ethoxylated glycerides, such as ethoxylated glyceryl
monostearate.
[0748] (f) Alkyl esters of fatty acids having 10 to 20 carbon
atoms. Methyl, isopropyl and butyl esters of fatty acids are useful
herein. Examples include, but are not limited to, hexyl laurate,
isohexyl laurate, isohexyl palmitate, isopropyl palmitate,
isopropyl myristate, decyl oleate, isodecyl oleate, hexadecyl
stearate, decyl stearate, isopropyl isostearate diisopropyl
adipate, diisohexyl adipate, dihexyldecyl adipate, diisopropyl
sebacate, lauryl lactate, myristyl lactate, and cetyl lactate.
[0749] (g) Alkenyl esters of fatty acids having 10 to 20 carbon
atoms. Examples thereof include, but are not limited to, oleyl
myristate, oleyl stearate, and oleyl oleate.
[0750] (h) Fatty acids having 9 to 22 carbon atoms. Suitable
examples include, but are not limited to pelargonic, lauric,
myristic, palmitic, stearic, isostearic, hydroxystearic, oleic,
linoleic, ricinoleic, arachidonic, behenic, and erucic acids.
[0751] (i) Fatty alcohols having 10 to 20 carbon atoms, such as but
not limited to, lauryl, myristyl, cetyl, hexadecyl, stearyl,
isostearyl, hydroxystearyl, oleyl, ricinoleyl, behenyl, erucyl, and
2-octyl dodecyl alcohols.
[0752] (j) Fatty alcohol ethers, including, but not limited to,
ethoxylated fatty alcohols of 10 to 20 carbon atoms, such as, but
are not limited to, the lauryl cetyl, stearyl, isostearyl, oleyl,
and cholesterol alcohols having attached thereto from 1 to 50
ethylene oxide groups or 1 to 50 propylene oxide groups or mixtures
thereof.
[0753] (k) Ether-esters, such as fatty acid esters of ethoxylated
fatty alcohols.
[0754] (l) Lanolin and derivatives, including but not limited to,
lanolin, lanolin oil, lanolin wax, lanolin alcohols, lanolin fatty
acids, isopropyl lanolate, ethoxylated lanolin, ethoxylated lanolin
alcohols, ethoxylated cholesterol, propoxylated lanolin alcohols,
acetylated lanolin, acetylated lanolin alcohols, lanolin alcohols
linoleate, lanolin alcohols ricinoleate, acetate of lanolin
alcohols ricinoleate, acetate of ethoxylated alcohols-esters,
hydrogenolysis of lanolin, ethoxylated hydrogenated lanolin,
ethoxylated sorbitol lanolin, and liquid and semisolid lanolin
absorption bases.
[0755] (m) Polyhydric alcohols and polyether derivatives,
including, but not limited to, propylene glycol, dipropylene
glycol, polypropylene glycol [M.W. 2000-4000], polyoxyethylene
polyoxypropylene glycols, polyoxypropylene polyoxyethylene glycols,
glycerol, ethoxylated glycerol, propoxylated glycerol, sorbitol,
ethoxylated sorbitol, hydroxypropyl sorbitol, polyethylene glycol
[M.W. 200-6000], methoxy polyethylene glycols 350, 550, 750, 2000,
5000, poly)ethylene oxide) homopolymers [M.W. 100,000-5,000,000],
polyalkylene glycols and derivatives, hexylene glycol
(2-methyl-2,4-pentanediol), 1,3-butylene glycol, 1,2,6-hexanetriol,
ethohexadiol USP (2-ethyl-11,3-hexanediol), C.sub.15-C.sub.18
vicinal glycol and polyoxypropylene derivatives of
trimethylolpropane.
[0756] (n) Polyhydric alcohol esters, including, but not limited
to, ethylene glycol mono- and di-fatty acid esters, diethylene
glycol mono- and di-fatty acid esters, polyethylene glycol [M.W.
200-6000], mono- and di-fatty esters, propylene glycol mono- and
di-fatty acid esters, polypropylene glycol 2000 monooleate,
polypropylene glycol 2000 monostearate, ethoxylated propylene
glycol monostearate, glyceryl mono- and di-fatty acid esters,
polyglycerol poly-fatty acid esters, ethoxylated glyceryl
monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol
distearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty
acid esters, and polyoxyethylene sorbitan fatty acid esters.
[0757] (o) Wax esters, including, but not limited to, beeswax,
spermaceti, myristyl myristate, and stearyl stearate and beeswax
derivatives, including, but not limited to, polyoxyethylene
sorbitol beeswax, which are reaction products of beeswax with
ethoxylated sorbitol of varying ethylene oxide content that form a
mixture of ether-esters.
[0758] (p) Vegetable waxes, including, but not limited to, carnauba
and candelilla waxes.
[0759] (q) Phospholipids, such as lecithin and derivatives.
[0760] (r) Sterols, including, but not limited to, cholesterol and
cholesterol fatty acid esters.
[0761] (s) Amides, such as fatty acid amides, ethoxylated fatty
acid amides, and solid fatty acid alkanolamides.
[0762] The lotions further preferably contain from 1% w/w to 10%
w/w, more preferably from 2% w/w to 5% w/w, of an emulsifier. The
emulsifiers can be nonionic, anionic or cationic. Examples of
satisfactory nonionic emulsifiers include, but are not limited to,
fatty alcohols having 10 to 20 carbon atoms, fatty alcohols having
10 to 20 carbon atoms condensed with 2 to 20 moles of ethylene
oxide or propylene oxide, alkyl phenols with 6 to 12 carbon atoms
in the alkyl chain condensed with 2 to 20 moles of ethylene oxide,
mono- and di-fatty acid esters of ethylene oxides mono- and
di-fatty acid esters of ethylene glycol wherein the fatty acid
moiety contains from 10 to 20 carbon atoms, diethylene glycol,
polyethylene glycols of molecular weight 200 to 6000, propylene
glycols of molecular weight 200 to 3000, glycerol, sorbitol,
sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and
hydrophilic wax esters. Suitable anionic emulsifiers include, but
are not limited to, the fatty acid soaps, e.g. sodium, potassium
and triethanolamine soaps, wherein the fatty acid moiety contains
from 10 to 20 carbon atoms. Other suitable anionic emulsifiers
include, but are not limited to, the alkali metal, ammonium or
substituted ammonium alkyl sulfates, alkyl arylsulfonates, and
alkyl ethoxy ether sulfonates having 10 to 30 carbon atoms in the
alkyl moiety. The alkyl ethoxy ether sulfonates contain from 1 to
50 ethylene oxide units. Among satisfactory cationic emulsifiers
are quaternary ammonium, morpholinium and pyridinium compounds.
Certain of the emollients described in preceding paragraphs also
have emulsifying properties. When a lotion is formulated containing
such an emollient, an additional emulsifier is not needed, though
it can be included in the composition.
[0763] The balance of the lotion is water or a C.sub.2 or C.sub.3
alcohol, or a mixture of water and the alcohol. The lotions are
formulated by simply admixing all of the components together.
Preferably, the compound, is dissolved, suspended or otherwise
uniformly dispersed in the mixture.
[0764] Other conventional components of such lotions may be
included. One such additive is a thickening agent at a level from
1% to 10% w/w of the composition. Examples of suitable thickening
agents include, but are not limited to: cross-linked
carboxypolymethylene polymers, ethyl cellulose, polyethylene
glycols, gum, tragacanth, gum kharaya, xanthan gums and bentonite,
hydroxyethyl cellulose, and hydroxypropyl cellulose.
[0765] Creams
[0766] The creams are formulated to contain concentration effective
to deliver an anti-hyperalgesic effective amount of the compound to
the treated tissue, typically at between about 0.1%, preferably at
greater than 1% up to and greater than 50%, preferably between
about 3% and 50%, more preferably between about 5% and 15% of one
or more of the compounds provided herein. The creams also contain
from 5% to 50%, preferably from 10% to 25%, of an emollient and the
remainder is water or other suitable non-toxic carrier, such as an
isotonic buffer. The emollients, as described above for the
lotions, can also be used in the cream compositions. The cream may
also contain a suitable emulsifier, as described above. The
emulsifier is included in the composition at a level from 3% to
50%, preferably from 5% to 20%.
[0767] Solutions and Suspensions for Topical and Local
Administration
[0768] The solutions are formulated to contain an amount of one or
more compounds effective to deliver an anti-hyperalgesic amount,
typically at a concentration of between about 0.1-50% w/w,
preferably at least more than 1% w/w, more preferably more than 2%
w/w of one or more of the compounds provided herein. The balance is
water, a suitable organic solvent or other suitable solvent or
buffer. Suitable organic materials useful as the solvent or a part
of a solvent system are as follows: propylene glycol, polyethylene
glycol [M.W. 200-600], polypropylene glycol [M.W. 425-2025],
glycerine, sorbitol esters, 1,2,6-hexanetriol, ethanol,
isopropanol, diethyl tartrate, butanediol and mixtures thereof.
Such solvent systems can also contain water.
[0769] Solutions or suspensions used for local application can
include any of the following components: a sterile diluent, such as
water for injection, saline solution, fixed oil, polyethylene
glycol, glycerine, propylene glycol or other synthetic solvent;
antimicrobial agents, such as benzyl alcohol and methyl parabens;
antioxidants, such as ascorbic acid and sodium bisulfite; chelating
agnets, such as ethylenediaminetetraacetic acid [EDTA]; buffers,
such as acetates, citrates and phosphates; and agents for the
adjustment of tonicity such as sodium chloride or dextrose. Liquid
preparations can be enclosed in ampoules, disposable syringes or
multiple dose vials made of glass, plastic or other suitable
material. Suitable carriers may include physiological saline or
phosphate buffered saline [PBS], and the suspensions and solutions
may contain thickening and solubilizing agents, such as glucose,
polyethylene glycol, and polypropylene glycol and mixtures thereof.
Liposomal suspensions, may also be suitable as pharmaceutically
acceptable carriers. These may be prepared according to methods
known to those skilled in the art.
[0770] These compositions that are formulated as solutions or
suspensions may be applied to the skin, or may be formulated as an
aerosol or foam and applied to the skin as a spray-on. The aerosol
compositions typically contain from 25% to 80% w/w, preferably from
30% to 50% w/w, of a suitable propellant. Examples of such
propellants are the chlorinated, fluorinated and chlorofluorinated
lower molecular weight hydrocarbons. Nitrous oxide, carbon dioxide,
butane, and propane are also used as propellant gases. These
propellants are used as understood in the art in a quantity and
under a pressure suitable to expel the contents of the
container.
[0771] Suitably prepared solutions and suspension may also be
topically applied to the eyes and mucosa. Solutions, particularly
those intended for opthalmic use, may be formulated as 0.01%-10%
w/w isotonic solutions, pH about 5-7, with appropriate salts, and
preferably containing one or more of the compounds herein at a
concentration of about 0.1% w/w preferably greater than 1% w/w, up
to 50% w/w or more. Suitable opthalmic solutions are known [see,
e.g. U.S. Pat. No. 5,116,868, which describes typical compositions
of opthalmic irrigation solutions and solutions for topical
application]. Such solutions, which have a pH adjusted to about
7.4, contain, for example, 90-100 mM sodium chloride, 4-6 mM
dibasic potassium phosphate, 4-6 mM dibasic sodium phosphate, 8-12
mM sodium citrate, 0.5-1.5 mM magnesium chloride, 1.5-2.5 mM
calcium chloride, 15-25 mM sodium acetate, 10-20 mM D.L.-sodium
.beta.-hydroxybutyrate and 5-5.5 mM glucose.
[0772] The active compounds of the present invention can also be
mixed with other active materials, that do not impair the desired
action, or with materials that supplement the desired action,
including viscoelastic materials, such as hyaluronic acid, which is
sold under the trademark HEALON [solution of a high molecular
weight (MW of about 3 million) fraction of sodium hyaluronate;
manufactured by Pharmacia, Inc. see, e.g., U.S. Pat. Nos.
5,292,362, 5,282,851, 5,273,056, 5,229,127, 4,517,295 and
4,328,803], VISCOAT [fluorine-containing (meth) acrylates, such as,
1H, 2H, 2H-heptadecafluorodecylmethacrylate; see, e.g., U.S. Pat.
Nos. 5,278,126, 5,273,751 and 5,214,080; commercially available
from Alcon Surgical, Inc.], ORCOLON [see, e.g., U.S. Pat. No.
5,273,056; commercially available from Optical Radiation
Corporation], methylcellulose, methyl hyaluronate, polyacrylamide
and polymethacrylamide [see, e.g., U.S. Pat. No. 5,273,751]. The
viscoelastic materials are present generally in amounts ranging
from about 0.5 to 5.0% w/w, preferably 1 to 3% w/w of the conjugate
material and serve to coat and protect the treated tissues. The
compositions may also include a dye, such as methylene blue or
other inert dye, so that the composition can be seen when injected
into the eye or contacted with the surgical site during
surgery.
[0773] Gels
[0774] Gel compositions can be formulated by simply admixing a
suitable thickening agent to the previously described solution or
suspension composition. Examples of suitable thickening agents have
been previously described with respect to the lotions.
[0775] The gelled compositions contain an effective amount of one
or more of an antihyperalgesic amount, typically at a concentration
of between about 0.1-50% w/w or more of one or more of the
compounds provided therein; from 5% to 75% w/w, preferably from 10%
to 50% w/w, of an organic solvent as previously described; from
0.5% to 20% w/w, preferably from 1% to 10% w/w of the thickening
agent; the balance being water or other aqueous carrier.
[0776] Solids
[0777] Compositions of solid forms may be formulated as stick-type
compositions intended for application to the lips or other parts of
the body. Such compositions contain an effective amount of one or
more of the compounds provided therein. The amount is typically an
amount effective to deliver an anti-hyperyperalgesic amount,
typically at a concentration of between about 0.1-50% w/w or more
of one or more of the compounds provided herein. The solids also
contain from about 40% to 98% w/w, preferably from about 50% to 905
w/w, of the previously described emollients. This composition can
further contain from 1% to 20% w/w, preferably from 5% to 15% w/w,
of a suitable thickening agent, and, if desired or needed,
emulsifiers and water or buffers. Thickening agents previously
described with respect to lotions are suitably employed in the
composition in solid form.
[0778] Other ingredients such as preservatives, including
methyl-paraben or ethyl-paraben, perfumes, dyes or the like, that
are known in the art to provide desirable stability, fragrance or
color, or other desirable properties, such as shielding from
actinic rays from the sun, to compositions for application to the
skin may also be employed in a composition for such topical
application.
[0779] Additional Ingredients
[0780] 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:
[0781] a. Antibacterial Agents
[0782] 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;
[0783] Amphenicols, such as Azidamfenicol, Chloramphenicol,
Chloramphenicol Palmirate, Chloramphenicol Pantothenate,
Florfenicol, Thiamphenicol;
[0784] Ansamycins, such as Rifamide, Rifampin, Rifamycin and
Rifaximin;
[0785] .beta.-Lactams;
[0786] Carbapenems, such as Imipenem;
[0787] Cephalosporins, such as 1-Carba (dethia) Cephalosporin,
Cefactor, Cefadroxil, Cefamandole, Cefatrizine, Cefazedone,
Cefazolin, Cefixime, Cefinenoxime, Cefodizime, Cefonicid,
Cefoperazone, Ceforanide, Cefotaxime, Cefotiam, Cefpimizole,
Cefpirimide, Cefpodoxime Proxetil, Cefroxadine, Cefsulodin,
Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftizoxime,
Ceftriaxone, Cefuroxime, Cefuzonam, Cephacetrile Sodium,
Cephalexin, Cephaloglycin, Cephaloridine, Cephalosporin,
Cephalothin, Cephapirin Sodium, Cephradine and Pivcefalexin;
[0788] Cephamycins such as Cefbuperazone, Cefinetazole, Cefminox,
Cefetan and Cefoxitin;
[0789] Monobactams such as Aztreonam, Carumonam and Tigemonan;
[0790] Oxacephems such as Flomoxef and Moxolactam;
[0791] 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;
[0792] Lincosamides such as Clindamycin and Lincomycin;
[0793] Macrolides such as Azithromycin, Carbomycin, Clarithromycin,
Erythromycin(s) and Derivatives, Josamycin, Leucomycins,
Midecamycins, Miokamycin, Oleandomycin, Primycin, Rokitamycin,
Rosaramicin, Roxithromycin, Spiramycin and Troleandomycin;
[0794] Polypeptides such as Amphomycin, Bacitracin, Capreomycin,
Colistin, Enduracidin, Enviomycin, Fusafungine, Gramicidin(s),
Gramicidin S, Mikamycin, Polymyxin, Polymyxin B-Methanesulfonic
Acid, Pristinamycin, Ristocetin, Teicoplanin, Thiostrepton,
Tuberactinomycin, Tyrocidine, Tyrothricin, Vancomycin, Viomycin(s),
Virginiamycin and Zinc Bacitracin;
[0795] Tetracyclines such as Spicycline, Chlortetracycline,
Clomocycline, Demeclocycline, Doxycycline, Guamecycline,
Lymecycline, Meclocycline, Methacycline, Minocycline,
Oxytetracycline, Penimepicycline, Pipacycline, Rolitetracycline,
Sancycline, Senociclin and Tetracycline; and
[0796] others such as Cycloserine, Mupirocin, Tuberin.
[0797] b. Synthetic Antibacterials
[0798] 2,4-Diaminopyrimidines such as Brodimoprim, Tetroxoprim and
Trimethoprim;
[0799] Nitrofurans such as Furaltadone, Furazolium, Nifuradene,
Nifuratel, Nifurfoline, Nifurpirinol, Nifurprazine, Nifurtoinol and
Nitrofurantoin;
[0800] 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;
[0801] Sulfonamides such as Acetyl Sulfamethoxypyrazine, Acetyl
Sulfisoxazole, Azosulfamide, Benzylsulfamide, Chloramine-.beta.,
Chloramine-T, Dichloramine-T, Formosulfathiazole,
N.sup.2-Formyl-sulfisom- idine,
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,
Sulfanilamidomethanesul- fonic Acid Triethanolamine Salt,
4-Sulfanilamidosalicyclic Acid, N.sup.4-Sulfanilylsulfanilamide,
Sulfanilylurea, N-Sulfanilyl-3,4-xylamid- e, Sulfanitran,
Sulfaperine, Sulfaphenazole, Sulfaproxyline, Sulfapyrazine,
Sulfapyridine, Sulfasomizole, Sulfasymazine, Sulfathiazole,
Sulfathiourea, Sulfatolamide, Sulfisornidine and Sulfisoxazole;
[0802] Sulfones, such as Acedapsone, Acediasulfone, Acetosulfone,
Dapsone, Diathymosulfone, Glucosulfone, Solasulfone, Succisulfone,
Sulfanilic Acid, p-Sulfanilylbenzylamine,
p,p'-sulfonyldianiline-N,N'digalactoside, Sulfoxone and
Thiazolsulfone;
[0803] Others such as Clofoctol, Hexedine, Magainins, Methenamine,
Methenamine Anhydromethylene-citrate, Methenamine Hippurate,
Methenamine Mandelate, Methenamine Sulfosalicylate, Nitroxoline,
Squalamine and Xibornol.
[0804] c. Antifungal (Antibiotics)
[0805] 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.
[0806] d. Antifungal (Synthetic)
[0807] Allylamines such as Naftifine and terbinafine;
[0808] Imidazoles such as Bifonazole, Butoconazole, Chlordantoin,
Chlormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole,
Finticonazole, Isoconazole, Ketoconazole, Miconazole, Omoconazole,
Oxiconazole Nitrate, Sulconazole and Tioconazole;
[0809] Triazoles such as Fluconazole, Itraconazole,
Terconazole;
[0810] 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.
[0811] e. Antiglaucoma Agents
[0812] Antiglaucoma agents, such as Dapiprazoke, Dichlorphenamide,
Dipivefrin and Pilocarpine.
[0813] f. Anti-Inflammatory Agents
[0814] Corticosteroids, aminoarylcarboxylic Acid Derivatives such
as Etofenamate, Meclofenamic Acid, Mefanamic Acid, Niflumic
Acid;
[0815] 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;
[0816] Arylbutyric Acid Derivatives such as Butibufen and
Fenbufen;
[0817] Arylcarboxylic Acids such as Clidanac, Ketorolac and
Tinoridine;
[0818] Arylpropionic Acid Derivatives such as Bucloxic Acid,
Carprofen, Fenoprofen, Flunoxaprofen, Ibuprofen, Ibuproxam,
Oxaprozin, Piketoprofen, Pirprofen, Pranoprofen, Protizinic Acid
and Tiaprofenic Acid;
[0819] Pyrazoles such as Mepirizole;
[0820] Pyrazolones such as Clofezone, Feprazone, Mofebutazone,
Oxyphenbutazone, Phenylbutazone, Phenyl Pyrazolidininones,
Suxibuzone and Thiazolinobutazone;
[0821] Salicylic Acid Derivatives such as Bromosaligenin, Fendosal,
Glycol Salicylate, Mesalamine, 1-Naphthyl Salicylate, Olsalazine
and Sulfasalazine;
[0822] Thiazinecarboxamides such as Droxicam, Isoxicam and
Piroxicam;
[0823] 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.
[0824] g. Antiseptics
[0825] Guanidines such as Alexidine, Ambazone, Chlorhexidine and
Picloxydine;
[0826] 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;
[0827] Nitrofurans such as Furazolidone,
2-(Methoxymethyl)-5-Nitrofuran, Nidroxyzone, Nifuroxime, Nifurzide
and Nitrofurazone;
[0828] Phenols such as Acetomeroctol, Chloroxylenol,
Hexachlorophene, 1-Naphthyl Salicylate, 2,4,6-Tribromo-m-cresol and
3',4',5-Trichlorosalicylanilide;
[0829] Quinolines such as Aminoquinuride, Chloroxine,
Chlorquinaldol, Cloxyquin, Ethylhydrocupreine, Halquinol,
Hydrastine, 8-Hydroxyquinoline and Sulfate; and
[0830] others, such as Boric Acid, Chloroazodin, m-Cresyl Acetate,
Cupric sulfate and Ichthammol.
[0831] h. Antivirals
[0832] 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;
[0833] Others such as Acetylleucine Monoethanolamine, Acridinamine,
Alkylisooxazoles, Amantadine, Amidinomycin, Cuminaldehyde
Thiosemicarbzone, Foscarnet Sodium, Kethoxal, Lysozyme,
Methisazone, Moroxydine, Podophyllotoxin, Ribavirin, Rimantadine,
Stallimycin, Statolon, Thymosins, Tromantadine and Xenazoic
Acid.
[0834] Combinations and Kits
[0835] The compounds and compositions containing the compounds may
also be coated on bandages, mixed with bioadhesives or included in
dressings. Thus, combinations of bandages, bioadhesives, dressings
and other such materials and the compositions formulated as
described herein are provided. Kits containing these combinations,
which may also include compositions containing the above listed
agents, are also provided.
[0836] Articles of Manufacture
[0837] The compounds and compositions provided herein may be
packaged as articles of manufacture containing packaging material,
one or more of the compounds provided herein, which is effective
for ameliorating peripheral hyperalgesia, within the packaging
material, and a label that indicates that the compound, N-oxide,
acid, salt or other derivative thereof is used for treating
hyperalgesic conditions.
[0838] Methods of Treatment
[0839] Compositions for use with human skin preferably may be
applied at least once per day, or if necessary, to achieve the
desired result, more often, to the areas of the skin for which
treatment is sought. It is understood that the precise treatment
regimen depends upon the individual treated and may be ascertained
empirically depending upon the formulation, and particularly, the
age of the treated individual. Any regimen is acceptable as long as
the desired anti-hyperalgesic effects are achieved without
substantial deleterious or sustained undesirable side effects.
[0840] The methods for treating human skin are practiced by
applying to the skin, preferably at least daily, a composition
suitable for human skin treatment or treatment of mucosal membranes
and other body surface tissues, including the vagina, rectum,
mouth, eyes and other such tissues. The compositions may be
injected into joints or other inflamed areas.
[0841] Compositions may be combined with bandages, bioadhesives and
other dressings and applied to the body in combination
therewith.
[0842] The following examples are included for illustrative
purposes only and are not intended to limit the scope of the
invention.
EXAMPLE A
Capsules
[0843]
10 Active Compound 2.5 gm Corn starch 23.0 gm Lactose 145.0 gm Talc
15.0 gm Magnesium stearate 3.0 gm
[0844] The ingredients were mixed and were encapsulated using
techniques practiced in the art.
EXAMPLE B
Tablet
[0845]
11 Active Compound 150 gm Lactose 125 gm Corn starch 50 gm
Magnesium stearate 2.0 gm Liquid Petrolatum 2.0 gm
[0846] The ingredients were mixed, then put through U.S. Standard
Screens to produce fine granules. The granules were compressed into
tablets, each tablet containing about 150 mg of an active compound
of the present invention.
EXAMPLE C
Syrup
[0847]
12 Active Compound 25 gm Lemon Oil 2 ml Sucrose 650 gm Citric Acid
4 gm Benzoic Acid 3 gm Tragacanth 16 gm Deionized water q.s. 1000
ml
[0848] The ingredients, without the active compound, are dispersed
in water to make about 800 to 900 ml of solution. The active
compound is then added and the solution is stirred into a syrup.
Water is then added to make 1000 ml of the syrup.
EXAMPLE D
Parenteral Solution
[0849]
13 Active Compound 30 gm Methylparaben 3 gm Propylparaben 1 gm
Lidocaine 5 gm Deionized water q.s. 1000 ml
[0850] The ingredients are dissolved in water to provide a solution
followed by sterilization by filtration.
EXAMPLE E
Rectal Suppository
[0851]
14 Active Compound 80 gm Propylene glycol 95 gm Polyethylene glycol
4000 1800 gm
[0852] The active compound is added to the propylene glycol and
milled until a finely divided uniform mixture is formed. The
polyethylene glycol 4000 is melted and the propylene glycol
dispersion is added with stirring to obtain a suspension. The
suspension is poured into molds, allowed to solidify and removed
from the molds for packaging.
EXAMPLE F
Water-Washable Ointment
[0853]
15 Active Compound 1.4% w/w Lanolin alcohol 0.15 w/w Emulsifying
wax NF 7.5% w/w PEG-20 glycerides 5.0% w/w Petrolatum 86.0% w/w
[0854] The ingredients are melted together and mixed well until the
resulting ointment congeals.
EXAMPLE G
Oil-in-Water Cream
[0855]
16 Active Compound 10.0% w/w Benzyl alcohol 4.0% w/w Propylene
glycol 10.0% w/w Polyethylene glycol 400 10.0% w/w Petrolatum 20.0%
w/w Stearyl alcohol 10.0% w/w Poloxamer 10.0% w/w Water q.s. 100
Buffer to pH 7.0% w/w
[0856] In preparing the oil-in-water cream, water, propylene glycol
and polyethylene glycol 400 are heated to about 70 to 80.degree.
C., followed by adding a mixture of petrolatum, stearyl alcohol and
poloxamer and the mixture is stirred until homogeneous. The active
compound in benzyl alcohol is added and the mixture is homogenized.
The pH is then adjusted with a buffer to about 7.0.
EXAMPLE H
Aqueous Gel
[0857]
17 Active Compound 10.0% w/w Benzyl alcohol 4.0% w/w Hydroxyethyl
cellulose 3.0% w/w Water q.s. 100 Buffer to pH 7.0% w/w
[0858] The aqueous gel is prepared by mixing the active compound,
benzyl alcohol and adding the mixture to buffered water.
Hydroxyethyl cellulose is then added with stirring until the
mixture gels.
[0859] The disclosures of each patent, patent application and
publication cited or described in this document are hereby
incorporated herein by reference, in their entirety.
[0860] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims.
* * * * *