U.S. patent application number 12/319570 was filed with the patent office on 2009-05-14 for method for treating congestive heart failure.
This patent application is currently assigned to Synvista Therapeutics, Inc.. Invention is credited to John Egan, Sheng Ding Fang, Martin Gall, Sara Vasan, Dilip Wagle, Parmod Wagle.
Application Number | 20090124674 12/319570 |
Document ID | / |
Family ID | 27499106 |
Filed Date | 2009-05-14 |
United States Patent
Application |
20090124674 |
Kind Code |
A1 |
Egan; John ; et al. |
May 14, 2009 |
Method for treating congestive heart failure
Abstract
Provided, among other things, is a method of treating or
ameliorating or preventing an indication of the invention in an
animal, including a human comprising administering an effective
amount of a compound of the formula I: ##STR00001##
Inventors: |
Egan; John; (New York,
NY) ; Vasan; Sara; (New York, NY) ; Gall;
Martin; (Morristown, NJ) ; Fang; Sheng Ding;
(Mount kisco, NY) ; Wagle; Dilip; (Pune, IN)
; Wagle; Parmod; (Pune, IN) |
Correspondence
Address: |
MINTZ, LEVIN, COHN, FERRIS, GLOVSKY AND POPEO, P.C
ONE FINANCIAL CENTER
BOSTON
MA
02111
US
|
Assignee: |
Synvista Therapeutics, Inc.
Montvale
NY
|
Family ID: |
27499106 |
Appl. No.: |
12/319570 |
Filed: |
January 9, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10873056 |
Jun 21, 2004 |
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12319570 |
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09905188 |
Jul 13, 2001 |
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10873056 |
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60296435 |
Jun 6, 2001 |
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60259431 |
Dec 29, 2000 |
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60259242 |
Jan 2, 2001 |
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60218273 |
Jul 13, 2000 |
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Current U.S.
Class: |
514/367 ;
514/365 |
Current CPC
Class: |
A61K 31/421 20130101;
A61P 25/00 20180101; A61K 31/427 20130101; A61P 1/02 20180101; A61P
13/12 20180101; A61P 29/00 20180101; C07D 233/54 20130101; A61P
9/04 20180101; A61P 35/00 20180101; A61P 15/10 20180101; A61K
31/426 20130101; A61P 9/14 20180101; A61P 19/02 20180101; A61P 9/10
20180101; A61P 25/02 20180101; A61K 31/422 20130101; A61P 27/02
20180101; A61P 19/00 20180101; C07D 277/60 20130101; A61P 3/10
20180101; C07D 277/22 20130101; C07D 277/62 20130101; A61P 9/12
20180101; A61K 31/501 20130101; A61P 27/00 20180101; A61K 31/4164
20130101; A61P 17/00 20180101; A61K 31/4178 20130101; A61K 31/428
20130101; A61P 21/00 20180101; A61K 31/541 20130101; A61K 31/496
20130101; A61K 31/5377 20130101; A61P 9/00 20180101 |
Class at
Publication: |
514/367 ;
514/365 |
International
Class: |
A61K 31/426 20060101
A61K031/426; A61K 31/428 20060101 A61K031/428; A61P 9/00 20060101
A61P009/00 |
Claims
1. A method of treating or ameliorating congestive heart failure in
an subject in need thereof, comprising administering a
therapeutically effective amount of a pharmaceutical composition
comprising a compound of the formula I: ##STR00019## wherein
R.sup.1 and R.sup.2 are (a) independently selected from hydrogen,
acyloxyalkyl, alkenyl, alkyl, amino, (C.sub.2-C.sub.6)hydroxyalkyl,
and Ar, wherein Ar is C.sub.6 or C.sub.10 aryl; or (b) together
with their ring carbons R.sup.1 and R.sup.2 form a C.sub.6- or
C.sub.10-aromatic fused ring system; or (c) together with their
ring carbons R.sup.1 and R.sup.2 form a C.sub.5-C.sub.7 fused
cycloalkyl ring having up to two double bonds including the fused
double bond of the -olium or -onium containing ring, which
cycloalkyl ring can be substituted by one or more of the group
consisting of alkyl, alkoxycarbonyl, amino, aminocarbonyl, carboxy,
fluoro, or oxo substituents; Z is (a) hydrogen, or alkyl; or (b) or
a group of the formula --NR.sup.3R.sup.4; wherein R.sup.3 and
R.sup.4 are hydrogen; Y is (a) amino, or (b) a group of the formula
--CH(R.sup.5)--R.sup.6 wherein R.sup.5 is hydrogen or alkyl-;
R.sup.6 is (a) hydrogen, alkyl, wherein alkyl is optionally
substituted with alkoxycarbonyl, alkynyl, or Rs, wherein Rs is a
C.sub.6 or C.sub.10 aryl or a heterocycle containing 4-10 ring
atoms of which 1-3 are heteroatoms selected from the group
consisting of oxygen, nitrogen and sulfur; or (b) a group of the
formula --W--R.sup.7, wherein R.sup.7 is alkyl, alkoxy, hydroxy or
Rs, wherein W is --C(.dbd.O)--; (c) a group of the formula
--CH(OH)Rs; or (d) a group of the formula --W--N(R.sup.9)R.sup.10,
wherein [a] R.sup.9 is hydrogen and R.sup.10 is alkyl or
cycloalkyl, optionally substituted with (i) [C.sub.6 or
C.sub.10]aryl, or (ii) a 5- or 6-membered heteroaryl ring, wherein
the 6-membered heteroaryl ring contains one to three atoms of N,
and the 5-membered heteroaryl ring contains from one to three atoms
of N or one atom of O or S and zero to two atoms of N, said
heteroaryl ring can be optionally substituted with one or more
1-pyrrolidinyl, 4-[C.sub.6 or C.sub.10]arylpiperazin-1-yl,
4-[C.sub.6 or C.sub.10]arylpiperidin-1-yl, azetidin-1-yl, and
morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or
(C.sub.1-C.sub.3) alkylenedioxy groups, or fused to a substituted
phenyl or pyridine ring, wherein the ring fusion is at a
carbon-carbon double bond of the heteroaryl ring, or (iii) a
heterocycle containing 4-10 ring atoms of which 1-3 are heteroatoms
selected from the group consisting of oxygen, nitrogen and sulfur;
or [b] R.sup.9 is hydrogen and R.sup.10 is Ar; or [c] R.sup.9 and
R.sup.10 are both alkyl groups; or [d] R.sup.9 and R.sup.10
together with N form a heterocycle containing 4-10 ring atoms which
can incorporate up to one additional heteroatom selected from the
group of N, O or S in the ring, wherein the heterocycle is
optionally substituted with (C.sub.6- or C.sub.10)aryl, (C.sub.6-
or C.sub.10)arylalkyl, or a 5- or 6-membered heteroaryl ring,
wherein the 6-membered heteroaryl ring contains one to three atoms
of N, and the 5-membered heteroaryl ring contains from one to three
atoms of N or one atom of O or S and zero to two atoms of N, each
such heteroaryl can be optionally substituted with one or more
1-pyrrolidinyl, 4-[C.sub.6 or C.sub.10]arylpiperazin-1-yl,
4-[C.sub.6 or C.sub.10] arylpiperidin-1-yl, azetidin-1-yl,
morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or
(C.sub.1-C.sub.3)alkylenedioxy; or [f] R.sup.9 and R.sup.10 are
both hydrogen; Q is S; M is absent; X is a pharmaceutically
acceptable anion, or a pharmaceutically acceptable salt of the
compound, wherein aryl or Ar is optionally substituted with, in
addition to any substitutions specifically noted, one or more
substituents selected from the group consisting of acylamino,
acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino,
(C.sub.1-C.sub.3)alkylenedioxy, alkylsulfonyl, alkylsulfinyl,
.omega.-alkylenesulfonic acid, alkylthio, allyl, amino, ArC(O)--,
ArC(O)NH--, ArO--, Ar--, Ar-alkyl-, carboxy, carboxyalkyl,
cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy,
(C.sub.2-C.sub.6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic
acid, 1-pyrrolidinyl, 4-[C.sub.6 or C.sub.10]arylpiperazin-1-yl,
4-[C.sub.6 or C.sub.10]arylpiperidin-1-yl, azetidin-1-yl,
morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl; and wherein
heterocycle, except those of Ar, is optionally substituted with, in
addition to any substitutions specifically noted, acylamino,
alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,
alkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, amino,
ArC(O)--, ArO--, Ar--, carboxy, dialkylamino, fluoro, fluoroalkyl,
difluoroalkyl, hydroxy, mercapto, sulfamoyl, or trifluoromethyl;
and a pharmaceutically acceptable carrier, thereby treating or
ameliorating said congestive heart failure.
2. The method of claim 1, comprising administering a compound,
wherein R.sup.1 and R.sup.2 are both alkyl.
3. The method of claim 2, wherein alkyl is methyl.
4. The method of claim 1, comprising administering a compound,
wherein Z is hydrogen.
5. The method of claim 1, comprising administering a compound,
wherein Y is --CH.sub.2--C(.dbd.O)--Rs.
6. The method of claim 5, comprising administering a compound,
wherein Rs is C.sub.6 aryl.
7. The method of claim 1, wherein the compound is
3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium salt.
8. The method of claim 7, wherein the compound is
3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride.
9. The method of claim 7, wherein the compound is
3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide.
10. The method of claim 1, wherein the congestive heart failure is
associated with diastolic dysfunction.
11. The method of claim 1, wherein the congestive heart failure is
associated with left ventricle stiffening.
12. The method of claim 1, wherein the treatment or amelioration of
said congestive heart failure, breaks, reduces or inhibits the
formation of advanced glycoslyation end products or advanced
glycoslyation end product-mediated crosslinks.
13. The method of claim 1, wherein said subject is a mammal.
14. The method of claim 13, wherein said mammal is a human.
15. The method of claim 1, wherein the pharmaceutical composition
is administered via oral, parenteral, sublingual, buccal, rectal,
nasal, inhalation, ocular, vaginal, topical, pulmonary,
intramuscular, subcutaneous, intraperitoneal, intraarterial,
intravenous or intrathecal routes.
16. The method of claim 15, wherein the pharmaceutical composition
is administered orally as a tablet, chewable tablet, capsule, or
lozenge.
17. The method of claim 1, wherein the therapeutically effective
amount is from about 0.7 mg to about 280 mg daily.
18. The method of claim 1, wherein the therapeutically effective
amount is from about 0.5 mg to about 210 mg daily.
19. The method of claim 1, wherein the therapeutically effective
amount is 0.1 mg/kg to 4 mg/kg body weight daily.
20. The method of claim 19, wherein the therapeutically effective
amount is 1 mg/kg body weight daily.
Description
[0001] This patent application is a divisional application of U.S.
patent application Ser. No. 10/873,056, filed Jun. 21, 2004, which
is a continuation of U.S. patent application Ser. No. 09/905,188,
filed Jul. 13, 2001, which claims the benefit of U.S. Ser. No.
60/296,435, filed Jun. 6, 2001; U.S. Ser. No. 60/259,431, filed
Dec. 29, 2000; U.S. Ser. No. 60/259,242, filed Jan. 2, 2001; U.S.
Ser. No. 60/218,273, filed Jul. 13, 2000, each of which is
incorporated herein by reference in its entirety.
[0002] The present invention relates to methods for treating
certain fibrotic diseases or other indications.
[0003] Glucose and other sugars react with proteins by a
non-enzymatic, post-translational modification process called
non-enzymatic glycosylation. At least a portion of the resulting
sugar-derived adducts, called advanced glycosylation end products
(AGEs), mature to a molecular species that is very reactive, and
can readily bind to amino groups on adjacent proteins, resulting in
the formation of AGE cross-links between proteins. Recently a
number of classes of compounds have been identified whose members
inhibit the formation of the cross-links, or in some cases break
the cross-links. These compounds include, for example, the
thiazolium compounds described in U.S. Pat. No. 5,853,703. As AGEs,
and particularly the resulting cross-links, are linked to several
degradations in body function linked with diabetes or age, these
compounds have been used, with success, in animal models for such
indications. These indications include loss of elasticity in blood
vasculature, loss of kidney function and retinopathy.
[0004] Now, as part of studies on these compounds, it has been
identified that these compounds inhibit the formation of bioactive
agents, such as growth factors and inflammatory mediators, that are
associated with a number of indications. These agents include
vascular endothelial growth factor (VEGF) and TGF[beta]. As a
result, a number of new indications have been identified for
treatment with agents that inhibit the formation of, or more
preferably break, AGE-mediated cross-links. It is not unreasonable
to infer that the effects seen are due to the removal of
AGE-related molecules that provide a stimulus for the production or
release of these growth factors. Removal of such molecules is
believed to proceed in part due to the elimination of AGE-related
cross-links that lock the AGE-modified proteins in place. Moreover,
such compounds also reduce the expression of collagen in conditions
associated with excess collagen production. Regardless of the
mechanism, now provided are new methods of treating a number of
indications.
SUMMARY OF THE INVENTION
[0005] In one embodiment, the invention relates to a method of
treating or ameliorating or preventing an indication of the
invention in an animal, including a human comprising administering
an effective amount of a compound of the formula I:
##STR00002##
wherein the substituent groups are defined below. The invention
also relates to compounds of formula I.
[0006] The compounds used in the methods described here are first
agents, which are those described with reference to formula I, or
second agents, which are aminoguanidine or those compounds
described with reference to formula I. The second agents can be
used as an adjunct to treatment with a first agent, or as the
primary effective agent where noted.
[0007] Second agents are aminoguanidine or a compound of the
aminoguanidine class of formula A
##STR00003##
wherein R is an alkyl group, or a group of the formula
--N(R.sup.4)(R.sup.5) wherein R.sup.4 is hydrogen, and R.sup.5 is
an alkyl group or a hydroxyalkyl group; or R.sup.4 and R.sup.5
together with the nitrogen atom are a heterocyclic group containing
4-6 carbon atoms and, in addition to the nitrogen atom, 0-1 oxygen,
nitrogen or sulfur atoms; R.sup.1 is hydrogen or an amino group;
R.sup.2 is hydrogen or an amino group; R.sup.3 is hydrogen or an
alkyl group, wherein R and R.sup.1 cannot both be amino groups.
Preferably at least one of R.sup.1, R.sup.2, and R.sup.3 is other
than hydrogen. The compounds can be used as their pharmaceutically
acceptable acid addition salts, and mixtures of such compounds.
When aminoguanidine compounds are administered, they can be
administered by any route of pharmaceutical administration
including those discussed below for other first agents.
DETAILED DESCRIPTION OF THE INVENTION
[0008] Provided is a method of treating or ameliorating an
indication of the invention in an animal, including a human,
comprising administering an effective amount of (A) a compound of
the formula I:
##STR00004##
[0009] wherein
a. R.sup.1 and R.sup.2 are [0010] 1. independently selected from
hydrogen, acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl,
alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,
alkylamino, (C.sub.1-C.sub.3)alkylenedioxy, allyl, amino,
.omega.-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl,
cycloalkyl, dialkylamino, halo, hydroxy,
(C.sub.2-C.sub.6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic
acid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl,
azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl,
4-[C.sub.6 or C.sub.10]arylpiperidin-1-yl, 4-[C.sub.6 or
C.sub.10]arylpiperazin-1-yl, Ar {wherein, consistent with the rules
of aromaticity, Ar is C.sub.6 or C.sub.10 aryl or a 5- or
6-membered heteroaryl ring, wherein 6-membered heteroaryl ring
contains one to three atoms of N, and the 5-membered heteroaryl
ring contains from one to three atoms of N or one atom of O or S
and zero to two atoms of N, each heteroaryl ring can be fused to a
benzene, pyridine, pyrimidine, pyridazine, pyrazine, or
(1,2,3)triazine (wherein the ring fusion is at a carbon-carbon
double bond of Ar)}, Ar-alkyl, Ar--O, ArSO.sub.2--, ArSO--, ArS--,
ArSO.sub.2NH--, ArNH, (N--Ar)(N-alkyl)N--, ArC(O)--, ArC(O)NH--,
ArNH--C(O)--, and (N--Ar)(N-alkyl)N--C(O)--, or together R.sub.1
and R.sub.2 comprise methylenedioxy [in one embodiment,
independently selected from hydrogen, acylamino, acyloxyalkyl,
alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, (C.sub.1-C.sub.3)alkylenedioxy, allyl,
.omega.-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl,
cycloalkyl, halo, hydroxy, (C.sub.2-C.sub.6)hydroxyalkyl, mercapto,
nitro, sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl,
alkylthio, trifluoromethyl, Ar {wherein, consistent with the rules
of aromaticity, Ar is C.sub.6 or C.sub.10 aryl or a 5- or
6-membered heteroaryl ring, wherein 6-membered heteroaryl ring
contains one to three atoms of N, and the 5-membered heteroaryl
ring contains from one to three atoms of N or one atom of O or S
and zero to two atoms of N, each heteroaryl ring can be fused to a
benzene, pyrimidine, pyridazine, pyrazine, or (1,2,3)triazine
(wherein the ring fusion is at a carbon-carbon double bond of Ar)},
Ar-alkyl, Ar--O, ArSO.sub.2--, ArSO--, ArS--, ArSO.sub.2NH--, ArNH,
(N--Ar)(N-alkyl)N--, ArC(O)--, ArC(O)NH--, ArNH--C(O)--, and
(N--Ar)(N-alkyl)N--C(O)--]; or [0011] 2. together with their ring
carbons form a C.sub.6- or C.sub.10-aromatic fused ring system; or
[0012] 3. together with their ring carbons form a C.sub.5-C.sub.7
fused cycloalkyl ring having up to two double bonds including the
fused double bond of the -olium or -onium containing ring, which
cycloalkyl ring can be substituted by one or more of the group
consisting of alkyl, alkoxycarbonyl, amino, aminocarbonyl, carboxy,
fluoro, or oxo substituents [in one embodiment, together with their
ring carbons form a C.sub.5-C.sub.7 fused cycloalkyl ring having up
to two double bonds including the fused double bond of the -olium
or -onium containing ring, which cycloalkyl ring can be substituted
by one or more of the group consisting of alkyl, alkoxycarbonyl,
aminocarbonyl, carboxy, fluoro, or oxo substituents]; or [0013] 4.
together with their ring carbons form a 5- or 6-membered heteroaryl
ring, wherein the 6-membered heteroaryl ring contains one to three
atoms of N, and the 5-membered heteroaryl ring contains from one to
three atoms of N or one atom of O or S and zero to two atoms of N,
each heteroaryl ring may be optionally substituted with one or more
1-pyrrolidinyl-, 4-[C.sub.6 or C.sub.10]arylpiperazin-1-yl,
4-[C.sub.6 or C.sub.10]arylpiperidin-1-yl, azetidin-1-yl,
morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or
(C.sub.1-C.sub.3)alkylenedioxy groups [in one embodiment, together
with their ring carbons form a 5- or 6-membered heteroaryl ring,
wherein the 6-membered heteroaryl ring contains one to three atoms
of N, and the 5-membered heteroaryl ring contains from one to three
atoms of N or one atom of O or S and zero to two atoms of N, each
heteroaryl ring may be optionally substituted with one or more halo
or (C.sub.1-C.sub.3)alkylenedioxy groups]; or [0014] 5. together
with their ring carbons form a five to eight membered heterocycle,
wherein the heterocycle consists of ring atoms selected from the
group consisting of carbon, nitrogen, and S(O).sub.n, where n=0, 1,
or 2; b. Z is [0015] 1. hydrogen, alkyl, Ar--CH.sub.2; [0016] 2. a
group of the formula --NR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4
may be independently hydrogen, alkyl, Ar, or Ar-alkyl-; [0017] 3. a
group of the formula --CH(OR.sup.11)R.sup.12, wherein R.sup.11 is
hydrogen, methyl, ethyl or CH.sub.3C(O)--; and R.sup.12 is [C.sub.1
to C.sub.6]alkyl, Ar, or CO.sub.2R.sup.13 wherein R.sup.13 is
hydrogen methyl or ethyl; [0018] 4. a group of the formula
--C(CO.sub.2R.sup.13)(OR.sup.11)R.sup.12 [0019] 5. a group of the
formula --CH.sub.2WAr, wherein W is --(C.dbd.O)-- or --S(O).sub.n--
where n=1 or 2; or [0020] 6. a group of the formula
--CH.sub.2C.dbd.C--R.sup.14, wherein R.sup.14 is
(C.sub.1-C.sub.6)alkyl; c. Y is [0021] 1. amino, or [0022] 2. a
group of the formula --CH(R.sup.5)--R.sup.6 wherein [0023] (a)
R.sup.5 is hydrogen, alkyl-, cycloalkyl-, alkenyl-, alkynyl-,
aminoalkyl-, dialkylaminoalkyl-, (N--[C.sub.6 or
C.sub.10]aryl)(N-alkyl)aminoalkyl-, piperidin-1-ylalkyl-,
1-pyrrolidinylalkyl, azetidinylalkyl, 4-alkylpiperazin-1-ylalkyl,
4-alkylpiperidin-1-ylalkyl, 4-[C.sub.6 or
C.sub.10]arylpiperazin-1-ylalkyl, 4-[C.sub.6 or
C.sub.10]arylpiperidin-1-ylalkyl, azetidin-1-ylalkyl,
morpholin-4-ylalkyl, thiomorpholin-4-ylalkyl, piperidin-1-ylalkyl,
[C.sub.6 or C.sub.10C]aryl, or independently the same as R.sup.6
[in one embodiment, hydrogen or alkyl]; [0024] (b) R.sup.6 is
[0025] (1) hydrogen, alkyl (which can be substituted by
alkoxycarbonyl), alkenyl, alkynyl, cyano- or Rs, wherein Rs is a
C.sub.6 or C.sub.10 aryl or a heterocycle containing 4-10 ring
atoms of which 1-3 are heteroatoms selected from the group
consisting of oxygen, nitrogen and sulfur; or [0026] (2) a group of
the formula --W--R.sup.7, wherein R.sup.7 is alkyl, alkoxy, hydroxy
or Rs, wherein W is --C(.dbd.O)-- or --S(O).sub.n-- where n=1 or 2;
[0027] (3) a group of the formula --W--OR.sup.8 wherein R.sup.8 is
hydrogen or alkyl, [0028] (4) a group of the formula --CH(OH)Rs; or
[0029] (5) a group of the formula --W--N(R.sup.9)R.sup.10, wherein
[0030] [a] R.sup.9 is hydrogen and R.sup.10 is an alkyl or
cycloalkyl, optionally substituted by (i) [C.sub.6 or
C.sub.10]aryl, or (ii) a 5- or 6-membered heteroaryl ring, wherein
the 6-membered heteroaryl ring contains one to three atoms of N,
and the 5-membered heteroaryl ring contains from one to three atoms
of N or one atom of O or S and zero to two atoms of N, said
heteroaryl ring can be optionally substituted with one or more
1-pyrrolidinyl, 4-[C.sub.6 or C.sub.10]arylpiperazin-1-yl,
4-[C.sub.6 or C.sub.10]arylpiperidin-1-yl, azetidin-1-yl, and
morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or
(C.sub.1-C.sub.3)alkylenedioxy groups, or fused to a substituted
phenyl or pyridine ring, wherein the ring fusion is at a
carbon-carbon double bond of the heteroaryl ring [in one
embodiment, a 5- or 6-membered heteroaryl ring, wherein the
6-membered heteroaryl ring contains one to three atoms of N, and
the 5-membered heteroaryl ring contains from one to three atoms of
N or one atom of O or S and zero to two atoms of N, said heteroaryl
ring can be optionally substituted with one or more halo or
(C.sub.1-C.sub.3)alkylenedioxy groups, or fused to a substituted
phenyl], or (iii) a heterocycle containing 4-10 ring atoms of which
1-3 are heteroatoms selected from the group consisting of oxygen,
nitrogen and sulfur; or [0031] [b] R.sup.9 is hydrogen or lower
alkyl and R.sup.10 is Ar; or [0032] [c] R.sup.9 is hydrogen or
lower alkyl, and R.sup.10 is a heterocycle containing 4-10 ring
atoms of which 1-3 are heteroatoms are selected from the group
consisting of oxygen, nitrogen and sulfur, said heterocycle; or
[0033] [d] R.sup.9 and R.sup.10 are both alkyl groups; or [0034]
[e] R.sup.9 and R.sup.10 together with N form a heterocycle
containing 4-10 ring atoms which can incorporate up to one
additional heteroatom selected from the group of N, O or S in the
ring, wherein the heterocycle is optionally substituted with
(C.sub.6- or C.sub.10)aryl, (C.sub.6- or C.sub.10)arylalkyl, or a
5- or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl
ring contains one to three atoms of N, and the 5-membered
heteroaryl ring contains from one to three atoms of N or one atom
of O or S and zero to two atoms of N, each such heteroaryl can be
optionally substituted with one or more 1-pyrrolidinyl, 4-[C.sub.6
or C.sub.10]arylpiperazin-1-yl, 4-[C.sub.6 or
C.sub.10]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl,
thiomorpholin-4-yl, piperidin-1-yl, halo or
(C.sub.1-C.sub.3)alkylenedioxy [in one embodiment, R.sup.9 and
R.sup.10 together with N form a heterocycle containing 4-10 ring
atoms which can incorporate up to one additional heteroatom
selected from the group of N, O or S in the ring, wherein the
heterocycle is optionally substituted with (C.sub.6- or
C.sub.10)aryl, (C.sub.6- or C.sub.10)arylalkyl, or a 5- or
6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring
contains one to three atoms of N, and the 5-membered heteroaryl
ring contains from one to three atoms of N or one atom of O or S
and zero to two atoms of N, each such heteroaryl can be optionally
substituted with one or more halo or
(C.sub.1-C.sub.3)alkylenedioxy]; or [0035] [f] R.sup.9 and R.sup.10
are both hydrogen; or d. Q is N, O or S; e. M is absent when Q is O
or S; f. M is alkyl, vinyl or allyl, or independently the same as
Y; and g. X is a pharmaceutically acceptable anion, or (B) a
pharmaceutically acceptable salt of the compound, [0036] wherein
aryl or Ar can be substituted with, in addition to any
substitutions specifically noted, one or more substituents selected
from the group consisting of acylamino, acyloxyalkyl, alkanoyl,
alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylamino,
(C.sub.1-C.sub.3)alkylenedioxy, alkylsulfonyl, alkylsulfinyl,
.omega.-alkylenesulfonic acid, alkylthio, allyl, amino, ArC(O)--,
ArC(O)NH--, ArO--, Ar--, Ar-alkyl-, carboxy, carboxyalkyl,
cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy,
(C.sub.2-C.sub.6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic
acid, 1-pyrrolidinyl, 4-[C.sub.6 or C.sub.10]arylpiperazin-1-yl-,
4-[C.sub.6 or C.sub.10]arylpiperidin-1-yl, azetidin-1-yl,
morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl [in one
embodiment, aryl or Ar can be substituted with, in addition to any
substitutions specifically noted, one or more substituents selected
from the group consisting of acylamino, acyloxyalkyl, alkanoyl,
alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, (C.sub.1-C.sub.3)alkylenedioxy,
alkylsulfonyl, alkylsulfinyl, .omega.-alkylenesulfonic acid,
alkylthio, allyl, ArC(O)--, ArC(O)NH--, ArO--, Ar--, Ar-alkyl-,
carboxy, carboxyalkyl, cycloalkyl, halo, trifluoromethyl, hydroxy,
(C.sub.2-C.sub.6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic
acid]; and [0037] wherein heterocycles, except those of Ar, can be
substituted with, in addition to any substitutions specifically
noted, acylamino, alkanoyl, alkoxy, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylamino, alkylsulfonyl,
alkylsulfinyl, alkylthio, amino, ArC(O)--, ArO--, Ar--, carboxy,
dialkylamino, fluoro, fluoroalkyl, difluoroalkyl, hydroxy,
mercapto, sulfamoyl, or trifluoromethyl [in one embodiment,
heterocycles, except those of Ar, can be substituted with, in
addition to any substitutions specifically noted, acylamino,
alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,
alkylsulfonyl, alkylsulfinyl, alkylthio, ArC(O)--, ArO--, Ar--,
carboxy, fluoro, fluoroalkyl, difluoroalkyl, hydroxy, mercapto,
sulfamoyl, or trifluoromethyl].
[0038] In one embodiment, the compound of formula I, is that
wherein Y is according to formula --CH(R.sup.5)R.sup.6. In another
embodiment, the compound of formula I, is that of formula I,
wherein Y is according to formula --CH(R.sup.5)--W--R.sup.7. In
another embodiment, the compound of formula I, is that of formula
I, wherein Y is according to formula --CH(R.sup.5)--W--Rs. In
another embodiment, the compound of formula I, is that of formula
I, wherein R.sup.1 and R.sup.2 together with their ring carbons
form a C.sub.6- or C.sub.10-aromatic fused ring which can be
substituted by one or more halo, amino, alkyl, sulfonic acid,
alkylsulfonyl or .omega.-alkylenesulfonic acid groups, or a
C.sub.1-C.sub.3 alkylenedioxy group with the proviso that when Q is
nitrogen R.sup.1 and R.sup.2 do not form a C.sub.6 fused aromatic
ring. In another embodiment, the compound of formula I, is that of
the compound of formula I, wherein Q is S, and Y and Z are both
--NH.sub.2.
Certain Fibrotic Diseases
[0039] Among the indications that can be treated with the invention
are a number of indications linked to or associated with the
formation of excess collagen. Among these, a number of the
indications can be termed fibrotic diseases.
[0040] Such fibrotic diseases include systemic sclerosis, mixed
connective tissue disease, fibrodysplasia, fibrocystic disease;
sarcoidosis, myositis (e.g. polymyositis, primary idiopathic
polymyositis, childhood polymyositis, dermatomyositis, childhood
dermatomyositis, primary idiopathic dermatomyositis in adults,
inclusion body myositis, polymyositis or dermatomyositis associated
with malignant tumors). Dermatomyositis can be associated with
fibrosing or hypertrophic aspects, including fibrosing alveolitis
and pulmonary fibrosis. Treatment using the invention is expected
to treat, prevent, reduce or ameliorate such diseases or
hypertrophy, fibrotic hypertrophy or fibrosis in such diseases.
Amelioration includes reducing the rate of progression of a
disease.
[0041] Among these fibrotic diseases are diseases that have as a
manifestation fibrotic vascular intimal hypertrophy. These diseases
include vasculitis (including coronary artery vasculitis),
polyarteritis nodosa or temporal arteritis. Treatment using the
invention is expected to treat, prevent, reduce or ameliorate
vascular intimal hypertrophy in such diseases.
[0042] These fibrotic diseases further include diseases that have
as a manifestation fibrotic hypertrophy of skin and/or muscle
tissue. These diseases include scleroderma, eosinophilic fasciitis,
discoid lesions associated with lupus or discoid lupus or surgical
adhesions. Treatment using the invention is expected to treat,
prevent, reduce or ameliorate such indications or hypertrophy or
fibrosis of skin or muscle tissue.
[0043] Such fibrotic diseases further include diseases that have as
a manifestation fibrotic hypertrophy of nerve tissue. These
diseases include cerebrosclerosis, annular sclerosis. diffuse
sclerosis and lobar sclerosis. Treatment using the invention is
expected to treat, prevent, reduce or ameliorate such diseases, or
hypertrophy, fibrotic hypertrophy or fibrosis of nerve tissue in
such diseases.
[0044] These fibrotic diseases further include fibrotic lung
diseases that have as a manifestation fibrotic hypertrophy or
fibrosis of lung tissue. These diseases include pulmonary fibrosis
(or interstitial lung disease or interstitial pulmonary fibrosis),
idiopathic pulmonary fibrosis, the fibrotic element of
pneumoconiosis (which is associated with exposure to environmental
hazards such as smoking, asbestos, cotton lint, stone dust, mine
dust and other particles), pulmonary sarcoidosis, fibrosing
alveolitis, the fibrotic or hypertrophic element of cystic
fibrosis, chronic obstructive pulmonary disease, adult respiratory
distress syndrome and emphysema Treatment using the invention is
expected to treat, prevent, reduce or ameliorate such diseases, or
hypertrophy, fibrotic hypertrophy or fibrosis in such diseases.
[0045] Such fibrotic diseases further include diseases that have as
a manifestation fibrotic hypertrophy or fibrosis of prostate,
liver, the pleura (e.g., pleurisy, pleural fibrosis) or pancreas.
These diseases include benign prostatic hypertrophy (BPH) and
fibrosis of the liver. Treatment using the invention is expected to
treat, prevent, reduce or ameliorate such diseases, or hypertrophy,
fibrotic hypertrophy or fibrosis in such diseases.
[0046] These fibrotic diseases further include diseases that have
as a manifestation fibrotic hypertrophy or fibrosis of the bowel
wall, such as inflammatory bowel disease, including Crohn's
disease. Treatment using the invention is expected to treat,
prevent, reduce or ameliorate such diseases, or hypertrophy,
fibrotic hypertrophy or fibrosis in such diseases.
Arteriosclerosis, Atherosclerosis, Stiff Vessel Disease, Peripheral
Vascular Disease, Coronary Heart Disease, Stroke, Myocardial
Infarct, Cardiomyopathies, Restenosis
[0047] Arteriosclerosis is a disease marked by thickening,
hardening, and loss of elasticity in arterial walls, of which
atherosclerosis is a sub-type. Arteriosclerosis in turn falls
within the genus of stiff vessel diseases. Without limitation to
theory, it is believed that damage to the blood vessels of these
diseases is due to AGE-caused damage, either through protein
cross-linking or the stimulation of bioactive agents, or both.
Accordingly, the first agents are used to treat, prevent, reduce or
ameliorate stiff vessel disease, including arteriosclerosis and
atherosclerosis. Peripheral vascular disease is an indication that
overlaps with atherosclerosis but also covers disease which is
believed to have a stronger inflammatory component. First agents
are used to treat, prevent, reduce or ameliorate peripheral
vascular disease. Coronary heart disease is a form of
atherosclerosis of the coronary arteries. First agents are used to
treat, prevent, reduce or ameliorate coronary heart disease.
[0048] When the heart pumps blood into the vascular system, the
ability of the arteries to expand helps to push blood through the
body. When arteries become stiff, as they do in the natural process
of aging, the ability of the arteries to expand is diminished and
also has consequences for the heart. The heart has to work harder
to pump the blood into the stiff arteries, and eventually
hypertrophies (enlarges in size) to accomplish this. A
hypertrophied heart is an inefficient pump, and is one of the
disorders that leads to congestive heart failure. One compound
believed to work by a mechanism shared by the compounds of the
invention, 3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt,
showed an ability to reverse the stiffness of arteries in a Phase
IIa clinical trial, as measured by the ratio of stroke volume (ml)
to pulse pressure (mm Hg). The potential clinical benefit of this
is to lessen the effort that the heart must expend to push blood
throughout the body. The effect is also believed to contribute to
preventing hypertrophy and subsequent inefficiency of the heart,
which inefficiency would contribute to congestive heart
failure.
[0049] Stroke is a cardiovascular disease that occurs when blood
vessels supplying blood (oxygen and nutrients) to the brain burst
or are obstructed by a blood clot or other particle. Nerve cells in
the affected area of the brain die within minutes of oxygen
deprivation and loss of nerve cell function is followed by loss of
corresponding bodily function. Of the four main types of stroke,
two are caused by blood clots or other particles. The former two
are the most common forms of stroke, accounting for about 70-80
percent of all strokes.
[0050] Blood clots usually form in arteries damaged by
atherosclerosis. When plaque tears from the sheer forces of blood
flowing over an uneven, rigid cap atop the plaque site, thrombotic
processes become involved at the "injury" site. As a result, clots
can form. First agents are used to prevent, reduce or ameliorate
the risk of stroke in patients who have suffered previous strokes
or have otherwise been identified as at risk.
[0051] First agents can also be used to treat, prevent, reduce or
ameliorate peripheral vascular disease and periarticular
rigidity.
[0052] Treatment with the first agents during the relatively
immediate aftermath of a heart attack can be used to reduce the
size of the myocardial infarct resulting from the heart attack.
This treatment is preferably administered within six hours of the
heart attack, more preferably, within three hours. While the
dosages discussed below can be used with this indication, such as a
dose of 0.01-4.0 mg/kg administered orally or 0.01-2.0 mg/kg
administered intravenously, preferably within the time period
outlined above. Preferred routes of administration include i.v.
injection or i.v. drip. Thereafter, optional supplemental
administrations can be made with the dosages described below.
[0053] Atherosclerosis is a disease that involves deposition of
blood lipids in plaque in the arteries throughout the body. In
coronary arteries, accumulation of plaque progressively leads to
reduced coronary flow, with occlusion of the arteries causing focal
death of cardiac tissue (myocardial infarction, heart attack). If
the amount of tissue that dies is large enough, death ensures. In a
Phase IIa trial, one compound believed to work by a mechanism
shared by the compounds of the invention,
3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt, increased the
amount of circulating triglycerides (lipids). Consistent with the
known presence of AGEs in plaque, the result indicates that the
agent had a lipid mobilizing effect on arterial plaque. Reducing
local deposits of plaque should eventually lessen the risk of
myocardial infarction and death due to heart attacks.
[0054] Fibrotic diseases further include diseases that have as a
manifestation fibrotic hypertrophy of the heart. These diseases
include endomyocardial fibrosis (wherein endocardium and
subendocardium are fibrosed, such as in some manifestations of
restrictive cardiomyopathy), dilated congestive cardiomyopathy (a
disorder of myocardial function with heart failure in which
ventricular dilation and systolic dysfunction predominate),
hypertrophic cardiomyopathy (characterized by marked ventricular
hypertrophy with diastolic dysfunction in the absence of an
afterload demand), and other cardio-hypertrophies. In dilated
congestive cardiomyopathy, typically at presentation there is
chronic myocardial fibrosis with diffuse loss of myocytes. In
hypertrophic cardiomyopathy, usually the interventricular septum is
hypertrophied more than the left ventricular posterior wall
(asymmetric septal hypertrophy). Treatment using the invention is
expected to treat, prevent, reduce or ameliorate such diseases, or
hypertrophy, fibrotic hypertrophy or fibrosis in such diseases.
[0055] Hypertrophies of the heart can be diagnosed and monitored by
methods known in the art, such as by electrocardiogram,
echocardiography or magnetic resonance imaging. Such diagnostic
methods can be applied in particular for subjects having a risk
factor for such hypertrophy, such as congestive heart failure,
prior cardiac surgery or diabetes. In one aspect, the invention
comprises identifying cardio-hypertrophy with using biophysical
diagnostic tools, and administering an active agent of the
invention to treat, prevent, reduce or ameliorate such diseases, or
hypertrophy, fibrotic hypertrophy or fibrosis in such diseases. The
invention can further include monitoring cardio-hypertrophy during
the course of treatment with active agent.
[0056] Erosion or tearing of arterial wall plaque can occur due to
the rough and irregular shape of the plaque as it forms from
deposition of lipids and invasion of cells such as monocytes and
macrophages (foam cells). When erosion occurs platelets and other
components of the blood clotting system are activated, resulting in
formation of a clot (thrombus). When the thrombus grows to such as
state that blood flow is reduced, severe angina attacks that
characterize unstable angina can occur. Plaque forms irregular
shapes and in doing so creates shear stresses from the flow of
blood over this irregular form. It is the irregularity of plaque
shape that leads to the dislodging or tearing of the plaque, and to
the subsequent invasion of reactive cells. On the surface of plaque
is collagen, which is believed to contribute to the rigidity of the
irregular shape. Without limitation to theory, it is believed that
reducing the crosslinking of such a rigid collagen cap results in
smoother blood flow, with a reduced risk of angina-causing tears.
Accordingly, first agents are used to treat, prevent, reduce or
ameliorate unstable angina.
[0057] Faithful conduction of the electrical impulse from the
sinoatrial to the atrioventricular nodes depends upon close
apposition of myocardial cells. Excess production of collagen in
the heart, which occurs naturally with aging but more so in
diabetes and in conditions of heart disorders such as hypertension,
causes an increase in the distance between myocardial cells,
leading to atrial fibrillation. First agents are used to treat,
prevent, reduce or ameliorate atrial fibrillation.
[0058] The fibrotic indications further include restenosis, which
is the process of increasing artery closure following an operation
to open the artery, such as balloon angioplasty.
Bladder Elasticity
[0059] Indications that can be treated, prevented, reduced or
ameliorated with the first agents include loss of bladder
elasticity. Bladder elasticity is tied to the frequency of
urination, and the urgency of desire to urinate. Accordingly, the
invention can be used to treat, prevent, reduce or ameliorate
non-obstructive uropathy, a disorder characterized by an overactive
bladder that entails increased frequency of urination, a strong and
sudden desire to urinate (urgency) which may also be associated
with involuntary urinary leakage (urge incontinence).
Macular Degeneration
[0060] The effect of the first agents in reducing levels of other
endogenous bioactive agents, particularly VEGF and/or TGF[beta], is
believed to underlie effectiveness against macular degeneration or
macular edema. Again, however, the invention is not limited to
theory. Moreover, a anti-fibrotic effect or another effect against
tissue hypertrophy may contribute. Treatment using the invention is
expected to treat, prevent, reduce or ameliorate macular
degeneration or macular edema. In one aspect of the invention, the
treatment is used to treat, prevent, reduce or ameliorate the wet
form of macular degeneration. In the wet form, new blood vessel
growth has a greater contribution to the disease.
Amyotrophic Lateral Sclerosis (ALS)
[0061] ALS is associated with degradations of the motor neuron
system and/or the posterior column of the spinal cord. In ALS
patients, these structures tend to stain with AGE-reactive
antibodies. Treatment using the invention is expected to treat,
prevent, reduce or ameliorate ALS.
Rheumatoid Arthritis, Osteoarthritis, Bone Resorption
[0062] It is believed, without limitation to such theory, that
reducing AGE accumulation at the joints affected by rheumatoid
arthritis or osteoarthritis reduces stimulation of the production
of cytokines involved in inflammatory processes of the disease.
Treatment using the invention is expected to treat, prevent, reduce
or ameliorate rheumatoid arthritis or osteoarthritis. Similarly, it
is believed that reducing AGE accumulation at bone reduces
stimulation of bone resorption. Accordingly, the invention is used
to treat, prevent, reduce or ameliorate osteoporosis, bone loss or
brittle bone.
Dialysis
[0063] The first agents can be administered as part of a dialysis
exchange fluid, thereby preventing, limiting or ameliorating the
damage to tissue caused by the sugars found in such exchange fluid.
For example, first agents are expected to prevent, limit or
ameliorate the stiffening and sclerosing of peritoneal tissue that
occurs in peritoneal dialysis, as well as prevent, limit or
ameliorate the formation of new blood vessels in the peritoneal
membrane. In hemodialysis, first agents are expected to prevent,
limit or ameliorate the stiffening and sclerosing of red blood
cells and vasculature resulting from exposure to the sugars
exchanged into the blood during dialysis. Exchange fluids for
peritoneal dialysis typically contain 10-45 g/L of reducing sugar,
typically 25 g/L, which causes the formation of AGEs and consequent
stiffening and degradation of peritoneal tissue. Similarly,
hemodialysis fluids typically contain up to about 2.7 .mu.L of
reducing sugar, typically 1 to 1.8 g/L. Thus, the invention
provides methods by which the first agents are provided in these
fluids and thereby prevent, limit or ameliorate the damage that
would otherwise result. Alternatively, the invention provides
methods whereby the first agents are administered by the methods
described below to prevent, limit or ameliorate such damage from
dialysis. In hemodialysis, the exchange fluid preferably contains
0.006-2.3 mg/L of an agent of the invention, more preferably, 0.06
to 1.0 mg/L. In peritoneal dialysis, the exchange fluid preferably
contains 0.01 to 24 mg/L of an agent of the invention, or
preferably, 1.0 to 10 mg/L.
[0064] In one embodiment, preventing or ameliorating is effected
with a second agent. A preferred route of administration is
inclusion in the dialysis fluids. In hemodialysis, the exchange
fluid preferably contains 0.125 to 2.5 mg/L of aminoguanidine, more
preferably, 0.2 to 1.0 mg/L. In peritoneal dialysis, the exchange
fluid preferably contains 1.25 to 25 mg/L of aminoguanidine, or
preferably, 2.0 to 10 mg/L. In a preferred aspect of the invention,
the first agents are initially administered, and subsequently
second agents are used to moderate or limit damage thereafter.
Asthma
[0065] It is believed, without limitation to such theory, that the
first agents or second agents act to prevent, reduce or ameliorate
the small but significant thickening of the lung airways associated
with asthma. Moreover, the agents are believed to reduce
stimulation of the production of cytokines involved in inflammatory
processes of the disease. Accordingly, the agents are used to
treat, prevent, reduce or ameliorate asthma. In this embodiment,
one preferred route of administration is pulmonary, such as via an
aerosol, though peroral administration is also preferred.
Carpal Tunnel Syndrome
[0066] It is believed, without limitation to such theory, that the
first agents act to prevent, reduce or ameliorate fibrotic and
cytokine-induced elements of carpal tunnel syndrome. Accordingly,
the first agents are used to treat, prevent, reduce or ameliorate
carpal tunnel syndrome.
[0067] Fibrotic diseases also include Dupuytren's contracture, a
contracture of the palmar fascia often causing the ring and little
fingers to bend into the palm. Treatment using the invention is
expected to treat, prevent, reduce or ameliorate Dupuytren's
contracture, or hypertrophy, fibrotic hypertrophy or fibrosis in
Dupuytren's contracture.
[0068] In these embodiments, one preferred route of administration
is local injection.
Periodontal Disease
[0069] The incidence of periodontal disease is higher in subjects
with either insulin-deficient or insulin-resistant diabetes, with
consequent hyperglycemia. Again, without limitation to such theory,
it is believed that the first agents act to prevent, reduce or
ameliorate AGE-induced cytokine action to create or exacerbate
periodontal disease. Accordingly, the first or second agents are
used to treat, prevent, reduce or ameliorate periodontal disease.
In this embodiment, one preferred primary or supplemental route of
administration is via mouthwash, or compositions adapted for
delivery into the subgingival periodontal pocket (such as implants
and erodible microspheres). Peroral administration is again useful.
The mouthwash preferably contains 0.003-1.0 mg/L of a first agent,
more preferably, 0.01-0.1 mg/L.
Sickle Cell Anemia
[0070] It is believed, without limitation to such theory, that the
first agents act to prevent, reduce or ameliorate the restraint on
blood flow caused by sickling. Again without limitation to theory,
the mode of action is believed to be in reducing vascular as well
as blood cell inelasticity. Accordingly, the first agents are used
to treat, prevent, reduce or ameliorate a sickle cell anemia.
Erectile Dysfunction
[0071] Fibrotic diseases further include diseases that have as a
manifestation fibrotic disease of the penis, including Peyronie's
disease (fibrosis of the cavernous sheaths leading to contracture
of the investing fascia of the corpora, resulting in a deviated and
painful erection). Treatment using the invention is expected to
treat, prevent, reduce or ameliorate such diseases, or hypertrophy,
fibrotic hypertrophy or fibrosis in such diseases.
[0072] Without limitation to theory, it is believed that the first
agents act to prevent, reduce or ameliorate inelasticity of tissue
of the penis and/or fibrosis of tissue of the penis, such as
inelasticity or fibrosis of the cavernous sheaths leading to
contracture of the investing fascia of the corpora. At least
partial restoration of the resulting inelasticity is believed to
facilitate engorgement of the corpora cavernosa with blood.
Accordingly, the first agents are used to treat, prevent, reduce or
ameliorate erectile dysfunction.
Limited Joint Mobility
[0073] Limited Joint Mobility (LJM) is a disorder associated with
diabetes and typically involves the joints of the hands. The fourth
and fifth fingers are affected initially by limitation of motion.
AGE glycation and crosslinking of tendons (collagen) in the joints
is believed to contribute to the disease. It is believed, without
limitation to theory, that the first agents act to prevent, reduce
or ameliorate inelasticity, fibrous tissue or cytokine-induced
inflammation associated with limited joint mobility. Accordingly,
the first agents are used to treat, prevent, reduce or ameliorate
limited joint mobility.
Antineoplastic Applications
[0074] The first agents inhibit the stimulated formation of
bioactive agents, such as VEGF, associated with angiogenesis.
Angiogenesis is critical for both normal development and the growth
and metastasis of solid tumors. Accordingly, the first agents are
used to treat, prevent, reduce or ameliorate the growth of
neoplasms by limiting the formation of blood vessels needed to
sustain the neoplasms.
End Stage Renal Disease, Diabetic Nephropathy
[0075] Diabetic Nephropathy is a complication of diabetes that
evolves early, typically before clinical diagnosis of diabetes is
made. The earliest clinical evidence of nephropathy is the
appearance of low but abnormal levels (>30 mg/day or 20
.mu.g/min) of albumin in the urine (microalbuminuria), followed by
albuminuria (>300 mg/24 h or .about.200 .mu.g/min) that develops
over a period of 10-15 years. In patients with type 1 diabetes,
diabetic hypertension typically becomes manifest early on, by the
time that patients develop microalbuminuria. Once overt nephropathy
occurs, the glomerular filtration rate (GFR) falls over several
years resulting in End Stage Renal Disease (ESRD) in 50% of type 1
diabetic individuals within 10 years and in >75% of type 1
diabetics by 20 years of onset of overt nephropathy. Albuminuria
(i.e., proteinuria) is a marker of greatly increased cardiovascular
morbidity and mortality for patients with either type 1 or type 2
diabetes.
[0076] Without limitation to theory, it is believed that damage to
the glomeruli and blood vessels of the kidney is due to AGE-caused
damage, either through protein cross-linking or the stimulation of
bioactive agents, or both. Accordingly, the first agents are used
to treat, prevent, reduce or ameliorate damage to kidney in
patients at risk for ESRD. The first agents can also be used to
treat, prevent, reduce or ameliorate glomerulosclerosis.
Hypertension, Isolated Systolic Hypertension
[0077] Cardiovascular risk correlates more closely with the
systolic and the pulse pressure than with the diastolic pressure.
In diabetic patients, the cardiovascular risk profile of diabetic
patients is strongly correlated to duration of diabetes, glycemic
control and blood pressure. Structural matrix proteins contribute
to the function of vessels and the heart, and changes in the
physical behavior of cardiovascular walls are believed to be
important determinants of circulatory function. In elderly
individuals, the loss of compliance in the aorta leads to isolated
systolic hypertension, which in turn expands the arterial wall and
thereby diminishes the dynamic range of elasticity. In vivo studies
in rodents, canines and in primates indicate potential utility of
3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt in
substantially ameliorating vascular stiffening. For example, in a
dog model for diabetes, lower end diastolic pressure and increased
end diastolic volume, indicators of ventricular elasticity,
returned to a value at about the mid-point between the disease
impaired value and the value for control dogs. Treatment with
3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt lead to a
reduction in the mass of collagen in cardiovascular tissues. In
situ hybridization studies demonstrate that
3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt reduces the
expression of both Type IV collagen and TGFbeta.
[0078] Compared with that of a non-diabetic, the diabetic artery is
smaller as it is stiffer. As in isolated systolic hypertension in
which vessels stiffen with age and lose the dynamic range of
expansion under systole. First agents are used to treat, prevent,
reduce or ameliorate hypertension, including isolated systolic
hypertension and diabetic hypertension. Moreover, the same benefit
is anticipated for the more rare hypertensive disorder, pulmonary
hypertension. Pulmonary hypertension is a rare blood vessel
disorder of the lung in which the pressure in the pulmonary artery
(the blood vessel that leads from the heart to the lungs) rises
above normal levels and may become life threatening. The similarity
in development of elevated blood pressure in the pulmonary bed with
the increase in systemic blood pressure in diabetic hypertension
and in isolated systolic hypertension suggests similar mechanisms
are involved.
[0079] Pulse pressure is the difference between systolic and
diastolic blood pressure. In a young human, systolic pressure is
typically 120 mm Hg and diastolic pressure is 80 mm Hg, resulting
in a pulse pressure of 40 mm Hg. With age, in many individuals
pulse pressure increases, largely due to the increase in systolic
pressure that results from stiff vessel disease. In individuals
with pulse pressure greater than 60 mm Hg there is an increased
risk of death from cardiovascular morbidities. In a Phase IIa
trial, one compound believed to work by a mechanism shared by the
compounds of the invention,
3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt, reduced pulse
pressure in elderly patients with pulse pressures greater than 60
mm Hg in a statistically significant manner. This decrease in pulse
pressure was believed to be due primarily to the effect of the
agent on lowering the systolic blood pressure.
[0080] The agents of the invention are used to treat, prevent,
reduce or ameliorate reduced vascular compliance, elevated pulse
pressure, and hypertension. Moreover, the agents are used to reduce
pulse pressure, increase vascular compliance, or decrease the risk
of death.
Heart Failure
[0081] Congestive Heart Failure (CHF) is a clinical syndrome that
entails cardiac disease of the ventricle. Diastolic dysfunction is
a subset of heart failure in which the left ventricle stiffens with
age. The stiffening of the left ventricle that occurs in CHF and in
diastolic dysfunction is believed to result from increased
crosslinking of collagen fibers with age and/or fibrosis and
related hypertrophy. First agents are used to treat, prevent,
reduce or ameliorate heart failure.
Retinopathy
[0082] The effect of diabetes on the eye is called diabetic
retinopathy and involves changes to the circulatory system of the
retina. The earliest phase of the disease is known as background
diabetic retinopathy wherein the arteries in the retina become
weakened and leak, forming small, dot-like hemorrhages. These
leaking vessels often lead to swelling or edema in the retina and
decreased vision. The next stage is proliferative diabetic
retinopathy, in which circulation problems cause areas of the
retina to become oxygen-deprived or ischemic. New vessels develop
as the circulatory system attempts to maintain adequate oxygen
levels within the retina. Unfortunately, these new vessels
hemorrhage easily. In the later phases of the disease, continued
abnormal vessel growth and scar tissue may cause serious problems
such as retinal detachment. First agents are used to treat,
prevent, reduce or ameliorate diabetic retinopathy. The first
agents can be administered by the methods described below,
including by topical administration to the eye. The agents can also
be administered by intravitreal implant.
Cataracts, Other Damage to Lens Proteins
[0083] AGE-mediated crosslinking and/or fibrotic processes are
believed to contribute to cataract formation and formation of other
damage to lens proteins. First agents are used to treat, prevent,
reduce or ameliorate cataracts or other damage to lens
proteins.
Alzheimer's Disease
[0084] Considerable evidence exists implicating AGEs that form in
the neurofibrillary tangles (tau protein) and senile plaques
(beta-amyloid peptide) in early neurotoxic processes of Alzheimer's
disease. Insoluble human tau protein is likely crosslinked.
Glycation of insoluble tau from AD patients and experimentally
AGE-modified tau generate oxygen free radicals, resulting in the
activation of transcription via nuclear factor-kappa B, and
resulting in an increase in amyloid beta-protein precursor and
release of amyloid beta-peptides. Thus, A.G.E.-modified tau may
function as an initiator in a positive feedback loop involving
oxidative stress and cytokine gene expression. First agents are
used to treat, prevent, reduce or ameliorate Alzheimer's
disease.
Other Indications
[0085] For reasons analogous to those set forth above, the
invention is believed to be useful in treating, preventing,
reducing or ameliorating diabetes or its associated adverse
sequelae, and peripheral neuropathy. The agents, especially in
topical form, increase elasticity and/or reduce wrinkles in skin.
The agents further increase red blood cell deformability.
Combination Therapies
[0086] In cardiovascular therapies, first agents can be
administered concurrently or in a combined formulation with one or
more antioxidants. Examples of appropriate antioxidants are vitamin
A, vitamin B6, vitamin C, vitamin E, glutathione, .beta.-carotene,
.alpha.-lipoic acid, coenzyme Q10, selenium and zinc, which are
administered in effective amounts as is known in the art. Thus, the
invention further provides pharmaceutical compositions comprising
an agent of the invention in combination with an effective amount
of an antioxidant.
[0087] In treating heart failure, cardiomyopathy or heart attack,
first agents can be administered concurrently or in a combined
formulation with one or more angiotensin converting enzyme (ACE)
inhibitors, angiotensin II receptor antagonists, calcium channel
blockers, diuretics, digitalis or beta blockers. Examples of ACE
inhibitors include Captopril, Enalapril, Enalaprilat, Quinapril,
Lisinopril and Ramipril, which are administered in effective
amounts as is known in the art. Examples of angiotensin II receptor
antagonists include Losartan, Irbesartan, Eprosartan, Valsartan and
Candesartan, which are administered in effective amounts as is
known in the art. Examples of calcium channel blockers include
Amlopdipine, Bepridil, Diltiazem, Felodipine, Isradipine,
Nicardipine, Nifedipine, Nimodipine and Verapamil, which are
administered in effective amounts as is known in the art. Among
diuretics, preferred examples include Furosemide, Bumetanide,
Torsemide, Ethacrynic acid, Azosemide, Muzolimine, Piretanide,
Tripamide and Hydrochlorothiazide, which are administered in
effective amounts as is known in the art. Examples of beta
adrenergic antagonists include Metoprolol, Carvedilol, Bucindolol,
Atenolol, Esmolol, Acebutolol, Propranolol, Nadolol, Timolol,
Pindolol, Labetalol, Bopindolol, Carteolol, Penbutolol, Medroxalol,
Levobunolol, Bisoprolol, Nebivolol, Celiprolol and Sotalol, which
are administered in effective amounts as is known in the art. Thus,
the invention further provides pharmaceutical compositions
comprising an agent of the invention in combination with an
effective amount of an ACE inhibitor, diuretic, digitalis, beta
blocker, or combination thereof.
[0088] For treating diabetes or complications thereof, the
invention further provides pharmaceutical compositions comprising
an agent of the invention in combination with an effective amount
of a thiazolidinedione or "glitazone" diabetes drug, such as
Troglitazone, Rosiglitazone, and Pioglitazone.
[0089] In treating atherosclerosis, first agents can be
administered concurrently or in a combined formulation with one or
more statins (HMG CoA reductase inhibitors) or cholestyramine.
Examples of statins include Mevastatin, Lovastatin, Simvastatin,
Pravastatin and Fluvastatin, which are administered in effective
amounts as is known in the art. Thus, the invention further
provides pharmaceutical compositions comprising an agent of the
invention in combination with an effective amount of a statin,
cholestyramine, or both.
[0090] For a number of indications discussed, including sickle cell
enemia and diabetic complications, as well as wound healing and any
other indication in which increased tissue perfusion is a useful
means or adjunct to therapy, the first agents, or aminoguanidine or
other agents of the aminoguanidine class can be administered with
erythropoietin, which is administered in effective amount as is
known in the art. Erythropoietin includes stable forms of
erythropoietin such as are marketed by Amgen (Thousand Oaks,
Calif.).
[0091] For all indications, first agents can be administered
concurrently or in a combined formulation with aminoguanidine or
other agents of the aminoguanidine class, which are administered in
effective amounts as is known in the art.
[0092] The method of the invention is used to treat animals,
preferably mammals, preferably humans.
[0093] In accordance with the present invention, methods for
administering pharmaceutical compositions containing certain
compounds have been developed for treating the indications
described. These agents are either substituted thiazolium,
oxazolium, or imidazolium agents as shown in the Summary section
above.
[0094] Pharmaceutical compositions of the invention include
administering an effective amount of a compound of the formula
I.
[0095] The alkyl, and alkenyl groups referred to below include both
C1 to C6 linear and branched alkyl and alkenyl groups, unless
otherwise noted. Alkoxy groups include linear or branched C1 to C6
alkoxy groups, unless otherwise noted.
[0096] "Ar" (consistent with the rules governing aromaticity)
refers to a C.sub.6 or C.sub.10 aryl, or a 5 or 6 membered
heteroaryl ring. The heteroaryl ring contains at least one and up
to three atoms of N for the 6 membered heteroaryl ring. The 5
membered heteroaryl ring contains; (1) from one to three atoms of
N, or (2) one atom of O or S and zero to two atoms of N. The aryl
or heteroaryl is optionally substituted as set forth below.
Nonlimiting examples of heteroaryl groups include: pyrrolyl,
furanyl, thienyl, pyridyl, oxazolyl, pyrazolyl, pyrimidinyl, and
pyridazinyl.
[0097] "Ar" can be fused to either a benzene, pyridine, pyrimidine,
pyridazine, or (1,2,3) triazine ring.
[0098] "Rs" refers to a C.sub.6 or C.sub.10 aryl group (optionally
substituted as set forth below) or a heterocycle containing 4-10
ring members and 1-3 heteroatoms selected from the group consisting
of oxygen, nitrogen and sulfur (wherein said heterocycle is
optionally substituted as set forth below). Where Rs is a non
aromatic heterocycle containing sulfur atom as ring members, the
sulfur atoms can exist in various oxidation states, as S(O).sub.n,
where n is 0, 1, or 2.
[0099] As used herein, C.sub.6 or C.sub.10 aryl groups and
heterocycles containing 4 to 10 ring members are monocyclic or
bicyclic. The ring fusions of the bicyclic heterocycles are at
carbon-carbon bonds.
[0100] In certain embodiments of the invention, the thiazoliums,
imidazoliums, and oxazoliums of the invention contain R.sup.1 and
R.sup.2 substitutions that together with their ring carbons (the
C4-C5 carbons of the thiazoliums, imidazoliums, and oxazoliums)
form a fused C5 to C7 cycloalkyl ring having up to two double bonds
including the fused double bond (the C4-C5 double bond of the
thiazoliums, imidazoliums, and oxazoliums). The cycloalkyl ring can
be substituted by one or more of the group consisting of alkyl,
alkoxycarbonyl, amino, aminocarbonyl, carboxy, fluoro, and oxo
substituents. One of ordinary skill in the art will recognized that
where cycloalkyl groups contain double bonds, the sp.sup.2
hybridized carbon atoms can contain only one substituent (which can
not be amino- or oxo-). Sp.sup.3 hybridized carbon atoms in the
cycloalkyl ring can be geminally substituted with the exception
that (1) two amino groups and (2) one amino and one fluoro group
can not be substituted on the same sp.sup.3 hybridized carbon
atom.
[0101] In certain embodiments of the invention, the thiazoliums,
imidazoliums, and oxazoliums of the invention contain R.sup.1 and
R.sup.2 substitutions that together with their ring carbons (the
C4-C5 carbons of the thiazoliums, imidazoliums, and oxazoliums)
form a five to eight membered heterocycle (i.e. a bicyclic
heterocycle is formed). In these embodiments the heterocycle is
preferably not aromatic. Particular compounds within these
embodiments contain sulfur atoms in the ring fused to the
thiazoliums, imidazoliums, and oxazoliums. These sulfur atoms in
these particular compounds can exist in various oxidation states,
as S(O).sub.n, where n is 0, 1, or 2.
[0102] In certain embodiments of the invention, the thiazoliums,
imidazoliums, and oxazoliums of the invention contain R.sup.1 and
R.sup.2 substitutions that together with their ring carbons (the
C4-C5 carbons of the thiazoliums, imidazoliums, and oxazoliums)
form a five or six membered heteroaryl ring (i.e, a bicyclic
aromatic heterocycle is formed). A preferred bicyclic aromatic
heterocycle of the invention is a purine analog [Q is N and R.sup.1
and R.sup.2 together with their ring carbons (the C4 and C5 of the
imidazolium ring) form a pyrimidine ring].
[0103] In certain embodiments, the thiazoliums, imidazoliums, and
oxazoliums of the invention contain a Y group which can be
--CH(R.sup.5)--R.sup.6. In those embodiments where R.sup.5 is
alkenyl, preferably alkenyl is --C.dbd.C--R.sup.E, where R.sup.E is
alkyl, H, or hydroxy(C.sub.1-C.sub.6)alkyl. In those embodiments
wherein R.sup.5 is alkynyl, preferably alkynyl is
--C.ident.C--R.sup.F, where R.sup.F is alkyl, hydrogen, or
hydroxy(C.sub.1-C.sub.6)alkyl.
[0104] Aryl or Ar, can generally be substituted with, in addition
to any substitutions specifically noted one or more substituents
selected from the group consisting of acylamino, acyloxyalkyl,
alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylamino,
(C.sub.1-C.sub.3)alkylenedioxy, alkylsulfonyl [alkylS(O).sub.2--],
alkylsulfinyl [alkylS(O)--], .omega.-alkylenesulfonic acid
[-alkylSO.sub.3H where n=1-6)], alkylthio, allyl, amino, ArC(O)--,
ArO--, Ar--, Ar-alkyl-, carboxy, carboxyalkyl, cycloalkyl,
dialkylamino, halo, trifluoromethyl, hydroxy,
(C.sub.2-C.sub.6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic
acid [--SO.sub.3H], 1-pyrrolidinyl-, 4-[C6 or
C10]arylpiperazin-1-yl-, 4-[C6 or C10]arylpiperidin-1-yl,
azetidin-1-yl, morpholin-4-yl, and piperidin-1-yl.
[0105] Heterocycles, except those of Ar, can generally be
substituted with acylamino, alkanoyl, alkoxy, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylamino, alkylsulfonyl
[alkylS(O).sub.2--], alkylsulfinyl [alkylS(O)--], alkylthio, amino,
ArC(O)--, ArO--, Ar--, carboxy, dialkylamino, fluoro, fluoroalkyl,
difluoroalkyl, hydroxy, mercapto, sulfamoyl, or trifluoromethyl.
Preferably multiple substituents are located on different atoms of
the heterocyclic ring, with the proviso that alkyl, alkylcarbonyl,
and fluoro substituents can be substituted on the same carbon atom
of the heterocyclic ring. Heterocycles can be substituted with one
or more substituents.
[0106] The halo atoms can be fluoro, chloro, bromo or iodo. Chloro
and fluoro are preferred for aryl substitutions.
[0107] For the purposes of this invention, the compounds of formula
(I) are formed as biologically or pharmaceutically acceptable
salts. Useful salt forms include the halides (particularly bromides
and chlorides), tosylates, methanesulfonates, brosylates,
fumarates, maleates, succinates, acetates, mesitylenesulfonates,
and the like. Other related salts can be formed using similarly
non-toxic, and biologically or pharmaceutically acceptable
anions.
Representative, non-limiting examples of compounds of the present
invention are: [0108]
3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]thiazolium bromide [0109]
3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide [0110]
3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethy-
l)thiazolium bromide [0111]
3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dimethylt-
hiazolium chloride [0112]
3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(6-hydroxyhexyl)thiaz-
olium bromide [0113]
3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide [0114]
3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide
[0115] 3-(2-(2-furanyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide
[0116] 3-(2-(2-furanyl)-2-oxoethyl)-4-(2-hydroxypentyl)thiazolium
bromide [0117]
3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dimethylthia-
zolium bromide [0118]
3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide
[0119]
3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide [0120]
3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide [0121] 3-(2-(2-thienyl)-2-oxoethyl)-4,5-dimethylthiazolium
bromide [0122]
3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium
bromide [0123]
3-(2-(4-thiomorpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide
[0124]
3-(2-hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dimethylthiazolium
bromide [0125]
3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazoli-
um chloride [0126]
3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-dimethylthiazolium
bromide [0127]
3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide
[0128]
3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride [0129]
3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride [0130]
3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride [0131]
3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride [0132]
3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-octylthiazolium bromide
[0133] 3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium
bromide [0134]
3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dimethylt-
hiazolium chloride [0135]
3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dioctadecylthiazolium bromide
[0136]
3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dipentylthiazolium
bromide [0137]
3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-didodecylthiazolium bromide
[0138] 3-(2-(2-furanyl)-2-oxoethyl)-5-decylthiazolium bromide
[0139]
3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dioct-
ylthiazolium bromide [0140]
3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-diethylthiazolium bromide
[0141]
3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dipentylthiazolium
bromide [0142] 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]thiazolium
bromide [0143] 3-(2-(2-thienyl)-2-oxoethyl)thiazolium bromide
[0144]
3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-(6-hydroxyhexyl)thiazolium
bromide [0145] 3-(2-(4-thiomorpholinyl)-2-oxoethyl)thiazolium
bromide [0146]
3-(2-(hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dioctylthiazolium
bromide [0147]
3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-didecylthiazolium
bromide [0148] 3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dioctylthiazolium
bromide [0149]
3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dipropylthiazolium
chloride [0150]
3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4-methylthiazolium
chloride [0151]
3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-5-methylthiazolium
chloride [0152]
3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4-octylthiazolium
chloride [0153] 3-aminothiazolium mesitylenesulfonate; [0154]
3-amino-4,5-dimethylaminothiazolium mesitylenesulfonate; [0155]
2,3-diaminothiazolinium mesitylenesulfonate; [0156]
3-(2-methoxy-2-oxoethyl)thiazolium bromide; [0157]
3-(2-methoxy-2-oxoethyl)-4,5-dimethylthiazolium bromide; [0158]
3-(2-methoxy-2-oxoethyl)-4-methylthiazolium bromide; [0159]
3-(2-phenyl-2-oxoethyl)-4-methylthiazolium bromide; [0160]
3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide; [0161]
3-amino-4-methylthiazolium mesitylenesulfonate; [0162]
3-(2-methoxy-2-oxoethyl)-5-methylthiazolium bromide; [0163]
3-(3-(2-phenyl-2-oxoethyl)-5-methylthiazolium bromide; [0164]
3-[2-(4-bromophenyl)-2-oxoethyl]thiazolium bromide; [0165]
3-[2-(4-bromophenyl)-2-oxoethyl]-4-methylthiazolium bromide; [0166]
3-[2-(4-bromophenyl)-2-oxoethyl]-5-methylthiazolium bromide; [0167]
3-[2-(4-bromophenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;
[0168]
3-(2-methoxy-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium
bromide; [0169]
3-(2-phenyl-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium
bromide; [0170]
3-[2-(4-bromophenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium
bromide; [0171] 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide;
[0172] 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide;
[0173] 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride;
[0174] 3-(2-methoxy-2-oxoethyl)benzothiazolium bromide; [0175]
3-(2-phenyl-2-oxoethyl)benzothiazolium bromide; [0176]
3-[2-(4'-bromophenyl)-2-oxoethyl]benzothiazolium bromide; [0177]
3-(carboxymethyl)benzothiazolium bromide; [0178]
2,3-(diamino)benzothiazolium mesitylenesulfonate; [0179]
3-(2-amino-2-oxoethyl)thiazolium bromide; [0180]
3-(2-amino-2-oxoethyl)-4-methylthiazolium bromide; [0181]
3-(2-amino-2-oxoethyl)-5-methylthiazolium bromide; [0182]
3-(2-amino-2-oxoethyl)-4,5-dimethylthiazolium bromide; [0183]
3-(2-amino-2-oxoethyl)benzothiazolium bromide; [0184]
3-(2-amino-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium
bromide; [0185] 3-amino-5-(2-hydroxyethyl)-4-methylthiazolium
mesitylenesulfonate; [0186] 3-(2-methyl-2-oxoethyl)thiazolium
chloride; [0187] 3-amino-4-methyl-5-(2-acetoxyethyl)thiazolium
mesitylenesulfonate; [0188] 3-(2-phenyl-2-oxoethyl)thiazolium
bromide; [0189]
3-(2-methoxy-2-oxoethyl)-4-methyl-5-(2-acetoxyethyl)thiazolium
bromide; [0190]
3-(2-amino-2-oxoethyl)-4-methyl-5-(2-acetoxyethyl)thiazolium
bromide; [0191] 2-amino-3-(2-methoxy-2-oxoethyl)thiazolium bromide;
[0192] 2-amino-3-(2-methoxy-2-oxoethyl)benzothiazolium bromide;
[0193] 2-amino-3-(2-amino-2-oxoethyl)thiazolium bromide; [0194]
2-amino-3-(2-amino-2-oxoethyl)benzothiazolium bromide; [0195]
3-[2-(4-methoxyphenyl)-2-oxoethyl]thiazolium bromide; [0196]
3-[2-(2,4-dimethoxyphenyl)-2-oxoethyl]thiazolium bromide; [0197]
3-[2-(4-fluorophenyl)-2-oxoethyl]thiazolium bromide; [0198]
3-[2-(2,4-difluorophenyl)-2-oxoethyl]thiazolium bromide; [0199]
3-[2-(4-diethylaminophenyl)-2-oxoethyl]thiazolium bromide; [0200]
3-propargylthiazolium bromide; [0201]
3-propargyl-4-methylthiazolium bromide; [0202]
3-propargyl-5-methylthiazolium bromide; [0203]
3-propargyl-4,5-dimethylthiazolium bromide; [0204]
3-propargyl-4-methyl-5-(2-hydroxyethyl)-thiazolium bromide; [0205]
3-(2-[3-methoxyphenyl]-2-oxoethyl)thiazolium bromide; [0206]
3-(2-[3-methoxyphenyl]-2-oxoethyl)-4
methyl-5-(2-hydroxyethyl)thiazolium bromide; [0207]
3-(2-[3-methoxyphenyl)-2-oxoethyl)-benzothiazolium bromide; [0208]
2,3-diamino-4-chlorobenzothiazolium mesitylenesulfonate; [0209]
2,3-diamino-4-methylthiazolium mesitylenesulfonate; [0210]
3-amino-4-methyl-5-vinylthiazolium mesitylenesulfonate; [0211]
2,3-diamino-6-chlorobenzothiazolium [0212]
2,6-diamino-benzothiazole dihydrochloride; [0213]
2,6-diamino-3-[2-(4-methoxyphenyl)-2-oxoethyl]benzothiazolium
bromide; [0214]
2,6-diamino-3-[2-(3-methoxyphenyl)-2-oxoethyl]benzothiazolium
bromide; [0215]
2,6-diamino-3-[2-(4-diethylaminophenyl)-2-oxoethyl]benzothiazolium
bromide; [0216]
2,6-diamino-3-[2-(4-bromophenyl)-2-oxoethyl]benzothiazolium
bromide; [0217]
2,6-diamino-3-[2-(2-phenyl)-2-oxoethyl]benzothiazolium bromide;
[0218] 2,6-diamino-3-[2-(4-fluorophenyl-2-oxoethyl]benzothiazolium
bromide; [0219] 3-acetamido-4-methyl-5-thiazolyl-ethyl acetate
mesitylenesulfonate; [0220] 2,3-diamino-5-methylthiazolium
mesitylenesulfonate; [0221]
3-[2-(2-naphthyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)-thiazolium
bromide; [0222]
3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-4-methyl-5-(2-hydrox-
yethyl)thiazolium bromide; [0223]
3-[2-(2,6-dichlorophenethylamino)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)-
thiazolium bromide; [0224]
3-[2-dibutylamino-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium
bromide; [0225]
3-[2-(4-carbethoxyanilino)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazol-
ium bromide; [0226]
3-(2-(2,6-diisopropylanilino)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thia-
zolium bromide; [0227]
3-amino-4-methyl-5-[2-(2,6-dichlorobenzyloxy)ethyl]thiazolium
mesitylenesulfonate; [0228]
3-[2-(4-carbomethoxy-3-hydroxyanilino)-2-oxoethyl]-4-methyl-5-(2-hydroxye-
thyl)thiazolium bromide; [0229] 2,3-diamino-4,5-dimethylthiazolium
mesitylene sulfonate; [0230]
2,3-diamino-4-methyl-5-(2-hydroxyethyl)thiazolium mesitylene
sulfonate; [0231] 2,3-diamino-5-(3,4-trimethylenedioxy
phenyl)-thiazolium mesitylene sulfonate; [0232]
3-[2-(1,4-benzodioxan-6-yl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazo-
lium bromide; [0233]
3-[2-(3,4-trimethylenedioxyphenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl-
)thiazolium bromide; [0234]
3-(2-[3,4-benzodioxan-6-yl]-2-oxoethyl)thiazolium bromide; [0235]
3-[2-(3,4-trimethylenedioxyphenyl)-2-oxoethyl]thiazolium bromide;
[0236]
3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]thiazolium
bromide; [0237]
3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-4-methylthiaz-
olium bromide; [0238]
3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-5-methylthiazolium
bromide; [0239]
3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazoli-
um bromide; [0240]
3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-benzothiazolium
bromide; [0241]
1-methyl-3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]imidazolium
bromide; [0242] 3-[2-(4-n-pentylphenyl)-2-oxoethyl]thiazolium
bromide; [0243]
3-[2-(4-n-pentylphenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thi-
azolium bromide; [0244]
3-[2-(4-diethylaminophenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazo-
lium bromide; [0245]
3-(2-phenyl-2-oxoethyl)-4-methyl-5-vinylthiazolium bromide; [0246]
3-[2-(3,5-tert-butyl-4-hydroxyphenyl)-2-oxoethyl)-4-methyl-5-vinylthiazol-
ium bromide; [0247] 3-(2-tert-butyl-2-oxoethyl)thiazolium bromide
[0248]
3-(2-tert-butyl-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium
bromide; [0249]
3-(3'-methoxybenzyl)-4-methyl-5-(2-hydroxyethyl)thiazolium
chloride; [0250]
3-(2,6-dichlorobenzyl)-4-methyl-5-(2-hydroxyethyl)thiazolium
chloride; [0251]
3-(2-nitrobenzyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide;
[0252] 3[2-(4-chlorophenyl)-2-oxoethyl]thiazolium bromide;
[0253]
3[2-(4-chlorophenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazol-
ium bromide [0254]
3[2-(4-methoxyphenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium
bromide. [0255] 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]thiazolium
bromide [0256]
3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide [0257]
3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethy-
l)thiazolium bromide [0258]
3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dimethylt-
hiazolium chloride [0259]
3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(6-hydroxyhexyl)thiaz-
olium bromide [0260]
3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide [0261]
3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide
[0262] 3-(2-(2-furanyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide
[0263] 3-(2-(2-furanyl)-2-oxoethyl)-4-(2-hydroxypentyl)thiazolium
bromide [0264]
3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dimethylthia-
zolium bromide [0265]
3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide
[0266]
3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide [0267]
3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide [0268] 3-(2-(2-thienyl)-2-oxoethyl)-4,5-dimethylthiazolium
bromide [0269]
3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-hydroxyethylthiazolium
bromide [0270]
3-(2-(4-thiomorpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide
[0271]
3-(2-(hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dimethylthiazolium
bromide [0272]
3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl]-4,5-dimethylt-
hiazolium chloride [0273]
3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-dimethylthiazolium
bromide [0274]
3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide
[0275]
3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride [0276]
3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride [0277]
3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride [0278]
3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride [0279]
3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-octylthiazolium bromide
[0280] 3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium
bromide [0281]
3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dipropylt-
hiazolium chloride [0282]
3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dioctadecylthiazolium bromide
[0283]
3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dipentylthiazolium
bromide [0284]
3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-didodecylthiazolium bromide
[0285] 3-(2-(2-furanyl)-2-oxoethyl)-5-decylthiazolium bromide
[0286]
3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dioct-
ylthiazolium bromide [0287]
3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-diethylthiazolium bromide
[0288]
3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dipentylthiazolium
bromide [0289] 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]thiazolium
bromide [0290] 3-(2-(2-thienyl)-2-oxoethyl)thiazolium bromide
[0291]
3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-(6-hydroxyhexyl)thiazolium
bromide [0292] 3-(2-(4-thiomorpholinyl)-2-oxoethyl)thiazolium
bromide [0293]
3-(2-(hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dioctylthiazolium
bromide [0294]
3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-didecylthiazolium
bromide [0295] 3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dioctylthiazolium
bromide [0296]
3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dipropylthiazolium
chloride [0297]
3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4-methylthiazolium
chloride [0298]
3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-5-methylthiazolium
chloride [0299]
3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4-octylthiazolium
chloride [0300]
1-methyl-3-[2-(3-methoxyphenyl)-2-oxoethyl]imidazolium bromide;
[0301] 1-methyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]imidazolium
bromide; [0302]
1-methyl-3-[2-(2,4-dimethoxyphenyl)-2-oxoethyl]imidazolium bromide;
[0303] 1-methyl-3-[2-(4-diethylaminophenyl)-2-oxoethyl]imidazolium
bromide; [0304] 1-methyl-3-[2-amino-2-oxoethyl]imidazolium bromide;
[0305] 1-methyl-2-amino-imidazolium mesitylene sulfonate; [0306]
1-methyl-3-[2-phenyl-2-oxoethyl]imidazolium bromide; [0307]
3-amino-1-(ethoxycarbonylpentyl)imidazolium mesitylenesulfonate;
[0308]
1-(ethoxycarbonylpentyl)-3-[2-(3-methoxyphenyl)-2-oxoethyl]imidazolium
bromide; [0309]
1-methyl-3-[2-(4-bromophenyl)-2-oxoethyl]imidazolium bromide;
[0310] 1-methyl-3-[2-(4-fluorophenyl)-2-oxoethyl]imidazolium
bromide; [0311]
1-methyl-3-[2-(3,4-difluorophenyl)-2-oxoethyl]imidazolium bromide;
[0312]
1-(ethoxycarbonylpentyl)-3-[2-(4-methoxyphenyl)-2-oxoethyl]imidazolium
bromide; [0313] 1-(4-acetylphenyl)-3-amino-imidazolium
mesitylenesulfonate; [0314]
1-(ethoxycarbonylpentyl)-3-[2-(4-methoxyphenyl)-2-oxoethyl]imidazolium
bromide; [0315]
1-(ethoxycarbonylpentyl)-3-[2-(4-methylphenyl)-2-oxoethyl]imidazolium
bromide; [0316] 1-amino-3-benzoyl-imidazolium mesitylene sulfonate;
[0317] 1-methyl-3-(2-naphth-2-yl-2-oxoethyl)imidazolium bromide;
[0318] 1-methyl-3-[(4-biphen-1-yl)-2-oxoethyl]imidazolium bromide;
[0319]
1-methyl-3-[(3-trifluoromethylphenyl)-2-oxoethyl)]imidazolium
bromide; [0320]
1-methyl-3-[4-(2,4-difluorophenyl)-2-oxoethyl]imidazolium chloride;
[0321] 3-[2-(thien-2-yl)-2-oxoethyl]-1-methyl-5-imidazolium
bromide; [0322]
1-methyl-3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]imidazolium
bromide; [0323]
1-methyl-3-[2-(2,4-dichlorophenyl)-2-oxoethyl]imidazolium chloride;
[0324] 3-(2-phenyl-2-oxoethyl)-1-phenylimidazolium chloride; [0325]
3-(2-phenyl-2-oxoethyl)-1-ethylimidazolium chloride; [0326]
3-(2-phenyl-2-oxoethyl)-1-butylimidazolium chloride; [0327]
3-(2-phenyl-2-oxoethyl)-1-allylimidazolium chloride; [0328]
3-(2-trifluoromethylphenyl-2-oxoethyl)-4,5-dimethylthiazolium
bromide; [0329]
3-(2-trifluoromethylphenyl-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)-
thiazolium bromide; [0330]
3-(2-trifluoromethylphenyl-2-oxoethyl)-1-methylimidazolium bromide;
[0331] 3-(2-trifluoromethylphenyl-2-oxoethyl)-1-methylimidazolium
bromide; [0332] 1-butyl-3-amino-imidazolium-mesitylenesulfonate;
[0333] 3-[2-(thien-2-yl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0334]
3-[2-(pyrrolidin-1-yl)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0335] 3-(2-phenyl-2-oxoethyl)-1,2-dimethylimidazolium
chloride; [0336] 3-amino-1,2-dimethylimidazolium
mesitylenesulfonate; [0337]
3-[2-(pyrrolidin-1-yl)-2-oxoethyl]-1-ethylimidazolium chloride;
[0338] 3-[2-(pyrrolidin-1-yl)-2-oxoethyl]-1-phenylimidazolium
chloride; [0339]
3-[2-(pyrrolidin-1-yl)-2-oxoethyl]-1-methylimidazolium chloride;
[0340] 3-[2-(thien-2-yl)-2-oxoethyl]-1-ethylimidazolium bromide;
[0341] 3-[2-(thien-2-yl)-2-oxoethyl]-1-phenylimidazolium bromide;
[0342] 3-[2-(thien-2-yl-2-oxoethyl]-1,4,5-trimethylimidazolium
bromide; [0343]
3-[2-(pyrrolidin-2-yl)-2-oxoethyl]-1,4,5-trimethylimidazolium
chloride; [0344]
3-[2-(4-chlorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;
[0345] 3-[2-(4-bromophenyl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0346]
3-[2-(4-fluorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;
[0347]
3-[2-(2,4-difluorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0348]
3-[2-(2,4-dichlorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0349]
3-[2-(3,4-difluorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0350]
3-[2-(2-methoxyphenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;
[0351] 3-[2-(3-methoxyphenyl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0352]
3-[2-(4-methoxyphenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;
[0353]
3-[2-(2,4-dimethoxyphenyl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0354]
3-[2-(2,5-dimethoxyphenyl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0355]
3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0356]
3-[2-(4-methylphenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;
[0357]
3-[2-(4-diethylaminophenyl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0358] 3-[2-amino-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0359]
3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-1,2-dimethyl-imidazo-
lium bromide; [0360]
3-[2-(3,4-trimethylenedioxyphenyl)-2-oxoethyl]-1,2-dimethyl-imidazolium
bromide; [0361]
3-[2-(4-biphenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;
[0362]
3-[2-(3,5-dichloroanilino)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0363]
3-[2-(4-trifluoromethylphenyl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0364]
3-[2-(2,6-dichlorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0365]
3-[2-(thiomorpholin-4-yl)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0366]
3-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dimethylimidazolium chloride;
[0367] 3-[2-(piperidin-1-yl)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0368]
3-[2-hexamethyleneimino-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0369]
3-[2-heptamethyleneimino-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0370] 3-[2-naphthyl-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0371]
3-[2-(2-trifluoromethylphenyl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0372]
3-[2-(2-trifluoromethylphenyl)-2-oxoethyl]-2,4,5-trimethylthiazolium
bromide; [0373] 3-(2-methyl-2-oxoethyl)-1,2-dimethylimidazolium
chloride; [0374]
3-(2-phenyl-2-oxoethyl)-2-amino-1-methylbenzimidazolium chloride;
[0375] 3-[2-(thiomorpholin-4-yl)-2-oxoethyl]-1-methylimidazolium
chloride; [0376]
3-[2-(4-phenylpiperazin-1-yl)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0377]
3-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0378]
3-[2-{6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-naphthalyl)}-2-oxoethyl]--
1,2-dimethylimidazolium bromide; [0379]
3-[2-(1,4-benzodioxan-6-yl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0380]
3-[2-(phenyl)-2-oxoethyl]-5-chloro-3-methyl-1-ethylimidazolium
chloride; [0381]
3-[2-(phenyl)-2-oxoethyl]-4-methyl-2-ethylthiazolium chloride;
[0382] 3-(2-phenyl-2-oxoethyl)-1-methyl-2-aminoimidazolium
chloride; [0383]
3-[2-(pyrrolidin-2-yl)-2-oxoethyl]-2-amino-1-methylimidazolium
chloride; [0384]
3-(2-phenyl-2-oxoethyl)-1,2-dimethyl-5-nitroimidazolium chloride;
[0385] 3-[2-(4-acetylanilino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0386]
3-[2-(4-carboethoxyanilino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0387]
3-[2-(2,6-diisopropylanilino)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0388] 3-[2-anilino-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0389]
3-[(4-bromoanilino)-2-oxoethyl]-1,2-dimethylimidazolium chloride;
[0390]
3-[2-(4-[morpholin-4-yl]phenyl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0391]
3-[2-dibutylamino-2-oxoethyl]-1,2-dimethylimidazolium chloride;
[0392]
3-[2-(2,6-dichloro-phenethylamino)-2-oxoethyl]-1,2-dimethylimidazolium;
[0393]
3-[2-(3-hydroxy-4-methoxycarbonylanilino)-2-oxoethyl]-1,2-dimethyl-
imidazolium bromide; [0394]
3-[2-cyclopentylamino-2-oxoethyl]-1,2-dimethylimidazolium chloride;
[0395] 3-[2-neopentylamino-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0396]
3-[2-(pyridin-2-yl)-2-oxoethyl]-4,5-dimethylimidazolium bromide;
[0397] 3-(2-phenyl-2-oxoethyl)-1,4,5-trimethylimidazolium chloride;
[0398] 3-(2-phenyl-2-oxoethyl)-1,2,4,5-tetramethylimidazolium
chloride; [0399]
3-[2-(6-[1,2,3,4-tetrahydroquinolinyl])-2-oxoethyl]-1,2-dimethylim-
idazolium chloride; [0400]
3-[2-(2,6-difluorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0401] 1-vinyl-3-[2-phenyl-2-oxoethyl]imidazolium
chloride; [0402]
1-(4-hydroxyphenyl)-3-(2-phenyl-oxoethyl)imidazolium chloride;
[0403] 1-(4-acetylphenyl)-3-(2-phenyl-2-oxoethyl)imidazolium
chloride; [0404] 1-methyl-3-(2-phenyl-2-oxoethyl)benzimidazolium
chloride; [0405]
1,5-dicyclohexyl-3-(2-phenyl-2-oxoethyl)imidazolium chloride;
[0406]
1-(4-methoxycarbonylphenyl)-3-(2-phenyl-2-oxoethyl)imidazolium
chloride; [0407] 1-benzyl-3-(2-phenyl-2-oxoethyl)imidazolium
chloride; [0408]
1-(4-methoxyphenyl)-3-(2-phenyl-2-oxoethyl)imidazolium chloride;
[0409] 3-[2-(tert-butylamino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0410]
3-[2-(2,4-difluoroanilino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0411]
3-[2-(2,4,6-trimethylanilino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0412]
3-(2-cyclohexylamino-2-oxoethyl)-1,2-dimethylimidazolium chloride;
[0413]
3-[2-(4-carboxy-3'-hydroxyanilino)-2-oxoethyl)-1,2-dimethylimidazolium
chloride; [0414]
3-[2-([2-morpholin-4-yl]ethylamino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0415]
3-[2-(3-[2-methylpiperidin-1-yl]propylamino)-2-oxoethyl]-1,2-dimethylimid-
azolium chloride; [0416]
3-(2-veratrylamino-2-oxoethyl)-1,2-dimethylimidazolium chloride;
[0417] 3-[2-(thiazolidin-3-yl)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0418]
3-[2-(1-adamantanamino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0419]
3-[2-(2-adamantanamino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0420]
3-[2-(2-indanylamino)-2-oxoethyl]-1,2-dimethylimidazolium chloride;
[0421]
3-[2-(2'-[3''-chlorobenzoyl]-5-chloroanilino)-2-oxoethyl]-1,2-dimethylimi-
dazolium chloride; [0422]
3-[2-(4-ethoxycarbonylthiazol-2-yl)amino-2-oxoethyl]-1,2-dimethylimidazol-
ium chloride; [0423]
3-(cyclohexylamino-2-oxoethyl)-2,4,5-trimethylthiazolium chloride;
[0424] 3-[2-(2-chloroanilino)-2-oxoethyl]-1,2-dimethylimidazolium
bromide; [0425]
3-[2-(2-chloroanilino)-2-oxoethyl]-2,4,5-trimethylthiazolium
bromide; [0426]
3-[2-(3,4-dimethoxyphenethylamino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0427]
3-[2-(2,4-dichloroanilino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0428]
3-[2-(2,6-dichloroanilino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0429]
3-[(2-pyrrolidin-1-yl)-2-oxoethyl]-1,2,4,5-tetramethylimidazolium
chloride; [0430]
3-[2-(4-[pyrrolidin-1-yl]piperidin-1-yl)-2-oxoethyl]-1,2-dimethylimidazol-
ium chloride; [0431]
3-[2-(4-[piperidin-1-yl]piperidin-1-yl)-2-oxoethyl]-1,2-dimethylimidazoli-
um chloride; [0432]
3-[2-(2,6-difluoroanilino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0433]
3-(2-cyclobutylamino-2-oxoethyl)-1,2-dimethylimidazolium chloride;
[0434]
3-[2-(3,5-difluoroanilino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0435]
3-[2-(2-fluoroanilino)-2-oxoethyl]-1,2-dimethylimidazolium
chloride; [0436]
3-[2-(1R,2R,3R,5S-isopinocampheylamino)-2-oxoethyl]-1,2-dimethylim-
idazolium chloride; [0437]
3-[2-(1,3,3-trimethyl-6-azabicyclo[3,2,1]octanyl)-2-oxoethyl]-1,2-dimethy-
limidazolium chloride; [0438]
3-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-oxoethyl]-1,2-d-
imethylimidazolium chloride; [0439]
3-[2-(1,2,3,4-tetrahydro-1-naphthylamino)-2-oxoethyl]-1,2-dimethylimidazo-
lium chloride; [0440] 1-(4-methoxyphenyl)-3-aminoimidazolium
mesitylenesulfonate; [0441] 1-benzyl-3-aminoimidazolium
mesitylenesulfonate; [0442] 1-vinyl-3-aminoimidazolium
mesitylenesulfonate; [0443] 1-methyl-3-aminoimidazolium
mesitylenesulfonate; [0444]
1-(4-methoxycarbonylphenyl)-3-aminoimidazolium mesitylenesulfonate;
[0445] 3-(2-phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium; [0446]
S(-) 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium chloride;
[0447] R(-) 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium
chloride; [0448]
3-[2-(2-Hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;
[0449] 3-[2-(3-Hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide;
[0450] 3-[2-(4-Hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide; [0451]
3-(2-phenyl-2-oxoethyl)-4-methyl-5-(hydroxymethyl)-thiazolium
chloride; [0452]
3-[2-(2,4-dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide; [0453]
3-[2-(3,5-dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide; [0454]
3-[2-(2,5-dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide; [0455]
3-[2-(3,4-dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride; [0456]
3-[2-(2',3'-dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium;
[0457] thiamine hydrochloride; [0458]
(1-ethyl-hexanoate)-3-[2-(4-chlorophenyl)-2-oxoethyl]imidazolium
bromide; [0459]
3-[2-[6-[1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-naphthalyl]]-2-oxo-
ethyl]thiazolium bromide; [0460]
3-[2-(3,5-dichloroanilino)-2-oxoethyl]thiazolium bromide; [0461]
3-[2-(4-biphenyl)-2-oxoethyl]thiazolium bromide; [0462]
Cocarboxylase (diphosphate ester of thiamine HCl); [0463]
monophosphate ester of thiamine HCl; [0464]
3-[2-(9H-fluoren-2-yl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;
[0465]
3-[2-{6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-naphthalyl)}-2-oxoethyl]--
4,5-dimethylthiazolium bromide; [0466]
3-[2-{5-(3-phenylisoxazolyl)}-2-oxoethyl]-4,5-dimethylthiazolium
bromide; [0467]
3-[2-(4-biphenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;
[0468]
3-[2-(3,5-dichloroanilino)-2-oxoethyl]-4,5-dimethylthiazolium
bromide; [0469]
3-[2-{6-[1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-naphthalyl]}-2-oxoethyl]--
4-methyl-5-(2-hydroxyethyl)thiazolium bromide; [0470]
3-[2-(3-phenylisoxazol-5-yl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiaz-
olium bromide; [0471]
3-[2-(4-biphenyl)-2-oxoethyl]-4-methyl-5-(2'-hydroxyethyl)thiazolium
bromide; [0472]
3-[2-(3,5-dichloroanilino)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazol-
ium bromide; [0473]
3-{[2-(3-methoxybenzoyl)amino]benzyl}-4,5-dimethylthiazolium
bromide; [0474]
3-[2-(2-amino-5-carboethoxymethylene-thiazolyl)-2-oxoethyl]-4,5-di-
methylthiazolium chloride; [0475]
3-[2-(morpholin-4-yl-2-oxoethyl]-4,5-dimethylthiazolium bromide;
[0476]
3-[2-(2,6-dimethylmorpholin-4-yl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide; [0477]
3-[2-(piperidin-1-yl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;
[0478] 3-[2-(fur-2-yl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;
[0479]
3-[2-[6-(2-oxo-1,2,3,4-tetrahydroquinolinyl)]-2-oxoethyl]-4,5-dimethylthi-
azolium bromide; [0480]
3-[2-(pyrrolidin-1-yl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;
[0481] 3-[2-(4-carboxyanilino)-2-oxoethyl)-4,5-dimethylthiazolium
chloride; [0482]
3-[2-(2-{3-methylbenzo[b]thienyl})-2-oxoethyl]-4,5-dimethylthiazol-
ium bromide; [0483]
3-[2-(4-phenylpiperazin-1-yl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide; [0484]
3-[2-(4-fluorophenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;
[0485] 3-[2-(4-methoxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide; [0486]
3-[2-(4-trifluoromethyl)-2-oxoethyl]-4,5-dimethyl-thiazolium
bromide; [0487]
3-[2-(2,4-difluorophenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide; [0488]
3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride; [0489] 3-[2-tert-butyl-2-oxoethyl]-4,5-dimethylthiazolium
chloride; [0490]
3-[2-(2,4-dichlorophenyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride; [0491]
3-[2-(4-Diethylaminophenyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride; [0492] 3-(2-methyl-2-oxoethyl)-4,5-dimethylthiazolium
chloride; [0493]
3-[2-(2,6-dichlorophenyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride; [0494] 3-(2-phenyl-2-oxoethyl)-4-phenylthiazolium
chloride; [0495]
3-[2-(2,4-dichlorophenyl)-2-oxoethyl]-4-phenylthiazolium chloride;
[0496] 3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]-4-phenylthiazolium
bromide; [0497] 3-(2-methyl-2-oxoethyl)-4-methyl-5-(hydroxyethyl)
thiazolium chloride; [0498]
3-[2-(2,4-dichlorophenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazoli-
um; [0499]
3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxye-
thyl)thiazolium chloride; [0500]
3-(1-methyl-2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride;
[0501] 3-(phenylthiomethyl)-4,5-dimethylthiazolium chloride; [0502]
3-[2-thien-2-yl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; [0503]
3-[2-(2-thien-2-yl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium
bromide; [0504] 3-[2-phenyl-2-oxoethyl]-4,5-cyclohexenyl-thiazolium
bromide; [0505]
3-[2-(2,4-dichlorophenyl)-2-oxoethyl]-4,5-cyclohexeno-thiazolium
chloride; [0506]
3-(2-phenyl-2-oxoethyl)-4,5-cyclopenteno-thiazolium bromide; [0507]
3-[2-(2,4-dichlorophenyl)-2-oxoethyl]-4,5-cyclopenteno-thiazolium
chloride; [0508]
3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]-4,5-cyclopenteno-thiazolium
bromide; [0509]
3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]-4,5-cyclopenteno-thiazolium
bromide; [0510] 3-(2-cyanomethyl)-4,5-cyclohexeno-thiazolium
bromide; [0511] 3-(2-cyanomethyl)-4,5-cyclopenteno-thiazolium
bromide; [0512] 3-(2-cyanomethyl)-4,5-dimethyl-thiazolium bromide;
[0513] 3-(2-methyl-2-oxoethyl)-4,5-cyclopenteno-thiazolium
chloride; [0514]
3-(2-cyanomethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide;
[0515]
3-(2-phenyl-2-oxoethyl)-4-methyl-5-(hydroxyethylsuccinyl)thiazolium
chloride; [0516]
3-[2-(thien-2-yl)-2-oxoethyl]-2,4,5-trimethylthiazolium bromide;
[0517] 3-amino-4-methyl-5-(2-hydroxyethyl)-thiazolium bromide;
[0518] 3-(2-phenyl-2-oxoethyl)-2,4,5-trimethylthiazolium chloride;
[0519] 3-amino-2,4,5-trimethylthiazolium mesitylenesulfonate;
[0520]
3-[2-(4-{2-methoxyphenyl}piperazin-1-yl)-2-oxoethyl]-4,5-dimethylthiazoli-
um chloride; [0521] 3-[2-hydroxy-2-oxoethyl]-4,5-dimethylthiazolium
chloride; [0522] 3-(2-phenyl-2-oxoethyl)-2-aminothiazolium
chloride; [0523]
3-[2-(thiomorpholin-4-yl)-2-oxoethyl]-5-hydroxyethyl-4-methylthiaz-
olium chloride; [0524]
3-[2-(4-trifluoromethylphenyl)-2-oxoethyl]-2,4,5-trimethylthiazolium
bromide; [0525] 3-[2-phenyl-2-oxoethyl]-2-isobutylthiazolium
chloride; [0526]
3-[2-(thiomorpholin-4-yl)-2-oxoethyl)-2,4,5-trimethylthiazolium
chloride; [0527] 3-(2-amino-2-oxoethyl)-2-methylbenzothiazolium
chloride; [0528]
3-[2-(4-acetanilino)-2-oxoethyl]-2,4,5-trimethylthiazolium
chloride; [0529]
3-[2-(4-carboethoxyanilino)-2-oxoethyl]-2,4,5-trimethylthiazolium
bromide; [0530]
3-[2-(2,6-diisopropylanilino)-2-oxoethyl]-2,4,5-trimethylthiazolium
bromide; [0531]
3-[(4-bromoanilino)-2-oxoethyl]-2,4,5-trimethylthiazolium chloride;
[0532] 3-[2-(2-naphthyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide; [0533]
3-[2-([3-phenylisoxazol-5-yl])-2-oxoethyl]thiazolium bromide;
[0534] 3-methyl-4,5-dimethylthiazolium chloride; [0535]
3-ethyl-4,5-dimethylthiazolium bromide; [0536]
3-[2-(4'-acetoxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;
[0537]
3-[2-phenyl-2-oxoethyl]-4-methyl-5-(ethoxycarbonyl)thiazolium
chloride; [0538] 3-[2-(4-diethylaminophenyl)-2-oxoethyl]thiazolium
chloride; [0539] 1-methyl-3-(2-cyanomethyl)imidazolium bromide;
[0540] 3-(2-cyanomethyl)-4,5-dimethylthiazolium bromide; [0541]
3-(2-cyanomethyl)-4,5-cyclopentenothiazolium bromide; [0542]
3-(2-cyanomethyl)-4,5-cyclohexenothiazolium bromide; [0543]
1-methyl-3-(2-cyanomethyl)imidazolium bromide; [0544]
1-vinyl-3-(2-cyanomethyl)imidazolium chloride; [0545]
1-allyl-3-(2-cyanomethyl)imidazolium chloride; [0546]
1-(4-acetylphenyl)-3-(2-cyanomethyl)imidazolium chloride; [0547]
1-phenyl-3-(2-cyanomethyl)imidazolium chloride; [0548]
1-(4-methoxyphenyl)-3-(2-cyanomethyl)imidazolium chloride; [0549]
1-(4-methoxycarbonylphenyl)-3-(2-cyanomethyl-imidazolium chloride;
[0550] 3-(2-cyanomethyl)-1-methylbenzimidazolium chloride; [0551]
1,5-dicyclohexyl-3-(2-cyanomethyl)imidazolium bromide; as well as
other biologically or pharmaceutically acceptable salts
thereof.
[0552] Compounds of the general formula I wherein the R.sup.1,
R.sup.2, X, Y, and Z are defined as above can be prepared by the
methods of U.S. Pat. Nos. 5,656,261; 5,853,703; and 6,007,865; or
as described below. Moreover, certain of the compounds are
conveniently prepared by chemical syntheses that are well-known in
the art. In addition, certain of the compounds are well-known and
readily available from chemical supply houses or can be prepared by
synthetic methods specifically published therefor. The chemical
reagents shown in the schemes below provide nonlimiting examples of
means well known in the art to carry out the reaction steps
shown.
[0553] Compounds of the invention wherein Y is
CH(R.sup.5)--C(O)--R.sup.7 can be prepared according to the
synthetic route depicted in Scheme 1 (wherein R.sup.1, R.sup.2,
R.sup.5, R.sup.7, M, Q, and Z are as described above, and X is a
halide). An acetyl derivative with a suitable a .alpha. leaving
group, for example, an .alpha.-halo acetyl derivative, can be used
to alkylate a suitably substituted thiazole, oxazole, or imidazole.
The alkylation reaction may be conducted at elevated temperatures
in a suitable solvent, for example, acetonitrile or ethanol, or
without solvent.
##STR00005##
[0554] Compounds of the invention wherein R.sup.6 is a group of the
formula --CH(OH)Rs may be prepared as shown in Schemes 2 and 3 (see
below). In the nonlimiting exemplary synthetic schemes below, some
product compounds are shown as specific optical isomers and others
are shown as racemic compounds. One skilled in the art will
appreciate that appropriate reaction conditions and reagents, that
are well known in the art, can be used to customize the degree of
reaction stereoselectivity. Thus, isolated stereoisomers are within
the scope of compounds of the invention. For example, compound 2
can be obtained as a racemic mixture from compound 1 or as an S
(compound 2a) or R stereoisomer depending on the reducing agent
employed. Substitution of comparable reagents to achieve different
stereoselectivity, even when not shown explicitly by the scheme, is
well known in the art at the time of filing. Moreover, synthetic
processes and stereoselective purifications, such as chromatography
on stereoselective media can be used to achieve 90%, 95%, 98%, 99%
or better isomeric purity, such that compositions substantially
free of the non-desired isomer can be prepared.
[0555] A synthetic scheme for making compounds of the formula I
wherein Y is CH.sub.2CH(OH)Rs is shown in Scheme 2. A hydroxyl is
incorporated into a nucleophile used to derivatize a thiazole
compound, as follows:
##STR00006##
where Lv is a leaving group such as chloro. In a related synthesis,
Compound 1 is reduced with a stereoselective reducing agent such as
(-) DIP-chloride [(-)-B-chlorodiisopinocampheylborane] or (+)
DIP-chloride [(+)-B-chlorodiisopinocampheylborane]. For
example:
##STR00007##
Substitution of (+) DIP-chloride results predominately in the
mirror image to compound 3a.
[0556] Scheme 4 exemplifies methods of preparing compounds of the
formula I wherein Y is a group of the formula --CH.sub.2R.sup.6
wherein R.sup.6 is a substituted or unsubstituted benzoyl moiety.
In this particular preparation, acetophenones substituted in the
phenyl moiety with hydroxy groups are derivatized to add a leaving
group to the alpha methyl group, and the resulting intermediate is
then used to alkylate thiazoles, as exemplified below:
##STR00008##
[0557] In another synthesis, the preparation of compounds of the
formula I wherein R.sup.2 is --CH.sub.2OH are exemplified.
Formamide is first converted to thioformamide by reaction with
phosphorus pentasulfide. Thioformamide is reacted with ethyl
2-chloroacetoacetate in dry dioxane as follows:
##STR00009##
Compound 8 can then be reacted with a suitable alkylating agent to
make a compound of the invention.
[0558] Where R.sup.1 is --CH.sub.2OH and R.sup.2 is --CH.sub.3 in
Formula I, the route shown in Scheme 6 can be used. The preparation
of a thiazole analog containing a 4-hydroxymethyl group, for
example, is shown below:
##STR00010##
Compound 10 can then be alkylated with a suitable alkylating agent
to make a compound of the invention.
[0559] Note that reaction conditions indicated in the various
reaction schemes are exemplary: such conditions as solvent and
temperature are subject to modification within ordinary skill.
[0560] A useful synthetic route for the preparation of compounds of
formula I wherein Y is --CH(R.sup.5)CN is shown in Scheme 7.
##STR00011##
wherein M, Q, R.sup.1, R.sup.2, R.sup.5, Y and Z are as described
in the text above, and X is a halide, mesitylenesulfonate or other
biologically acceptable anion. In Scheme 7, the appropriately
substituted imidazole, oxazole, or thiazole of formula 11 is
contacted with a (e.g.) halo substituted acetonitrile of formula 12
to produce compounds of the formula 13. The reaction can be
performed without any added solvent, or an anhydrous solvent can be
utilized as the solvent medium. When a solvent is used,
acetonitrile is a typical solvent for this reaction. Reaction times
vary according to particular reactants and conditions, but are
usually in the range of a few minutes to 48 hours at a temperature
of 25-130.degree. C.
[0561] Compounds of the formula 17 (below), wherein Y contains a
carboxamido moiety, can be synthesized according to method depicted
in Scheme 8. An appropriately substituted amine can be condensed
with an activated acetyl analog (for example, an acid chloride or
acid anhydride), containing an additional leaving group alpha to
the carbonyl group, to provide the carboxamide 15. Compound 15 can
then be used to alkylate the heterocycle 16 to yield a compound of
the invention 17.
##STR00012##
[0562] Other alkylation conditions can also be used. For example,
thiazoles and imidazoles can be alkylated at the 1-position or the
2-position by vapor phase alkylation over an appropriate solid
catalyst, using the corresponding alcohol as the alkyl source. See,
Ono et al., in Catalysis by Microporous Materials, Studies in
Surface Science and Catalysis, Vol. 94, Beyer et al., Eds., 1995,
polypeptide. 697-704. Appropriate catalysts include zeolite H--Y,
zeolite H-ZSM-5 and H.sub.3PW.sub.12O.sub.40 supported on silica.
Reaction conditions typically include high temperatures, such as
260 and 300.degree. C.
[0563] In addition, N-aryl substituted thiazoliums, oxazoliums and
imidazoliums can also be prepared. For example, fluoro phenyl
compounds such as 4-fluorobenzoic acid methyl ester can be used to
substitute the N.sup.1 nitrogen of imidazole to make
methyl-4-(1H-imidazol-1-yl)benzoate. See, Morgan et al., J. Med.
Chem. 33: 1091-1097, 1990. These aryl substituted imidazoliums can
then be reacted with an alkylating agent, for example, an
.alpha.-haloacetophenone analog, to prepare a compound of the
invention. Also, the amine functions of imidazoles or
amine-substituted thiazoles can be acylated by dehydration or other
methods known in the art.
[0564] 3-Aminothiazoliums, 3-aminooxazoliums, and
1-alkyl-3-aminoimidazoliums can be prepared by reaction with
O-mesitylene sulfonylhydroxylanine in methylene chloride. The
product mesitylenesulfonate salts can be converted to their
chloride salts through ion exchange with strongly basic anion
exchange resins.
[0565] Substituted oxazole intermediate that are suitable
intermediates for the alkylation reactions, such as those shown in
Schemes 1 and 7, can be prepared by methods known in the art. For
instance, 2-unsubstituted oxazoles can be formed by condensation of
formamide with either .alpha.-hydroxy or .alpha.-haloketones
intermediates (H. Bredereck, R. Gommpper, H. G. v. Shuh and G.
Theilig, in Newer Methods of Preparative Organic Chemistry, Vol.
III, ed. W. Foerst, Academic press, New York, 1964, p. 241). The
intermediates can cyclize under acid conditions to form the oxazole
ring (Scheme 9). In addition, 2,4-disubstituted oxazoles can be
prepared from .alpha.-haloketones and amides at higher temperatures
using the same method.
##STR00013##
[0566] Oxazoles can be prepared by cyclization reactions of
isonitriles (van Leusen, A. M. Lect. Heterocycl. Chem. 1980, 5,
S111; Walborsky, H. M.; Periasamy, M. P. in The Chemistry of
Functional Groups, suppl. C, Patai, S., Rappoport, Z., Eds,
Wiley-Interscience, 1983, p. 835; Hoppe, D. Angew. Chem. Int. Edn.
Engl., 1974, 13, 789: Schollkopf, U. Angew. Chem. Int. Ed. Engl.,
1977, 16, 339). For example, as shown below in Scheme 10, the
tosylmethyl isocyanide can be deprotonated by a base and reacted
with a suitable electrophile (e.g. an aldehyde). The intermediate
can cyclize and aromatize to provide the desired oxazole
intermediate. The intermediate can then be N-alkylated by the
above-described methods to furnish a compound of the invention.
Other methods for preparing oxazole intermediates include
1,5-dipolar cyclization of acylated nitrile ylides (Taylor E. C.;
Turchi, I. J. Chem. Rev., 1979, 79, 181: Huisgen, R. Angew. Chem.
Int. Edn. Engl. 1980, 19, 947).
##STR00014##
[0567] Benzoxazole intermediates substituted at the 2 position can
be prepared from 2-aminophenols by acylation with, for example,
with an acid chloride and cyclization (Scheme 11). The intermediate
can then be N-alkylated by the above-described methods to furnish a
compound of the invention.
##STR00015##
[0568] To treat the indications of the invention, an effective
amount of a pharmaceutical compound will be recognized by
clinicians but includes an amount effective to treat, reduce,
ameliorate, eliminate or prevent one or more symptoms of the
disease sought to be treated or the condition sought to be avoided
or treated, or to otherwise produce a clinically recognizable
change in the pathology of the disease or condition.
[0569] Pharmaceutical compositions can be prepared to allow a
therapeutically effective quantity of the compound of the present
invention, and can include a pharmaceutically acceptable carrier,
selected from known materials utilized for this purpose. See, e.g.,
Remington, The Science and Practice of Pharmacy, 1995; Handbook of
Pharmaceutical Excipients, 3.sup.rd Edition, 1999. Such
compositions can be prepared in a variety of forms, depending on
the method of administration, such as sublingual, rectal, nasal,
vaginal, topical (including the use of a patch or other transdermal
delivery device), by pulmonary route by use of an aerosol, or
parenteral, including, for example, intramuscular, subcutaneous,
intraperitoneal, intraarterial, intravenous or intrathecal.
[0570] In addition to the subject compound, the compositions of
this invention can contain a pharmaceutically-acceptable carrier.
The term "pharmaceutically-acceptable carrier", as used herein,
means one or more compatible solid or liquid filler diluents or
encapsulating substances that are suitable for administration to an
animal, including a mammal or human. The term "compatible", as used
herein, means that the components of the composition are capable of
being comingled with the subject compound, and with each other,
such that there is no interaction that would substantially reduce
the pharmaceutical efficacy of the composition under ordinary use.
Preferably when liquid dose forms are used, the compounds of the
invention are soluble in the components of the composition.
Pharmaceutically-acceptable carriers should, of course, be of
sufficiently high purity and sufficiently low toxicity to render
them suitable for administration to the animal being treated.
[0571] Some examples of substances which can serve as
pharmaceutically-acceptable carriers or components thereof are
sugars, such as lactose, glucose and sucrose; starches, such as
corn starch and-potato starch; cellulose and its derivatives, such
as sodium carboxymethyl cellulose, ethyl cellulose, and methyl
cellulose; powdered tragacanth; malt; gelatin; talc; solid
lubricants, such as stearic acid and magnesium stearate; calcium
sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame
oil, olive oil, corn oil and oil of theobroma; polyols such as
propylene glycol, glycerine, sorbitol, mannitol, and polyethylene
glycol; alginic acid; emulsifiers, such as the Tween.TM. brand
emulsifiers; wetting agents, such sodium lauryl sulfate; coloring
agents; flavoring agents; tableting agents, stabilizers;
antioxidants; preservatives; pyrogen-free water; isotonic saline;
and phosphate buffer solutions. The choice of a
pharmaceutically-acceptable carrier to be used in conjunction with
the subject compound is basically determined by the way the
compound is to be administered. If the subject compound is to be
injected, the preferred pharmaceutically-acceptable carrier is
sterile, physiological saline, with a blood-compatible suspending
agent, the pH of which has been adjusted to about 7.4.
[0572] If the preferred mode of administering the subject compound
is perorally, the preferred unit dosage form is therefore tablets,
capsules, lozenges, chewable tablets, and the like. Such unit
dosage forms comprise a safe and effective amount of the subject
compound, which is preferably from about 0.7 or 3.5 mg to about 280
mg/70 kg, more preferably from about 0.5 or 10 mg to about 210
mg/70 kg. The pharmaceutically-acceptable carrier suitable for the
preparation of unit dosage forms for peroral administration are
well-known in the art. Tablets typically comprise conventional
pharmaceutically-compatible adjuvants as inert diluents, such as
calcium carbonate, sodium carbonate, mannitol, lactose and
cellulose; binders such as starch, gelatin and sucrose;
disintegrants such as starch, alginic acid and crosscarmelose;
lubricants such as magnesium stearate, stearic acid and talc.
Glidants such as silicon dioxide can be used to improve flow
characteristics of the powder-mixture. Coloring agents, such as the
FD&C dyes, can be added for appearance. Sweeteners and
flavoring agents, such as aspartame, saccharin, menthol,
peppermint, and fruit flavors, are useful adjuvants for chewable
tablets. Capsules typically comprise one or more solid diluents
disclosed above. The selection of carrier components depends on
secondary considerations like taste, cost, and shelf stability,
which are not critical for the purposes of this invention, and can
be readily made by a person skilled in the art.
[0573] Peroral compositions also include liquid solutions,
emulsions, suspensions, and the like. The
pharmaceutically-acceptable carriers suitable for preparation of
such compositions are well known in the art. Such liquid oral
compositions preferably comprise from about 0.012% to about 0.933%
of the subject compound, more preferably from about 0.033% to about
0.7%. Typical components of carriers for syrups, elixirs, emulsions
and suspensions include ethanol, glycerol, propylene glycol,
polyethylene glycol, liquid sucrose, sorbitol and water. For a
suspension, typical suspending agents include methyl cellulose,
sodium carboxymethyl cellulose, cellulose (e.g. Avicel.TM.,
RC-591), tragacanth and sodium alginate; typical wetting agents
include lecithin and polyethylene oxide sorbitan (e.g. polysorbate
80). Typical preservatives include methyl paraben and sodium
benzoate. Peroral liquid compositions may also contain one or more
components such as sweeteners, flavoring agents and colorants
disclosed above.
[0574] Other compositions useful for attaining systemic delivery of
the subject compounds include sublingual and buccal dosage forms.
Such compositions typically comprise one or more of soluble filler
substances such as sucrose, sorbitol and mannitol; and binders such
as acacia, microcrystalline cellulose, carboxymethyl cellulose and
hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners,
colorants, antioxidants and flavoring agents disclosed above may
also be included.
[0575] Compositions can also be used to deliver the compound to the
site where activity is desired; such as eye drops, gels and creams
for ocular disorders.
[0576] Compositions of this invention include solutions or
emulsions, preferably aqueous solutions or emulsions comprising a
safe and effective amount of a subject compound intended for
topical intranasal administration. Such compositions preferably
comprise from about 0.01% to about 10.0% w/v of a subject compound,
more preferably from about 0.1% to about 2.0%. Similar compositions
are preferred for systemic delivery of subject compounds by the
intranasal route. Compositions intended to deliver the compound
systemically by intranasal dosing preferably comprise similar
amounts of a subject compound as are determined to be safe and
effective by peroral or parenteral administration. Such
compositions used for intranasal dosing also typically include safe
and effective amounts of preservatives, such as benzalkonium
chloride and thimerosal and the like; chelating agents, such as
edetate sodium and others; buffers such as phosphate, citrate and
acetate; tonicity agents such as sodium chloride, potassium
chloride, glycerin, mannitol and others; antioxidants such as
ascorbic acid, acetylcystine, sodium metabisulfote and others;
aromatic agents; viscosity adjustors, such as polymers, including
cellulose and derivatives thereof; and polyvinyl alcohol and acids
and bases to adjust the pH of these aqueous compositions as needed.
The compositions may also comprise local anesthetics or other
actives. These compositions can be used as sprays, mists, drops,
and the like.
[0577] Other preferred compositions of this invention include
aqueous solutions, suspensions, and dry powders comprising a safe
and effective amount of a subject compound intended for atomization
and inhalation administration. Such compositions are typically
contained in a container with attached atomizing means. Such
compositions also typically include propellants such as
chlorofluorocarbons 12/11 and 12/114, and more environmentally
friendly fluorocarbons, or other nontoxic volatiles; solvents such
as water, glycerol and ethanol, including cosolvents as needed to
solvate or suspend the active agent; stabilizers such as ascorbic
acid, sodium metabisulfite; preservatives such as cetylpyridinium
chloride and benzalkonium chloride; tonicity adjustors such as
sodium chloride; buffers; and flavoring agents such as sodium
saccharin. Such compositions are useful for treating respiratory
disorders, such as asthma and the like.
[0578] Other preferred compositions of this invention include
aqueous solutions comprising a safe and effective amount of a
subject compound intended for topical ocular administration. Such
compositions preferably comprise from about 0.01% to about 0.8% w/v
of a subject compound, more preferably from about 0.05% to about
0.3%. Such compositions also typically include one or more of
preservatives, such as benzalkonium chloride or thimerosal;
vehicles, such as poloxamers, modified celluloses, povidone and
purified water; tonicity adjustors, such as sodium chloride,
mannitol and glycerin; buffers such as acetate, citrate, phosphate
and borate; antioxidants such as sodium metabisulfite, butylated
hydroxy toluene and acetyl cysteine; acids and bases can be used to
adjust the pH of these formulations as needed.
[0579] Other preferred compositions of this invention useful for
peroral administration include solids, such as tablets and
capsules, and liquids, such as solutions, suspensions and emulsions
(preferably in soft gelatin capsules), comprising a safe and
effective amount of a subject compound. Such compositions can be
coated by conventional methods, typically with pH or time-dependent
coatings, such that the subject compound is released in the
gastrointestinal tract at various times to extend the desired
action. Such dosage forms typically include, but are not limited
to, one or more of cellulose acetate phthalate, polyvinylacetate
phthalate, hydroxypropyl methyl cellulose phthalate, ethyl
cellulose, Eudragit.TM. coatings, waxes and shellac.
[0580] The compounds of the invention are administered by ocular,
oral, parenteral, including, for example, using formulations
suitable as eye drops. For ocular administration, ointments or
droppable liquids may be delivered by ocular delivery systems known
to the art such as applicators or eye droppers. Such compositions
can include mucomimetics such as hyaluronic acid, chondroitin
sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol,
preservatives such as sorbic acid, EDTA or benzylchromium chloride,
and the usual quantities of diluents and/or carriers. See,
Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing,
Easton, Pa., 1980, as well as later editions, for information on
pharmaceutical compounding.
[0581] Numerous additional administration vehicles will be apparent
to those of ordinary skill in the art, including without limitation
slow release formulations, liposomal formulations and polymeric
matrices.
[0582] In another preferred embodiment, the pharmaceutically
effective amount is approximately 0.1 or 0.5 to 4 mg/kg body weight
daily. Still more preferably, the pharmaceutically effective amount
is approximately 1 mg/kg body weight daily. In a preferred
embodiment, the amount is administered in once daily doses, each
dose being approximately 1 mg/kg body weight.
[0583] The activity of the compounds of the invention in breaking,
reversing or inhibiting the formation of AGE's or AGE-mediated
crosslinks can be assayed by any of the methods described in U.S.
Pat. No. 5,853,703.
[0584] The following examples further illustrate the present
invention, but of course, should not be construed as in any way
limiting its scope.
EXAMPLE
[0585] Rats received a daily intraperitoneal dose of 10 mg/kg
3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt (compound A)
(n=14) or placebo (n=15) for 30 days. The animals then underwent a
thoracotomy and the left anterior descending coronary artery
ligated. The chest was then closed and the animals allowed to
recover for 14 days while continuing to be treated with compound A
or placebo. The animals were then sacrificed and the hearts removed
for histological examination. The weight of the infarcted tissue
was 0.16.+-.0.04 g for the placebo treated animals compared to
0.11.+-.0.05 g for the compound A treated animals (p=0.04). The
thickness of the ventricular wall in the infarcted zone was also
reduced in the compound A treated animals compared to placebo
(2.72.+-.0.13 mm vs. 2.56.+-.0.22 mm, p=0.09).
Example 1
3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium chloride:
2-Chloro-1-phenylethanol
[0586] 2-Chloroacetophenone (5.0 g, 32 mmol) was dissolved in
methanol (25 mL) and cooled to 0.degree. C. Sodium borohydride (1.2
g, 32 mmol) was added and stirred at 0.degree. C. for 30 minutes.
The reaction mixture was neutralized by adding conc. HCl to pH 7.0
and evaporated to dryness. The residue was dissolved in ethanol (30
mL) and filtered, washed with ethanol. The ethanol was evaporated
to dryness. The residue was dissolved in methylene chloride (20 mL)
and dried over sodium sulfate. The methylene chloride solution was
filtered and evaporated to give the desired product as an oil;
yield 4.84 g (5.6%).
3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium Chloride
[0587] The neat mixture of 2-chloro-1-phenylethanol (2.34 g, 14.9
mmol) and 4,5-dimethylthiazole (1.69 g, 14.9 mmol) were heated with
stirring at 135.degree. C. for 28 hrs. It was cooled to room
temperature and water (30 mL) was added to the reaction mixture
with stirring, and then was extracted with ether (30 mL). The water
layer was treated with actived carbon and evaporated to dryness. It
was crystallized from a mixture of acetonitrile and ether to give a
racemic product as prisms; 0.39 g (9.7%); mp. 201-203.degree.
C.
Example 2
S 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium Chloride
S(-) 2-chloro-1-phenylethanol
[0588] 2-Chloroacetophenone (3 g., 19.4 mmol) was treated with (-)
DIP-chloride (6.7 g., 20.9 mmol) in anhydrous THF (20 mL) at
dry-ice bath temperature and left overnight. The temperature was
raised to room temperature and THF was removed in vacuo. The
residue was dissolved in ether (100 mL). The diethanolamine (4.58
g., 42.6 mmol) was added and the mixture stirred at room
temperature for 5 hrs. The separated solid was filtered and the
filtered cake was washed with hexane (40 mL) and ether (30 mL). The
combined filtrates were evaporated to dryness to give 6.36 g of
crude product. This was purified by silica gel column
chromatography using 1% ether and petroleum ether 1.71 g (56%) of
the desired product was obtained as an oil.
S 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium Chloride
[0589] The neat mixture of S(-) 2-chloro-1-phenylethanol (2.78 g.,
17.8 mmol) and 4,5-dimethylthiazole (2 g., 17.7 mmol) were heated
with stirring at 135.degree. C. for 25 hrs. It was cooled to room
temperature and water (30 mL) was added to the reaction mixture
with stirring. The solution was extracted with ether (30 mL). The
ether extract was again extracted with water (30 mL). The combined
water layer was evaporated to dryness and the residue was
crystallized with a mixture of acetonitrile and methyl tert-butyl
ether. Yield: 0.63 g. (7.7%); mp. 189-190.degree. C.;
[.alpha.].sub.D.sup.25 -51.765 (Water, c=1.7732).
Example 3
R(+) 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium
Chloride
R(+) 2-chloro-1-phenylethanol
[0590] 2-Chloroacetophenone (6.25 g., 40.4 mmol) was treated with
(+) DIP-chloride (18 g., 56.1 mmol) in anhydrous THF (40 mL) at
dry-ice bath temperature and left overnight. The temperature was
raised to room temperature and THF was removed in vacuo. The
residue was dissolved in ether (210 mL). The diethanolamine (9 g.,
8 5.6 mmol) was added and the mixture stirred at room temperature
for 5 hrs. The separated solid was filtered and the filtered cake
was washed with ether (150 mL). The combined filtrates were
evaporated to dryness to give 15.53 g. of crude product. This was
purified by silica gel column chromatography using 1% ether and
petroleum ether 4.32 g. (68%) of the desired product as an oil.
R(+) 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium
Chloride
[0591] The neat mixture of R(+) 2-chloro-1-phenylethanol (4.32 g.,
27.6 mmol) and 4,5-dimethylthiazole (3.12 g, 27.6 mmol) were heated
with stirring at 135.degree. C. for 25 hrs. It was cooled to room
temperature and water (30 mL) was added to the reaction mixture
with stirring. The solution was extracted with ether (30 mL). The
ether extract was again extracted with water (30 mL). The combined
water layer was evaporated to dryness and the residue was
crystallized with a mixture of acetonitrile and methyl tert-butyl
ether. Yield: 0.44 g. (5.4%); mp. 187-189.degree. C.;
[.alpha.].sub.D.sup.25+52.009 (Water, c=1.7824).
Example 4
3-[2-(2',3' or
4'-monohydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
Bromide
2-Bromo-4'-hydroxyacetophenone
[0592] Copper (II) bromide (6 g, 26.9 mmol) was suspended in ethyl
acetate (50 mL) and 4'-hydroxyacetophenone (2 g, 14.7 mmol)
dissolved in chloroform (20 mL) was added to the suspension. The
reaction mixture was refluxed for 8 hrs. and filtered hot through
celite pad. The filtrate was evaporated to dryness to give the
desired crude brown colored compound (mp=115-118.degree. C.; yield:
3.03 g, 96%). The NMR spectrum and TLC [silica gel, Hexanes:EtOAc
(1:1, v/v)] was in agreement with the desired product. It was used
as such in the next step of the reaction without further
purification.
[0593] This method was used to prepare:
(i) 2-Bromo-2'-hydroxyacetophenone from 2'-hydroxyacetophenone and
copper (II) bromide. Yield: 3.30 g. (95%; oil). (ii)
2-Bromo-3'-hydroxyacetophenone from 3'-hydroxyacetophenone and
copper (II) bromide. Yield: 3.20 g. (92%; oil).
3-[2-(4-Hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
Bromide
[0594] The neat mixture of 2-bromo-4'-hydroxyacetophenone (3 g, 15
mmol) and 4,5-dimethylthiazole (1.71 g, 15 mmol) was heated at
110.degree. C. for 3 hrs. It was dissolved in acetonitrile (15 mL)
and cooled to room temperature. Tert-butyl methyl ether (5 mL) was
added and the reaction mixture kept at room temperature overnight.
The product crystallized was filtered, washed well with a mixture
of acetonitrile and tert-butyl methyl ether (1:1, v/v) and dried.
It was recrystallized from a mixture of acetonitrile, ethyl alcohol
and tert-butyl methyl ether. Yield: 3.18 g (64%); mp.
245-247.degree. C. (dec.).
[0595] This method was used to prepare:
(i) 3-[2-(2-Hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide from 2-bromo-2'-hydroxyacetophenone and
4,5-dimethylthiazole. Yield: 2.05 g. (38%), mp=208-209.degree. C.
(ii) 3-[2-(3-Hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide from 2-bromo-3'-hydroxyacetophenone and
4,5-dimethylthiazole. Yield: 1.52 g. (47%), mp=235-237.degree.
C.
Example 5
3-(2-Phenyl-2-oxoethyl)-4-methyl-5-(hydroxymethyl)thiazolium
Chloride
Thioformamide
[0596] To formamide (20 g, 443 mmol) dissolved in anhydrous THF
(100 mL) was added phosphorous pentasulfide (P.sub.2S.sub.5) (20 g,
45 mmol) while maintaining the temperature at 30-35.degree. C. The
mixture was stirred overnight at room temperature, filtered and
stripped of THF. The crude product was suspended in ethyl acetate
(40 mL) and cooled at -78.degree. C. overnight, filtered and dried
in vacuo at room temperature to give thioformamide (10.6 g, 39%).
See Rynbrandt, R. H., Nishizawa, E. E., Balogoyen, D. P., Mezdoza,
A. K., Annis, K. A.; J. Med. Chem. 1981, 24, 1507-1510.
4-Methyl-5-(ethoxycarbonyl)thiazole
[0597] Thioformamide (7.5 g, 122.72 mmol), ethyl
2-chloroacetoacetate (16.4 g, 99.52 mmol) and magnesium carbonate
(20 g, 237.22 mmoL) were taken dioxane (100 mL) and heated at
110.degree. C. for 4 hrs. The reaction mixture was cooled to room
temperature and filtered to remove magnesium carbonate. The solvent
was evaporated to dryness and the residue was taken in ether (200
mL) and washed successively with 0.5 M NaOH solution (200
mL.times.2) and saturated brine solution (100 mL) and dried over
Na.sub.2SO.sub.4. It was filtered and evaporated to give
4-methyl-5-(ethoxycarbonyl)thiazole as an oil which was purified by
silica gel column chromatography using hexanes:EtOAc (8:2, v/v) as
a eluent; yield: 3.28 g (17%).
4-Methyl-5-(hydroxymethyl)thiazole
[0598] A 250-mL, three necked round-bottomed flask fitted with a
100-mL dropping funnel, a nitrogen-inlet tube, and a reflux
condenser was added lithium aluminum hydride (1 g, 26.35 mmol) and
anhydrous ether (50 mL). To the dropping funnel was added
4-methyl-5-(ethoxycarbonyl)-thiazole (3 g, 17.3 mmol) and anhydrous
ether (25 mL). While the suspension of lithium aluminum hydride was
gently stirred under a nitrogen atmosphere, the solution of
4-methyl-5-(ethoxycarbonyl)thiazole was added dropwise at a rate
maintaining a gentle reflux. When the addition was complete, the
mixture was heated at reflux for 4 hrs. After the mixture had
returned to room temperature, anhydrous ether (100 mL) was added.
The gray reaction mixture was hydrolyzed by addition, in small
parts, of a sufficient amount of wet sodium sulfate. The reaction
mixture was filtered through a sintered-glass funnel. The organic
layer separated and dried over Na.sub.2SO.sub.4. It was filtered
and evaporated to give desired compound as an oil; yield: 590 mg
(26%).
3-(2-Phenyl-2-oxoethyl)-4-methyl-5-(hydroxymethyl)thiazolium
Chloride
[0599] The neat reaction of 4-methyl-5-(hydroxymethyl)thiazole (590
mg, 4.57 mmol) and 2-chloroacetophenone (710 mg, 4.59 mmol) was
heated at 110.degree. C. The mixture solidified within 15 minutes.
Acetonitrile (10 mL) was added and the mixture refluxed for another
3 hrs. It was cooled to room temperature and tert-butyl methyl
ether (5 mL) was added and the reaction mixture was left overnight
at room temperature. The product crystallized was filtered and
washed well with a mixture of hexanes:EtOAc (1:1, v/v) and dried.
It was recrystallized from a mixture of
actonitrile/ethanol/tert-butyl methyl ether; yield 130 mg (10%);
mp. 240-242.degree. C. (dec.).
Example 6
3-[2-(Disubstituted-dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
Bromide
2-Bromo-2',4'-dihydroxyacetophenone
[0600] Copper (II) bromide (6 g, 26.9 mmol) was suspended in ethyl
acetate (50 mL) and 2',4'-dihyroxyacetophenone (2 g, 13.1 mmol)
dissolved in chloroform (20 mL) was added to the suspension. The
reaction mixture was refluxed for 8 hrs. and filtered hot through
celite pad. The filtrate was evaporated to dryness to give crude
oil (3.0 g, 96%). The NMR spectrum and TLC [silica gel,
Hexanes:EtOAc (1:1, v/v)] was in agreement with the desired
product. It was used as such in the next step of the reaction
without further purification.
[0601] This method was used to prepare:
(i) 2-Bromo-3',5'-dihydroxyacetophenone from
3',5'-dihydroxyacetophenone and copper (II) bromide. (ii)
2-Bromo-2',5'-dihydroxyacetophenone from
2',5'-dihydroxyacetophenone and copper (II) bromide. Yield: 2.99 g;
99%
3-[2-(2,4-Dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
Bromide
[0602] The neat mixture of 2-bromo-2',4'-dihydroxyacetophenone (3
g, 13 mmol) and 4,5-dimethylthiazole (1.71 g, 13.3 mmol) was heated
at 110.degree. C. for 3 hrs. It was dissolved in acetonitrile (15
mL) and cooled to room temperature. Tert-butyl methyl ether (5 mL)
was added and the reaction mixture kept at room temperature
overnight. The product crystallized was filtered, washed well with
a mixture of acetonitrile and tert-butyl methyl ether (1:1, v/v)
and dried. It was recrystallized from a mixture of methanol and a
few drops of water. Yield: 2.5 g (50%); mp. 257-260.degree. C.
(dec.).
[0603] This method was used to prepare:
(i) 3-[2-(3,5-Dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide in 55% yield from 2-bromo-3',5'-dihydroxyacetophenone and
4,5-dimethylthiazole; mp. 257-258.degree. C. Yield: 2.05 g (21%).
(ii) 3-[2-(2,5-Dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
bromide in 57% yield from 2-bromo-2,5-dihydroxyacetophenone and
4,5-dimethylthiazole; mp. 231-232.degree. C. Yield: 4.03 g (52%).
(iii) 3-[2-(3,4-Dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium
chloride in 60% yield from commercially available
2-chloro-3',4'-dihydroxyacetophenone and 4,5-dimethylthiazole; mp.
260-263.degree. C. (dec.); yield: 3.9 g (48%).
Example 7
Preparation of 1-methyl-3-(cyanomethyl)imidazolium Bromide
##STR00016##
[0605] A mixture of 1-methylimidazole (1 g, 12.2 mmol) and
bromoacetonitrile (1.46 g, 12.2 mmol) were combined and stirred. An
exothermic reaction was produced and the product precipitated from
the reaction mixture. After cooling the reaction mixture is allowed
to cool to room temperature acetonitrile (CH.sub.3CN) (2 mL) is
added. The crude product is recovered by filtration and washed with
additional CH.sub.3CN. The crude product is dissolved in H.sub.2O,
treated with decolorizing carbon and evaporated in vacuo to
dryness. The product is further purified by recrystallization from
a mixture of ethanol EtOH, CH.sub.3CN and diethyl ether to yield
1-methyl-3-(2-cyanomethylene)-imidazolium bromide as a white
crystalline solid: mp 165-167.degree. C.
Example 8
Preparation of 3-(cyanomethyl)-4,5-dimethylthiazolium Bromide
##STR00017##
[0607] A mixture of 4,5-dimethylthiazole and bromoacetonitrile were
heated with stirring at 95.degree. C. for 1 hour. The product
precipitated from the mixture within 30 minutes. After cooling to
room temperature, the product a solution of 30% v/v of diethyl
ether: CH.sub.3CN (10 mL) was added with stirring. The crude
product was recovered by filtration, and recrystallized from a
mixture of EtOH and CH.sub.3CN to yield 2.136 g of
3-(cyanomethyl)-4,5-dimethylthiazolium bromide as needles: mp
184-186.degree. C. (dec.).
Example 9
Preparation of 3-(cyanomethyl)-4,5-cyclohexenothiazolium
Bromide
##STR00018##
[0609] A mixture of thioformamide (0.8 g), 2-chlorocyclohexan-1-one
(1.73 g), MgCO.sub.3 (1.5 g) was refluxed in dioxane (12 mL) for 30
h. The reaction mixture was evaporated in vacuo, and the
concentrated poured into diethyl ether (30 mL). The resulting
ethereal solution was washed with 1% NaOH solution (3.times.15 mL).
The combined NaOH solution was back extracted with diethyl ether.
The ether layers were combined, washed with saturated NaCl solution
until neutral, and then dried over Na.sub.2SO.sub.4. The ethereal
solution was evaporated in vacuo to afford 1.02 g of
4,5-cyclohexenothiazole.
[0610] A mixture of 4,5-cyclohexenothiazole (1 g, 7.2 mmol) and
bromoacetonitrile (0.863 g, 7.2 mmol) were heated at 120.degree. C.
for 1 h. After cooling the reaction mixture was treated with a
solution of 30% diethyl ether in CH.sub.3CN (10 mL). The product
was recovered by filtration and washed with additional 30% diethyl
ether in CH.sub.3CN. The product was recrystallized from a mixture
of EtOH and CH.sub.3CN to yield 0.752 g of
3-(cyanomethyl)-4,5-cyclohexenothiazolium bromide as a crystalline
solid: mp 215-217.degree. C. (dec.).
[0611] The preparation of
3-(2-cyanomethyl)-4,5-cyclopentenothiazolium bromide from
2-chlorocyclopentan-1-one is conducted as in the above
procedure.
Example 10
Preparation of
3-[2-(1-pyrrolidinyl)-2-oxoethyl]-1,2-dimethylimidazolium
Chloride
N-(chloroacetyl)pyrrolidine
[0612] Pyrrolidine (63.9 g, 0.9 mole) was taken up in
CH.sub.2Cl.sub.2 (640 mL) and cooled to 0.degree. C. in a salt-ice
water bath. To the stirred mixture was added chloroacetyl chloride
(101.8 g in 450 mL of CH.sub.2Cl.sub.2, 0.9 mole) dropwise
maintaining the internal temperature below 15.degree. C. After
adding the chloroacetyl chloride, the mixture was stirred for one
hour at 5.degree. C. Sodium hydroxide solution (7 M, 190 mL) was
added with vigorous stirring such that the inside temperature did
not exceed 20.degree. C. The mixture was stirred for 15 minutes and
the aqueous layer was separated. The organic layer was washed with
saturated sodium bicarbonate solution (2.times.200 mL), water
(1.times.200 mL) and dried over anhydrous sodium sulfate. The
solvent was removed in vacuo and the residue was recrystallized
from hexane to give 64.5 g (48.6% yield) of white plate crystals;
mp 43.degree. C.
3-[2-(1-pyrrolidinyl)-2-oxoethyl]-1,2-dimethylimidazolium
Chloride
[0613] A mixture of N-(chloroacetyl)pyrrolidine (2.0 g, 13.55 mmol)
and 1,2-dimethylimidazole (1.3 g, 13.5 mmol) were heated neat at
110.degree. C. for 3 hours. To the reaction mixture was added
acetonitrile (5 mL), and heating was continued for 20 minutes.
Tert-butyl methylether (10 mL) was added, and the resulting mixture
was allowed to stand at room temperature overnight. The product was
recovered by filtration, and washed with a mixture of tert-butyl
methyl ether and acetonitrile (7:3 v/v, 50 mL). The crude product
was recrystallized from a mixture of acetonitrile and tert-butyl
methyl ether to obtain 1.23 g (41%) of a white solid; mp
191-193.degree. C.
Example 11
Preparation of 1-butyl-3-aminoimidazolium Mesitylene Sulfonate
[0614] An ice-cold solution of 1-butylimidazole (7.0 g, 16.30 mmol)
in anhydrous CH.sub.2Cl.sub.2 (35 mL) was treated dropwise with a
solution of O-mesitylene sulfonylhydroxylamine (17.8 g, 16.50 mmol)
in CH.sub.2Cl.sub.2 (70 mL). After stirring for 6 hours in the
ice-bath, ether (210 mL) was added with stirring over the course of
1 hour. The resulting mixture was allowed to stand at -16.degree.
C. overnight. The product was recovered by filtration, and washed
with a mixture of CH.sub.2Cl.sub.2:ether (3:1 v/v) to yield a white
amorphous powder; 16.70 g. The crude product was recrystallized
from a mixture of CH.sub.2Cl.sub.2 (80 mL) and ether (80 mL) to
give 12.40 g; mp 71-73.degree. C.
DEFINITION
[0615] Heterocycle. Except where heteroaryl is separately recited
for the same substituent, the term "heterocycle" includes
heteroaryl.
[0616] All publications and references, including but not limited
to patents and patent applications, cited in this specification are
herein incorporated by reference in their entirety as if each
individual publication or reference were specifically and
individually indicated to be incorporated by reference herein as
being fully set forth. Any patent application to which this
application claims priority is also incorporated by reference
herein in its entirety in the manner described above for
publications and references.
[0617] While this invention has been described with an emphasis
upon preferred embodiments, it will be obvious to those of ordinary
skill in the art that variations in the preferred devices and
methods may be used and that it is intended that the invention may
be practiced otherwise than as specifically described herein.
Accordingly, this invention includes all modifications encompassed
within the spirit and scope of the invention as defined by the
claims that follow.
* * * * *