U.S. patent application number 09/729750 was filed with the patent office on 2001-04-05 for pyridyl substituted thiazoles.
Invention is credited to Macina, Orest Taras, Riviello, Christopher Mark, Sircar, Ila, Sircar, Jagadish Chandra, Yu, Dingwei Tim.
Application Number | 20010000178 09/729750 |
Document ID | / |
Family ID | 23054136 |
Filed Date | 2001-04-05 |
United States Patent
Application |
20010000178 |
Kind Code |
A1 |
Yu, Dingwei Tim ; et
al. |
April 5, 2001 |
PYRIDYL SUBSTITUTED THIAZOLES
Abstract
Disclosed is a novel class of thiazole, thiadiazole, and
oxadiazole compounds which are substituted at their nuclear carbons
by aromatic moieties. These compounds exhibit antifungal activity
against a variety of fungi including strains which have proven to
be resistant to treatment with known antifungal agents such as
Fluconazole.
Inventors: |
Yu, Dingwei Tim; (Easton,
PA) ; Macina, Orest Taras; (Pittsburgh, PA) ;
Sircar, Ila; (Clarks Summit, PA) ; Sircar, Jagadish
Chandra; (Clarks Summit, PA) ; Riviello, Christopher
Mark; (Old Forge, PA) |
Correspondence
Address: |
Joseph W. Molasky & Associates
4 S. Limekiln Pike
Chalfont
PA
18914
US
|
Family ID: |
23054136 |
Appl. No.: |
09/729750 |
Filed: |
December 5, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09729750 |
Dec 5, 2000 |
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09275863 |
Mar 25, 1999 |
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6156776 |
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Current U.S.
Class: |
514/342 ;
546/270.4 |
Current CPC
Class: |
C07D 277/28
20130101 |
Class at
Publication: |
514/342 ;
546/270.4 |
International
Class: |
C07D 41/04; A61K
031/39 |
Claims
What is claimed is:
1. A compound of the formula: 33wherein: Ar is phenyl, thienyl or
pyridyl substituted by R.sup.1 and R.sup.2; where R.sup.1, R.sup.2
are the same or different and represent hydrogen, halo, alkyl,
alkenyl, alkynyl, aryl, alkoxy, aryloxy, alkylthio, amino, hydroxy,
cyano, nitro, carboxy, aminocarbonyl or aminosulfonyl, alkylamino,
dialkylamino, acylamino, dialkylaminosulfonyl or alkylaminosulfonyl
or taken together R.sup.1 and R.sup.2 may be combined to form
--O--(CH.sub.2).sub.n--O-- where n is an integer having a value of
1 or 2; R.sup.3 and R.sup.4 are the same or different and represent
hydrogen, alkyl which may be optionally substituted by amino,
alkylamino, dialkylamino, hydroxy, cyano, carboxy alkenyl, alkynyl
or acyl, taken together R.sup.3 and R.sup.4 may be combined to form
--(CH.sub.2)m--Q--(CH.sub.2)m'-- where Q is selected from among
CH.sub.2, O, S(O).sub.n or NR.sup.7 where n is an integer having a
value of 0, 1, or 2; R.sup.7 is lower alkyl and m and m' are
integers having a value of 2 with the proviso that when Q is
CH.sub.2, m' may also have a value of 1; R.sup.5 is H, halo, OR,
OH, NO.sub.2, NH.sub.2 and NHCOR where R is alkyl, lower alkyl or
aryl; X is N, O or S. Y is N or S; with the proviso when X is O or
S, Y must be N; Z is N, CR.sup.8, where R.sup.8 is hydrogen, halo,
lower alkyl or alkoxycarbonyl; with the proviso that X, Y, Z cannot
all represent N at the same time; VR.sup.3R.sup.4 represents
heterocyclic rings selected from among pyrrole, immidazole,
1,3,4-triazole,1,2,4-triazole and pyrazole linked via the nitrogen;
V is N, O, or S; and P is 1-3; and the non-toxic pharmacologically
acceptable salts thereof.
2. A compound according to claim 1 of the formula; 34wherein:
R.sup.1, R.sup.2, R.sup.3, R.sup.4 R.sup.5' p -and V are each as
defined in claim 1 and R.sup.6 is hydrogen, halogen, carboxy,
alkoxycarbonyi, lower alkyl, hydroxy and lower alkoxy; and the
nontoxic pharmaceutically acceptable salts thereof.
3. A compound according to claim 1 of the formula: 35wherein:
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, p and V are as defined
in claim 1 and the nontoxic pharmaceutically acceptable salts
thereof.
4. A compound according to claim 1 of the formula: 36wherein:
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, p and V are as defined
in claim 1 and the nontoxic pharmaceutically acceptable salts
thereof.
5. A compound according to claim 1 of the formula: 37wherein:
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, p and V are as defined
in claim 1 and the nontoxic pharmaceutically acceptable salts
thereof.
6. A compound according to claim 2 of the formula: 38wherein:
R.sup.1, R.sup.2, R.sup.3, R.sup.4 are as defined in claim 1; and
the nontoxic pharmaceutically acceptable salts thereof.
7. A compound according to claim 4 of the formula: 39wherein:
R.sup.1, R.sup.2, R.sup.3, R.sup.4 are as defined in claim 1 and X
is O or S; and the nontoxic pharmaceutically acceptable salts
thereof.
8. A compound according to claim 5 of the formula: 40wherein:
R.sup.1, R.sup.2 R.sup.3, R.sup.4 are as defined in claim 1; and
the nontoxic pharmaceutically acceptable salts thereof.
9. An azole according to claim 1 selected from the group consisting
of 41wherein: A.sub.R is selected from among pyridyl, halo
substituted pyridyl and 42where R.sup.8 is hydrogen, halo, nitro,
amino, triflouromethoxy, pyrrolyl, lower alkoxy, trifluoromethyl,
cyano, lower alkynyl and trimethylsilyl lower alkynyl; and R.sup.9
is hydrogen, nitro, lower alkoxy or cyano; X is S or O; Y is CH or
N; Z is CH or N; B is lower alkylene or lower alkynylene; D is
SR.sup.10, OR.sup.11 or N(R.sup.12R.sup.13) wherein R.sup.10 is
di-lower alkylaminalkyl; R.sup.11 is lower alkenyl, lower alkynyl
or lower alkoxyakyl; R.sup.12 and R.sup.13 are the same or
different and represent hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, furfuryl, lower alkoxyalkyl, lower cycloalkyl, lower
dialkylaminoalkyl, hydroxy-lower alkyl, lower alkylaminoalkyl,
mononuclear lower alkyl, di-lower alkylaminoalkylcarbonyl or, taken
together, R.sup.12 and R.sup.13 may be combined to form
--CH.sub.2CH.sub.2N(R.sup.14)CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2SCH.sub.2CH.sub.2-- where R.sup.14 represents
lower alkyl; and R.sup.15 is hydrogen, nitro, amino, lower
alkanamido or hydroxy; and the nontoxic pharmacologically
acceptable salts thereof.
10. An azole according to claim 9 of the formula: 43wherein:
R.sup.8 is hydrogen, halo, nitro, amino, triflouromethoxy,
pyrrolyl, lower alkoxy, trifluoromethyl, cyano, lower alkynyl,
trimethylsilyl lower alkynyl; and R.sup.9 is hydrogen, nitro, lower
alkoxy or cyano; R.sup.12 and R.sup.13 are the same or different
and represent hydrogen, lower alkyl, lower alkenyl, lower alkynyl,
furfuryl, lower alkoxyalkyl, lower cycloalkyl, lower
dialkylaminoalkyl, hydroxy-lower alkyl, lower alkylaminoalkyl,
mononuclear lower alkyl, di-lower alkylaminoalkylcarbonyl or, taken
together, R.sup.12 and R.sup.13 may be combined to form
--CH.sub.2CH.sub.2N(R.sup.14)CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2SCH.sub.2CH.sub.2-- wherein R.sup.14 represents
lower alkyl, R.sup.15 is hydrogen, nitro, amino, lower alkanamido
or hydroxy; and n is an integer having a value of 1 to 3, and the
nontoxic pharmacologically acceptable salts thereof.
11. A thiazole according to claim 10 of the formula: 44wherein:
R.sup.16 is hydrogen, halo, nitro, lower alkoxy, cyano,
trifluoromethyl or lower alkyl; R.sup.17 is hydrogen, nitro,
halogen or cyano; R.sup.18 and R.sup.19 are the same or different
and represent hydrogen, lower alkyl, lower alkenyl, di-lower
alkylaminoalkyl, hydroxy lower alkyl and lower alkylaminoalkyl; and
R.sup.20 is hydrogen or hydroxy, and the nontoxic pharmacologically
acceptable salts thereof.
12. An azole according to claim 9 of the formula: 45wherein: X is S
or; R.sup.21 is selected from among hydrogen and lower alkoxy;
R.sup.22 is selected from among hydrogen and nitro; and R.sup.23
and R.sup.24 are lower alkyl, and the nontoxic pharmacologically
acceptable salts thereof.
13. An azole according to claim 9 of the formula 46wherein: E is
SR.sup.26 or NR.sup.27R.sup.28 wherein R.sup.26 is di-lower
alkylaminoalkyl R.sup.27 and R.sup.28 are the same or different and
represent lower alkyl and lower alkenyl, and the nontoxic
pharmacologically acceptable salts thereof.
14.
Allylaminomethyl)phenyl]-thiazole2-(4'-nitrophenyl)-4-[4"-(N-methyl-N--
allylaminomethyl)phenyl]-thiazole.
15.
2-(3'-nitrophenyl)-4-[4"-(N-methyl-N-allylaminomethyl)phenyl]thiazole.
16.
2-(4'-methoxy-3-nitrophenyl)-4-[4"-(dimethylaminomethyl)phenyl]thiazol-
e.
17.
2-(4'-methoxy-3-nitrophenyl)-4-[4"-N-methyl-N-allylaminomethyl)phenyl]-
thiazole.
18. A pharmaceutical composition comprising an effective amount of
a compound of claim 1 in combination with a pharmaceutically
acceptable carrier.
19. A method for treating a fungal infection which comprises
administering to a mammalian host an effective amount of the
compound of claim 1 in unit dosage form.
20. A method for preparing the compounds of claim 1 using disclosed
process schemes.
Description
1. This invention relates to a novel class of substituted azoles
and, more specifically, diaryl substituted thiazoles, diaryl
substituted thiadiazoles and diaryl substituted oxadiazoles,
compounds which are useful in the treatment of fungal infections in
mammals including humans. These compounds are active against a
broad spectrum of fungi such as Candida albicans, Candida
parpsilosis, Candida tropicalis, Candida Krusei, Cryptococcus
neoformans, Aspergillus fumigatus and Torulopsis glabrata.
Moreover, compounds within this series are also active against
Fluconazole resistant strains and isolates.
BACKGROUND OF THE INVENTION
2. Opportunistic fungal infections are responsible for increased
morbidity and mortality among patients suffering from AIDS and
other immunocompromised diseases including infections resulting
from neutropenia, cancer chemotherapy and organ transplantation
(Annals N.Y. Acad. Sc., 544:1-3).
3. Moreover, until recently, the treatment of deep seated fungal
infections has lagged behind the treatment of bacterial infections
and only a few systemic agents are available for combatting these
invasive pathogens.
4. Current therapy provides for administering polyenes such as
amphotericin B, allylamines such as Naftafin and Terbinafin and
azoles such as Fluconazole, Itraconazole and Ketoconazole.
Amphotericin B, once the treatment of choice, is no longer favored
due to the acute and chronic toxicities associated with its
use.
5. Also, antifungal azoles are fungistatic, not fungicidal, and
this has resulted in azole resistant fungi, that is, fungi strains
and isolates which are resistant to treatment with Fluconazole and
other known antifungal agents (New Engl. J. Med., 1944, 330:
263-272.)
KNOWN PRIOR ART
6. Azole compounds in which hydroxy and/or carboxy groups comprise
the molecular structure are known to be useful in combatting
pathogenic fungi.
7. For example, British Patent No. 2,099,818 and U.S. Pat. No.
4,404,216 disclose Fluconazole 1
8. a triazole derivative which has played an important role in
protecting against a variety of fungi.
9. Also, DE-4124942 discloses azoles of the following structure
having antithrombotic and fibrinogen-binding activities: 2
1 Q.sup.1 = A-B-C-N< Q.sup.2 = A-B-C-CH< Q.sup.3 = A-B-C-C=
Q.sup.4 = F-E-D-N< Q.sup.5 = F-E-D-CH< Q.sup.6 = F-E-D-C=
10. wherein: one of X.sup.1-X.sup.5=Q.sup.1-Q.sup.3, a
second=Q.sup.4-Q.sup.6, a third=S, SO, N, R.sup.1N, R.sup.2C,
(R.sup.2).sub.2C, a fourth=O, S, N, SO.sub.2, R.sup.2C, CO, and a
fifth=R.sup.2C, (R.sup.2).sub.2C, N; A=cyano, (substituted)
phenylene, pyridinylene, pyrazinylene, triazinylene,
C=(substituted) phenylene, pyridinylene, pyrimidinylene,
pyrazinylene, pyridazinylene, triazinylene, cycloalkylene)
cycloalkylene, D=(substituted) alkylene, alkeylene, etc.; E=bond,
alkylene, etc., F=carboxy, (substituted) alkoxycarbonyl; R.sup.1=H,
alkyl, aralkyl, aryl, heteroaryl; R=H, Cl, Br, alkyl, aralkyl,
aryl, heteroaryl, alkoxy, R.sup.1O.sub.2C, (R.sup.1).sub.2N, etc.
These compounds are said to have antithrombotic and
fibrinogen-binding activity. The closest example is
4-(4-amidinophenyl)-2-[4(2-carboxyethyl)- phenyl]thiazole. 3
11. WO-9209586 (EP 0 513387 A1) discloses thiazole derivatives
represented by the following structure useful as superoxide radical
inhibitors: 4
12. wherein:
13. R.sup.1 is substituted phenyl, pyridyl, thienyl, carbostyril,
pyrazyl, pyrrolyl, quinolyl, 3,4-dihydrocarbostyril;
14. R.sup.2 is hydrogen, halo, alkyl, phenyl, alkoxycarbonyl,
alkylamino, and the like;
15. X is sulfur or oxygen;
16. R.sup.3 is Q (supra) wherein R is hydroxyl, carboxylic acid,
alkyl, alkenyl and m is 0-2 or, R.sup.3 may be T (supra), wherein
R.sup.4 is hydrogen or alkyl and R is aminoalkyl.
17. The structure activity relationship (SAR) of the above series
has been published in the J. Med. Chem. 1995, 38, 353-358 where the
following general structure is shown: 5
18. WO-9324472 (EP 0 600092 A1) discloses compounds of the
following structure as an active oxygen inhibitor: 6
19. wherein:
20. R.sup.1 is Ph which may be substituted by 1 to 3 alkoxy groups;
and
21. R.sup.2 is a substituted pyridylcarbonyl which may be
substituted by alkoxycarbonyl, carboxyl, a 5 to 15 membered mono-,
di-, or tricyclic heterocyclic ring residue having 1 to 3 N, O or
S, atoms, or a phenylmoiety of the formula: 7
22. wherein, R.sup.3 represents carboxyl, lower alkoxycarbonyl,
hydroxyl substituted lower alkyl, lower alkoxy, tri-lower
alkyl-substituted silyloxy, hydroxy, or hydrogen; R.sup.4
represents hydrogen, lower alkenyl or lower alkyl; R.sup.5
represents an amino-lower alkoxycarbonyl which may be substituted
further by lower alkyl, amino-lower alkoxy, or lower alkoxy or the
like.
23. U.S. Pat. No. 4,791,200 describes compounds of the following
structure useful as antisecretory agents: 8
24. wherein:
25. R is C1 to C4 alkyl, phenyl, phenyl substituted by CF.sub.1,
halo selected from I, Br or Cl, C1-C3 alkyl, alkoxy, acetamido,
nitro, cyano, alkyamino or dialkylamino having 1-4 carbons or
pyridyl.
26. R.sup.1 is H or C1-C4 alkyl,
27. R.sup.2 is H, C1-C4 alkyl, C1-C3 alkoxy or, Cl Br or I,
28. R.sup.3 or R.sup.4 are --O--(CH.sub.2).sub.m--NR.sup.5R.sup.6
wherein m =1-3.
29. Patel and Colah in Bull Haff Instt. (1977), 5, 72-74 disclose
p-(2-substituted-4-thiazolyl)phenylacetic acid and
p-(2-substituted-4-thiazolyl)phenoxyacetic acids useful in treating
tuberculosis and fungi: 9
30. wherein R.sup.1 is CH.sub.2CCOOH or OCH.sub.2COOH, and
31. Ar is phenyl, substituted phenyl or benzyl and the like.
32. Kirke et al in Bull, Haffkine Inst., (1977), 5, 75-7, and
(1974), 2, 28-31 disclose a series of thiazolyl-phenoxyacetic acids
and derivatives having in vitro antituberculosis and antifungal
activity against T. rubrum and T. mentagrophytes.
33. Anne et al in Antimicrob. Agents Chemother., (1980), 18(2),
231-9 disclose diaryloxadiazole derivatives having only very weak
activity against Candida albican (MIC.sub.50>60 .mu.g/ml) as,
for example: 10
SUMMARY OF THE INVENTION
34. This invention relates to diaryl substituted azoles and
pharmaceutically acceptable salts thereof useful as antifungal
agents.
35. This invention also includes methods for preparing said azoles
and antifungal compositions containing these compounds or a
pharmaceutically acceptable salt thereof as the active
ingredient.
36. The azoles of this invention are compounds of the general
formula: 11
37. wherein:
38. Ar is phenyl, thienyl, pyridyl substituted with R.sup.1R.sup.2
where R.sup.1, R.sup.2 are independently hydrogen or halogen such
as F, Cl, Br and I; alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy,
alkylthio, amino, hydroxyl, cyano, nitro, COOH, aminocarbonyl or
aminosulfonyl, alkylamino, diakylamino, acylamino,
dialkylaminosulfonyl, alkylaminosulfonyl, alkylamino, dialkylamino,
acylamino, dialkylaminosulfonyl, alkylaminosulfonyl or, taken
together, R.sup.1, R.sup.2 may form a ring
--O--(CH.sub.2).sub.n--O-- wherein n=1,2.
39. R.sup.3, R.sup.4 are independently hydrogen, C1-C16 alkyl which
may optionally be substituted with amino, dialkylamino, hydroxy,
cyano, carboxy; alkenyl, alkynyl, acyl or, taken together, R.sup.3
and R.sup.4 may be --(CH.sub.2)m--Q--(CH.sub.2)m'-- where m'=m=2,
Q=CH.sub.2,O, S(O).sub.n, n=0-2, NR.sup.7 wherein R.sup.7 is C1-C3
alkyl with the proviso that when Q is CH.sub.2, m' can also be
1.
40. R.sup.5 is H, halogen as defined above, OR, OH, NO.sub.2,
NH.sub.2 or NHCOR where R is lower alkyl, alkyl or aryl, and the
like.
41. X is N, O or S;
42. Y is N or S, with the proviso when X=O or S, Y must be N;
43. Z is N or CR.sup.8, where R.sup.8 is hydrogen, halogen such as
Cl, Br or I, lower alkyl or alkoxycarbonyl, with the proviso that
X, Y and Z cannot all be N at the same time.
44. V is N, O or S, and when V is N, it may also be combined with
R.sup.3 and R.sup.4 to form a heterocycle such as pyrrole,
imidazol-1,2,4,-triazole, 1,3,4-triazole and pyrazole, and when V
is O or S, R.sup.3 and R.sup.4 combine to form a single substituent
having the definition of R.sup.4 alone; and
45. P is an integer having a value of 1-3.
46. Specifically, this invention relates to thiazoles of the
formula: 12
47. wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, p and V
are each as defined above in formula (I) and R.sup.6 is hydrogen,
halogen, carboxy, alkoxy carbonyl, lower alkyl, hydroxy and lower
alkoxy and the nontoxic pharmacologically acceptable salts
thereof.
48. This invention also relates to thiadiazoles of the following
formula: 13
49. wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4.sub.1 R.sup.5, p
and v are each as defined above in formula (I) , and the nontoxic
pharmaceutically acceptable salts thereof.
50. This invention also relates to thiadiazoles of the formula:
14
51. wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, p and V
are as defined above in formula (I), and the nontoxic
pharmaceutically acceptable salts thereof.
52. This invention also relates to oxadiazoles of the formula:
15
53. wherein: R.sup.1, R.sup.2.sub.1 R.sup.3, R.sup.4, R.sup.5, p
and V are as defined above in formula (I), and the nontoxic
pharmaceutically acceptable salts thereof.
54. More specifically, this invention relates to thiazoles of the
formula: 16
55. wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4, are as defined
above in formula (I), and the nontoxic pharmaceutically acceptable
salts thereof.
56. This invention also relate to diazoles of the formula: 17
57. wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4 are as defined
above and X is O or S, and pharmaceutically acceptable salts
thereof.
58. Alternatively and according to another embodiment, the
preferred products of this invention are those represented by the
formulae identified as VIII-XIIl hereinbelow.
59. In general, the preferred products are those which conform to
formula VIII and formula IX: 18
60. wherein:
61. A.sub.8 is selected from among pyridyl, halo substituted
pyridyl and 19
62. where R.sup.8 is hydrogen, halo, nitro, amino,
triflouromethoxy, pyrrolyl, lower alkoxy, trifluoromethyl, cyano,
lower alkynyl and trimethylsilyl lower alkynyl; and R.sup.9 is
hydrogen, nitro, lower alkoxy or cyano;
63. X is S or O;
64. Y is CH or N;
65. Z is CH or N;
66. B is lower alkylene or lower alkynylene;
67. D is SR.sup.10, OR.sup.11 or N(R.sup.12R.sup.13) wherein
R.sup.10 is di-lower alkylaminoalkyl; R.sup.11 is di-lower
alkylaminoalkyl, lower alkenyl, lower alkynyl or lower alkoxyakyl;
R.sup.12 and R.sup.13 are the same or different and represent
hydrogen, lower alkyl, lower alkenyl, lower alkynyl, furfuryl,
lower alkoxyalkyl, lower cycloalkyl, lower dialkylaminoalkyl,
hydroxy-lower alkyl, lower alkylaminoalkyl, mononuclear lower
alkyl, di-lower alkylaminoalkylcarbonyl or, taken together,
R.sup.12 and R.sup.13 may be combined to form
--CH.sub.2CH.sub.2N(R.sup.14)CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2SCH.sub.2CH.sub.2-- where R.sup.14 represents
lower alkyl; and
68. R.sup.15 is hydrogen, nitro, amino, lower alkanamido or
hydroxy; and the nontoxic pharmacologically acceptable salts
thereof.
69. Another preferred embodiment are the thiazole compounds
represented by formula X: 20
70. wherein:
71. R.sup.8 is hydrogen, halo, nitro, amino, triflourometnoxy,
pyrrolyl, lower alkoxy, trifluoromethyl, cyano, lower alkynyl,
trimethylsilyl lower alkynyl; and R.sup.9 is hydrogen, nitro, lower
alkoxy or cyano;
72. R.sup.12 and R.sup.13 are the same or different and represent
hydrogen, lower alkyl, lower alkenyl, lower alkynyl, furfuryl,
lower alkoxyalkyl, lower cycloalkyl, lower dialkylaminoalkyl,
hydroxy-lower alkyl, lower alkylaminoalkyl, mononuclear lower
alkyl, di-lower alkylamincalkylcarbonyl or, taken together,
R.sup.12 and R.sup.13 may be combined to form
--CH.sub.2CH.sub.2N(R.sup.14)CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2SCH.sub.2CH.sub.2-- wherein R.sup.14 represents
lower alkyl;
73. R.sup.15 is hydrogen, nitro, amino, lower alkanamido or
hydroxy, and
74. n is an integer having a value of 1 to 3, and the nontoxic
pharmacologically acceptable salts thereof.
75. Still another preferred embodiment are thiazoles of the
following formula: 21
76. wherein:
77. R.sup.16 is hydrogen, halo, nitro, lower alkoxy, cyano,
trifluoromethyl or lower alkyl;
78. R.sup.17 is hydrogen, nitro, halogen or cyano;
79. R.sup.18 and R.sup.19 are the same or different and represent
hydrogen, lower alkyl, lower alkenyl, di-lower alkylaminoalkyl,
hydroxy lower alkyl and lower alkylaminoalkyl; and
80. R.sup.20 is hydrogen or hydroxy, and the nontoxic
pharmacologically acceptable salts thereof.
81. Another preferred embodiment provides for diazoles having the
formula: 22
82. wherein
83. R.sup.21 is selected from among hydrogen and lower alkoxy;
84. R.sup.22 is selected from among hydrogen and nitro; and
85. R.sup.23 and R.sup.24 are lower alkyl, and the nontoxic
pharmacologically acceptable salts thereof.
86. Also included among the preferred embodiments are thiadiazoles
of formula XIII: 23
87. wherein:
88. E is SR.sup.26 or NR.sup.27R.sup.28 wherein R.sup.26 is
di-lower alkylaminoalkyl R.sup.27 and R.sup.28 are the same or
different and represent lower alkyl and lower alkenyl, and the
nontoxic pharmacologically acceptable salts thereof.
89. The aforecited compounds are useful in the treatment of broad
spectrum fungal infections, and they are also active against a
variety of fungi and fungal isolates including
Fluconazole-resistant isolates and strains. These compounds are
useful for this purpose when used in the concentration range of 250
.mu.g/ml and below.
90. Appropriate compounds of formula I to XIII are useful in the
free base form, in the form of base salts where possible, and in
the form of acid addition salts. In practice, use of the salt form
is equivalent to use of the base form.
91. Pharmaceutically acceptable salts within the scope of this
invention are those derived from mineral acids such as hydrochloric
acid and sulfuric acid and the like including organic acids such as
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
and the like. These afford the corresponding hydrochloride,
sulfate, ethanesulfonate, benzenesulfonate, p-hydrochloride and the
like, respectively; however, this invention is not limited to those
mentioned above since equivalent salts will be apparent to those
skilled in this art.
92. Examples of pharmaceutically acceptable base addition salts
include organic bases which are nontoxic and of such strength as to
form usable salts. These organic bases form a class whose limits
are readily understood by those skilled in the art, and for the
purposes of illustration, they include mono-, di, and
trialkylamines such as methylamine, dimethylamine, and
triethylamine; mono-, di-, or trihydroxyalkylamines such as mono-,
di-, or triethanolamine, amino acids such as arginine and lysine;
quanidine; N-methyl-glucosamine; N-methylglucamine; L-glutamine;
N-methylpiperazine; morpholine; ethylenediamine;
N-benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the
like. (See, for example, "Pharmaceutical Salts," J. Pharm. Sci.,
66(1) :1-19 (1977).) Salts of inorganic bases include sodium,
potassium, calcium or the like.
93. The acid addition salts of said basic compounds are prepared
either by dissolving the free base of compound I to XIII in aqueous
or aqueous alcohol solution of other suitable solvents containing
appropriate acid and isolating the salt by evaporating the
solution, or by reacting the free base of compound I to XIII,
having an acid group thereon with a base such that the reactions
are in an organic solvent, in which case, the salt separates
directly or can be obtained by concentration of the solution. Salts
can also be prepared by adding base to an aqueous alcohol solution
of another salt.
94. Generally, the compounds of formulas (I) to (XIII) can be
prepared by the processes identified as 1-9 hereinbelow:
95. Process 1 (Scheme 1): 24
96. In this process (Scheme 1), the substituted thiobenzamide (2)
is prepared according to the literature procedure (Tetrahedron, 41,
(22) , 5061, 1985, M. Cava and M. Levinson) by refluxing benzamide
(1) with Lawesson's reagent in dry benzene or toluene (M.
Levinson). A condensation reaction between the thiobenzamide and
.alpha.-haloacetophenone derivatives in solvent such as low
alcohol, THF, CH.sub.3CN, etc., gives 2,4-diarylthiazole compounds
(3) (Organic Synthesis, Coll. III, 332). The NBS bromination of the
compound (3) affords the bromomethyl products (4a) and/or (4b) ,
which are converted to compounds (5) and (6) respectively by
reacting with appropriate nucleophile as shown in Scheme 1.
Compound (5) can also be de-brominated by catalytic hydrogenation
to give compound (6).
97. Process 2 (Scheme 2): 25
98. An alternative synthetic pathway is illustrated in Scheme 2,
which involves the bromination of ethyl 4-acetylbenzoate with
bromine in ether in the presence of catalytic amount of aluminum
chloride, The .alpha.-bromoacetophenone compound (7) is then
condensed with appropriate thiobenzamide (2) as described before to
form the diarylthiazole derivatives (8) Subsequent reduction of the
ester with LAH followed by bromination with carbontetrabromide and
triphenylphosphine yields the bromide (4a) which upon nucleophilic
substitution produces the target product (6). Compound (6) can also
be prepared through the mesylated intermediate (9), which is
prepared by the reduction of compound (8) with LAH followed by
mesylation with methanesulfonyl chloride.
99. A compound represented by the general formula (II) wherein
p=2-3 can be prepared by the process as shown in Scheme 3 and
Scheme 4:
100. Process 3 (Scheme 3): 26
101. Compound (11) is obtained by condensation and cyclization
thiobenzamide (2) and a-bromoaceophenone (10), which is made by the
bromination reaction as described before. By refluxing compound
(11) in acetone with excess amount of Nal produces the iodoanalog
(12) which on reaction with nucleophile produces product (13).
102. Process 4 (Scheme 4)
103. In order to prepare a compound represented by the general
formula (II) wherein p=3, a palladium-catalyzed C--C coupling
reaction between the 4-(p-brornophenyl)thiazole derivatives (14)
and an acetylenic reactant is employed. Catalytic hydrogenation of
the coupling product (15) gives the extended three carbon side
chain compounds (16) in very good yield (Scheme 4). 27
104. Process 5 (Scheme 5) 28
105. Primary amine sidechain compounds (18) can be prepared from
the bromo compounds (4a) by the use of methenamine followed by
cleavage of the resulting quaternary amine salts with ethanolic HCl
(Organic Synthesis, Coll. V, 212). The secondary amine sidechain
compounds (21) (Scheme 5) are prepared by acetylation of compounds
(18) with trifluoroacetic anhydride to give the amide analogs (19)
quantitatively. Treatment of the compound (19) with NaH in
anhydrous DMF followed by alkylation with alkyl halide affords
compound (20), which can be converted to the secondary amine
products (21) by cleavage of the trifluoroacetyl group in a basic
media. Compound (21) is transformed to target compounds (6) by
treatment with base such as K.sub.2CO.sub.3 and appropriate alkyl
halide.
106. Process 6 (Scheme 6) 29
107. The .alpha.-bromoacetophenones with the desired dialkylamino
alkyl groups (23) are synthesized and coupled with substituted
thiobenzamides (2) to give target compounds (Scheme 6). 4'-Methyl
acetophenone or derivatives thereof are treated with NBS in
CCl.sub.4 under refluxing condition to give the corresponding
benzylbromides (22) which are subsequently treated with the
requisite dialkylamines at room temperature to give the
dialkylamino alkyl derivatives (23). These compounds are purified
via flash chromatography, converted to the corresponding HCl salt,
and brominated with Br.sub.2 to give .alpha.-bromoacetophenones
(24) Compounds (24) are reacted with substituted thiobenzamides (2)
under refluxing EtOH or similar solvent to give the target
compounds (25) as a mixture of HCl and HBr salts. These are
converted to the free base and purified via flash chromatography as
needed. Compounds wherein R.sup.7 is not hydrogen are further
derivatized to additional targets. For example, compound (25)
(R.sup.7=NH.sub.2) which is eventually treated with Ac.sub.2O to
give the N-acetylamino compound (27) (R.sup.7=NHCOCH.sub.3)
108. Process 7 (Scheme 7) 30
109. Following the procedure described in process 1, the desired
thiobenzamnide (2) is reacted with
3'methoxy-.alpha.-bromoacetophenone in refluxing EtOH to give the
thiazole (28). This compound is demethylated with BBr.sub.3 under
standard condition to give the corresponding phenol (29). This is
treated with a mixture of paraformaldehyde and requisite
dialkylamine under refluxing EtOH to give target dialkylaminomethyl
compounds (30).
110. Process 8 (Scheme 8)
111. A compound represented by the general formnula (III) can be
prepared by the process as shown in Scheme 8: 31
112. On the basis of a known procedure (Adv. Heterocycl. Chem.,
1982, 32, 285), p-methylbenzimidate hydrochloride (31) is prepared
by bubbling hydrogen chloride gas through a cooled solution of
p-tolunitrile in mixed solvents (1:1=chloroform and methanol).
Treatment of benzimidate (31) with ammonia/methanol solution gives
amidine hydrochloride (32) with ammonia/methanol solution gives
amidine hydrochloride (32) quantitatively. The amidine (32) is then
reacted with one equivalent of perchloromethylmercaptan in the
presence of triethylamine at zero degree to give a cyclized
product, 5-chloro-1,2,4-thiadiazole (33) as yellow solid. Coupling
of 5-chloro-1,2,4-thiadiazole with substituted aryl. Grignard
Reagents in dry THF provides the desired diaryl 1,2,4-thiadiazoles
(34) (J. Am. Chem. Soc., 1985, 107, 2033 and organometallics, 1993,
12, 3468). Subsequent bromination followed by nucleophilic
substitution as described in Preparation Process 1, affords the
final product (36).
113. Process 9 (Scheme 9)
114. A compound represented by the general formula (IV) and (V) can
be prepared by Ltie following process: 32
115. The N,N'-diacylhydrazine compound (J. Chem.Soc, (C), 1970,
1397) (37) is prepared by acylation of the substituted
benzhydrazide at zero degree with p-methylbenzoyl chloride. The
N,N'-diacylhydrazine compound (37) is heated either with thionyl
chloride to produce the cyclized product, 1,3,4-oxadiazole (38a) or
with Lawesson's Reagent* to exchange the oxygen to give sulfur and
then cyclize to 1,3,4-thiadiazoles (38b). *Lawesson's Reagent is
(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-disulfide and the use of
the reagent in various processes is described by M. D. Cara and M.
I. Levinson in Tetrahedron; Vol. 41: pages 5061 et seq. (1985). The
cyclized products (38a & 38b) are treated with
N-bromosuccinimide to give bromomethyl compounds (39a & 39b)
which are reacted with appropriate nucleophiles to afford desired
products (40a) and (40b) respectively.
116. One of ordinary skill in the art will recognize variations in
the sequence and variations in the appropriate reaction conditions
from the analogous reactions shown or otherwise known which may be
appropriately used in the processes above to make the compounds of
Formulae I to XIII herein.
EXAMPLE 1
117.
2-(4'-fluorophenyl)4-[4"-(N-methyl-N-allylaminomethyl)phenyl]thiazole-
(VI: R.sub.1=H, R.sub.2=4-F, R.sub.3=Me, R.sub.4=allyl, V=N
(Process 1, Scheme 1)
118. 4-Fluorobenzamide (5.0 g, 35.9 mmol) in benzene (100 ml) is
added Lawesson's reagent (7.27 g, 18.0 mmol) and the resulting
solution is heated to reflux for 1 hour. The solution is cooled to
room temperature, concentrated and water (150 ml) added. The
mixture is heated to reflux for 3 hours, and cooled to room
temperature. The precipitate is filtered and dried under vacuum to
yield 4-fluorothiobenzamide as a yellow solid (4.1 g, 71%).
119. .sup.1H NMR (CDCl.sub.3) .delta.7.09 (t, 2H), 7.90 (dd,
2H).
120. To a solution of the crude product of 4-fluorothiobenzamide
(2.0 g, 12.9 mmol) in EtOH (30ml) is added
2-bromo-4'methylacetophenone (2.75 g, 12.9 mmol). The mixture is
heated to reflux for 24 hours. The course of the reaction is
followed by thin layer chromatography. Upon completion of the
reaction the solution is cooled to room temperature and the white
precipitate filtered and dried under vacuum to yield
2-(4'-fluorophenyl)-4-(p-tolyl) thiazole (1.54 g, 54%).
121. .sup.1H NMR (DMSO.sub.d6) : .delta.2.35 (s, 1H), 7,28 (d, 2H),
7.38 (t, 2H), 7.94 (d, 2H), 8.08 (dd, 2H), 8.11 (s, 1H).
122. To a solution of 2-(4'-fluorophenyl)-4-(p-tolyl)-thiazole
(1.49 g, 5.5 mmol) in CCl.sub.4 (50 ml) is added NBS (1.09 g, 6.1
mmol) and benzoyl peroxide (50 mg) and the reaction mixture is
heated to reflux. An additional 50 mg of benzoyl peroxide is added
every hour for 4 hours. The mixture is refluxed for 24 hours and
then filtered through celite. The mother liquor is concentrated to
yield a yellow oil which is triturated with pentane and filtered to
yield 2-(4'-fluorophenyl) -4-[p-(bromomethyl)phenyl)]thiazole (1.45
g, 75%).
123. .sup.1H NMR (DMSO.sub.d6) .delta.4.77 (s, 2H), 7.39 (t, 2H),
7.58 (d, 2H), 8.08 (m, 2H), 8.22 (s, 1H).
124. To a solution of
2-(4'-fluorophenyl)-4-(p-bromomethylphenyl)-thiazole (1.00 g, 2.87
mmol) in EtOH (20 ml) is added dropwise N-methyl allylamine (0.45
g, 6.00 mmol) in EtOH (10 ml). The solution is stirred at room
temperature for 12 hours and the solvent is removed under reduced
pressure to yield a green oil. The oil is taken up in
CH.sub.2Cl.sub.2 (30 ml) and washed with 1N NaOH (30 ml) and brine
(30 ml). The organic layer is dried over anhydrous K.sub.2CO.sub.3
and concentrated. The residue is chromatographed on a silica gel
column eluting with MeOH:CHCl.sub.3 (5:95) to yield a yellow oil.
The resulting oil is dissolved in MeOH (5ml) to which is added
excess HCl/MeOH solution (1096 w/w, lml) and stirred for 1 hour.
The solvent is removed under reduced pressure, and the residue
recrystallized from isopropanol to yield the title compound as HCI
salt as a brown solid (0.43 g, 40%).
125. .sup.1H NMR (DMSO.sub.d6) .delta.2.60 (d, 3H), 3.70 (m, 2H),
4.35 (m, 2H), 5.51 (s, 1H), 5.59 (d, 1H), 6.08 (m, 1H), 7.40 (t,
2H), 7.72 (d, 2H), 8.12 (m, 4H), 8.30 (s1, H).
EXAMPLE 1a
126.
2-(4'-Chlorophenyl)-4-[[4'-(2-N,N-dimethylaminoethyl)thio]methyl]phen-
yl]thiazole(II: R.sup.1=H.sup.2=4--Cl, V=S, R.sup.3,
R.sup.4=CH.sub.2CH.sub.2NMe.sub.2, R.sup.6=H)
127. Replacing 4-fluorobenzamide with 4-chlorobenzamide in the
above experiment the compound
2-(4'-chlorophenyl)-4-[(p-bromomethyl)phenyl]thia- zole is
obtained. 2-Dimethylaminoethanethiol hydrochloride (0.7 g, 5.0
mmol) is added to a slurry of NaH (60%, 0.44 g, 11 mmol) in THF
(20ml) and the suspension stirred for 1 h. A solution of the above
bromomethyl compound (1.82 g, 5.0 mmol) in THF (20 ml) is added
with stirring and the reaction mixture stirred for 4 h. THF is
distilled, the residue is poured into water and the mixture is
extracted with EtOAc. The EtOAc extract is washed with brine,
dried, stripped and the residue chromatographed (SiO.sub.2, 100 g,
CHCl.sub.3 --CHCl.sub.3/MeOH 5%) to give the title compound as a
soft solid (0.75 g), mp. 51-52.degree. C.
128. .sup.1H NMR (CDCl.sub.3): 2.20 (s, 6 H), 2.40-2.60 (m, 4 H),
3.80 (s, 2 H) 7.35-7.50 (m, 5 H), 7.85-8.00 (m, 4 H).
EXAMPLE 1b
129. 2-(4'-Chlorophenyl-4 -[[4
-(N-methylpiperazinyl)methyl]phenyl]thiazol- e (II: R.sup.1=H,
R.sup.2=4-Cl, V=N, R.sup.3R.sup.4=(CH.sub.2CH.sub.2).sub- .2NMe,
R.sup.6=H)
130. To a suspension of
2-(4'chlorophenyl)-4-[(p-bromomethyl)-phenyl]-thia- zole (1.0 g,
2.74 mmol) and anhydrous K.sub.2CO.sub.3 (0.83 g, 6 mmol) in DMF
(15 ml) is added a solution of N-methyl piperazine (0.3 ml, 2.74
mmol) in DMF (1 ml) with stirring. The reaction mixture is stirred
for 18 h at rt. It is poured into water (100 ml) and the organic
material is extracted with EtOAc. The EtOAc layer is washed with
brine, dried, stripped, and the residue chromatographed (SiC.sub.2,
30 g, CHCl.sub.3/CHCl.sub.3/MeOH 5%) to give the title compound
(0.43 g), mp. 110-111.degree. C.
131. .sup.1H NMR (CDCl.sub.3) 2.25 (s, 6 H), 2.35-2.60 (br s, 8 H),
3.55 (s, 2 H), 7.35-7.50 (m, 5 H), 7.90-8.05 (m, 4 H).
132. Additional examples are shown in Table I.
EXAMPLE 2
133.
2-(4'-methoxyphenyl)-4-[4"-(N-allyl-N-methylamino-methyl)phenyl]thiaz-
ole (VI: R.sub.1=H, R.sub.2=4-MeO, R.sub.3=Me, R.sub.4=allyl)
(Process 2, Scheme 2)
134. To a solution of ethyl 4-acetylbenzoate (5.12 g, 26.6 mmol) in
ether (50 ml) containing aluminium chloride (0.025 g, 0.19 mmol) is
added bromine (1.31 ml, 26.6 mmol) and the reaction mixture is
stirred for 2 h. The reaction mixture is poured into saturated
NaHCO.sub.3 solution and stirred for 30 min. and the layers are
separated. The organic layer is washed with NaHCO.sub.3, H.sub.2O,
dried over MgSC.sub.4, concentrated to half of its volume and
refrigerated overnight. The resulting solid is filtered to yield
ethyl 4-(2'-bromoacetyl) benzoate (5.89 g, 81.6%) as white
crystals.
135. .sup.1H NMR (CDCl.sub.3): .delta.1.42 (t, 3H), 4.42 (q, 2H),
4.48 (s, 3H), 8.04 (d, 2H), 8.16 (d, 2H).
136. To a solution of 4-methoxythiobenzamide (1.50 g. 8.97 mmol) in
ethanol (50 ml) is added ethyl 4-(2'-bromoacetyl)-benzoate (2.43 g,
8.97 mmol) and the reaction mixture is heated to reflux for 4
hours. The reaction mixture is cooled to room temperature and the
precipitate is filtered to yield ethyl
p-[2-(4'-methoxy)phenyl-thiazol-4-yl]benzoate (2.15 g, 70.1%) as a
light yellow solid.
137. .sup.1H NMR (CDCl.sub.3): .delta.1.42 (t, 3H), 3.87 (s, 3H),
4.40 (q, 3H), 6.98 (d, 2H), 7.53 (s, 1H), 7.96-8.14 (m, 6H).
138. To a slurry of LAH (167 mg, 4.41 mmol) in dry THF (10 ml) is
added dropwise a solution of ethyl
p-[2-(4.sup.1-methoxyphenyl)-thiazol-4-yl]be- nzoate (500 mg, 1.47
mmol) in dry THF (10 ml) and the reaction mixture is stirred at
room temperature for 18 hours. A solution of saturated
(NH.sub.4).sub.2SO.sub.4 (20 ml) is added to the reaction mixture
and stirred for 30 min. The precipitate is filtered, and the
aqueous layer is washed thoroughly with ethyl acetate. The combined
organic layer is washed with H.sub.2O and brine, dried over
MgSO.sub.4 and concentrated in vacuo to yield
2-(4'-methoxyphenyl)-4-(4"-hydroxymethylphenyl)-thiazole (360 mg,
82.2 %) as a white solid.
139. .sup.1H NMMR (CDCl.sub.3) .delta.3.89 (s, 3H), 4.76 (s, 2H),
6.98 (d, 2H), 7.42 (s, 1H), 7.46 (d, 2H), 7.97-8.02 (m, 4H).
140. To a solution of
2-(4'-methoxyphenyl)4-(4"-hydroxymethylphenyl)-thiaz- ole (355 mg,
1.13 mmol) in dry THF (10 ml) at 0.degree. C. is added
triphenylphosphine (446 mg, 1.70 mmol) and carbon tetrabromide (564
mg, 1.70 mmol). The reaction mixture is stirred for 17.5 h at
0.degree. C. The precipitate is filtered and the filtercake is
washed with THF. The filtrate is concentrated in vacuum and
purified by column chromatography eluting with 10% ethyl
acetate/hexane to yield 2-(4'-methoxyphenyl)-4-(4"-
-bromomethylphenyl)-thiazole (285 mg, 70%) as a white solid.
141. .sup.1H NMR (CDCl.sub.3): .delta.3.88 (s, 3H), 4.56 (s, 2H),
6.98 (d, 2H), 7.43 (s, 1H), 7.46 (d, 2H) 7.95-8.01 (m, 4H).
142. The above bromomethyl compound is aminated following the
procedure as described in Example 1 giving the title compound
2-(4'-methoxyphenyl)-4-[-
4"-(N-allyl-N-methylaminomethyl)phenyl]-thiazole in 95% yield.
143. .sup.1H NMR (CDCl.sub.3) .delta.2.51 (s,3H), 3.56-3.90 (m,
2H), 3.85 (s, 3H), 4.19-4.46 (m, 2H), 5.51-5.60 (m, 2H), 5.98-6.29
(m, 1H), 7.11 (d, 2H), 7.70 (d, 2H), 7.98 (d, 2H), 8.12 (d, 2H),
8.20 (s, 1H) , 11.12 (br s, 1H).
EXAMPLE 2a
144. (Process 2, Scheme 2)
145.
2-(4-Pyridyl)-4-[[4"-(N-methyl-N-propylamino)methyl]phenyl]thiazole
(I, R.sub.1R.sup.2-Ar=4-py, R.sub.3=propyl, R.sub.4=Me, R.sup.5=H,
p=1, V=N)
146. 2-(4-Pyridyl)-4-[(4"-hydroxymethyl)phenyl]thiazole is prepared
by following the above procedure in Example 2.
147. A solution of methanesulfonylchloride (0.75 mL, 9.11 mmol) in
THF (5 mL) is added with stirring to an ice-cold solution of the
above alcohol (0.83 g, 3.09 mmol) in THF (70 mL) containing
Et.sub.3N (0.92 mL, 9.11 mmol). After the addition is over the
reaction mixture is allowed to warm up to room temperature and
eventually refluxed for 2 h to complete the reaction. The reaction
mixture is cooled and filtered. The residue is washed with
CHCl.sub.3 and dried to give the desired compound as a yellow solid
(0.45 g).
148. .sup.1H NMR (DMSO.sub.d6) .delta.2.35 (s, 3 H), 4.84 (s, 2 H),
7.59 (d, 2 H), 8.13 (d, 2 H) 8.43 (d, 2 H), 8.95 (d, 2 H).
149. A solution of the above mesylate (0.45 g, 1.3 mmol) and
N-methyl-N-propyl amine (0.33 mL, 3.25 mmol) in THF (50 mL) is
heated at 55.degree. C. for 18 h. The reaction mixture is stripped
and flash chromatographed (SiO.sub.2, CHCl.sub.3/MeOH 5%) to give
0.238 g of title compound.
150. .sup.1H NMR (CHCl.sub.3): .delta.0.86 (t, 3 H), 1.38-1.60 (m,
2 H), 2.13 (s, 3 H), 2.30 (t, 2 H), 3.49 (s, 2 H), 7.40 (d, 2 H),
7.95-8.04 (dd, 4 H), 8.32 (s, 1 H), 8.75 (d, 2 H).
151. It was converted to dihydrochloride salt, mp. 192-195 .degree.
C.
152. Additional examples are shown in Table I.
EXAMPLE 3
153. (Process 3, Scheme 3)
154.
2-(4'-methoxyphenyl)-4-[4-[2-(N,N-dimethylamino)-ethyl]phenyl]thiazol-
e (II: R.sup.1=H, R.sup.2=4-CH.sub.3O, R.sup.3=R.sup.4=CH.sub.3,
R.sup.5=H, R.sup.6=H, V=N, p=2)
155. To a solution of 4'-(2-chloroethyl)acetophenone (5.00 g, 27.37
mmol) and aluminum chloride (0.30 g, 2.73 mmol) in anhydrous
diethyl ether (75 ml) is added bromine (4.37 g, 27.37 mmol)
dropwise. After 18 hours the solution is concentrated and the
residue is taken up in CHCl.sub.3 (75 ml) and washed with water (75
ml). The organic layer is dried over MgSO.sub.4 and concentrated to
yield 7.91 g crude bromo product as a dark oil which is used as is
without further purification.
156. A mixture of .alpha.-bromo-4'-(2-chloroethyl)acetophenone,
(1.56 g, 5.98 mmol) and 4-methoxythicbenzamide (1.00 g, 5.98 mmol)
is heated to reflux in EtOH (25 ml) for 2 hours. The mixture is
then cooled to 5.degree. C. and the precipitate filtered and dried
to yield 2-(4-methoxyphenyl)-4-[4-(2-chloroethyl)phenyl]thiazole
(0.90 g, 46%).
157. A solution of
2-(4'-methoxyphenyl)-4-[4-(2-chloroethyl)phenyl]-thiazo- le (0.30
g, 0.71 mmol) and excess (2 ml) dimethyl amine/EtOH solution (19%
w/w) in THF (10 ml) is placed into a sealed reaction vessel and
heated to 80.degree. C. for 20 hours. The solution is then
concentrated and the residue taken up in CHCl.sub.3(20 ml) and
washed with saturated NaHCO.sub.3 (20 ml). The organic layer is
dried over MgSO.sub.4 and concentrated to yield an oil which is
purified on a silica gel column eluting with 10% MeOH/CHCl.sub.3 to
yield the title compound as an off white solid (90mg, 37%).
158. .sup.1H NMR (CDCl.sub.3) .delta.2.33 (s, 6H), 2,60 (m, 2H),
2.80 (m, 2H), 3.86 (s,3H), 6.97 (d, 2H), 7.27 (d, 2H), 7.35 (s,
1H), 7.89 (d, 2H) , 7.97 (di 2H) .
159. Additional examples are shown in Table I.
EXAMPLE 4
160. (Process 4, Scheme 4)
161.
2-(4'-Fluorophenyl)-4-[4'-[3-(N,N-dimethylamino)-propyl]phenyl]thiazo-
le (II: R.sup.1=H, R.sup.2=4-F, p=3, V=N,
R.sup.3=R.sup.4=CH.sub.3)
162. To a solution of p-fluorothiobenzamide (0.39 g, 2.5 mmol) in
20 mL of abs. EtOH is added 2,4'-dibromoacetophenone (0.7 g, 2.5
mmol) all at once. The reaction mixture is stirred at room
temperature for 3 hours and then chilled in ice bath. The
precipitate is collected by filtration, washed with cold EtOH (5
ml.times.2) and dried in vacuum to give
2-(4'-fluorophenyl)-4-(4'-bromophenyl)thiazole as a white fluffy
crystaline solid (1.55 g, 93%). mp.158-9.degree. C.
163. .sup.1H NMR (CDCl.sub.3): .delta.7.16 (t, 2H), 7.47 (s, 1H),
7.58 (d, 2H), 7.87 ()d, 2H), 8.02 (m, 2H).
164. In a 100 ml flask is placed triphenylphosphine (80 mg, 10 %) ,
PdCl.sub.2 (40 mg, 5 %) and
2-(4'-fluorophenyl)-4-(4'-bromophenyl)thiazol- e (0.98 g, 2.9 mmol)
in 20 mL of diethylamine. After stirring for 15 min under N.sub.2
atmosphere, CuI (30 mg, 5 %) and 1-dimethylamino-2-propyne (0.27 g,
3.18 mmol) in 20 ml of acetonitrile are added to the mixture. After
18 h of heating, the solvent is evaporated under reduced pressure
and the residue is filtered through silica gel pad (50 g) using
CHCl.sub.3 (400 mL) and 2% MeOH in CHCl.sub.3(400 mL). A large
portion of unreacted 2-(4'-fluorophenyl)-4-(4'-bromophenyl)thiazole
is recovered after removal of chloroform filtrate (0.55 g, 56%).
The second part of the filtrate (2% MeOH in CHCl.sub.3) is
concentrated and the residual solid is then purified over silca gel
column eluting with 2% MeOH in CHCl.sub.3.
2-(4'-fluorophenyl)-4-[4'-(3-dimethylamino-2-propyn-1-yl)phen-
yl]thiazole is obtained after concentration and trituration with
hexane (0.25 g, 27% yield), mp. 98-9.degree. C.
165. .sup.1H NMR (CDCl.sub.3) .delta.2.39 (s, 6H) , 3.50 (s, 2H),
7.16 (t, 2H), 7.48 (s, 1H), 7.51 (d, 2H), 7.93 (d, 2H), 8.03 (m,
2H).
166. A warm solution of
2-(4'-fluorophenyl)-4-[4'-(1-dimethylamino-2-propy-
n-3-yl)phenyl]thiazole (0.2 g, 0.6 mmol) in abs. EtOH (20 mL)
containing a catalytic amount of palladium on activated carbon (5
%, 20 mg) is shaked under hydrogen atomsphere (30 psi) for 2 h.
After removal of the catalyst by filtration, the filtrate is
concentrated to give
2-(4'-fluorophenyl)-4-[4'-(3-N,N-dimethylaminopropyl)phenyl]thiazole
as desired product (0.18 g, 89 %)
167. .sup.1H NMR (CDCl.sub.3): .delta.1.65 (m, 2H), 2.24 (s, 6H),
2.32 (t, 2H), 2.69 (t, 2H), 7.14 (t, 2H), 7.27 (d, 2H), 7.40 (s,
1H), 7.89 (d, 2H), 8.02 (m, 2H).
168. Additional examples are shown in Table I.
EXAMPLE 5
169. (Process 5, Scheme 5)
170. 2 -(4'-Chlorophenyl
4-[[4-(N-pentyl)aminomethyl]phenyl]thiazole (VI: R.sub.1=H,
R.sub.2=4-Cl, R.sub.3=n-pentyl, R.sup.4=H)
171. To a boiling solution of methenamine (1.1 g, 7.85 mmol) in
CCl.sub.4 (80 mL) is added dropwise a solution of
2-(4'-chlorophenyl)-4-[4'-bromome- thyl)phenyl]thiazole (Scheme 1;
2.6 g, 7.13 mmol) in CHCl.sub.3 (40 mL). The reaction mixture is
refluxed for 3 h under N.sub.2 and cooled. The white precipitate is
filtered and the residue washed with a small volume of CHCl.sub.3
and air dried to give the quaternary salt (2.7 g). Conc. HCl (4 mL)
is added dropwise with stirring to a suspension of the above salt
(2.7 g) in EtOH (30 mL) and the reaction mixture is heated to
reflux for 3 h. It is cooled, filtered and the residue is washed
with a small volume of EtOH and dried to give the desired amine
hydrochloride (1.97 g). mp. >320.degree. C. .sup.1H NMR
(DMSO-d.sub.6): .delta.4.05 (s, 2 H), 7.43-7.63 (m, 4 H), 7.95-8.13
(m, 5 H).
172. To an aqueous suspension of the above salt is added an aqueous
solution of NaOH (6 N) to pH 12, and the free base is extracted
with CH.sub.2Cl.sub.2. The extract is dried and evaporated to give
the corresponding amine, 2-(4'-chlorophenyl)-4-[4-(aminomethyl)
phenyl]thiazole (1.4 g).
173. .sup.1H NMR (DMSO-d.sub.6): .delta.3.75 (s, 2 H), 7.43 (d, 2
H), 7.60 (d, 2 H), 7.98 (d, 2 H), 8.06 (d, 2 H), 8.16 (s, 1 H).
174. A solution of trifluoroacetic anhydride (0.85 mL, 6 mmol) in
THF (5 mL) is added dropwise to a solution of the above amine (1.4
g, 4.7 mmol) in THF (15 mL) and the reaction mixture stirred for 18
h at room temperature. The THF is evaporated and the residue
triturated with a small volume of ether. The solid is filtered,
washed with hexane, and dried to give
2-(4'-chlorophenyl)-4-[4'-trifluoroacetylamino-methyl)pheny-
l]thiazole (1.56 g).mp.174-175.degree. C.
175. .sup.1H NMR (CDCl.sub.3): .delta.4.58 (d, 2 H), 6.58 (br s, 1
H), 7.30-7.48 (m, 4 H), 7.51 (s, 1 H), 7.91-8.05 (m, 4 H).
176. A solution of the above compound (0.59 g, 1.48 mmol) in DMF (5
mL) is added to a slurry of NaH (60%, 70 mg, 1.77 mmol) in DMF (2
mL) under nitrogen. The reaction mixture is stirred at room
temperature until the gas evolution ceased (.sup..about.1 h).
n-Iodopentane (0.5 g, 2.5 mmol) is added, and the reaction mixture
is heated at 100.degree. C. (oil bath) for 3 h. The reaction
mixture is cooled, poured into water (50 mL) and the organic
material is extracted with EtOAc. The EtOAc layer is washed with
brine, dried and stripped to yield a solid which is chromatographed
(SiO.sub.2, 0-5% MeOH/CH.sub.2Cl.sub.2) to give the desired
compound (0.5 g).
177. .sup.1H NMR (CDCl.sub.3): .delta.0.88 (t, 3H), 1.10-1.41 (m,
4H), 1.45-1.80 (m, 2H), 3.34 (t, 2H), 4.68 (d, 2H), 7.33 (d, 2H),
7.40-7.60 (m, 3H), 7.92-8.22 (m, 4H).
178. A solution of the above trifluoroacetylamide (1.05 g, 2.25
mmol) and aqueous KOH (25%, 6 mL, 2.68 mmol) in acetone (30 mL) is
heated under reflux for 18 h. Acetone is distilled, and the residue
is partitioned between water(15 mL) and EtOAc (25 mL). The organic
layer is separated and the aqueous layer is extracted with EtOAc
(3.times.20 mL). The combined organic extract is washed with brine,
dried, and chromatographed (SiO.sub.2, 0-5% MeOH/CH.sub.2Cl.sub.2)
to give the title compound (0.8 g).sub.1 mp. 70-72.degree. C.
179. .sup.1H NMR (CDCl.sub.3): 0.88 (t, 3 H), 1.12-1.45 (m, 4 H),
1.45-1.80 (m, 2 H), 2.64 (t, 2 H), 3.55(br s, 1 H), 3.85 (s, 2 H),
7.32-7.52 (m, 5 H), 7.83-8.13 (m, 4 H).
EXAMPLE 5a
180. 2-(4'-Chlorophenyl-4-[[4'-(N-cyclopropyl,
N-methyl)-aminomethyl]pheny- l]thiazole (VI: R.sub.1=H,
R.sub.2=4-Cl, R.sub.3=c-propyl, R.sub.4=Me)
181. Iodomethane (0.1 mL, 2.1 mmol) is added to a stirred mixture
of
2-(4'-chlorophenyl-4-[[4'-(N-cyclopropyl)aminomethyl]phenyl]thiazole
(prepared as in Example 5) (0.2 g, 0.6 mmol) and anhydrous
K.sub.2CO.sub.3 (0.2 g, 1.4 mmol) in THF (15 mL). It is stirred for
16 h and filtered, The residue is washed with CH.sub.2Cl.sub.2, the
washings and the filtrate are evaporated, and the residual oil is
chromatographed (SiO.sub.2, 0-2% MeOH/CH.sub.2Cl.sub.2) to give 50
mg of the title compound.
182. Additional examples are shown in Table I, herein below.
EXAMPLE 6
183. (Process 6, Scheme 6)
184.
2-(4'-Cyanophenyl-4-[[4'-(N,N-dimethyl)aminomethyl]phenyl]thiazole
(VI: R.sub.1=H, R.sub.2=4-CN, R.sub.3=R.sub.4=Me)
185. To a mixture of 4'-methylacetophenone (30 g, 0.22 mol) and NBS
(39.9 g, 0.22 mol) in CCl.sub.4 (200 mL) is added 0.2 g of
benzoylperoxide and the reaction mixture is heated under reflux for
6 h. Additional benzoylperoxide (0.2 g) is added and the mixture
refluxed for 16 h. It is cooled and filtered. The filtrate is
stripped to yield an oil (47.9 g). .sup.1H NMR indicates
.sup..about.75% of the desired bromide which is used as is for the
next step.
186. Dimethylamine (19% in EtOH, 21.2 g, 0.47 mol) is added
dropwise to a solution of the above bromide (47.8 g, 15 0.22 mol)
in CH.sub.2Cl.sub.2(100 mL) at 0.degree. C. with stirring. After
the addition is over the ice bath is removed, and the solution is
stirred for 16 h at room temperature. The solvent is evaporated and
the residue is taken up in CHCl.sub.3 The chloroform solution is
washed successively with saturated NaHCO.sub.3, brine, dried and
stripped. The residue is chromatographed (SiO.sub.2, 2-10%
MeOH/CH.sub.2Cl.sub.2) to give 15 g of
4'-(N,N-dimethylamino)methylacetphone. The amine is converted to
the corresponding HCl salt.
187. Bromine (1.36 mL; 26.5 mmol) is added dropwise to a solution
of the above HCl salt (5.6 g, 26.5 mmol) in CHCl.sub.3 (60 mL) at
0.degree. C. with stirring. The reaction mixture is stirred at room
temperature for 2 h and the solvent evaporated yielding a brown
solid (9 g).
188. .sup.1H NMR (CDCl.sub.3): .delta.2.81 (s, 6 H), 4.26 (s, 2 H),
4.44 (s, 2 H), 7.89 (d, 2 H), 8.07 (d, 2 H)
189. A mixture of the above phenacyl bromide (1.54 g, 4.57 mmol)
and 4-cyanothiobenzamide (0.74 g, 4.57 mmol) in EtOH (15 ml) is
heated under reflux for 2 h. It is cooled and filtered to give a
yellow solid (1.17 g). The solid is partitioned between CHCl.sub.3
and saturated NaHCO.sub.3 solution, The organic layer is separated,
washed with brine, dried and evaporated to give 0.77 g of a solid.
It is purified via column chromatography (SiO.sub.2, 0-2%
MeOH/CH.sub.2Cl.sub.2) to give 0.46 g of the title compound, mp.
121-122.degree. C.
190. .sup.1H NMR (CDCl.sub.3): .delta.2.37 (s, 6 H), 3.47 (s, 2 H),
7.42 (d, 2 H), 7.57 (s, 1 H), 7.77 (d, 2H), 7.92 (d, 2 H), 8.13 (d,
2 H).
EXAMPLE 6a
191.
2-(4'-Fluorophenyl-4-[[[4'-(N,N-dimethyl)aminomethyl]-3-nitro]phenyl]-
thiazole (II: R.sub.1=H, R.sub.2=4-F, R.sub.3=R.sub.4=Me,
R.sub.6=H, R.sub.5=3-NO.sub.2, V=N, p=1)
192. Replacing 4'-methylacetophenone with
4'-methyl-3'-nitroacetophenone and following the above procedure
the compound 4'-(N,N-dimethylamino)meth- yl-3'-nitroacetophenone is
obtained. This is converted to the HCl salt and brominated to give
.alpha.-bromo-4'-methyl-3'-nitroacetophenone.
193. A mixture of
.alpha.-bromo-4'-(N,N-dimethylaminomethyl)-3'-nitroaceto- phenone
(2.38 g, 6.23 mmol) and 4-fluorothiobenzamide (0.97 g, 6.23 mmol)
in EtOH (150 mL) is heated under reflux for 6 h. EtOH is stripped
and the residue is taken up in EtOAc. The EtOAc solution is washed
successively with saturated Na.sub.2CO.sub.3 and brine, dried, and
stripped. The residue is triturated with isopropyl alcohol and
filtered to give 1.37 g of the title compound, mp. 112.degree.
C.
194. .sup.1H NMR (CDCl.sub.3) .delta.2.25 (s, 6 H), 3.75 (s, 2 H),
7.17 (t, 2 H), 7.57 (s, 1 H), 7.69 (d, 1H), 7.98-8.18 (m, 3 H),
8.45 (d, 1 H).
EXAMPLE 6b
195. 2-(4'-
Fluorophenyl-4-[[[4'-(N,N-dimethyl)aminomethyl]-3'-amino]pheny-
l]thiazole (II: R.sub.1=H, R.sub.2=4-F, R.sub.3=R.sub.4=Me,
R.sub.6=H, R.sub.5=NH.sub.2, V=N, p=1)
196. A solution of the above nitro compound (Example 6a, 0.65 g) in
EtOH (80 mL) and HCl (0.2 mL) is reduced under catalytic condition
(5% Pd/C, 250 mg). After the reduction is complete (18 h) the
catalyst is filtered and the filtrate is evaporated to dryness. The
residue is partitioned between CH.sub.2Cl.sub.2 and saturated
Na.sub.2CO.sub.3. The organic layer is washed with water, dried and
stripped to give 0.47 g of the title compound, mp. 108-109.degree.
C.
197. .sup.1H NMR (CDCl.sub.3): .delta.2.21 (s, 6 H) , 3.45 (s, 2 H)
, 7.05 (t, 2 H), 7.14 (s, 1 H), 7.18-7.23 (d, 1 H), 7.31 (d, 1 H),
7.40 (s, 1 H), 7.97-8.08 (dd, 2 H).
EXAMPLE 6c
198. 2-(4'-
Fluorophenyl-4-[[[4'-(N,N-dimethyl)aminomethyl]-3'-acetylamino-
]phenyl]thiazole (II: R.sub.1=H, R.sub.2=4-F, R.sub.3=R.sub.4=Me,
R.sub.6H, R.sub.5=NHCOCH.sub.3, V=N, p=1)
199. Acetic anhydride (0.4 mL) is added to a solution of the above
am,ne (Example 6b,0.47 g) in anhydrous THF (10 mL) and the solution
is stirred at room temperature for 18 h. THF is evaporated and the
residue is taken up in CHCl.sub.3. The CHCl.sub.3 solution is
washed thoroughly with water, dried and stripped to yield a soft
solid. It is triturated with ether and filtered to give 0.21 g of
the title compound as a white solid, mp. 128.5.degree. C.
200. .sup.1H NMR (CDCl.sub.3) .delta.2.15 (s, 3 H), 2.30(s, 6 H),
3.50 (s, 2 H), 7.10-7.20 (m, 3 H), 7.50 (s, 1 H), 7.65-7.75 (d, 1
H), 8.00-8.10 (dd, 2 H), 8.80 (s, 1 H), 10.75 (br s, 1 H).
201. Additional examples are shown in Table I, herein below.
EXAMPLE 7
202. (Process 7, Scheme 7)
203. 2-(3'-
Nitrophenyl-4-[[[4'-(N,N-dimethylamino)methyl]-3'-hydroxy]phen-
yl]thiazole (II: R.sub.1=H, R.sub.2=3-NO.sub.2,
R.sub.3=R.sub.4CH.sub.3, R.sub.5=3-OH, R.sub.6=H, V=N, p=1)
204. A mixture of 3-nitrobenzenethioamide (2.73 g, 15 mmol) and
3-methoxy-.alpha.-[bromoacetophenone (3.43 g, 15 mmol) in EtOH (30
mL) is heated under reflux for 18 h. It is cooled and filtered to
give 4 g of 2-(3'-nitrophenyl)-4[(3'-methoxy)phenyl]thiazole as a
yellow solid, mp. 122-123.degree. C.
205. .sup.1H NMR (CDCl.sub.3): .delta.3.94 (s, 3 H), 6.90-7.01 (dd,
1 H), 7.32-7.48 (t, 1 H), 7.50-7.75 (m, 4 H), 8.22-8.45 (dd,dd 2
H), 8.90 (dd, 1 H).
206. To an ice-cold solution of the above methylether (0.77 g, 2.46
mmol) in CH.sub.2Cl.sub.2 (10 mL) is added a solution of BBr.sub.3
in CH.sub.2Cl.sub.2 (1M, 4.9 mL). The solution is stirred at
0.degree. C. for 0.5 h and then at room temperature for 18 h. It is
quenched with 12 mL of water, and the mixture is stirred for 0.5 h
and filtered. The residue is washed thoroughly with water, followed
by ether and dried to give 0.55 g of
2-(3'-nitrophenyl)-4[(3'-hydroxy)phenyl]thiazole.
207. A mixture of the above hydroxy compound (0.55 g, 1.93 mmol),
p-formaldehyde (0.3 g), (Me).sub.2NH/EtOH (19%, 2.2 mL) in EtOH (7
mL) is refluxed for 8 h. EtOH is evaporated, and the residue is
poured into water, and the solution is taken up in
CH.sub.2Cl.sub.2. The organic layer is washed with brine, dried,
stripped, and the residue chromatographed (SiC.sub.2,
MeOH/CH.sub.2Cl.sub.22%) to yield 0.15 g of the title compound, mp.
157-160.degree. C.
208. .sup.1H NMR (CDCl.sub.3): .delta.2.32 (s, 6 H), 3.67 (s, 2 H),
7.00-7.01 (dd, 1 H), 7.40-7.48 (m, 2 H), 7.53 (s, 1 H), 7.65 (t, 1
H), 8.22-8.45 (dd,dd 2 H), 8.85 (m, 1 H).
209. Additional examples are shown in Table I, herein below.
EXAMPLE 8
210. (Process 8, Scheme 8)
211.
5-(4'-Fluorophenyl)-3-[4"-(N-methyl-N-allylaminomethyl)-phenyl]-1,2,4-
-thiadiazole (III: R.sup.1=H, R.sup.2=4-F, R.sup.3=CH.sub.3,
R.sup.4=allyl, R.sup.5=H, V=N, p=1)
212. To a solution of p-tolunitrile (10.1 g, 86.21 mmol) in 100 ml
CHCl.sub.3:MeOH (1:1) cooled to 5.degree. C. in an ice-water bath
is bubbled HCl for 1 hour to reach saturation. The solution is
stirred at 10.degree. C. for 43 hours, then concentrated under
reduced pressure to yield p-methylbenzimidate hydrochloride as pale
yellow crystals (15.98g, 99%).
213. .sup.1H NMR (CDCl.sub.3) .delta.2.44 (s, 3H), 4.52 (s, 3H),
7.36 (d, 2H), 8.29 (d, 2H).
214. To a solution of p-methylbenzimidate hydrochloride (8.00 g,
43.09 mmol) in MeOH (100 ml) is added NH.sub.3/MeOH solution
(2.68M, 24.12 ml, 64.64 mmol). Upon the addition of the NH.sub.3,
the mixture has a pH around 8.5. To this solution is added ammonium
chloride (2.30 g, 43.09 mmol). The reaction mixture is stirred at
room temperature for 20 hours, then cooled in refrigerator and the
precipitate is removed by filtration. The mother liquor is
concentrated to yield the crude product which is taken up in a
limited amount of cold EtOH and the white precipitate is filtered.
The beige filtrate is concentrated to yield p-methylbenzamidine
hydrochloride as an off-white solid (7.15g, 97%).
215. .sup.1H NMR (DMSO.sub.d6) .delta.2.41 (s, 3H), 7.43 (d, 2H),
7.78 (d, 2H) 9.24-9.39 (broad d, 3H).
216. To a mixture of p-methylbenzamidine hydrochloride (5.1 g, 30.0
mmol) in CHCl.sub.3 (100 ml) is added triethyl amine (15.12 g, 20.9
ml, 150.0 mmol) and cooled to 5.degree. C. in an ice-water bath. To
the mixture is slowly added perchloromethyl mercaptan (95%, 6.16 g,
31.5 mmol) in CHCl.sub.3(10 ml) over 1 hour. The yellow solution is
allowed to warm up to room temperature. After 2 hours the mixture
is washed with water (100 ml.times.2) and brine (100 ml). The
organic layer is dried over MgSO.sub.4 and the solvent is removed
under reduced pressure to yield a brown oil. The oil is purified on
a bed of silica gel, eluting with 1:1 CHCl.sub.3:hexanes to yield
3-(p-tolyl)-5-chloro-1,2,4-thiadiazole as a yellow solid (2.78g,
44%).
217. .sup.1H NMR (CDCl.sub.3) : .delta.2.41 (s, 3H), 7.30(d, 2H),
8.13 (d, 2H).
218. A mixture of 3-(p-tolyl)-5-chloro-1,2,4-thiadiazole (0.50 g,
2.37 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II)
chloride catalyst (1.41g, 2.61 mmol) in anhydrous THF (20 ml) is
cooled in an ice-water bath. To this mixture is added slowly
4-fluorophenyl-magnesium bromide (1.0M in THF, 2.5 ml, 2.49 mmol)
with exclusion of both moisture and oxygen. The mixture is allowed
to warm to room temperature and stirred for 18 hours under N.sub.2.
The mixture is filtered through celite and concentrated. The
residue is taken up in CHCl.sub.3 (50 ml) and washed with brine (50
ml.times.2). The organic layer is dried over magnesium sulfate and
concentrated. The residue is purified on a silica gel column,
eluting with 3:7 CHCl.sub.3:hexanes to yield
5-(4'-fluorophenyl)-3-(p-tol- yl)-1,2,4-thiadiazole (0.20 g,
31%).
219. .sup.1H NMR (CDCl.sub.3) .delta.2.43 (s, 3H), 7.21-7.32 (m,
4H), 8.06 (m, 2H), 8.24 (d, 2H).
220. To a solution of
5-(4'-fluorophenyl)-3-(p-tolyl)-1,2,4-thiadiazole (0.16 g, 0.59
mmol) in CCl.sub.4 (20 ml) is added NBS (0.11 g, 0.59 mmol) and the
mixture is heated to reflux for 36 hours. The mixture is cooled to
room temperature and filtered through celite. The mother liquor is
concentrated. The residue is taken up in chloroform (30 ml) amd
washed with water (30 ml). The organic layer is dried over
MgSO.sub.4 and concentrated to yield
5-(4'-fluorophenyl)-3-(p-bromomethylphenyl)-1,2,4-t- hiadiazole,
(0.22 g) as crude product which is used as is without further
purification.
221. .sup.1H NMR (CDCl.sub.3): .delta.4.55 (s, 2H), 7.19 (d, 2H),
7.54 (d, 2H), 8.06 (m, 2H), 8.35 (d, 2H).
222. To a solution of
5-(4'-fluorophenyl)-3-(4"-bromomethylphenyl)-1,2,4-t- hiadiazole
(0.19 g, 0.54 mmol) in chloroform (15 ml) is added slowly
N-methyl-allylamine (0.14 g, 1.62 mmol) in chloroform (5 ml). The
solution is stirred at room temperature for 12 hours and washed
with water (30 ml). The organic layer is dried over K.sub.2CO.sub.3
and concentrated. The resulting oil is chromatographed on a silica
gel column, eluting with ethyl acetate:hexanes (30:60) to yield the
title compound as an oil. (0.10 g, 55%)
223. .sup.1H NMR (CDCl.sub.3): .delta.2.23 (s, 3H), 3.05 (d, 2H),
3.57 (s, 2H), 5.12-5.30 (m, 2H), 5.85-6.05 (m, 1H), 7.19 (d, 2H),
7.45 (d, 2H), 8.07 (m, 2H), 8.32 (d, 2H).
224. Additional examples are shown in Table I, herein below.
EXAMPLE 9
225. (Process 9, Scheme 9)
226. 1,3,4-Thiadiazoles and 1,3,4-Oxadiazoles
227.
2-(3'-Nitrophenyl)-5-[4"-(N,N-dimethylaminomethyl)phenyl]-1,3,4-thiad-
iazole (IV: R.sup.1=H, R.sup.2=3-NO.sub.2,
R.sup.3=R.sup.4=CH.sub.3, R.sup.5=H, V=N, p=1)
228. To a solution of 3-nitrobenzhydrazide (2.16 g, 11.92 mmol) in
pyridine (40ml) cooled to 0.degree. C. in an ice bath is added
dropwise p-toluoyl chloride (1.94 g, 11.92 mmol). The mixture is
allowed to warm to room temperature and stirred for 12 hours. The
mixture is quenched with 350 mL of water and stirred for thirty
minutes. The precipitate is filtered and dried in a vacuum oven to
yield 1-[(4-methyl)benzoyl]-2-(3-n- itrobenzoyl)hydrazine as a pale
yellow solid. (2.94 g, 82%).
229. .sup.1H NMR (DMSO.sub.d6) .delta.2.40 (s, 3H), 7.35 (d, 2H),
7.86 (d, 2H), 7.87 (t, 1H), 8.37 (d, lH), 8.45 (d, 1H), 8.76 (s,
1H), 10.58 (s, 1H), 10.90 (s, 1H).
230. A mixture of 1-[(4-methyl)benzoyl]-2-(3-nitrobenzoyl)hydrazine
(1.40 g, 4.68 mmol) and Lawsson's Reagent (0.95 g, 2.34 mmol) in
benzene (25ml) is slowly heated to 60.degree. C. After 3 hours the
solution is concentrated, quenched with 35 ml of water and heated
to reflux for 12 hours. The mixture is then cooled to room
temperature and the precpitate is collected by filtration. The
precipitate is then taken up in chloroform (100 ml) and the
insoluble portion is removed by filtration. The filtrate is then
dried over MgSO.sub.4 and concentrated to yield
2-(3'-nitrophenyl)-5-(p-tolyl)-1,3,4-thiadiazole as a pale yellow
solid. (0.67 g, 48%).
231. .sup.1H NMR(CDCl.sub.3): .delta.2.45 (s, 3H), 7.35 (d, 2H),
7.73 (t, 1H), 7.92 (d, 2H), 8.38 (t, 2H), 8.81 (s, 1H).
232. To a solution of
2-(3'-nitrophenyl)-5-(p-tolyl)-1,3,4-thiadiazole (0.66 g, 2.22
mmol) in CCl.sub.4 (75 ml) is added NBS (0.43 g, 2.44 mmol) and
refluxed for 12 hours. The mixture is then concentrated and the
residue is taken up in chloroform (50 ml) and washed with saturated
NaHCO.sub.3 (50 ml) and brine (50 ml). The organic layer is dried
over MgSO.sub.4 and concentrated to yield
2-(3'-nitrophenyl)-5-(p-bromomethylp- henyl)-1,3,4-thiadiazole as a
tan solid. (0.69 g, 83%).
233. .sup.1H NMR (CDCl.sub.3) .delta.4.51 (s, 2H) , 7.55 (d, 21),
7.72 (t, 1H), 8.01 (d, 2H), 8.39 (t, 2H), 8.80 (s, 1H).
234. To a suspension of
2-(3'-nitrophenyl)-5-(p-bromomethylphenyl)-1,3,4-t- hiadiazole
(0.69 g, 1.83 mmol) in warm EtOH (25 ml) is added excess dimethyl
amine/EtOH solution (.sup..about.19% w/w, 3 ml) and stirred at room
temperature. After 12 hours the solution is concentrated and the
residue is taken up in chloroform (50 ml) and washed with saturated
NaHCO.sub.3 (50 ml) and brine (50 ml). The organic layer is dried
over K.sub.2CO.sub.3 and concentrated to yield a brown solid which
is chromatographed on a silica gel column, eluting with 10%
MeOH/CHCl.sub.3 to yield the title compound as a tan solid. (0.26
g, 37%)
235. .sup.1H NMR (CDCl.sub.3): .delta.2.29 (s, 6H), 3.50 (s, 2H),
7.50 (d, 2H), 7.72 (t, 1H), 7.97 (d, 2H), 8.39 (t, 2H), 8.82 (s,
1H).
EXAMPLE 9a
236.
2-(3'-Nitrophenyl)-5-[4"-(N,N-dimethylaminomethyl)phenyl]-1,3,4-oxadi-
azole (V: R.sup.1=H, R.sup.2=3-NO.sub.2, R.sup.3=R.sup.4CH.sub.3,
R.sup.5=H, V=N, p=1)
237. A suspension of
1-[(4-methylbenzoyl)]-2-(3-nitrobenzoyl)hydrazine (1.37 g, 4.58
mmol) in 20 ml thionyl chloride is heated to reflux for 12 hours.
The solution is concentrated and the residue is taken up in
chloroform (50 ml) and washed with water (50 ml) and brine (50 ml).
The organic layer is dried over MgSC.sub.4 and concentrated to
yield 2-(3'-nitrophenyl)-5-(p-tolyl)-1,3,4-oxadiazole as a yellow
solid. (1.12 g, 87%).
238. .sup.1H NMR (CDCl.sub.3).delta.2.47 (s, 3H), 7.39 (d, 2H),
7.76 (t, 1H), 8.07 (d, 2H), 8.42 (d, 1H), 8.80 (d, 1H), 8.95 (s,
1H).
239. To a solution of
2-(3'-nitrophenyl)-5-(p-tolyl)-1,3,4-oxadiazole (1.00 g, 3.56 mmol)
in CCl.sub.4 (25 ml) is added NBS (0.43 g, 3.74 mmol) and the
mixture is heated to reflux. After 24 hours the solution is
concentrated and the residue taken up in chloroform (100 m) and
washed with saturated NaHCO.sub.3 (50 ml) and brine (50 ml). The
organic layer is dried over MgSO.sub.4 and concentrated to yield
2-(3'-nitrophenyl)-5-[(p-bromomethyl)phenyl]-1,3,4-oxadiazole as a
tan solid. (0.69 g, 83%).
240. .sup.1H NMR (CDCl.sub.3) .delta.4.55 (s, 2H), 7.59 (d, 2H),
7.78 (t, 1H), 8.16 (d, 2H), 8.45 (d, 1H), 8.52 (d, 1H), 8.96 (s,
1H).
241. To a suspension of 2-(3'-nitrophenyl)
5-[-(p-bromomethyl)phenyl]-1,3,- 4-oxadiazole (0.50 g, 1.39 mmol)
in warm EtOH (25 ml) is added excess dimethyl amine/EtOH solution
(.sup..about.199 w/w, 3 ml) and stirred at room temperature for 12
hours. The solution is then concentrated and the residue taken up
in chloroform (30 ml) and is washed with saturated NaHCO.sub.3 (30
ml) and brine (30 ml). The organic layer is dried over
K.sub.2CO.sub.3 and concentrated to yield a brown oil which is
chromatographed on a silica gel column eluting with 10%
MeOH/CHCl.sub.3 to yield the title compound as a tan solid. (0.22
g, 49%).
242. .sup.1H NMR (CDCl.sub.3) .delta.2.25 (s, 6H), 3.52 (s, 2H),
7.54 (d,2H), 7.77 (t, 1H), 8.12 (d, 2H), 8.40 (d, 1H), 8.54 (d,1H),
8.95 (s, 1H).
243. By following the process schemes described in the preceding
Examples the following compurnds have also been prepared.
2TABLE I Process Example Scheme Name 1d 1
2-(4'-fluorophenyl)-4-[4"-(N-methyl-N- (2-fur-
furyl)aminomethyl)phenyl]thiazole 1e 1
2-(4'-fluorophenyl)-4-[4"-(N-butyn-1- oxymethyl)phenyl]thiazole 1f
1 2-(4'-fluorophenyl)-4-(4"-(N-methyl-N-
propargylaminomethyl)phenyl]thiazole 1g 1 2-(4'-chlorophenyl)-4-[4-
"-(N-methyl-N- allylaminomethyl)phenyl]thiazole 1h 1
2-(4'-nitrophenyl)-4-[4"-(N-methyl-N- allylaminomethyl)phenyl]th-
iazole 1i 1 2-(4'-fluorophenyl)-4-[4"-(2-(t-
butyoxy)ethoxymethyl)phenyl]thiazole 1j 1 2-(2'-nitrophenyl)-4-[4"-
-(N-methyl-N- allylaminonomethyl)phenyl]thiazole 1k 1
2-(3'-nitrophenyl)-4-[4"-(N-methyl-N- allylaminomethyl)phenyl]th-
iazole 1l 1 2-(4'-fluorophenyl)-4-[4"-(2-
propenyloxymethyl)phenyl]thiazole 1m 1 2-(4'-fluorophenyl)-4-[4"-(-
N- cyclopropylaminomethyl)phenyl]thiazole 1n 1
2-(4'-fluorophenyl)-4-[4"-(N- allylaminomethyl)phenyl]thiazole 1o 1
2-(4'-nitrophenyl)-4-[4"-(N-methyl-N-
propylaminomethyl)phenyl]thiazole 1p 1 5-bromo-2-(4'-nitrophenyl)--
4-[4"-(N- methyl-N-allyl- aminomethyl)phenyl]thiazole 1q 1
2-[4'-(1H-pyrrol-1-yl)phenyl]-4-[4"- (N-methyl-N-
propylmethyl)phenyl]thiazole 1r 1 2-(4'-aminophenyl)-4-[4"-(N-m-
ethyl-N- propylmethyl)phenyl]thiazole 1s 1
2-(4'-nitrophenyl)-4-[4"- (diallylaminomethyl)phenyl]thiazole 1t 1
2-(4'-nitorophenyl)-4-[4"- (dipropylaminomethyl)phenyl]- -thiazole
6d 6 2-(4'-trifluoromethylphenyl)-4-[4"-(N- methyl-N-allylamino-
methyl)phenyl]thiazole 2c 2 2-(4'-pyridyl)-4-[4"-(N-methyl-N-
propylaminomethyl)phenyl]thiaz- ole 6e 6
2-(4'-cyanophenyl)-4-[4"-(N-methyl-N-
propylaminomethyl)phenyl]-thiazole 1u 1 2-(4'-chlorophenyl)-4-[4"--
(N-methyl-N- (2-dimethylaminoethyl)aminomethyl)- phenyl]thiazole 6f
6 2-(2'-fluoro-4'- trifluoromethylphenyl)-4-[4"-(N-
methyl-N-propylamino- methyl)phenyl]thiazole 1v 1
2-(4'-nitrophenyl)-4-[4"- (diisopropylaminomethyl)- phenyl]thiazole
1x 1 2-(4'-nitrophenyl)-4-[4"- (dimethylaminomethyl)phenyl]thiazole
1y 1 2-(2'-fluorophenyl)-4-[4"-(N-methyl-N-
allylaminomethyl)phenyl]thiazole 1z 1 2-(4'-trifluoromethoxyphenyl-
)-4-[4"- (N-methyl-N-allylaminomethyl)- phenyl]thiazole 1aa 1
2-(3'-nitrophenyl)-4-[4"- (dimethylaminomethyl)phen- yl]-thiazole
1bb 1 2-(3'-nitrophenyl)-4-[4"-(N-methyl-N-
propylaminomethyl)phenyl]thiazole 1cc 1 2-(4'-nitrophenyl)-4-[4"-[-
(2- diethylaminoethoxy)- methyl]phenyl]thiazole 1dd 1
2-(3'-nitrophenyl)-4-[4"-(N-methyl-N- (2-methoxyethyl)aminomethyl)-
phenyl]thiazole 6g 6 2-(4'-iodophenyl)-4-[4"-(N-methyl-N-
propylaminomethyl)phenyl]-t- hiazole 1ee 1
2-(4'-chlorophenyl)-4-[4"-(N-methyl-N-
(2-hydroxyethyl)aminomethyl)- phenyl]thiazole 6h 6
4-[4'-methyl-N-propylamino- methyl)phenyl]-2-(pyrid-3"-yl)thiazo-
le 1ss 1 2-(4'-chlorophenyl)-4-[4"-[[2- (diethylamino)ethyl]-
thiomethyl]phenyl]thiazole 6i 6
2-[4'-(trimethylsilylethynyl)phenyl]- 4-[4"-(N-methyl-N-propylam-
ino- methyl)phenyl]thiazole 6j 6 2-(4'-ethynylphenyl)-4-[4-
"-N-methyl-N- propylaminomethyl)phenyl]thiazole 1ff 1
2-(4'-chlorophenyl)-4-[4"-[(4- ethylpiperazin-1-yl)methyl]-
phenyl]thiazole 6k 6 2-(4'-methoxy-3'-nitrophenyl)-4-[4"-
(N-methyl-N-propylamino- methyl)phenyl]thiazole 6l 6
2-(4'-methoxy-3'-nitrophenyl)-4-[4"- (dimethylaminomethyl)phenyl-
]thiazole 1gg 1 2-(4'-chlorophenyl)-4-[4"-
[[3(dimethylamino)propyl]aminomethyl]- phenyl]thiazole 1hh 1
2-(3'-nitrophenyl)-4-[4"-(N- hydroxymethylaminomethyl)-
phenyl]thiazole 1ii 1 2-(3'-nitrophenyl)-4-[4"-(N-methyl-N-
(2-phenylethyl)aminomethyl)- phenyl]thiazole 8a 8
5-(4'-fluorophenyl)-3-[4"-(N-methyl-N- allylaminomethyl)phenyl-
]-1,2,4- thiadiazole 8b 8 5-phenyl-3-[4"-(N-methyl-N-
allylaminomethyl)phenyl]-1,2,4- thiadiazole 1tt 1
2-(4'-chlorophenyl)-4-[4"-(N-methyl-N- (2-N-methylaminoethyl)-am-
ino- methyl)phenyl]thiazole 5c 5 2-(4'-chlorophenyl)-4-[4"- -(N-
octylaminoethyl)amino- methyl)phenyl]thiazole 6n 6
2-(3'-cyanophenyl)-4-[4"-(N-methyl-N-
propylaminomethyl)phenyl]thiazole 6o 6 2-(3'-cyanophenyl)-4-[4"-
(dimethylaminomethyl)phenyl]thiazole 6u 6
2-(6"-chloropyrid-3"-yl)-4-[4'-(N- allyl-N-methyl-
aminomethyl)phenyl]thiazole 8c 8 5-(4'-methoxyphenyl)-3-[4"-(N-met-
hyl- N-allylaminomethyl)phenyl]-1,2,4- thiadiazole 6p 6
2-(4'-methyl-3'-nitrophenyl)-4-[4"-(N- methyl-N-propylaminomethyl)-
phenyl]thiazole 1jj 1 2-(4'-chlorophenyl)-4-[4"-(N-(2-
dimethylaminoethyl)aminomethyl)- phenyl] thiazole 5d 5
2-(3'-nitrophenyl)-4- [amidinothiomethyl)phenyl]thiazole 5e 5
2-(4'-chlorophenyl)-4-{4-[- .alpha.-((2- dimethylaminoethyl)
amino)acetyl- aminomethyl]phenyl}thiazole 1kk 1
2-(4'-methoxy-3'-nitrophenyl)-4-- [4"- (N-methyl-N-allylamino-
methyl)phenyl]thiazole 9b 9 2-(3'-nitrophenyl)-5-[4"-(N-methyl-N-
allylaminomethyl)phenyl]-1,3,4- oxadiazole 9d 9
2-(3'nitrophenyl)-5-[4"-(N-methyl-N- allylaminomethyl)phenyl]-1,-
3,4- thiadiazole 1ll 1 2-(4'-methoxy-3'-nitrophenyl)-4-[4"- -
(N-methyl-N-(2-hydroxy-ethyl)amino- methyl)phenyl]thiazole 6q 6
2-(2'-fluoro-4'- trifluoromethylphenyl)-4-[4"-(di-
methyl-aminomethyl)phenyl]thia- zole 8d 8
5-(4'-methoxyphenyl)-3-[4"- (dimethylaminomethyl)phenyl]-1,2,4-
thiadiazole 8e 8 5-(4'-methoxyphenyl)-3-[4"-((2-
dimethylaminoethyl)thiomethyl)ph- enyl]- 1,2,4-thiadiazole 5f 5
2-(4'-bromophenyl)-4-[4"- aminomethylphenyl]thiazole 1mm 1
2-(4'-methoxy-3'-nitropheny- l)-4-[4"- (N-methyl-N-(2-
methylaminoethyl)amino- methyl)phenyl]thiazole 9f 9
2-(4'-chlorophenyl)-5-[4"- (dimethylaminomethyl)phenyl]-1,3,4-
oxadiazole 9g 9 2-(4'-chlorophenyl)-5-[4"-
(dimethylaminomethyl)phenyl]-1,3,4- thiadiazole 9h 9
2-(4'-chlorophenyl)-5-[4"-(N-methyl-N-
allylaminomethyl)phenyl]-1,3,4- thiadiazole 9i 9
2-(4'-chlorophenyl)-5-[4"-(N-methyl-N- allylaminomethyl)phenyl]--
1,3,4- oxadiazole 1nn 1 2-(3'nitro-4'-methoxyphenyl)-4-[4"- [(2-
diethylaminoethylthio)methyl]phenyl]th i-azole 1oo 1
2-(3',4'-dimethoxyphenyl)-4-[4"- (dimethylaminomethyl)ph-
enyl]thiazole 9j 9 2-(4'-methoxyphenyl)-5-[4"-
(dimethylaminomethyl)phenyl]-1,3,4- oxadiazole 9k 9
2-(4'-methoxyphenyl)-5-[4"-(N-methyl- N-allylaminomethyl)phenyl]-
-1,3,4- oxadiazole 1pp 1 2-(3'-nitrophenyl)-4-[4"-[(2-
dimethylaminoethyl- thio)methyl]phenyl]thiazole 6t 6
2-(4'-fluorophenyl)-4-[3"-acetamido- 4"-(dimethylaminomethyl)phe-
nyl]- thiazole 1qq 1 2-(4'-chlorophenyl)-4-[4"-[(4-
methylpiperazin-1- yl)methyl]phenyl]thiazole 1rr 1
2-(4'-chlorophenyl)-4-[4"-[(2- dimethylaminoethyl-
thio)methyl]phenyl]thiazole 7b 7 2-(3'-nitrophenyl)-4-[3"-hydroxyl-
-4"- (N-methylpiperazino)methylphenyl]- thiazole 3a 3
2-(4'-fluorophenyl)-4-[4"-(2- dimethylaminoethyl)phenyl]thi- azole
3b 3 2-(3'-nitrophenyl)-4-[4"-(2-
dimethylaminoethyl)phenyl]thiazole 3d 3 2-(4'-methoxyphenyl)-4-[4"-
-[2-(N- allyl-N-methylamino)ethyl]phenyl]- thiazole 3e 3
2-(4'-methoxyphenyl)-4-[4"-[2-(N- methylpiperazino)ethyl]-
phenyl]thiazole 91 9 2-(3'-nitrophenyl)-5-[4"-
(thiomorpholinomethyl)phenyl]-1,3,4- thiadiazole 4a 4
2-(4'-fluorophenyl)-4-[4"-(3- dimethylaminopropynyl)phenyl]thiaz-
ole 4b 4 2-(4'-methoxyphenyl)-4-[4"-(3-
dimethylaminopropynyl)phenyl]thiazole 4d 4 2-(4'-methoxyphenyl)-4--
[4"-(3- dimethylaminopropyl)phenyl]thiazole
244. Organisms
245. Three strains of Candida (Candida parpsilosis, Candida
tropicalis, Candida albicans-ATCC 36082) as well as Cryptococcus
neoformans were used for the initial testing. Active compounds were
then tested against fluconazole resistant Candida albicans, Candida
krusei, Torulopsis glabrata, and Cryptococcus neoformans along with
Sporothrix shenkii and Aspergillus flavus in the secondary round of
testing. All clinical strains used in this study were blood culture
isolates from the Clinical Microbiology Laboratory of Harbor-UCLA
Medical Center, Torrance, Calif. The organisms were maintained on
Sabourahd Dextrose Agar slants at 4.degree. C. For experimentation,
singlet suspensions of each organism were prepared by growing the
yeast overnight at 27.degree. C. on a rotating drum in
yeast-nitrogen base broth (YNB) with amino acids (Difco, Detroit,
Mich.), pH 7.0 with 0.05M morpholinepropanesulfonic acid (MOPS).
The suspension was then centrifuged and washed twice with 0.85%
NaCl. This was followed by sonication of the washed cell suspension
for 4s (Branson Sonifier, model 350, Danbury, Conn.). The singlet
blastospores were counted in a hemocytometer and adjusted to the
desired concentration in 0.85% NaCl.
246. Antifungal Activity
247. The antifungal activity of the compounds and Fluconazole
against the Candida and Cryptococcus strains were determined using
a modification of a broth microdilution technique. Test compounds
were diluted in DMSO to a 1.0 mg/ml ratio then diluted to 64
.mu.g/ml in YNB broth, pH 7.0 with MOPS (Fluconazole was used as
the control). This was to provide a working solution of each
compound. Using a 96-well plate, wells 1 and 3 through 12 were
prepared with YNB broth, ten fold dilutions of the compound
solution were made in wells 2 through 11 (concentration ranges were
64 to 0.125 .mu.g/ml) Well one served as a sterility control and
blank for the spectrophotometric assays. Well twelve served as a
growth control. The microtiter plates were inoculated with 10 ul in
each of well 2 through 11 (final inoculum size was 10.sup.4
organisms/ml). Inoculated plates were incubated for 48 hrs., at
35.degree. C. The MIC values were determined spectrophotometrically
by measuring the absorbance at 420 nm (Automatic Microplate Reader,
DuPont Instruments, Wilmington, Del.) after agitation of the plates
for 2 min with a vortex-mixer (Vorte-Genie 2 Mixer, Scientific
Industries, Inc., Bolemia, N.Y.). The MIC endpoint was defined as
the lowest drug concentration exhibiting approximately 50% (or
more) reduction of the growth compared with the control well. With
the turbidity assay this was defined as the lowest drug
concentration at which turbidity in the well was <50% of the
control (IC.sub.50) Minimal Cytolytic Concentrations (MCC) were
determined by subculturing all wells from the 96-well plate onto a
Sabourahd Dextrose Agar (SDA) plate and incubated for 1 to 2 days
at 35.degree. C. and the viability was checked.
248. The following Table II demonstrates the antifungal activities
of a selected number of examples.
3 TABLE II C. Crypto. Example # MIC.sup.a MCC.sup.b MIC MCC MIC MCC
MIC MCC 1h 0.5.sup.c 2 0.25 1 0.125 0.5 0.5 2 1k 0.5 1 0.25 0.5
0.25 0.25 0.25 0.5 1o 1 4 1 4 2 32 0.125 2 1x 1 2 1 2 1 2 2 2 5b 1
4 1 4 1 4 1 4 6k 1 2 0.5 2 1 2 1 1 6l 0.5 1 0.25 0.5 0.25 1 0.25
0.5 1gg 1 2 1 4 1 2 1 2 6p 1 8 1 4 2 16 1 4 1kk 1 2 0.25 1 1 2 0.5
2 9c 1 4 1 1 1 1 2 4 7a 1 4 1 0.25 1 2 1 4 1 4.sup.c 16 4 16 4 16 4
16 1g 2 8 4 8 2 8 2 8 1n 8 16 4 8 8 16 8 8 2b 4 16 2 16 4 16 4 16
6e 4 4 2 4 2 16 0.5 1 1u 8 8 4 4 4 4 4 4 6f 8 16 4 8 2 8 4 8 1aa 4
4 4 4 4 4 4 4 1ee 4 16 2 16 4 8 2 16 6m 4 8 4 4 4 8 4 4 1tt 4 16 4
16 2 16 2 4 6o 2 4 2 8 2 >64 8 16 1jj 8 8 4 4 4 4 8 8 1ll 8 8 2
2 4 4 2 8 6g 8 4 4 2 8 4 4 4 9j 4 32 8 8 0.5 0.5 0.25 8 1gg 4 8 4 8
4 8 4 8 1rr 4 8 4 8 4 8 4 8 Fluconazole 0.25 >64 0.5 >64 0.25
>64 1.0 >64 0.5 >64 1.0 >64 1.0 >64 0.5 >64 Amp-B
0.25 0.25 <0.03 Naftifine 32 4.0 .sup.aMIC = Minimum inhibitory
concentration (50% Inhibition) .sup.bMCC = Minimum cytolytic
concentration .sup.cAll values are given in .mu.g/ml
* * * * *