U.S. patent application number 10/770019 was filed with the patent office on 2004-08-12 for 2-ureido-thiazole derivatives, process for their preparation, and their use as antitumor agents.
Invention is credited to Amici, Raffaella, Isacchi, Antonella, Pevarello, Paolo, Traquandi, Gabriella, Villa, Manuela, Vulpetti, Anna.
Application Number | 20040157827 10/770019 |
Document ID | / |
Family ID | 10841640 |
Filed Date | 2004-08-12 |
United States Patent
Application |
20040157827 |
Kind Code |
A1 |
Pevarello, Paolo ; et
al. |
August 12, 2004 |
2-Ureido-thiazole derivatives, process for their preparation, and
their use as antitumor agents
Abstract
Compounds which are 2-ureido-1,3-thiazole derivatives of formula
(I) wherein R is a halogen atom, a nitro group, an optionally
substituted amino group or it is a group, optionally further
substituted, selected from: i) straight or branched C1-C6 alkyl;
ii) C3-C6 cycloalkyl; iii) aryl or arylalkyl with from 1 to 6
carbon atoms within the straight or branched alkyl chain; R1 is an
optionally substituted group selected from: i) straight or branched
C1-C6 alkyl; ii) 3 to 6 membered carbocycle or 5 to 7 membered
heterocycle ring, iii) aryl or arylcarbonyl; iv) arylalkyl with
from 1 to 6 carbon atoms within the straight or branched alkyl
chain: R2 is hydrogen, a straight or branched C1-C4 alkyl or C2-C4
alkenyl or alkynyl group; or, taken together with the nitrogen atom
to which they are bonded, R1 and R2 form a substituted or
unsubstituted group selected from: i) an optionally benzocondensed
or bridged 5 to 7 membered heterocycle; or ii) a 9 to 11 membered
spiro-heterocyclic compound; or a pharmaceutically acceptable salt
thereof; are useful for treating cell proliferative disorders
associated with an altered cell dependent kinase activity.
Inventors: |
Pevarello, Paolo; (Pavia,
IT) ; Amici, Raffaella; (Piacenza, IT) ;
Traquandi, Gabriella; (Milano, IT) ; Villa,
Manuela; (Lurago d'Erba (Como), IT) ; Vulpetti,
Anna; (Brugherio (Milano), IT) ; Isacchi,
Antonella; (Milano, IT) |
Correspondence
Address: |
AKIN, GUMP, STRAUSS, HAUER & FELD
711 LOUISIANA STREET
SUITE 1900 SOUTH
HOUSTON
TX
77002
US
|
Family ID: |
10841640 |
Appl. No.: |
10/770019 |
Filed: |
February 2, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10770019 |
Feb 2, 2004 |
|
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09830668 |
Apr 30, 2001 |
|
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09830668 |
Apr 30, 2001 |
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PCT/EP99/08307 |
Oct 27, 1999 |
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Current U.S.
Class: |
514/217.1 ;
514/326; 514/370 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
35/02 20180101; A61P 31/12 20180101; A61P 11/00 20180101; A61P
17/06 20180101; C07D 417/12 20130101; C07D 471/04 20130101; C07D
277/48 20130101; A61P 13/08 20180101; A61P 37/00 20180101; C07D
417/14 20130101; A61P 25/28 20180101; A61P 35/04 20180101; C07D
471/10 20130101; C07D 277/62 20130101; A61P 19/02 20180101; A61P
43/00 20180101; A61P 35/00 20180101; A61P 13/12 20180101; C07D
491/10 20130101 |
Class at
Publication: |
514/217.1 ;
514/370; 514/326 |
International
Class: |
A61K 031/55; A61K
031/454; A61K 031/427 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 30, 1998 |
GB |
9823873.6 |
Claims
We claim:
1. A method of treating, arresting, alleviating, or reducing cell
proliferative disorders associated with an altered cell dependent
kinase activity in a patient comprising administering a
2-ureido-1,3-thiazole derivative of formula (I) 12wherein R is a
halogen atom, a nitro group, an optionally substituted amino group
or it is a group, optionally further substituted, selected from: i)
straight or branched C.sub.1-C.sub.6 alkyl; ii) C.sub.3-C.sub.6
cycloalkyl; iii) aryl or arylalkyl with from 1 to 6 carbon atoms
witliiii the straight or branched alkyl chain; R.sub.1 is an
optionally further substituted group selected from: i) straight or
branched C.sub.1-C.sub.6; ii) 3 to 6 membered carbocycle or 5 to 7
membered heterocycle ring; iii) aryl or arylcarbonyl; iv) arylalkyl
with from 1 to 6 carbon atoms within the straight or branched alkyl
chain; R.sub.2 is hydrogen, a straight or branched C.sub.1-C.sub.4
alkyl or C.sub.2-C.sub.4 alkenyl or alkynyl group; or, taken
together with the nitrogen atom to which they are bonded, R.sub.1
and R.sub.2 form a substituted or unsubstituted group selected
from: i) an optionally benzocondensed or bridged 5 to 7 membered
heterocycle; or ii) a 9 to 11 membered spiro-heterocyclic compound;
or a pharmaceutically acceptable salt thereof to the patient.
2. The method according to claim 1 wherein the cell proliferative
disorder is selected from the group consisting of cancer,
Alzheimer's disease, viral infections, auto-immune diseases or
neurodegenerative disorders.
3. The method according to claim 1 wherein cell proliferative
disorder is selected from the group consisting of a carcinoma,
squamous cell carcinoma, hematopoietic tumor of myeloid lineage,
hematopoietic tumor lymphoid lineage, tumor of mesenchymal origin,
tumor of the central nervous system, tumor of the peripheral
nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma,
xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer
and Kaposi's sarcoma.
4. The method according to claim 1 wherein the cell proliferative
disorder is selected from the group consisting of benign prostate
hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis,
psoriasis, vascular smooth cell proliferation associated with
atherosclerosis, pulmonary fibrosis, arthrithis glomerulonephritis
and post-surgical stenosis and restenosis.
5. 2-ureido-1,3-thiazole derivative of formula (I) 13wherein R is a
halogen atom, a nitro group, an optionally substituted amino group
or it is a group, optionally further substituted, selected from: i)
straight or branched C.sub.1-C.sub.6 alkyl; ii) C.sub.3-C.sub.6
cycloalkyl; iii) aryl or arylalkyl with from 1 to 6 carbon atoms
within the straight or branched alkyl chain; R.sub.1 is an
optionally further substituted group selected from: i) straight or
branched C.sub.1-C.sub.6 alkyl; ii) 3 to 6 membered carbocycle or 5
to 7 membered heterocycle ring; iii) aryl or arylcarbonyl; iv)
arylalkyl with from 1 to 6 carbon atoms within the straight or
branched alkyl chain; R.sub.2 is hydrogen, a straight or branched
C.sub.1-C.sub.4 alkyl or C.sub.2-C.sub.4 alkenyl or alkynyl group;
or, taken together with the nitrogen atom to which they are bonded,
R.sub.1 and R.sub.2 form a substituted or unsubstituted group
selected from: i) an optionally benzocondensed or bridged 5 to 7
membered heterocycle; or ii) a 9 to 11 membered spiro-heterocyclic
compound; or a pharmaceutically acceptable salt thereof; provided
that: a) when R is a chlorine atom and R.sub.2 is hydrogen, then
R.sub.1 is not methyl, phenyl or trifluoromethylphenyl; and b) when
R is methyl and R.sub.2 is hydrogen, then R.sub.1 is not
4-(5-oxazolyl)phenyl.
6. 2-amino-1,3-thiazole derivative of formula (I) 14wherein R is a
halogen atom, a nitro group, an optionally substituted amino group
or it is a group, optionally further substituted, selected from: i)
straight or branched C.sub.1-C.sub.6 alkyl; ii) C.sub.3-C.sub.6
cycloalkyl; iii) aryl or arylalkyl with from 1 to 6 carbon atoms
within the straight or branched alkyl chain; R.sub.1 is an
optionally further substituted group selected from: i) straight or
branched C.sub.1-C.sub.6 alkyl; ii) 3 to 6 membered carbocycle or 5
to 7 membered heterocycle ring; iii) aryl or arylcarbonyl; iv)
arylalkyl with from 1 to 6 carbon atoms within the straight or
branched alkyl chain; R.sub.2 is hydrogen, a straight or branched
C.sub.1-C.sub.4 alkyl or C.sub.2-C.sub.4 alkenyl or alkynyl group;
or, taken together with the nitrogen atom to which they are bonded,
R.sub.1 and R.sub.2 form a substituted or unsubstituted group
selected from: i) an optionally benzocondensed or bridged 5 to 7
membered heterocycle; or ii) a 9 to 11 membered spiro-heterocyclic
compound; or a pharmaceutically acceptable salt thereof, provided
that: a) when R is chlorine or bromine and R.sub.2 is hydrogen,
then R.sub.1 is not unsubstituted C.sub.1-C.sub.3 alkyl, phenyl,
trifluoromethylphenyl or an optionally substituted phenylcarbonyl;
b) when R is methyl and R.sub.2 is hydrogen, then R.sub.1 is not
methyl, phenyl or 4-(5-oxazolyl)phenyl; c) when R is nitrophenyl
and R.sub.2 is hydrogen, then R.sub.1 is not haloalkyl; d) when R
is bromine or chlorine, then R.sub.1 and R.sub.2 are not both
methyl groups.
7. The derivative according to claim 6, wvherein R is a halogen
atom, a straight or branched C.sub.1-C.sub.4 alkyl group, a phenyl
group, a cycloalkyl groulp; R.sub.2 is hydrogen and R.sub.1 is an
optionally substituted group selected from alkyl, aryl or
arylakyl.
8. The derivative according to claim 6, wherein R is a halogen atom
or is selected from the group consisting of nitro, amino,
alkylamino, hydroxyalkylamino, arylamino, C.sub.3-C.sub.6
cycloalkyl, straight or branched C.sub.1-C.sub.6 alkyl optionally
substituted by hydroxy, alkylthio, alkoxy, amino, alkylamino,
alkoxycarbonylalkylamino, alkylcarbonyl, alkylsulfonyl,
alkoxycarbonyl, carboxy, and aryl each optionally substituted by
one or more hydroxy, halogen, nitro, alkoxy, aryloxy, alkylthio,
arylthio, amino, alkylamino, dialkylamino, N-alkyl-piperazinyl,
4-morpholinyl, arylamino, cyano, alkyl, phenyl, aminosulfonyl,
aminocarbonyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or
carboxy, or R is an aryl group optionally substituted by one or
more hydroxy, halogen, nitro, alkoxy, aryloxy, alkylthio, arylthio,
amino, alkylamino, dialkylamino, N-alkyl-piperazinyl,
4-morpholinyl, arylamino, cyano, alkyl, phenyl, aminosulphonyl,
aminocarbonyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or
carboxy; R.sub.1 is a straight or branched C.sub.1-C.sub.6 alkyl
group or an aryl group, each optionally substituted as above
reported for R; R.sub.2 is a hydrogen atom; and pharmaceutically
acceptable salts thereof provided that: a) when R is chlorine or
bromine then R.sub.1 is not unsubstituted C.sub.1-C.sub.3 alkyl,
phenyl, trifluoromethylphenyl or an optionally substituted
phenylcarbonyl; b) when R is methyl then R.sub.1 is not methyl,
phenyl or 4-(5oxazolyl)phenyl; c) when R is nitrophenyl then
R.sub.1 is not haloalkyl.
9. A process for preparing the derivative according to claim 6,
comprising: a) reacting a compound of formula (II) when R.sub.2 is
a hydrogen atom 15with a compound of formula (III) wherein R is as
defined in claim 6 R.sub.1-NCO (III) wherein R.sub.1 is as defined
in claim 6; or b) reacting a compound of formula (IV) when R.sub.2
is as defined in claim 6 16with a compound of formula (V) wherein R
is as defined in claim 6 17wherein R.sub.1 and R.sub.2 are as
defined in claim 6; and optionally converting a
2-ureidol-3-thiazole derivative of formula (I) into another such
derivative of formula (I), a salt thereof, or a mixture thereof
10. A process for preparing the derivative according to claim 6,
comprising reacting a compound of formula (II) 18wherein R is as
defined in claim 6, with 4-nitrophenyl-chloroformate, or a polymer
supported form of it, thus obtaining a compound of formula (VI), or
a polymer supported form of it, 19wherein R is as defined in claim
6; and reacting a compound of formula (VI) with a compound of
formula (V) 20wherein R.sub.1 and R.sub.2 are as defined in claim
6; and optionally, converting a 2-ureidol-1,3-thiazole derivative
of formula (I), or a polymer supported form of it, into another
such derivative of formula (I), a salt thereof or a mixture
thereof.
11. A pharmaceutical composition comprising at least one
pharmaceutically acceptable carrier or diluent and the derivative
of formula (I) according to claim 1.
12. A method of treating, arresting, alleviating, or reducing tumor
angiogenesis and metastasis inhibition in a patient, comprising
administering a 2-ureido-1,3-thiazole derivative of formula (I)
21wherein R is a halogen atom, a nitro group, an optionally
substituted amino group or it is a group, optionally further
substituted, selected from: i) straight or branched C.sub.1-C.sub.6
alkyl; ii.) C.sub.3-C.sub.6 cycloalkyl; iii) aryl or arylalkyl with
from 1 to 6 carbon atoms within the straight or branched alkyl
chain; R.sub.1 is an optionally further substituted group selected
from: i) straight or branched C.sub.1-C.sub.6 ii) 3 to 6 membered
carbocycle or 5 to 7 membered heterocycle ring; iii) aryl or
arylcarbonyl; iv) arylalkyl with from 1 to 6 carbon atoms within
the straight or branched alkyl chain; R.sub.2 is hydrogen, a
straight or branched C.sub.1-C.sub.4 alkyl or C.sub.2-C.sub.4
alkenyl or alkynyl group; or, taken together with the nitrogen atom
to which they are bonded, R.sub.1 and R.sub.2 form a substituted or
unsubstituted group selected from: i) an optionally benzocondensed
or bridged 5 to 7 membered heterocycle; or ii) a 9 to 11 membered
spiro-heterocyclic compound; or a pharmaceutically acceptable salt
thereof to the patient.
13. A compound of formula (I) according to claim 5, whenever
appropriate in the form of pharmaceutically acceptable salts,
selected from the group consisting of: 1)
N-(5-isopropyl-1,3-thiaz-ol-2-yl)-N'-phenyl-urea; 2)
N-(5-bromo-1,3-thiazol-2-yl)-N'-phenyl-urea; 3)
N-(5-phenyl-1,3-thiazol-2- -yl)-N'-phenyl-urea; 4)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-phenyl-urea; 5)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-sulfamoyl-phenyl)-urea; 6)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-sulfamoyl-phenyl)-urea; 7)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-sulfamoyl-phenyl)-urea; 8)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-sulfamoyl-phenyl)-urea; 9)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-methoxy-phenyl)-urea; 10)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-methoxy-phenyl)-urea; 11)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-methoxy-phenyl)-urea; 12)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-methoxy-phenyl)-urea; 13)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-chloro-phenyl)-urea; 14)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-chloro-phenyl)-urea; 15)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-chloro-phenyl)-urea; 16)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-chloro-phenyl)-urea; 17)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-chloro-phenyl)-urea; 18)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-chloro-phenyl)-urea; 19)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-chloro-phenyl)-urea; 20)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-chloro-phenyl)-urea; 21)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-chloro-phenyl)-urea; 22)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(2-chloro-phenyl)-urea; 23)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(2-chloro-phenyl)-urea; 24)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(2-chloro-phenyl)-urea; 25)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-methoxy-phenyl)-urea; 26)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-methoxy-phenyl)-urea; 27)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-melthoxy-phenyl)-urea; 28)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-methoxy-phenyl)-urea; 29)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-hydroxy-phenyl)-urea; 30)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-hydroxy-phenyl)-urea; 31)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-hydroxy-phenyl)-urea; 32)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-hydroxy-phenyl)-urea; 33)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-hydroxy-phenyl)-urea; 34)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-hydroxy-phenyl)-urea; 35)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-hydroxy-phenyl)-urea; 36)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-hydroxy-phenyl)-urea; 37)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-methoxy-phenyl)-urea; 38)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(2-methoxy-phenyl)-urea; 39)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(2-methoxy-phenyl)-urea; 40)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(2-methoxy-phenyl)-urea; 41)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-hydroxy-phenyl)-urea; 42)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(2-hydroxy-phenyl)-urea; 43)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(2-hydroxy-phenyl)-urea; 44)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(2-hydroxy-phenyl)-urea; 45)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-nitro-phenyl)-urea; 46)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-nitro-phenyl)-urea; 47)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-nitro-phenyl)-urea; 48)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-nitro-phenyl)-urea; 49)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-amino-phenyl)-urea; 50)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-amino-phenyl)-urea; 51)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-amino-phenyl)-urea; 52)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-amino-phenyl)-urea; 53)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-nitro-phenyl)-urea; 54)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-nitro-phenyl)-urea; 55)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-nitro-phenyl)-urea; 56)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-nitro-phenyl)-urea; 57)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-amino-phenyl)-urea; 58)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-amino-phenyl)-urea; 59)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-amino-phenyl)-urea; 60)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-amino-phenyl)-urea; 61)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-benzyl-urea; 62)
N-(5-bromo-1,3-thiazol-2-yl)-N'-benzyl-urea; 63)
N-(5-phenyl-1,3-thiazol-- 2-yl)-N'-benzyl-urea; 64)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-benyzl-ure- - a; 65)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(pyrid-3-yl)-urea; 66)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(pyrid-3-yl)-urea; 67)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(pyrid-3-yl)-urea; 68)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(pyrid-3-yl)-urea; 69)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(pyrid-4-yl)-urea; 70)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(pyrid-4-yl)-urea; 71)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(pyrid-4-yl)-urea; 72)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(pyrid-4-yl)-urea; 73)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(pyrid-2-yl)-urea; 74)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(pyrid-2-yl)-urea; 75)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(pyrid-2-yl)-urea; 76)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(pyrid-2-yl)-urea; 77)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(benzothiophen-2-yl)-urea; 78)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(benzothiophen-2-yl)-urea; 79)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(benzothiophen-2-yl)-urea;
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(benzothiophen-2-yl)-urea;
80) N-(5-isopropyl-1,3-thiazol-2-yl)-4-morpholine carboxamide; 81)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-methlyphenyl)urea; 82)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-fluorophenyl)urea; 83)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-cyanophenyl)urea; 84)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-cyanophenyl)urea; 85)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,6-dimethylphenyl)urea; 86)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-fluorobenzyl)urea; 87)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-acetylphenyl)urea; 88)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-acetylphenyl)urea; 89)
3-({[(5-isopropyl-1,3-thiazol-2-yl)amino[carbonyl}amino)benzoic
acid; 90)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-isopropylphenyl)urea; 91)
3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzamide;
92) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-methoxybenzyl)urea; 93)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-butylphenyl)urea; 94)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-trifluromethylphenyl)urea;
95) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-3-bromophenyl)urea; 96)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-cyclohexylphenyl)urea; 97)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-phenoxyphenyl)urea; 98)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-benzyloxyphenyl)urea; 99)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,5-dimethylphenyl)urea; 100)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,3-dimethylphenyl)urea; 101)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-methoxy[1,1'-biphenyl]-4-yl)urea;
102)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-3,4-dihydro-2(1H)-isoquinoline
carboxamide; 103)
N-benzyl-N'-(5-isopropyl-1,3-thiazol-2-yl)-N-methylurea- -; 104)
N-(5-isopropyl-1,3-thiazol-2-yl)-6,7-dimethoxy-3,4-dihydro-2(1H)-i-
soquinoline carboxamide; 105)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(3-chlo-
r-o-4-methyl)-phenyl]urea; 106)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(3-ch-
lo-ro-6-methyl)phenyl]urea; 107)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,5-- dim-ethoxyphenyl)urea;
108) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,4-dimet-
hoxy-phenyl)urea; 109)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(2-methoxy-5-c-
hloro-)phenyl]urea; 110)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-((2-chloro-4--
methox-yphenyl)urea; 111)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,5-dichlor- ophenyl-)urea;
112) N-[(1,1'-biphenyl)-2-yl]-N'-(5-isopropyl-1,3-thiazol-2-
-yl)urea-; 113)
N-ethyl-N'-(5-isopropyl-1,3-thiazol-2-yl)-N-phenylurea; 114)
N-[4-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-2-methox-
yphen-yl]acetamide; 115)
2-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl-
}amino-)-N-phenylbenzamide 116)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-mor- pholino-phenyl)urea;
117) N-[41-({[(5-isopropyl-1,3-thiazol-2-yl)amino]car-
bonyl}am-ino)phenyl]-N-methyl acetamide; 118)
N-[2-{[cyclohexyl(methyl)ami-
no]methyl-}phenyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea; 119)
N-[3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-4-methoxyphen-
-yl]acetamide; 120)
N-(5-isopropyl-1,3-thiazol-2-yl)-4-(4-methoxyphenyl)-1- -piperazine
carboxamide; 121) N-(2-furylmethyl)-N'-(5-isopropyl-1,3-thiazo-
l-2-yl)urea; 122)
N-(4-fluorophenyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea- ; 123)
N-(2-methoxybenzyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea; 124)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]ure-
-a; 125)
N-(3,4-dimethoxybenzyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea; 126)
N-(5-isopropyl-1,3-thiazol-2-yl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.-
5]decane-8-carboxamide; 127)
n-(5-isopropyl-1,3-thiazol-2-yl)-1,4-dioxa-8--
azaspiro[4.5]decane-8-carboxamide; 128)
N-(5-isopropyl-1,3-thiazol-2-yl)-N- -
'-[2-(1-piperidinyl)ethyl]urea; 129)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-
-[-2-(1-morpholinyl)ethyl]urea; 130)
4-(4-flurorphenyl)-N-(5-isopropyl-1,3- -th-
iazol-2-yl)-1-piperazine carboxamide; 131)
N-[4-(4-chlorophenyl)-3-et-
hyl-5-isoxazolyl]-N'-(5-isopropyl-1,3-thiazol-2-yl)urea; 132)
4-[(4-fluorophenyl)(hydroxy)methyl]-N-(5-isopropyl-1,3-thiazol-2-yl)-1-pi-
-peridine carboxamide; 133)
N-(3-ethynylphenyl)-N'-(5-isopropyl-1,3-thiazo- l-2-yl)urea; 134)
N-(2-methoxy-3-fluorophenyl)-N'-(5-isopropyl-1,3-thiazol-
-2-yl)urea; 135)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-oxo-1-piperidinyl)- u-rea;
136) N-(3-acetylaminophenyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
137)
N-[3-(2-furyl)-1H-pyrazol-5-yl]-N'-(5-isopropyl-1,3-thiazol-2-yl)ure-
-a; 138)
N-{4-[ethyl(isopropyl)amino]phenyl}-N'-(5-isopropyl-1,3-thiazol-2-
-yl)urea; 139)
N-(1,3-benzodioxol-5-yl)-N'-(5-isopropyl-1,3-thiazol-2-yl)u- r-ea;
140)
5-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-1-phen-
yl-1H-pyrazole-4-carboxamide; 141)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-- py-ridinylmethyl)urea;
142) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-pyrazin- yl)-urea; 143)
n-(5-isopropyl-1,3-thiazol-2-yl)-N'-(5-phenyl-1,3,4-oxadiaz-
ol-2-yl)urea; 144)
N-(5-isopropyl-1,3-thiazol-2-yl)-4-(2-oxo-2,3-dihydro-1-
H-benzimidazol-1-yl)-1-piperidine carboxamide; 145)
N-(1,3-benzothiazol-6-yl) N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
146)
N-(1,3-dimethyl-1H-pyrazol-5-y-l)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
147)
N-(3-phenyl-1-methyl-1H-pyr-azol-5-yl)-N'-(5-isopropyl-1,3-thiazol-2-
-yl)urea; 148)
N-(5-isopropyl-1,3-thiazol-2-yl)-3-hydroxy-1-piperidine
carboxamide; 149)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-methyl-1,3-dioxo-
-2,3-dihydro-1H-is-oindol-5-yl)urea; 150)
N-(3-isopropyl-1,3-thiazol-2-yl)- -4-benzyl-1-piperaz-ine
carboxamide; 151) N-(5-isopropyl-1,3-thiazol-2-yl)-
-4-methyl-1-piperazi-ne carboxamide; 152)
4-hydroxy-N-(5-isopropyl-1,3-thi- azol-2-yl)-1-piperidi-ne
carboxamide; 153) N-(5-isopropyl-1,3-thiazol-2-yl-
)-3-azabicyclo[3.2.2]n-onane-3-carboxamide; 154)
N-(5-isopropyl-1,3-thiazo- l-2-yl)-4-(4-acetylphen-yl)-1-piperazine
carboxmide; 155)
4-[bis(4-fluorophenyl)-N-(5-isopropyl-1,-3-thiazol-2-yl)-1-piperazine
carboxamide; 156)
N-(5-isopropyl-1,3-thiazol-2-yl)-4-oxo-2,3,4,5-tetrahyd-
ro-1H-1,5-benzodiazepine-1-carboxamide; 157)
N-(5-isopropyl-1,3-thiazol-2--
yl)-N'-(5,6,7,8-tetrahydro-1-naphtalenyl)ure-a; 158)
N-(4-phenyl-2-thiazolyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
159)
4-(4-fluorobenzoyl)-N-(5-isopropyl-1,3-thiazol-2-yl)-1-piperidine
carboxamide; 160)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-1,3-dihydro-2-benzo-
-furan-5-yl)urea; 161)
N-(5-isopropyl-1,3-thiazol-2-yl)-4'-(2-pyrimidinyl-- 1-piperazine
carboxamide; 162) N-(5-isopropyl-1,3-thiazol-2-yl)-3-oxo-3,4--
dihydro-1(2H)-quinoxaline; 163)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(1H-in- -dazol-6-yl)urea; 164)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-chlorobenzyl- )-urea; 165)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,4-dichlorobenzyl)urea; 166)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-flurobenzyl)urea; 167)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,4-dichlorobenzyl)urea; 168)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,4-difluorobenzyl)urea; 169)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,5-difluorobenzyl)urea; 170)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-2,6-difluorobenzyl)urea; 171)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(4-hydroxy-3-methoxy)benzyl]urea;
172) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(5-methyl-2-furyl)urea;
173)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-methylsulfonylbenzyl)urea;
174)
N-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-N'-(5-isopropyl-1,3-thiaz-
-ol-2-yl)urea; 175)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-chlorobenzyl)ur- e-a; 176)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-pyridinylmethyl)urea; 177)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,5-dimethoxybenzyl)urea; 178)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-pyridinylmethyl)urea; 179)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-trifluorobenzyl)urea; 180)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,4,5-trimethoxybenzyl)urea;
181) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,4-dimethoxybenzyl)urea;
182)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-dimethylaminobenzyl)urea;
183) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,5-dimethoxybenzyl)urea;
184)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(2-chloro-6-phenoxy)benzyl]urea;
185)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(1R,2S)-2-hydroxy-2,3-dihydro-1-
-H-inden-1-yl]urea; 186)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(3-hydroxy-4-
-methyl)phenyl]urea; 187)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[4-(1H-benzi-
m-idazol-2-yl)phenyl]urea; 188)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-phe-
ny-l-1H-pyrazol-5-yl)urea; 189)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-met- hyl-6-quinolinyl)urea;
190) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[4-(cyanom-
eth-yl)phenyl]urea; 191)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-quinolinyl- )ure-a; 192)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(1-oxo-2,3-dihydro-1H-ind-
en-5-yl)urea; 193)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-oxo-1,3-dihydro--
2-ben-zofuran-5-yl)urea; 194)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(5-oxo-5-
,6,7,8-tetrahydro-2-naphtalenyl)urea; 195)
methyl-3-(<[(5-isopropyl-1,3-
-thiaz-ol-2-yl)amino]carbonyl}amino)-4-methylbenzoate; 196)
methyl-4-(<[(5-isopropyl-1,3-thiazol-2-yl)arnino]carbonyllamino)-3-met-
h-ylbenzoate; 197) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-imidazo
[1,2-a]pyri-din-2-yl-phenyl)urea; 198)
ethyl-4-(<[(5-isopropyl-1,3-thi-
azol-2-yl)amino]carbonyl}amino)benzoate; 199)
(2R)-1-benzyl-2-(<[(5-iso-
propyl-1,3-th-iazol-2-yl)amino]carbonyl}amino)propanamide; 201)
2-chloro-5-({[(5-isoprop-yl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzoic
acid; 202)
3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzoi- c
acid; 203)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(5-methyl-3-isoxazolyl)ur- ea;
204) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,6-dimethoxyphenyl)urea;
205) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,3-dmethoxybenzyl)urea;
206) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,4-difluorobenzyl)urea;
207) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,4-dimethylphenyl)urea;
208)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(1H-benzimidazol-5-yl)urea;
209)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(R)-phenylglicinamido]urea;
210) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-phenoxyacetamido)urea;
211)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(S)-phenylglicinamido}urea;
212)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-{2-[(1-methyl-1H-imidazol-2-yl)methox-
-y]phenyl}urea; 213)
N-(3-iodophenyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)ure- a-; 214)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[3-(3-methoxy-1-propnyl)pheny-
l]-urea; 215)
N-{3-[3-(dimethylamino)-1-propynyl)phenyl}-N'-(5-isopropyl-1-
,3-thiazol-2-yl)urea; 216)
N-[4-({[(5-isopropyl-1,3-thiazol-2-yl)amino]car-
bon-yl}amino)phenyl]methanesulfonamide; 217)
2-[3-({[(5-isopropyl-1,3-thia-
zol-2-yl)amino]carbonyl}amino)anilino]acetamide; 218)
N-[3-(3-hydroxy-1-butyny-l)phenyl]-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
219)
N-(imidazo[1,2-a]pyridin-2-yl-methyl)-N'-(5-isopropyl-1,3-thiazol-2--
yl)ur-ea; 220)
2-{[{[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}(2-propy-
nyl)amino]methyl}benzenesulfonamide; 221)
N-(1H-indol-6yl)-N'-(5-isopropyl- -1,3-t-hiazol-2-yl)urea; 222)
N-[(1S)-2-hydroxy-1-phenylethyl]-N'-(5-isopr-
opyl-1,-3-thiazol-2-yl)urea; 223)
N-(1H-indol-5-yl)-N'-(5-isopropyl-1,3-th- iazol-2-yl)urea; 224)
N-[(1R-2-hydroxy-1-phenylethyl]-N'-(5-isopropyl-1,3--
thiazol-2-yl)urea; 225)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-butylurea; 226)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-benzoylurea; 227)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,6-dimethylphenyl)urea; 228)
N-(5-methyl-1,3-thiazol-2-yl)-N'-benzylurea; 229)
N-(5-methyl-1,3-thiazol- -2-yl)-N'-butylurea; 230)
N-(5-methyl-1,3-thiazol-2-yl)-4-morpholinecarbox- -amide; 231)
N-(5-methyl-1,3-thiazol-2-yl)-N'-phenylurea; 232)
N-(5-methyl-1,3-thiazol-2-yl)N'-(4-methoxybenzylurea; 233)
N-(5-methyl-1,3-thiazol-2-yl)-N'-(4-fluorophenyl)urea; 234)
N-[(1-ethyl-2-pyrrolidinyl)methyl]-N'-(5-methyl-1,3-thiazol-2-yl)urea;
235)
N-(5-methyl-1,3-thiazol-2-yl)-N'-(5-hydroxy-1H-pyrazol-3-yl)urea;
236) N-(5-methyl-1,3-thiazol-2-yl)-N'-(3-pyridinyl)urea; 237)
N-(4-fluorophenyl)-N'-(5-methyl-1,3-thiazol-2-yl)urea.
14. The method according to claim 1, wherein the optionally
substituted group of R, R.sub.1, and R.sub.2 of formula (I) is
optionally substituted with at least one member selected from the
group consisting of halogen, nitro, oxo, carboxy, cyano, alkyl,
perfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
heterocyclyl, amino, alkylamino, alkoxycarbonylalkylamino,
dialkylamino, arylamino, diarylamino, alkylsulfonylamino,
arylureido, carbonylamino groups, formylamino, alkylcarbonylamino,
alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino,
oxygen-substituted oximes, alkoxycarbonylalkoxyimino- ,
alkoxyimino, hydroxy, alkoxy, aryloxy, alkylcarbonyloxy,
arylcarbonyloxy, cycloalkenyloxy, carbonyl, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthio, arylthio, alkylsulphonyl,
arylsulphonyl, alkylsulphinyl, arylsulphinyl, arylsulphonyloxy,
aminosulfonyl, alkylaminosulphonyl, and dialkylaminosulphonyl.
15. The derivative according to claim 6, wherein the optionally
substituted group of R, R.sub.1, and R.sub.2 of formula (I) is
opptionally substituted with at least one member selected from the
group consisting of halogen, nitro, oxo, carboxy, zyan, alkyl,
perfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
heterocyclyl, amino, alkylamino, alkoxycarbonylalkylamino,
dialkylamino, arylamino, diarylamino, alkylsulfonylamino,
arylureido, carbonylamino groups, formylamino, alkycarbonylamino,
alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino,
oxygen-substituted oximes, alkoxycarbonylalkoxyimino- ,
alkoxyimino, hydroxy, alkoxy, aryloxy, alkylcarbonyloxy,
arylcarbonyloxy, cycloalkenyloxy, carbonyl, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthio, arylthio, alkylsulphonyl,
arylsulphonyl, alkylsulphinyl, arylsulphinyl, arylsulphonyloxy,
aminosulfonyl, alkylaminosulphonyl, and dialkylaminosulphonyl.
16. The derivative according to claim 6, wherein the optionally
substituted group of R, R.sub.1, and R.sub.2 of formula (I) is
optionally substituted with at least one member selected from the
group consisting of halogen, nitro, oxo, carboxy, cyano, alkyl,
perfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
heterocyclyl, amino, alkylamino, alkoxycarbonylalkylamino,
dialkylamino, arylamino, diarylamino, alkylsulfonylamino,
arylureido, carbonylamino groups, formylamino, alkylcarbonylamino,
alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino,
oxygen-substituted oximes, alkoxycarbonylalkoxyimino- ,
alkoxyimino, hydroxy, alkoxy, aryloxy, alkylcarbonyloxy,
arylcarbonyloxy, cycloalkenyloxy, carbonyl, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthio, arylthio, alkylsulphonyl,
arylsulphonyl, alkylsulphinyl, arylsulphinyl, arylsulphonyloxy,
aminosulfonyl, alkylaminosulphonyl, and dialkylaminosulphonyl.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 09/830,668, filed Apr. 30, 2001, which is a 371 of
PCT/EP99/08307, filed Oct. 27, 1999, which claims priority to GB
9823873.6, filed Oct. 30, 1998. The entirety of each of these
applications are hereby incorporated by reference herein for all
purposes.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to 2-ureido-thiazole
derivatives and, more in particular, it relates to
2-ureidol-1,3-thiazoles, to a process for their preparation, to
pharmaceutical compositions containing them and to their use as
therapeutic agents, particularly in the treatment of cancer and
cell proliferative disorders.
[0004] 2. Description of the Related Art
[0005] Several cytotoxic drugs such as, e.g. fluorouracil (5-FU),
doxorubicin and camptothecins result to damage DNA or to affect
cellular metabolic pathways and thus cause, in many cases, an
indirect block of the cell cycle.
[0006] Therefore, by producing an irreversible damage to both
normal and tumor cells, these agents result in a significant
toxicity and side-effects.
[0007] In this respect, compounds capable of being highly specific
antitumor agents by selectively leading to tumor cell arrest and
apoptosis, with comparable efficacy but reduced toxicity than the
currently available drugs, are desirable.
[0008] It is well known in the art that progression through the
cell cycle is governed by a series of checkpoint controls,
otherwise referred to as restriction points, which are regulated by
a family of enzymes known as the cyclin-dependent kinases
(cdk).
[0009] In their turn, the cdks themselves are regulated at many
levels such as, for instance, binding to cyclins.
[0010] A normal progression through the cell cycle is controlled by
the coordinated activation and inactivation of different cyclin/cdk
complexes. In G1, both cyclin D/cdk4 and cyclin E/cdk2 are thought
to mediate the onset of S-phase. Progression through S-phase
requires the activity of cyclin A/cdk2 whereas the activation of
cyclin A/cdc2 (cdk1) and cyclin B/cdc2 are required for the onset
of metaphases.
[0011] For a general reference to cyclins and cyclin-dependent
kinases see, for instance, Kevin R. Webster et al. in Exp. Opin.
Invest. Drugs, 1998, Vol. 7(6), 865-887.
[0012] Checkpoint controls are defective in tumor cells due, in
part, to disregulation of cdk activity. For example, altered
expression of cyclin E and cdk's has been observed in tumor cells,
and deletion of the cdk inhibitor p27 KIP gene in mice has been
shown to result in a higher incidence of cancer.
[0013] Increasing evidence supports the idea that the cdks are
rate-limiting enzymes in cell cycle progression and, as such,
represent molecular targets for therapeutic intervention. In
particular, the direct inhibition of cdk/cyclin kinase activity
should be helpful in restricting the unregulated proliferation of a
tumor cell.
BRIEF SUMMARY OF THE INVENTION
[0014] It has now been found that the 2-ureidol-1,3-thiazoles of
the invention are endowed with cdk/cyclin kinase inhibitory
activity and are thus useful in therapy as antitumor agents whilst
lacking, in terms of both toxicity and side effects, the
aforementioned drawbacks known for currently available antitumor
drugs.
[0015] More specifically, the compounds of this invention are
useful in the treatment of a variety of cancers including, but not
limited to: carcinoma such as bladder, breast, colon, kidney,
liver, lung, including small cell lung cancer, esophagus,
gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate,
and skin, including squamous cell carcinoma; hematopoietic tumors
of lymphoid lineage, including leukemia, acute lymphocitic
leukemia, acute lymphoblastic leukemia, B-cell lymphoma,
T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy
cell lymphoma and Burkett's lymphoma; hematopoietic tumors of
myeloid lineage, including acute and chronic myelogenous leukemias,
myelodysplastic syndrome and promyelocytic leukemia; tumors of
mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;
tumors of the central and peripheral nervous system, including
astrocytoma, neuroblastoma, glioma and schwannomas; other tumors,
including melanoma, seminoma, teratocarcinoma, osteosarcoma,
xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer
and Kaposi's sarcoma.
[0016] Due to the key role of cdks in the regulation of cellular
proliferation, these 2-ureido-1,3-thiazole derivatives are also
useful in the treatment of a variety of cell proliferative
disorders such as, for instance, benign prostate hyperplasia,
familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis,
vascular smooth cell proliferation associated with atherosclerosis,
pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical
stenosis and restenosis.
[0017] The compounds of the invention can be useful in the
treatment of Alzheimer's disease, as suggested by the fact that
cdk5 is involved in the phosphorylation of tau protein (J.
Biochem., 117, 741-749, 1995).
[0018] The compounds of this invention, as modulators of apoptosis,
could be useful in the treatment of cancer, viral infections,
prevention of AIDS development in HIV-infected individuals
autoimmune diseases and neurodegenerative disorder.
[0019] The compounds of this invention could be useful in
inhibiting tumor angiogenesis and metastasis.
[0020] The compounds of this invention may also act as inhibitors
of other protein kinases, e.g. protein kinase C, her2, raf1, MEK1,
MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase,
weel kinase, Src, Ab1 and thus be effective in the treatment of
diseases associated with other protein kinases.
[0021] Several 2-ureido-1,3-thiazole derivatives are known in the
art, particularly as herbicides or as synthetic intermediates for
preparing herbicides [see, for a general reference, U.S. Pat. No.
3,726,891 in the name of Shell Co., and C.A. 83(1975):114381].
[0022] Just few examples among them are N'methyl- and
N'-ehtyl-N-(5-bromo-2-thiazolyl)-urea; N'-methyl-, N'-ethyl- or
N'-phenyl-N-(5-chloro-2-thiazolyl)-urea;
N-(5-chloro-2-thiazolyl)-N',N'-d- -imethyl-urea;
N-(5-bromo-2-thiazolyl)-N',N'-dimethyl-urea; N'-methyl- and
N'-phenyl-N-(5-methyl-2-thiazolyl)-urea.
[0023] Other 2-ureido-1,3-thiazole derivatives have been described
in the art as therapeutic agents.
[0024] Among them are N-methyl- and
N-phenyl-N'-(5-chloro-2-thiazolyl)-ure- -a which have been
described as sedative and antiinflammatory agents in FR N. 7428
(Melle-bezons) or N-[4-(5-oxazolyl)phenyl]-N'-(5-methyl-2-thiazol-
-yl)-urea, described as inosine 5'-monophosphate dehydrogenase
inhibitor (IMFDH) in WO 97/40028 (Vertex Pharmaceuticals Inc.).
DETAILED DESCRIPTION OF THE INVENTION
[0025] Accordingly, the present invention provides the use of a
compound which is a 2-ureido-1,3-thiazole derivatives of formula
(I) 1
[0026] wherein
[0027] R is a halogen atom, a nitro group, an optionally
substituted amino group or it is a group, optionally further
substituted, selected from:
[0028] i) straight or branched C.sub.1-C.sub.6 alkyl;
[0029] ii) C.sub.3-C.sub.6 cycloalkyl;
[0030] iii) aryl or arylalkyl with from 1 to 6 carbon atoms within
the straight or branched alkyl chain;
[0031] R.sub.1 is an optionally further substituted group selected
from:
[0032] i) straight or branched C.sub.1-C.sub.6 alkyl;
[0033] ii) 3 to 6 membered carbocycle or 5 to 7 membered
heterocycle ring;
[0034] iii) aryl or arylcarbonyl;
[0035] iv) arylalkyl with from 1 to 6 carbon atoms within the
straight or branched alkyl chain;
[0036] R.sub.2 is hydrogen, a straight or branched C.sub.1-C.sub.4
alkyl or C.sub.2-C.sub.4 alkenyl or alkynyl group; or, taken
together with the nitrogen atom to which they are bonded,
[0037] R.sub.1 and R.sub.2 form a substituted or unsubstituted
group selected from:
[0038] i) an optionally benzocondensed or bridged 5 to 7 membered
heterocycle; or
[0039] ii) a 9 to 11 membered spiro-heterocyclic compound; or a
pharmaceutically acceptable salt thereof; in the manufacture of a
medicament for treating cell proliferative disorders associated
with an altered cell dependent kinase activity.
[0040] According to a preferred embodiment of the invention, the
said cell proliferative disorder is selected from the group
consisting of cancer, Alzheimer's disease, viral infections,
autoimmune diseases or neurodegenerative disorders.
[0041] Preferably, the cancer is selected from the group consisting
of carcinoma, squamous cell carcinoma, hematopoietic tumors of
myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors
of the central and peripheral nervous system, melanoma, seminoma,
teratocarcinoma, osteosarcoma, xenoderoma pigmentosum,
keratoctanthoma, thyroid follicular cancer and Kaposi's
sarcoma.
[0042] According to another preferred embodiment of the invention,
the cell proliferative disorder is selected from the group
consisting of benign prostate hyperplasia, familial adenomatosis
polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell
proliferation associated with atherosclerosis, pulmonary fibrosis,
arthritis glomerulonephritis and post-surgical stenosis and
restenosis.
[0043] In addition, being useful in the treatment of cell
proliferative disorders associated with an altered cell dependent
kinase activity, hence cell cycle inhibition or cdk/cyclin
dependent inhibition, the compounds of formula (I) of the invention
also enable tumor angiogenesis and metastasis inhibition.
[0044] As above reported, some of the compounds of formula (I) of
the invention have been reported in the art as useful therapeutic
agents, for instance as antiinflaimmatory, sedative and analgesic
agents.
[0045] Therefore, it is a further object of the present invention a
compound which is a 2-ureido-1,3-thiazole derivative of formula (I)
2
[0046] wherein
[0047] R is a halogen atom, a nitro group, an optionally
substituted amino group or it is a group, optionally further
substituted, selected from:
[0048] i) straight or branched C.sub.1-C.sub.6 alkyl;
[0049] ii) C.sub.3-C.sub.6 cycloalkyl;
[0050] iii) aryl or arylalkyl with from 1 to 6 carbon atoms within
the straight or branched alkyl chain;
[0051] R.sub.1 is an optionally further substituted group selected
from:
[0052] i) straight or branched C.sub.1-C.sub.6 alkyl;
[0053] ii) 3 to 6 membered carbocycle or 5 to 7 membered
heterocycle ring;
[0054] iii) aryl or arylcarbonyl;
[0055] iv) arylalkyl with from 1 to 6 carbon atoms within the
straight or branched alkyl chain;
[0056] R.sub.2 is hydrogen, a straight or branched C.sub.1-C.sub.4
alkyl or C.sub.2-C.sub.4 alkenyl or alkynyl group; or, taken
together with the nitrogen atom to which they are bonded,
[0057] R.sub.1 and R.sub.2 form a substituted or unsubstituted
group selected from:
[0058] i) an optionally benzocondensed or bridged 5 to 7 membered
heterocycle; or
[0059] ii) a 9 to 11 membered spiroheterocyclic compound; or a
pharmaceutically acceptable salt thereof; for use as a inedicament;
provided that:
[0060] a) when R is a chlorine atom and R.sub.2 is hydrogen, then
R.sub.1 is not methyl, phenyl or trifluoromethylphenyl; and
[0061] b) when R is methyl and R.sub.2 is hydrogen, then R.sub.1 is
not 4-(5-oxazolyl)phenyl.
[0062] Among the compounds of formula (I) above reported, several
derivatives result to be novel.
[0063] Therefore, the present invention further provides a compound
which is a 2-amino-1,3-thiazole derivative of formula (I) 3
[0064] wherein
[0065] R is a halogen atom, a nitro group, an optionally
substituted amino group or it is a group, optionally further
substituted, selected from:
[0066] i) straight or branched C.sub.1-C.sub.6 alkyl;
[0067] iii) C.sub.3-C.sub.6 cycloalkyl;
[0068] iv) aryl or arylalkyl with from 1 to 6 carbon atoms within
the straight or branched alkyl chain;
[0069] R.sub.1 is an optionally further substituted group selected
from:
[0070] i) straight or branched C.sub.1-C.sub.6 alkyl;
[0071] ii) 3 to 6 membered carbocycle or 5 to 7 membered
heterocycle ring;
[0072] iii) aryl or arylcarbonyl;
[0073] iv) arylalkyl with from 1 to 6 carbon atoms within the
straight or branched alkyl chain;
[0074] R.sub.2 is hydrogen, a straight or branched C.sub.1-C.sub.4
alkyl or C.sub.2-C.sub.4 alkenyl or alkynyl group; or, taken
together with the nitrogen atom to which they are bonded,
[0075] R.sub.1 and R.sub.2 form a substituted or unsubstituted
group selected from:
[0076] i) an optionally benzocondensed or bridged 5 to 7 membered
heterocycle; or
[0077] ii) a 9 to 11 membered spiro-heterocyclic compound; or a
pharmaceutically acceptable salt thereof; provided that:
[0078] a) when R is chlorine or bromine and R.sub.2 is hydrogen,
then R.sub.1 is not unsubstituted C.sub.1-C.sub.3 alkyl, phenyl,
trifluoromethylphenyl or an optionally substituted
phenylcarbonyl;
[0079] b) when R is methyl and R.sub.2 is hydrogen, then R.sub.1 is
not methyl, phenyl or 4-(5-oxazolyl)phenyl;
[0080] c) when R is nitrophenyl and R.sub.2 is hydrogen, then
R.sub.1 is not haloalkyl;
[0081] d) when R is bromine or chlorine, then R.sub.1 and R.sub.2
are not both methyl groups.
[0082] The compounds of formula (I) may have asymmetric carbon
atoms and may therefore exist either as racemic admixtures or as
individual optical isomers.
[0083] Accordingly, all the possible isomers and their admixtures
and of both the metabolites and the pharmaceutically acceptable
bioprecursors (otherwise referred to as prodrugs) of the compounds
of formula (I), as well as the uses thereof, are also within the
scope of the present invention.
[0084] In the present description, unless otherwise specified, with
the term halogen atom we intend a chlorine, bromine, fluorine or
iodine atom
[0085] With the term optionally substituted amino group we intend
an amino group wherein one or both hydrogen atoms are optionally
replaced by other substituents which are the same or different, as
set forth below.
[0086] With the term straight or branched C.sub.1-C.sub.6 alkyl we
intend a group such as, for instance, methyl, ethyl, n.propyl,
isopropyl, n.butyl, isobutyl, sec-butyl, tert-butyl, n.pentyl,
n.hexyl and the like.
[0087] With the term straight or branched C.sub.2-C.sub.4 alkenyl
or alkynyl group we intend a group such as, for instance, vinyl,
allyl, isopropenyl, 1-, 2- or 3-butenyl, isobutylenyl, ethynyl, 1-
or 2-propynyl, butynyl and the like.
[0088] With the term C.sub.3-C.sub.6 cycloalkyl we intend a
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
[0089] With the term aryl, either as such or as arylalkyl,
arylcarbonyl and the like, we intend a mono-, bi- or poly- either
carbocyclic as well as heterocyclic hydrocarbon with from 1 to 4
ring moieties, either fused or linked to each other by single
bonds, wherein at least one of the carbocyclic or heterocyclic
rings is aromatic.
[0090] Examples of aryl groups are phenyl, biphenyl, .alpha.- or
.beta.-naphthyl, tetrahydronaphthyl, indenyl, dihydroindenyl,
pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl,
dihydroisoindolyl, imidazolyl, imidazopyridyl, benzimidazolyl,
dihydrobenzimidazolyl, 1,2-methylenedioxyphenyl, thiazolyl,
isothiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, furyl,
benzotetrahydrofuranyl, benzofuranyl, dihydrobenzofuranyl,
oxazolyl, isoxazolyl, thienyl, benzothienyl, tetrazolyl,
quinolinyl, isoquinolinyl, dihydroisoquinolinyl, quinoxalinyl,
dihdroquinoxalinyl, oxadiazolyl, tetrahydrobenzodiazepin-yl and the
like.
[0091] With the term 3 to 6 membered carbocycle, hence encompassing
but not limited to C.sub.3-C.sub.6 cycloalkyl groups, we also
intend an unsaturated carbocyclic hydrocarbon such as, for
instance, cyclopentylene or cyclohexylene.
[0092] With the term 5 to 7 membered heterocycle, hence
encompassing aromatic heterocycles also referred to as aryl groups,
we further intend a saturated or partially unsaturated 5 to 7
membered carbocycle wherein one or more carbon atoms are replaced
by heteroatoms such as nitrogen, oxygen and sulphur.
[0093] Examples of 5 to 7 membered heterocycles, optionally
benzocondensed or further substituted, are 1,3-dioxolane, pyran,
pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline,
piperidine, piperazine, N-alkyl-piperazine, morpholine,
tetrahydrofuran, and the like.
[0094] With the term bridged heterocycles we intend a system at
least comprising two rings, one of which being a nitrogen
containing heterocycle, having two or more atoms in common such as,
for instance, azabicyclo[3.2.2]nonane.
[0095] With the term 9 to 11 membered spiro heterocycle we intend a
system at least comprising two rings, one of which being a nitrogen
containing heterocycle, having one carbon atom in common such as,
for instance, 1,4-dioxa-8-azaspro[4.5]decane and
1,3,8-triazaspiro[4.5]decane.
[0096] According to the above indicated substituent meanings, any
of the above R, R.sub.1 and R.sub.2 groups may be optionally
substituted in any of the free positions by one or more groups, for
instance 1 to 6 groups, selected from: halogen, nitro, oxo groups
(.dbd.O), carboxy, cyano, alkyl, perfluorinated alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, heterocyclyl, amino groups and
derivatives thereof such as, for instance, alkylamino,
alkoxycarbonylalkylamino, dialkylamino, arylamino, diarylamino,
alkylsulfonylamino or arylureido; carbonylamino groups and
derivatives thereof such as, for instance, formylamino,
alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino,
alkoxycarbonylamino; oxygen-substituted oximes such as, for
instance, alkoxycarbonylalkoxyimino or alkoxyimino; hydroxy groups
and derivatives thereof such as, for instance, alkoxy, aryloxy,
alkycarbonyloxy, arylcarbonyloxy, cycloalkenyloxy; carbonyl groups
and derivatives thereof such as, for instance, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl; sulfurated derivatives such as, for instance,
alkylthio, arylthio, alkylsulphonyl, arylsulphonyl, alkylsulphinyl,
arylsulphinyl, arylsulphonyloxy, aminosulfonyl, alkylaminosuiphonyl
or dialkylaminosulphonyl. In their turn, whenever appropriate, each
of the above possible substituents on R, R.sub.1 and R.sub.2 may be
further substituted by one or more of the aforementioned
groups.
[0097] Examples of compounds of formula (I) wherein P, R.sub.1 and
R.sub.2 groups are substituted by one or more of the aforementioned
substituents which, in their turn, are optionally further
substituted as set forth above, are given below.
[0098] Pharmaceutically acceptable salts of the compounds of
formula (I) are the acid addition salts with inorganic or organic,
e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric,
phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic,
oxalic, malonic, malic, maleic, tartaric, citric, benzoic,
cinnamic, mandelic, methanesuiphonic, isethionic and salicylic
acid, as well as the salts with inorganic or organic bases, e.g.
alkali or alkaline-earth metals, especially sodium, potassium,
calcium or magnesium hydroxides, carbonates or bicarbonates,
acyclic or cyclic amines, preferably methylamine, ethylamine,
diethylamine, triethylamine or piperidine.
[0099] The compounds of formula (I) may have asymmetric carbon
atoms and may therefore exist either as racemic admixtures or as
individual optical isomers.
[0100] Accordingly, the use as an antitumor agent of all the
possible isomers and their admixtures and of both the metabolites
and the pharmaceutically acceptable bio-precursors (otherwise
referred to as pro-drugs) of the compounds of formula (I) are also
within the scope of the present invention.
[0101] Preferred compounds of the invention are the compounds of
formula (I) wherein R is a halogen atom, a straight or branched
C.sub.1-C.sub.4 alkyl group, a phenyl or a cycloalkyl group;
R.sub.2 is hydrogen and R.sub.1 is an optionally substituted group
selected from alkyl, aryl or arylakyl.
[0102] Even more preferred, within this class, are the compounds of
formula (I) wherein R is bromine or chlorine, a straight or
branched C.sub.1-C.sub.4 alkyl group, a phenyl or a cycloalkyl
group; R.sub.2 is hydrogen and R.sub.1 is an optionally substituted
aryl or an arylalkyl or heterocyclyl-alkyl group with from 1 to 4
carbon atoms within the alkyl chain.
[0103] Another class of preferred compounds of the invention are
compounds of formula (I) 4
[0104] wherein
[0105] R is a halogen atom or is selected from the group consisting
of nitro, amino, alkylamino, hydroxyalkylamino, arylamino,
C.sub.3-C.sub.6 cycloalkyl, straight or branched C.sub.1-C.sub.6
alkyl optionally substituted by hydroxy, alkylthio, alkoxy, amino,
alklamino, alkoxycarbonylalkylamino, alkylcarbonyl, alkylsulfonyl,
alkoxycarbonyl, carboxy, aryl optionally substituted by one or more
hydroxy, halogen, nitro, alkoxy, aryloxy, alkylthio, arylthio,
amino, alkylamino, dialkylamino, N-alkyl-piperazinyl,
4-morpholinyl, arylamino, cyano, alkyl, phenyl, aminosulfonyl,
aminocarbonyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or
carboxy, or R is an aryl group optionally substituted by one or
more hydroxy, halogen, nitro, alkoxy, aryloxy, alkylthio, arylthio,
amino, alkylamino, dialkylamino, N-alkyl-piperazinyl,
4-morpholinyl, arylamino, cyano, alkyl, phenyl, aminosuiphonyl,
aminocarbonyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or
carboxy;
[0106] R.sub.1 is a straight or branched C.sub.1-C.sub.6 alkyl
group or an aryl group, each optionally substituted as above
reported for R;
[0107] R.sub.2 is a hydrogen atom; and pharmaceutically acceptable
salts thereof;
[0108] provided that:
[0109] a) when R is chlorine or bromine then R.sub.1 is not
unsubstituted C.sub.1-C.sub.3 alkyl, phenyl, trifluoromethylphenyl
or an optionally substituted phenylcarbonyl;
[0110] b) when R is methyl then R.sub.1 is not methyl, phenyl or
4-(5-oxazolyl)phenyl;
[0111] c) when R is nitrophenyl then R.sub.1 is not haloalkyl.
[0112] Another class of preferred compounds of formula (I) are
those wherein R is a straight or branched C.sub.1-C.sub.6 alkyl
group and, together with the nitrogen atom to which they are
bonded, R.sub.1 and R.sub.2 form a substituted or unsubstituted,
optionally either benzocondensed or bridged 5 to 7 membered
heterocycle, or 9 to 11 membered spiro-heterocycle.
[0113] Still another class of preferred compounds of formula (I)
are those wherein R is a straight or branched C.sub.1-C.sub.6 alkyl
group; R.sub.2 is a straight or branched C.sub.1-C.sub.4 alkyl or
C.sub.2-C.sub.4 alkenyl or alkynyl group and R.sub.1 is an aryl or
arylalkyl group with from 1 to 4 carbon atoms within the straight
or branched alkyl chain.
[0114] Examples of preferred compounds of the invention, whenever
appropriate in the form of pharmaceutically acceptable salts, e.g.
hydrobromide or hydrochloride salt, are the following:
[0115] 1) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-phenyl-urea;
[0116] 2) N-(5-bromo-1,3-thiazol-2-yl)-N'-phenyl-urea;
[0117] 3) N-(5-phenyl-1,3-thiazol-2-yl)-N'-phenyl-urea;
[0118] 4) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-phenyl-urea;
[0119] 5)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-sulfamoyl-phenyl)-urea;
[0120] 6)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-sulfamoly-pheny)-urea;
[0121] 7)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-sulfamoyl-phenyl)-urea;
[0122] 8)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-sulfamoyl-phenyl)-urea;
[0123] 9)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-methoxy-phenyl)-urea;
[0124] 10)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-methoxy-phenyl)-urea;
[0125] 11)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-methoxy-phenyl)-urea;
[0126] 12)
N-(5-cycloproyl-1,3-thiazol-2-yl)-N'-(3-methoxy-phenyl)-urea;
[0127] 13)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-chloro-phenyl)-urea;
[0128] 14)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-chloro-phenyl)-urea;
[0129] 15)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-chloro-phenyl)-urea;
[0130] 16)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-chloro-phenyl)-urea;
[0131] 17)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-chloro-phenyl)-urea;
[0132] 18)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-chloro-phenyl)-urea;
[0133] 19)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-chloro-phenyl)-urea;
[0134] 20)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-chloro-phenyl)-urea;
[0135] 21)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-chloro-phenyl)-urea;
[0136] 22)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(2-chloro-phenyl)-urea;
[0137] 23)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(2-chloro-phenyl)-urea;
[0138] 24)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(2-chloro-phenyl)-urea;
[0139] 25)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-methoxy-phenyl)-urea;
[0140] 26)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-methoxy-phenyl)-urea;
[0141] 27)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-methoxy-phenyl)-urea;
[0142] 28)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-methoxy-phenyl)-urea;
[0143] 29)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-hydroxy-phenyl)-urea;
[0144] 30)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-hydroxy-phenyl)-urea;
[0145] 31)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-hydroxy-phenyl)-urea;
[0146] 32)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-hydroxy-phenyl)-urea;
[0147] 33)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-hydroxy-phenyl)-urea;
[0148] 34)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-hydroxy-phenyl)-urea;
[0149] 35)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-hydroxy-phenyl)-urea;
[0150] 36)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-hydroxy-phenyl)-urea;
[0151] 37)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-methoxy-phenyl)-urea;
[0152] 38)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(2-methoxy-phenyl)-urea;
[0153] 39)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(2-methoxy-phenyl)-urea;
[0154] 40)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(2-methoxy-phenyl)-urea;
[0155] 41)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-hydroxy-phenyl)-urea;
[0156] 42)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(2-hydroxy-phenyl)-urea;
[0157] 43)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(2-hydroxy-phenyl)-urea;
[0158] 44)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-2-hydroxy-phenyl)-urea;
[0159] 45)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-nitro-phenyl)-urea;
[0160] 46)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-nitro-phenyl)-urea;
[0161] 47)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-nitro-phenyl)-urea;
[0162] 48)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-nitrol-phenyl)-urea;
[0163] 49)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-amino-phenyl)-urea;
[0164] 50)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-amino-phenyl)-urea;
[0165] 51)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-amino-phenyl)-urea;
[0166] 52)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-amino-phenyl)-urea;
[0167] 53)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-nitro-phenyl)-urea;
[0168] 54)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-nitro-phenyl)-urea;
[0169] 55)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-nitro-phenyl)-urea;
[0170] 56)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-nitro-phenyl)-urea;
[0171] 57)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-amino-phenyl)-urea;
[0172] 58)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-amino-phenyl)-urea;
[0173] 59)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-amino-phenyl)urea;
[0174] 60)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-amino-phenyl)-urea;
[0175] 61) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-benzyl-urea;
[0176] 62) N-(5-bromo-1,3-thiazol-2-yl)-N'-benzyl-urea;
[0177] 63) N-(5-phenyl-1,3-thiazol-2-yl)-N'-benzyl-urea;
[0178] 64) N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-benzyl-urea;
[0179] 65)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(pyrid-3-yl)-urea;
[0180] 66) N-(5-bromo-1,3-thiazol-2-yl)-N'-(pyrid-3-yl)-urea;
[0181] 67) N-(5-phenyl-1,3-thiazol-2-yl)-N'-(pyrid-3-yl)-urea;
[0182] 68)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(pyrid-3-yl)-urea;
[0183] 69) N-(5-bromo-1,3-thiazol-2-yl)-N'-(pyrid-4-yl)-urea;
[0184] 70)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(pyrid-4-yl)-urea;
[0185] 71) N-(5-phenyl-1,3-thiazol-2-yl)-N'-(pyrid-4-yl)-urea;
[0186] 72)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(pyrid-4-yl)-urea;
[0187] 73)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(pyrid-2-yl)-urea;
[0188] 74) N-(5-bromo-1,3-thiazol-2-yl)-N'-(pyrid-2-yl)-urea;
[0189] 75) N-(5-phenyl-1,3-thiazol-2-yl)-N'-(pyrid-2-yl)-urea;
[0190] 76)
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(pyrid-2-yl)-urea;
[0191] 77)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(benzothiophen-2-yl)-urea;
[0192] 78)
N-(5-bromo-1,3-thiazol-2-yl)-N'-(benzothiophen-2-yl)-urea;
[0193] 79)
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(benzothiophen-2-yl)-urea; N-(5-
cyclopropyl-1,3-thiazol-2-yl)-N'-(benzothiophen-2-yl)-urea;
[0194] 80) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-morpholine
carboxamide;
[0195] 81)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-methylphenyl)urea;
[0196] 82)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-fluorophenyl)urea;
[0197] 83)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-cyanophenyl)urea;
[0198] 84)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-cyanophenyl)urea;
[0199] 85)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,6-dimethylphenyl)urea;
[0200] 86)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-fluorobenzyl)urea;
[0201] 87) N-(5-isopropyl-1,3-thiazol-2-yl)-N'-acetylphenyl)
urea;
[0202] 88)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-acetylpheny)urea;
[0203] 89)
3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzoic
acid;
[0204] 90)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-isopropylphenyl)urea;
[0205] 91)
3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzami-
de;
[0206] 92)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-methoxybenzyl)urea;
[0207] 93)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-butylphenyl)urea;
[0208] 94)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-trifluoromethylphenyl)ur-
-ea;
[0209] 95)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-3-bromophenyl)urea;
[0210] 96)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-cyclohexylphenyl)urea;
[0211] 97)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-phenoxyphenyl)urea;
[0212] 98)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-benzloxyphenyl)urea;
[0213] 99)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,5-dimethylphenyl)urea;
[0214] 100)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,3-dimethylphenyl)urea;
[0215] 101)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-metnoxy[1,1-biphenyl]-4-
-yl)urea;
[0216] 102)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-3,4-dihydro-2(1H)-isoquino-
-line carboxamide;
[0217] 103)
N-benzyl-N'-(5-isopropyl-1,3-thiazol-2-yl)-N'-methylurea;
[0218] 104)
N-(5-isopropyl-1,3-thiazol-2-yl)-6,7-dimethoxy-3,4-dihydro-2(1-
-H)-isoquinoline carboxamide;
[0219] 105)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(3-chloro-4-methyl)-pheny-
l]urea;
[0220] 106)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(3-chloro-6-methyl)phenyl-
-]urea;
[0221] 107)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,5-dimethoxyphenyl)urea;
[0222] 108)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,4-dimethoxyphenyl)urea;
[0223] 109)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(2-methoxy-5-chloro)pheny-
l]urea;
[0224] 110)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-((2-chloro-4-methoxyphenyl-
-)urea;
[0225] 111)
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,5-dichlorophenyl)urea;
[0226] 112)
N-[(1,1'-biphenyl)-2-yl]-N'-(5-isopropyl-1,3-thiazol-2-yl)urea-
-;
[0227] 113)
N-ethyl-N'-(5-isopropyl-1,3-thiazol-2-yl)-N-phenylurea;
[0228] 114)
N-[4-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-2--
methoxyphenyl]acetamide;
[0229] 115)
2-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-N-phe-
nylbenzamide;
[0230] 116)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2-morpholinophenyl)urea;
[0231] 117)
N-[4-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)phe-
nyl]-N-methyl acetamide;
[0232] 118)
N-(2-{[cyclohexyl(methyl)amino]methyl}phenyl)-N-(5-isopropyl-1-
-,3-thiazol-2-yl)urea;
[0233] 119)
N-[3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-4--
methoxyphenyl]acetamide;
[0234] 120)
N-(5-isopropyl-1,3-thiazol-2-yl)-4-(4-methoxyphenyl)-1-piperaz-
-ine carboxamide;
[0235] 121)
N-(2-furylmethyl)-N-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0236] 122)
N-(4-fluorophenyl)-N-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0237] 123)
N-(2-methoxybenzyl)-N-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0238] 124)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-[2-(1-methyl-1H-pyrrol-2-yl-
-)ethyl]urea;
[0239] 125)
N-(3,4-dimethoxybenzyl)-N-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0240] 126)
N-(5-isopropyl-1,3-thiazol-2-yl)-4-oxo-1-phenyl-1,3,8-triazasp-
iro[4.5]decane-8-carboxamide;
[0241] 127)
n-(5-isopropyl-1,3-thiazol-2-yl)-1,4-dioxa-8-azaspiro[4.5]deca-
-ne-8-carboxamide;
[0242] 128)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-[2-(1-piperidinyl)ethyl]ure-
-a;
[0243] 129)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-[2-(1-morpholinyl)ethyl]ure-
-a;
[0244] 130)
4-(4-fluorophenyl)-N-(5-isopropyl-1,3-thiazol-2-yl)-1-piperazi- -ne
carboxamide;
[0245] 131)
N-[4-(4-chlorophenyl)-3-ethyl-5-isoxazolyl]-N-(5-isopropyl-1,3-
-thiazol-2-yl)urea;
[0246] 132)
4-[(4-fluorophenyl)(hydroxy)methyl]-N-(5-isopropyl-1,3-thiazol-
-2-yl)-1-piperidine carboxamide;
[0247] 133)
N-(3-ethynylphenyl)-N-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0248] 134)
N-(2-methoxy-3-fluorophenyl)-N-(5-isopropyl-1,3-thiazol-2-yl)u-
-rea;
[0249] 135)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(4-oxo-1-piperidinyl)urea;
[0250] 136)
N-(3-acetylaminophenyl)-N-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0251] 137)
N-[3-(2-furyl)-1H-pyrazol-5-yl]-N-(5-isopropyl-1,3-thiazol-2-y-
l)urea;
[0252] 138)
N-{4-[ethyl(isopropyl)amino]phenyl}-N-(5-isopropyl-1,3-thiazol-
-2-yl)urea;
[0253] 139)
N-(1,3-benzodioxol-5-yl)-N-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0254] 140)
5-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-1-phe-
nyl-1H-pyrazole-4-carboxamide;
[0255] 141)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(4-pyridinylmethyl)urea;
[0256] 142)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2-pyrazinyl)urea;
[0257] 143)
n-(5-isopropyl-1,3-thiazol-2-yl)-N-(5-phenyl-1,3,4-oxadiazol-2-
-yl)urea;
[0258] 144)
N-(5-isopropyl-1,3-thiazol-2-yl)-4-(2-oxo-2,3-dihydro-1H-benzi-
midazol-1-yl)-1-piperidine carboxamide;
[0259] 145)
N-(1,3-benzothiazol-6-yl)-N-(5-isopropyl-1,3-thiazol-2-yl)area-
-;
[0260] 146)
N-(1,3-dimethyl-1H-pyrazol-5-yl)-N-(5-isopropyl-1,3-thiazol-2--
yl)urea;
[0261] 147)
N-(3-phenyl-1-methyl-1H-pyrazol-5-yl)-N-(5-isopropyl-1,3-thiaz-
-ol-2-yl)urea;
[0262] 148) N-(5-isopropyl-1,3-thiazol-2-yl)-3-hydroxy-1-piperidine
carboxamide;
[0263] 149)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2-methyl-1,3-dioxo-2,3-dih-
ydro-1H-isoindol-5-yl)urea;
[0264] 150) N-(5-isopropyl-1,3-thiazol-2-yl)-4-benzyl-1-piperazine
carboxamide;
[0265] 151) N-(5-isopropyl-1,3-thiazol-2-yl)-4-methyl-1-piperazine
carboxamide;
[0266] 152) 4-hydroxy-N-(5-isopropyl-1,3-thiazol-2-yl)-1-piperazine
carboxmide;
[0267] 153)
N-(5-isopropyl-1,3-thiazol-2-yl)-3-azabicyclo[3.2.2]nonane-3-c-
arboxamide;
[0268] 154)
N-(5-isopropyl-1,3-thiazol-2-yl)-4-(4-acetylphenyl)-1-piperazi- -ne
carboxamide;
[0269] 155)
4-[bis(4-fluorphenyl)-N-(5-isopropyl-1,3-thiazol-2-yl)-1-piper-
-azine carboxmide;
[0270] 156)
N-(5-isopropyl-1,3-thiazol-2-yl)-4-oxo-2,3,4,5-tetrahydro-1H-1-
,5-benzodiazepine-1-carboxamide;
[0271] 157)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(5,6,7,8-tetrahydro-1-napht-
alenyl)urea;
[0272] 158)
N-(4-phenyl-2-thiazolyl)-N-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0273] 159)
4-(4-fluorobenzolyl)-N-(5-isopropyl-1,3-thiazol-2-yl)-1-piperi-
-dine carboxamide;
[0274] 160)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-1,3-dihydro-2-benzofuran-5--
yl)urea;
[0275] 161)
N-(5-isopropyl-1,3-thiazol-2-yl)-4-(2-pyrimidinyl)-1-piperazin- -e
carbexamide;
[0276] 162) N-(5-isopropyl-1,3-thiazol-2-yl)-3-oxo-3,4-dihydro-1
(2H)-quinoxaline;
[0277] 163)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(1H-indazol-6-yl)urea;
[0278] 164)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2-chlorobenzyl)urea;
[0279] 165)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2,4-dichlorobenzyl)urea;
[0280] 166)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(3-fluorobenzyl)urea;
[0281] 167)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(3,4-dichlorobenzyl)urea;
[0282] 168)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2,4-difluorobenzyl)urea;
[0283] 169)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2,5-difluorobenzyl)urea;
[0284] 170)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-2,6-difluorobenzyl)urea;
[0285] 171)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-[(4-hydroxy-3-methoxy)benzy-
l]urea;
[0286] 172)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(5-methyl-2-furyl)urea;
[0287] 173)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(4-methylsulfonylbenzyl)ure-
-a;
[0288] 174)
N-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-N-(5-isopropyl-
-1,3-thiazol-2-yl)urea;
[0289] 175)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(4-chlorobenzyl)urea;
[0290] 176)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2-pyridinylmethyl)urea;
[0291] 177)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(3,5-dimethoxybenzyl)urea;
[0292] 178)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(3-pyridinylmethyl)urea;
[0293] 179)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(4-trifluorobenzyl)urea;
[0294] 180)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(3,4,5-trimethoxybenzyl)ure-
-a;
[0295] 181)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2,4-dimethoxybenzyl)urea;
[0296] 182)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(4-dimethylaminobenzyl)urea-
-;
[0297] 183)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2,5-dimethoxybenzyl)urea;
[0298] 184)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-[(2-chloro-6-phenoxy)benzyl-
-]urea;
[0299] 185)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-[(1R,2S)-2-hydroxy-2,3-dihy-
dro-1H-inden-1-yl]urea;
[0300] 186)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-[(3-hydroxy-4-methyl)phenyl-
-]urea;
[0301] 187)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-[4-(1H-benzimidazol-2-yl)ph-
enyl]urea;
[0302] 188)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(3-phenyl-1H-pyrazol-5-yl)u-
-rea;
[0303] 189)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2-methyl-6-quinolinyl)urea-
-;
[0304] 190)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-[4-(cyanomethyl)phenyl]urea-
-;
[0305] 191)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2-quinolinyl)urea;
[0306] 192)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(1-oxo-2,3-dihydro-1H-inden-
-5-yl)urea;
[0307] 193) N-(5-isopropyl-1,3-thiazol-2-yl)-N-(3-oxo-1
,3-dihydro-2-benzofuran-5-yl)urea;
[0308] 194)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(5-oxo-5,6,7,8-tetrahydro-2-
-naphtalenyl)urea;
[0309] 195)
methyl-3-(<[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}am-
-ino)-4-methylbenzoate;
[0310] 196)
methyl-4-(<[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}am-
-ino)-3-methylbenzoate;
[0311] 197)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(4-imidazo[1,2-a]pyridin-2--
yl-phenyl)urea;
[0312] 198)
ethyl-4-(<[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}ami-
no)benzoate;
[0313] 199)
(2R)-1-benzyl-2-(<[(5-isopropyl-1,3-thiazol-2-yl)amino]carb-
onyl}amino)propanamide;
[0314] 200)
2-hydroxy-5-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}be-
nzoic acid;
[0315] 201)
2-chloro-5-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}ami-
no)benzoic acid;
[0316] 202)
3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzoi- -c
acid;
[0317] 203)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(5-methyl-3-isoxazolyl)urea-
-;
[0318] 204)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2,6-dimethoxyphenyl)urea;
[0319] 205)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2,3-dimethoxybenzyl)urea;
[0320] 206)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(3,4-difluorobenzyl)urea;
[0321] 207)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2,4-dimethylphenyl)urea;
[0322] 208)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(1H-benzimidazol-5-yl)urea;
[0323] 209)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-[(R)-phenylglicinamido]urea-
-;
[0324] 210)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2-phenoxyacetamido)urea;
[0325] 211)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-[(S)-phenylglicinamido}urea-
-;
[0326] 212)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-{2-[(1-methyl-1H-imidazol-2-
-yl)methoxy]phenyl}urea;
[0327] 213)
N-(3-iodophenyl)-N-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0328] 214)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-[3-(3-methoxy-1-propynyl)ph-
enyl]urea;
[0329] 215)
N-{3-[3-(dimethylamino)-1-propynyl]phenyl}-N-(5-isopropyl-1,3--
thiazol-2-yl)urea;
[0330] 216)
N-[4-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)phe-
nyl]methanesulfonamide;
[0331] 217)
2-[3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)ani-
lino]acetamide;
[0332] 218)
N-[3-(3-hydroxy-1-butynyl)phenyl]-N-(5-isopropyl-1,3-thiazol-2-
-yl)urea;
[0333] 219)
N-(imidazo[1,2-a]pyridin-2-yl-methyl)-N-(5-isopropyl-1,3-thiaz-
-ol-2-yl)urea;
[0334] 220)
2-{[{[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}(2-propynyl-
)amino]methyl}benzenesulfonamide;
[0335] 221)
N-(1H-indol-6-yl)-N-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0336] 222) N-[(I
S)-2-hydroxy-1-phenylethyl]-N-(5-isopropyl-1,3-thiazol-2-
-yl)urea;
[0337] 223)
N-(1H-indol-5-yl)-N-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0338] 224) N-[(1
R-2-hydroxy-1-phenylethyl]-N-(5-isopropyl-1,3-thiazol-2--
yl)urea;
[0339] 225) N-(5-isopropyl-1,3-thiazol-2-yl)-N-butylurea;
[0340] 226) N-(5-isopropyl-1,3-thiazol-2-yl)-N-benzoylurea;
[0341] 227)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(2,6-dimethylphenyl)urea;
[0342] 228) N-(5-isopropyl-1,3-thiazol-2-yl)-N-benzylurea;
[0343] 229) N-(5-isopropyl-1,3-thiazol-2-yl)-N-butylurea;
[0344] 230)
N-(5-isopropyl-1,3-thiazol-2-yl)-4-morpholinecarboxamide;
[0345] 231) N-(5-isopropyl-1,3-thiazol-2-yl)-N-phenylurea;
[0346] 232)
N-(5-isopropyl-1,3-thiazol-2-yl)N-(4-methoxybenzylurea;
[0347] 233)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(4-fluorophenyl)urea;
[0348] 234)
N-[(1-ethyl-2-pyrrolidinyl)methyl]-N-(5-isopropyl-1,3-thiazol--
2-yl)urea;
[0349] 235)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(5-hydroxy-1H-pyrazol-3-yl)-
-urea;
[0350] 236)
N-(5-isopropyl-1,3-thiazol-2-yl)-N-(3-pyridinyl)urea;
[0351] 237)
N-(4-fluorophenyl)-N-(5-isopropyl-1,3-thiazol-2-yl)urea.
[0352] The compounds of formula (I) object of the present invention
and the salts thereof can be obtained, for instance, by a process
comprising:
[0353] a) when R.sub.2 is a hydrogen atom
[0354] reacting a compound of formula (II) 5
[0355] wherein R is as defined above, with a compound of formula
(III)
R.sub.1--NCO (III)
[0356] wherein R.sub.1 is as defined above; or
[0357] b) when R.sub.2 is a hydrogen atom or has the meanings above
reported
[0358] reacting a compound of formula (IV) 6
[0359] wherein R is as defined above, with a compound of formula
(V) 7
[0360] wherein R.sub.1 and R.sub.2 are as defined above; and, if
desired, converting a 2-ureidol,3-thiazole derivative of formula
(I) into another such derivative of formula (I), and/or into a salt
thereof.
[0361] The compounds of formula (I) can alternatively be obtained
by a process comprising:
[0362] reacting a compound of formula (II) wherein R is as
described above with 4-nitrophenyl-chloroformate, or a polymer
supported form of it, thus obtaining a compound of formula (VI), or
a polymer supported form of it, 8
[0363] wherein R is as described above; and reacting a compound of
formula (VI) with a compound of formula (V) 9
[0364] wherein R.sub.1 and R.sub.2 are as described above; and, if
desired, converting a 2-ureidol,3-thiazole derivative of formula
(I), or a polymer supported form of it, into another such
derivative of formula (I), and/or into a salt thereof.
[0365] More particularly, when referring to the process performed
by using polymer supported species, the synthetic pathway can be
summarized as follows: 10
[0366] In addition, when referring to the process performed by
using polymer supported species, conventional reaction conditions
are well known to the skilled man.
[0367] It is further clear to the man skilled in the art that if
the compound of formula (I), prepared according to the above
processes, is obtained as an admixture of isomers, their separation
into the single isomers of formula (I) according to conventional
technigues is still within the scope of the present invention.
[0368] Likewise, the conversion into the free
2-ureidol-1,3-thiazole derivative (I) of a corresponding salt
thereof, according to well-known procedures in the art, is still
within the scope of the invention.
[0369] The above process-variants are analogy processes which can
be carried out according to well known methods.
[0370] The reaction between a compound of formula (II) and a
compound of formula (III), or the reaction between a compound of
formula (IV) and a compound of formula (V), can be carried out in a
suitable solvent such as, for instance, dichloromethane,
chloroform, tetrahydrofuran, diethyl ether, 1,4-dioxane,
acetonitrile, toluene or acetone, at a temperature ranging from
room temperature to reflux for a time varying between about 1 to 96
hours.
[0371] The reaction of a compound of formula (II) to give a
compound of formula (VI) is carried out with
4-nitrophenylchloroformate, or a polymer supported form of it, in
the presence of a tertiary base such as, for instance,
triethylamine, N-methylmorpholine, N,N-diisopropylethylamine or
pyridine, in a suitable solvent such as toluene, dichloromethane,
chloroform, diethylether, tetrahydrofuran, acetonitrile, dioxane or
N,N-dimethylformamide, at a temperature ranging from approximately
-10.degree. C. to room temperature.
[0372] The reaction between a compound of formula (VI) and a
compound of formula (V) to give a compound of formula (I) can be
carried out in a suitable solvent such as toluene, dichloromethane,
chloroform, diethylether, tetrahydrofliran, acetonitrile,
1,4-dioxane or N,N-dimethylformamide, at a temperature ranging from
about room temperature to reflux. In the above-mentioned scheme, as
far as the solid phase approach is concerned, compound (VIII) can
be prepared by reacting compound (VII) with 4-mercaptophenol in the
presence of a base such as potassium tert-butoxide, potassium
carbonate or potassium sodium hydroxide and in a suitable solvent
such as N,N-dimethylformamide at a temperature ranging from 40 to
60.degree. C. The reaction between compound (VIII) and
p-nitrophenylchloroformate to give compound (IX) can be carried out
in presence of a base such as N-methylmorpholine, triethylamine or
N,N-diisopropyethylamine in a suitable solvent such as
dichloromethane, chloroform, 1,4-dioxane or N,N-dimethylformamide
at room temperature.
[0373] The reaction between compound (IX) and the compound of
formula (II), wherein R is as described above, thus obtaining the
compound of formula (X), can be carried out in a suitable solvent
such as dichloromethane, chloroform, toluene or
N,N-dimethylformamide at room temperature for a time varying
between about 2 to 22 hours.
[0374] The reaction between the compound of formula (X), wherein R
is as described above, and the compound of formula (V) wherein
R.sub.1 and R.sub.2 are as described above, thus obtaining the
compound of formula (I), can be carried out in the presence of a
base such as triethylarnine, N,N-diisopropylethylamine or
N-methylmorpholine in a suitable solvent such as toluene,
acetonitrile or N,N-dimethylformamide at a temperature ranging from
room temperature to 100.degree. C.
[0375] Also the optional conversion of a compound of formula (I)
into another compound of formula (I) can be carried out according
to known methods.
[0376] As an example, the nitro group of a compound of formula (I)
may be converted into an amino group by treatment, for example,
with stannous chloride in concentrated hydrochloric acid and by
using, if necessary, an organic solvent such as acetic acid,
1,4-dioxane and tetrahydrofuran, at a temperature varying between
room temperature and about 100.degree. C.
[0377] Likewise, an alkylthio or an arylthio group may be converted
into the corresponding alkylsulfonyl and arylsulfonyl group by
reaction, for example, with m-chloroperbenzoic acid in a suitable
solvent such as dichloromethane or chloroform, at a temperature
varying from about -5.degree. C. and room temperature.
[0378] The optional salification of a compound of formula (I) or
the conversion of a salt into the free compound as well as the
separation of a mixture of isomers into the single isomers may be
carried out by conventional methods.
[0379] The compounds of formula (II) and (IV) according to the
above processes are known compounds or can be obtained according to
known methods.
[0380] For example, a compound of formula (II) wherein R is as
defined above can be obtained by reacting a compound of formula
(XI) 11
[0381] wherein X is a bromine or chlorine atom, with thiourea in a
suitable solvent such as methanol, ethanol, tetrahydrofuran,
1,4-dioxane or toluene, at a temperature varying between room
temperature and reflux, for a suitable time ranging from about 1
hour to about 24 hours.
[0382] A compound of formula (IV) can be obtained, for instance, by
reacting a compound of formula (II) wherein R is as defined above
with bis(trichloromethyl) carbonate or trichloromethyl
chloroformate in the presence, if necessary, of a tertiary base
such as triethylamine, N,N-diisopropylethylamine or pyridine, in a
suitable solvent such as dichloromethane, chloroform or toluene, at
a temperature ranging from about -20.degree. C. to reflux.
[0383] The compounds of formula (III), (V) and (XI) are well-known
commercially available compounds or, alternatively, may be
conventionally prepared according to known methods in organic
chemistry.
[0384] When preparing the compounds of formula (I) according to the
process object of the present invention, optional functional groups
within both the starting materials or the intermediates thereof,
which could give rise to unwanted side reactions, need to be
properly protected according to conventional techniques.
[0385] Likewise, the conversion of these latter into the free
deprotected compounds may be carried out according to known
procedures.
[0386] Pharmacology
[0387] The compounds of formula (I) are active as cdk/cyclin
inhibitors as they gave positive results when tested according to
the following procedure.
[0388] The compounds of formula (I) are therefore useful to
restrict the unregulated proliferation of tumor cells, hence in
therapy in the treatment of various tumors such as, for instance,
carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder
carcinoma, colon carcinoma, ovary and endometrial tumors, sarcomas,
e.g. soft tissue and bone sarcomas, and the hematological
malignancies such as, e.g., leukemias.
[0389] In addition, the compounds of formula (I) are also useful in
the treatment of other cell proliferative disorders such as
psoriasis, vascular smooth cell proliferation associated with
atherosclerosis and post-surgical stenosis and restenosis and in
the treatment of Alzheimer's disease.
[0390] The inhibiting activity of putative cdk/cyclin inhibitors
and the potency of selected compounds was determined through a
method of assay based on the use of the MultiScreen-PH 96 well
plate (Millipore), in which a phosphocellulose filter paper was
placed at each well bottom allowing binding of positive charged
substrate after a washing/filtration step.
[0391] When a radioactivity labelled phosphate moiety was
transferred by the ser/threo kinase to the filter-bound histone,
light emitted was measured in a scintillation counter.
[0392] The inhibition assay of cdk2/Cyclin A activity was performed
according to the following protocol:
[0393] Kinase reaction: 1.5 .mu.M histone Hi substrate, 25 .mu.M
ATP (0.5 .mu.Ci P.sup.33.gamma.-ATF), 30 ng Cyclin A/cdk2 complex,
10 .mu.M inhibitor in a final volume of 100 .mu.l buffer (TRIS HCl
10 mM pH 7.5, MgCl.sub.2 10 mM, 7.5 mM DTT) were added to each well
of a 96 U bottom well plate. After 10 min at 37.degree. C.
incubation, reaction was stopped by 20 .mu.l EDTA 120 mM.
[0394] Capture: 100 .mu.l were transferred from each well to
MultiScreen plate, to allow substrate binding to phosphocellulose
filter. Plates were then washed 3 times with 150 .mu.l/well PBS
Ca.sup.++/Mg.sup.++ free and filtered by MultiScreen filtration
system.
[0395] Detection: filters were allowed to dry at 37.degree. C.,
then 100 .mu.l/well scintillant were added and .sup.33p labelled
histone Hi was detected by radioactivity counting in the Top-Count
instrument.
[0396] Results: data were analysed and expressed as % inhibition
referred to total activity of enzyme (=100%).
[0397] All compounds showing inhibition .gtoreq.50% were further
analysed in order to study and define potency (IC50) as well as the
kinetic-profile of inhibitor through Ki calculation.
[0398] IC50 determination: the protocol used was the same described
above, where inhibitors were tested at concentrations ranging from
0.0045 to 10 .mu.M. Experimental data were analyzed by the computer
program GraphPad Prizm.
[0399] Ki calculation: either the concentration of ATP and histone
H1 substrate were varied: 4, 8, 12, 24, 48 .mu.M for ATP
(containing proportionally diluted P.sup.33.gamma.-ATP) and 0.4,
0.8, 1.2, 2.4, 4.8 .mu.M for histone were used in absence and
presence of two different, properly chosen inhibitor
concentrations.
[0400] Experimental data were analysed by the computer program
SigmaPlot for Ki determination, using a random bireactant system
equation: 1 v = v max ( A ) ( B ) aK A K B 1 + ( A ) K A + ( B ) K
B + ( A ) ( B ) aK A K B
[0401] where A=ATP and B=histone H1.
[0402] Following the method above described, a representative
compound of formula (I) of the invention, which is
N-(5-isopropyl-1,3-thiazol-2-yl)-N- -'-(3,5-dimethylphenylurea,
showed an inhibiting activity towards the cdk2/cyclin A complex
corresponding to 0.56 .mu.M (IC50).
[0403] In addition, the inhibiting activity of putative cdk/cyclin
inhibitors and the potency of selected compounds was determined
through a method of assay based on the use of a SPA (Scintillation
Proximity Assay) 96 well plate assay. The assay is based on the
ability of streptavidin coated SPA beads to capture a biotinylated
peptide derived from a phosphorylation site of histone.
[0404] When a radioactivity labelled phosphate moiety was
transferred by the ser/threo kinase to the biotinylated histone
peptide, light emitted was measured in a scintillation counter.
[0405] The inhibition assay of cdk5/p25 activity was performed
according to the following protocol:
[0406] Kinase reaction: 1.0 .mu.M biotinylated histone peptide
substrate, 0.25 uCi P33gATP, 4 nm cdk2/p25 complex, 0-100 .mu.M
inhibitor in a final volume of 100 .mu.l buffer (Hepes 20 mM pH
7.5, MgC12 15 mM, 1 mM DTT) were added to each well of a 96 U
bottom well plate. After 20 mm at 37.degree. C. incubation, the
reaction was stopped by the addition of 500 ug SPA beads in
phosphate-buffered saline containing 0.1% Triton X-100, 50 uM ATP
and 5 mM EDTA. The beads were allowed to settle, and the
radioactivity incorporated in the 33P-labelled peptide was detected
in a Top Count scintillation counter.
[0407] Results: Data were analyzed and expressed as % Inhibition
using the formula:
100.times.(1-(Unknown-Bkgd)/(Enz. Control-Bkgd))
[0408] IC50 values were calculated using a variation of the four
parameter logistics equation:
Y=100/[1+10{circumflex over ( )}((Log EC50-X)*Slope)]
[0409] Where X=log (uM) and Y=% Inhibition.
[0410] The compounds of formula (I) are therefore useful to
restrict the unregulated proliferation of tumor cells, hence in
therapy in the treatment of various tumors such as, for instance,
carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder
carcinoma, colon carcinoma, ovary and endometrial tumors, sarcomas,
e.g. soft tissue and bone sarcomas, and the hematological
malignancies such as, e.g., leukemias.
[0411] In addition, the compounds of formula (I) are also useful in
the treatment of other cell proliferative disorders such as
psoriasis, vascular smooth cell proliferation associated with
atherosclerosis and post-surgical stenosis and restenosis and in
the treatment of Alzheimer's disease.
[0412] The compounds of the present invention can be administered
either as single agents or, alternatively, in combination with
known anticancer treatments such as radiation therapy or
chemotherapy regimen in combination with cytostatic or cytotoxic
agents.
[0413] As an example, the above compounds can be administered in
combination with one or more chemotherapeutic agents such as, for
instance, taxane, taxane derivatives, CPT-11, camptothecin
derivatives, anthracycline glycosides, e.g. doxorubiein or
epirubicin, etoposide, navelbine, vinblastine, carboplatin,
cisplatin and the like, optionally within liposomal formulations
thereof.
[0414] The compounds of formula (I) of the present invention,
suitable for administration to a mammal, e.g. to humans, can be
administered by the usual routes and the dosage level depends upon
the age, weight, conditions of the patient and the administration
route.
[0415] For example, a suitable dosage adopted for oral
administration of a compound of formula (I) may range from about 10
to about 500 mg pro dose, from 1 to 5 times daily. The compounds of
the invention can be administered in a variety of dosage forms,
e.g. orally, in the form of tablets, capsules, sugar or film coated
tablets, liquid solutions or suspensions; rectally in the form of
suppositories; parenterally, e.g. intramuscularly, or by
intravenous and/or intrathecal and/or intraspinal injection or
infusion.
[0416] The present invention also includes pharmaceutical
compositions comprising a compound of formula (I), or a
pharmaceutically acceptable salt thereof, in association with a
pharmaceutically acceptable excipient (which can be a carrier or a
diluent)
[0417] The pharmaceutical compositions containing the compounds of
the invention are usually prepared following conventional methods
and are administered in a pharmaceutically suitable form.
[0418] For example, the solid oral forms may contain, together with
the active compound, diluents, e.g. lactose, dextrose, saccharose,
sucrose, cellulose, corn starch or potato starch; lubricants, e.g.
silica, talc, stearic acid, magnesium or calcium stearate, and/or
polyethylene glycols; binding agents, e.g. starches, arabic gum,
gelatine, methylcellulose, carboxymethylcellulose or polyvinyl
pyrrolidone; disaggregating agents, e.g. a starch, alginic acid,
alginates or sodium starch glycolate; effervescing mixtures;
dyestuffs; sweeteners; wetting agents such as lecithin,
polysorbates, laurylsulphates; and, in general, non-toxic and
pharmacologically inactive substances used in pharmaceutical
formulations. Said pharmaceutical preparations may be manufactured
in known manner, for example, by means of mixing, granulating,
tabletting, sugar-coating, or filmcoating processes.
[0419] The liquid dispersions for oral administration may be e.g.
syrups, emulsions and suspensions.
[0420] The syrups may contain as carrier, for example, saccharose
or saccharose with glycerine and/or mannitol and/or sorbitol.
[0421] The suspensions and the emulsions may contain as carrier,
for examples a natural gum, agar, sodium alginate, pectin,
methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
[0422] The suspension or solutions for intramuscular injections may
contain, together with the active compound, a pharmaceutically
acceptable carrier, e.g. sterile water, olive oil, ethyl oleate,
glycols, e.g. propylene glycol, and, if desired, a suitable amount
of lidocaine hydrochloride. The solutions for intravenous
injections or infusions may contain as carrier, for example,
sterile water or preferably they may be in the form of sterile,
aqueous, isotonic saline solutions or they may contain as a carrier
propylene glycol.
[0423] The suppositories may contain together with the active
compound a pharmaceutically acceptable carrier, e.g. cocoa butter,
polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester
surfactant or lecithin.
[0424] The following examples illustrate but do not limit the
present invention.
EXAMPLE 1
[0425] Preparation of Methyl Cyclopropylacetate
[0426] Cyclopropylacetic acid (1.08 g; 10.57 mmol) was dissolved in
50 ml of methanol. The solution was cooled to 0.degree. C. and 5 ml
of sulfuric acid 96% were dropped under stirring. The solution was
maintained at room temperature overnight and then poured onto
ice-water, basified with 30% ammonium hydrate and finally extracted
with methylene chloride. The organic layer was dried over sodium
sulfate and evaporated to dryness to give 1.1 g of an oily product
(90% yield) which was used as such without any further
purification.
EXAMPLE 2
[0427] Preparation of 2-cyclopropylethanol
[0428] Sodium (85 mg; 0.004 mmol) was dissolved in 50 ml of
methanol and 8.7 g (0.23 mol) of sodium borohydride were added. A
solution of 3.7 g (0.032 mol) of methyl cyclopropylacetate,
prepared according to example 1, in 20 ml of methanol was dropped
to the mixture under stirring. The reaction was maintained at
reflux for 6 hours, then 300 ml of brine were added and the crude
extracted with methylene chloride.
[0429] The organic layer was dried over sodium sulfate and
evaporated to dryness to give 1.52 g (55% yield) of the title
compound.
EXAMPLE 3
[0430] Preparation of a Compound of Formula (VI):
2-cyclopropylethanal
[0431] Oxalyl chloride (1.24 ml; 14.18 mmol) was dissolved in 10 ml
of methylene chloride; after cooling to -60.degree. C. a solution
of 1.02 g (11.9 mmol) of 2-cyclopropylethanol, prepared according
to example 2, in 10 ml of methylene chloride was added dropwise.
The mixture was maintained under stirring for 30 minutes at the
same temperature, then 8.3 ml (59.5 mmol) of triethylamine were
added.
[0432] After 2 hours at 0.degree. C. water was added. The mixture
was diluted with methylene chloride and washed successively with 1M
hydrochloric acid, water, saturated sodium bicarbonate and finally
with brine. The organic layer was dried over sodium sulfate and
evaporated to dryness to give 0.31 g (30% yield) of the title
compound.
EXAMPLE 4
[0433] Preparation of a Compound of Formula (II):
2-amino-5-isopropyl-1,3-- thiazole
[0434] 3-Methylbutanaldehyde (2 ml; 18.6 mmol) was dissolved in 15
ml of dioxane.
[0435] A solution 2% v/v of bromine in dioxane (47.81 ml; 18.6
mmol) was dropped therein at 0.degree. C. The mixture was
maintained at room temperature under stirring for 2 hours, then
2.83 g (37.2 mmol) of thiourea and 10 ml of ethanol were added.
After 6 hours at room temperature the solution was evaporated to
dryness, the residue was dissolved in methylene chloride and the
product extracted with 1M hydrochloric acid; the aqueous layer was
made basic by using 30% ammonium hydrate and extracted again with
methylene chloride.
[0436] The organic phase was dried over sodium sulfate and
evaporated under vacuum. The residue was chromatographed on a
silica gel column, eluting with cyclohexane- ethylacetate to give
1.1 g (42% yield) of the title compound.
[0437] .sup.1H-NMR (DMSO-d.sup.6) .delta.ppm: 6.6 (s, 2H,
NH.sub.2); 6.58 (s, 1H, thiazole CH); 2.9 (m, 1H, CHMe.sub.2); 1.18
(s, 3H, MeCHMe); 1.17 (s, 3H, MeCHMe).
[0438] By analogous procedures the following compounds can be
prepared:
[0439] 2-amino-5-phenyl-1,3-thiazole; and
[0440] 2-amino-5-cyclopropyl-1,3-thiazole.
EXAMPLE 5
[0441] Preparation of a Compound of Formula (I):
N-(5-bromo-1,3-thiazol-2-- yl)-N'-phenyl-urea
[0442] Phenylisocyanate (1.7 ml; 15.6 mmol) was added to a solution
of 2-amino-5-bromol,3-thiazole hydrobromide (4 g; 15.6 mmol) and
triethylamine (2.1 ml; 15.6 mmol) in dichloromethane (70 ml),
maintained under magnetic stirring at room temperature. After about
4 days, methanol (7 ml) was added and the reaction mixture was then
washed with brine, dried over sodium sulfate and evaporated.
[0443] The residue was purified by chromatography on silica gel
(dichloromethane and then dichloromethane/methanol=90:10) to give
1.9 g (52%) of the title compound as a colourless solid (m.p.
166-169.degree. C./dec.).
[0444] .sup.1H-NMR (CDCl.sub.3) .delta.ppm: 10.50 (bs, 1H,
--NHCONHPh); 8.50 (bs, 1H, --NHCONHPh); 7.45 (d, J=7.6 Hz, 2H, o-Ph
hydrogens); 7.36 (dd, J=7.3 and 7.6 Hz, 2H, m-Ph hydrogens); 7.29
(s, 1H, thiazole CH); 7.16 (t, J=7.3 Hz, 1H, p-Ph hydrogens).
[0445] By analogous procedure, and by starting from the
corresponding isocyanate, the following compounds can be
prepared:
[0446] N-(5-phenyl-1,3-thiazol-2-yl)-N'-phenyl-urea
[0447] .sup.1H-NMR (DMSO-d.sup.6) .delta.ppm: 10.56 (bs, 1H,
--NHCONHPh); 8.99 (bs, 1H, NHCONHPh); 7.77 (s, 1H, thiazole CH);
7.6-7.0 (m, 10H, phenyl);
[0448]
N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-sulfamoyl-phenyl)-urea;
[0449]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-sulfamoyl-phenyl)-urea;
[0450] m.p.>200.degree. C.
[0451] .sup.1H-NMR (DMSO-d.sup.6) .delta.ppm: 10.58 (bs, 1H,
--NHCONHPh); 9.38 (bs, 1H NHCONHPh); 7.75 (d, 2H, H3 and H5 Ph);
7.61 (d, 2H, H2 and H6 Ph); 7.21 (s, 2H, SO.sub.2NH.sub.2); 7.02
(s, 1H, thiazole CH); 3.02 (m, 1H, CH(Me).sub.2); 1.22 (s, 3H,
MeCHMe); 1.21 (s, 3H, MeCHMe);
[0452] ESI(+)-MS; m/z 341 (100, (M+H).sup.+).
[0453] N-benzoyl-N'-(5-isopropyl-1,3-thiazol-2-yl)urea
[0454] m.p. 217-219.degree. C.
[0455] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.27 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.11 (m, 1H, CH.sub.3CHCH.sub.3); 7.18
(d, 1H, J=0.9, H thiazole); 7.54 (m, 2H, m-phenyl); 7.66 (m, 1H,
p-phenyl); 8.00 (m, 2H, o-phenyl); 11.50 (bs, 1H, NH); 11.80 (bs,
1H, NH).
[0456] ESI (+)MS: m/z 290 (70, (M+H).sup.+; m/z 169 (100,
(MH--C.sub.6H.sub.5CONH.sub.2).sup.+);
[0457]
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-sulfamoyl-phenyl)-urea;
[0458]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-sulfamoyl-phenyl)-urea;
[0459] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-methoxy-phenyl)-urea
m.p. 149-150.degree. C. .sup.1H-NMR (400 MHz-DMSO-d.sub.6)
.delta.ppm: 1.23 (d, 6H, J=6.8, CH.sub.3CHCH.sub.3); 3.06 (m, 1H,
CH.sub.3CHCH.sub.3); 3.72 (s, 3H, CH.sub.3); 7.02 (s, 1H, H
thazole); 6.57 (dd, 1H, J=8.3, 2.4, H-4'-phenyl); 6.93 (d, 1H,
J=8.3, H-6'-phenyl); 7.18 (m, 2H, H-5', H-2'-phenyl); 8.94 (s, 1H,
NH); 10.35 (bs, 1H, NH). ESI (+)MS: m/z 292 (100, (M+H).sup.+);
[0460] N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-methoxy-phenyl)-urea m.p.
190-191.degree. C.
[0461] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 7.44 (s, 1H,
H thiazole); 3.72 (s, 3H, CH.sub.3); 6.61 (dd, 1H, J=2.4, 7.8,
H-4'-phenyl); 6.94 (dd, 1H, J=2.0, 7.8, H-6'-phenyl); 7.13 (dd, 1H,
J=2.0, 2.0, H-2'-phenyl); 7.20 (dd, 1H, J=7.8, 7.8H-5'-phenyl);
8.95 (s, 1H, NH); 10.80 (S, 1H, NH). ESI (+)MS: m/z 328 (100,
(M+H).sup.+);
[0462]
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-methoxy-phenyl)-urea;
[0463]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-methoxy-phenyl)-urea;
[0464] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-phenyl-urea
[0465] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.07 (m, 1H, CH.sub.3CHCH.sub.3); 7.03
(m, 2H, H-thiazole+H-4'-phenyl); 7.29 (m, 2H, H-5', H-3'-phenyl);
7.43 (m, 2H, H-2', H-6'-phenyl); 8.91 (s, 1H, NH); 10.30 (bs, 1H,
NH). ESI (+)-MS: m/Z 262 (100, (M+H).sup.+);
[0466] N-(5-phenyl-1,3-thiazol-2-yl)-N'-phenyl-urea;
[0467] N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-phenyl-urea;
[0468] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-chloro-phenyl)-urea
m.p. 191-193.degree. C.
[0469] .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.16 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.00 (m, 1H, CH.sub.3CHCH.sub.3); 6.95
(d, 1H, J=1.0, H thiazole); 7.40 (d, 2H, J=8.9 m-phenyl); 7.26 (d,
2H, J=8.9 o-phenyl); 9.01 (bs, 1H, NH); 10.40 (bs, 1H, NH). ESI
(+)MS: m/z 296 (100, (M+H).sup.+);
[0470] N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-chloro-phenyl)-urea;
[0471] N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-chloro-phenyl)-urea;
[0472]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-chloro-phenyl)-urea;
[0473]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-chloro-phenyl)-urea;
[0474] N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-chloro-phenyl)-urea;
[0475] N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-chloro-phenyl)-urea;
[0476]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-chloro-phenyl)-urea;
[0477]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-chloro-phenyl)-urea
[0478] .sup.3H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.07 (m, 1H, CH.sub.3CHCH.sub.3); 7.07
(m, 2H, H-thiazole+H-4'-phenyl); 7.31 (dd, 1H, J=7.8, 7.8,
H-5'-phenyl); 7.47 (d, 1H, J=7.8H-3'-phenyl); 8.14 (d, 1H, J=7.8,
H-6'-phenyl); 8.80 (bs, 1H, NH); 11.01 (bs, 1H, NH). ESI (+)MS: m/z
296 (100, (M+H).sup.+);
[0479] N-(5-bromo-1,3-thiazol-2-yl)-N'-(2-chloro-phenyl)-urea m.p.
210-212.degree. C. .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm:
7.29 (s, 1H, H-thiazole); 7.02 (ddd, 1H, J=1.6, 7.6, 7.6,
H-4'-phenyl); 7.25 (ddd, 1H, J=1.6, 7.6, 7.6, H-5'-phenyl); 7.41
(dd, 1H, J=1.6, 7.6, H-3'-phenyl); 8.03 (dd, 1H, J=1.6, 7.6,
H-6'-phenyl); 8.58 (s, 1H, NH); 11.31 (bs, 1H, NH). ESI (+)MS: m/z
332 (100, (M+H).sup.+);
[0480] N-(5-phenyl-1,3-thiazol-2-yl)-N'-(2-chloro-phenyl)-urea;
[0481]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(2-chloro-phenyl)-urea;
[0482]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-methoxy-phenyl)-urea;
[0483] N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-methoxy-phenyl)-urea;
[0484]
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-methoxy-phenyl)-urea;
[0485]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-methoxy-phenyl)-urea;
[0486] N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-hydroxy-phenyl)-urea;
[0487]
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-hydroxy-phenyl)-urea;
[0488]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-hydroxy-phenyl)-area;
[0489] N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-hydroxy-phenyl)-urea;
[0490]
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-hydroxy-phenyl)-urea;
[0491]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-hydroxy-phenyl)-urea;
[0492] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-methoxy-phenyl)-urea;
m.p. 184-185.degree. C.;
[0493] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.7, CH.sub.3CHCH.sub.3); 3.07 (m, 1H, CH.sub.3CHCH.sub.3); 3.85
(s, 3H, OCH.sub.3); 6.92 (m, 1H, H-phenyl); 7.01 (m, 3H,
H-phenyl+H-thiazole); 8.07 (d, 1H, J=8.3, H-6'-phenyl); 8.80 (bs,
1H, NH); 10.82 (s, 1H, NH). ESI(+)-MS: m/z 292 (100,
(M+H).sup.+);
[0494] N-(5-bromo-1,3-thiazol-2-yl)-N'-(2-methoxy-phenyl-urea m.p.
218-220.degree. C.
[0495] .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 3.79 (s, 3H,
CH.sub.3O); 6.90-7.98 (2 m, 4H, phenyl); 7.36 (s, 1H, H thiazole);
8.57 (s, 1H, NH); 11.13 (bs, 1H, NH). ESI (+)MS: m/z 328 (100,
(M+H).sup.+
[0496]
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(2-methoxy-phenyl)-urea;
[0497]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(2-methoxy-phenyl)-urea;
[0498] N-(5-bromo-1,3-thiazol-2-yl)-N'-(2-hydroxy-phenyl)-urea;
[0499]
N-(5-phenyl-1,3-thiazol-2-yl)-N'-(2-hydroxy-phenyl)-urea;
[0500]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(2-hydroxy-phenyl)-urea;
[0501]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-nitro-phenyl)-urea;
[0502] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.14 (m, 1H, CH.sub.3CHCH.sub.3); 7.04
(s, 1H, H-thiazole); 7.74 (d, 2H, J=9.3, H-2', H-6'-phenyl); 8.18
(d, 2H, J=9.3, H-3', H-5'-phenyl); 9.65 (bs, 1H, NH); 11 (bs, 1H,
NH). ESI(+)-MS; m/z 307 (100, (M+H).sup.+);
[0503] N-(5-bromo-1,3-thiazol-2-yl)-N'-(4-nitro-phenyl)-urea;
[0504] N-(5-phenyl-1,3-thiazol-2-yl)-N'-(4-nitro-phenyl)-urea;
[0505]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(4-nitro-phenyl)-urea;
[0506] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-nitro-phenyl)-urea;
m.p. 220-222.degree. C.
[0507] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=6.9, CH.sub.3CHCH.sub.3); 3.05 (m, 1H, CH.sub.3CHCH.sub.3); 7.04
(s, 1H, H thiazole); 7.56 (dd, 1H, J=8.2, 8.2, H-5-phenyl); 7.77
(d, 1H, J=8.2, H-6'-phenyl); 7.83 (dd, 1H, J=8.2, 1.5,
H-4'-phenyl); 8.58 (d, 1H, J=1.5, H-2'-phenyl); 9.45 (s, 1H, NH);
10.60 (bs, 1H, NH).
[0508] ESI (+)MS: m/z 307 (100, (M+H).sup.+);
[0509] N-(5-bromo-1,3-thiazol-2-yl)-N'-(3-nitro-phenyl)-urea;
[0510] N-(5-phenyl-1,3-thiazol-2-yl)-N'-(3-nitro-phenyl)-urea;
[0511]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(3-nitro-phenyl)-urea;
[0512] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-benzyl-urea
[0513] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 4.31
(d, 2H, J=6.35, CH.sub.2); 6.96 (m, 1H, NH--CH.sub.2); 7.27 (m, 5H,
phenyl). ESI (+)MS: m/z 276 (100, (M+H).sup.+);
[0514] N-(5-bromo-1,3-thiazol-2-yl)-N'-benzyl-urea;
[0515] N-(5-phenyl-1,3-thiazol-2-yl)-N'-benzyl-urea;
[0516] N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-benzyl-urea;
[0517] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(pyrid-3-yl)-urea;
[0518] N-(5-bromo-1,3-thiazol-2-yl)-N'-(pyrid-3-yl)-urea;
[0519] N-(5-phenyl-1,3-thiazol-2-yl)-N'-(pyrid-3-yl)-urea;
[0520] N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(pyrid-3-yl)-urea;
[0521] N-(5-bromo-1,3-thiazol-2-yl)-N'-(pyrid-4-yl)-urea;
[0522] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(pyrid-4-yl)-urea;
[0523] N-(5-phenyl-1,3-thiazol-2-yl)-N'-(pyrid-4-yl)-urea;
[0524] N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(pyrid-4-yl)-urea;
[0525] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(pyrid-2-yl)-urea;
[0526] N-(5-bromo-1,3-thiazol-2-yl)-N'-(pyrid-2-yl)-urea;
[0527] N-(5-phenyl-1,3-thiazol-2-yl)-N'-(pyrid-2-yl)-urea;
[0528] N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(pyrid-2-yl)-urea;
[0529]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(benzothiophen-2-yl)-urea;
[0530]
N-(5-bromo-1,3-thiazol-2-yl)-N'-(benzothiophen-2-yl)-urea;
[0531] N-(5-phenyl-1,3-thiazol-2-yl)-N'-(benzothiophen-2-yl)-urea;
and
[0532]
N-(5-cyclopropyl-1,3-thiazol-2-yl)-N'-(benzothiophen-2-yl)-urea;
EXAMPLE 6
[0533] Preparation of a Compound of Formula (VI):
4-nitrophenyl-5-isopropy- -1-1,3-thiazol-2-ylcarbamate
[0534] To a solution of 4 g (28.13 mmol) of
5-isopropyl-2-amino-1,3-thiazo- -le in 30 ml of anhydrous
dichloromethane 5.7 g (28.13 mmol) of 4-nitrophenyl chloroformate
were added dropwise at 0.degree. C. under nitrogen. Then 2.3 ml of
pyridine were added. The mixture was maintained at room temperature
under stirring overnight and then filtered, giving 6.96 g (80%
yield) of the title compound as a white solid. m.p. 157-159.degree.
C.
[0535] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.06 (m, 1H, CH.sub.3CHCH.sub.3); 7.05
(s, 1H, H thiazole); 6.91 (d, 2H, J=9.2, H-3',5'-phenyl); 8.10 (d,
2H, J=9.2, H-2',6'-phenyl); 11.00 (bs, 1H, NH). El-MS: m/z 307
(0.5, M.sup.+); m/z 168 ((CH3).sub.2--CH-thiazole-NCO).sup.+; m/z
153 (100, (CH.sub.3--CH-thiazole-NCO).sup.+); m/z 139 (45,
(OH--C.sub.6H.sub.4--NO.- -sub.2).sup.+).
EXAMPLE 7
[0536] Preparation of a Compound of Formula (I):
N-(5-isopropyl-1,3-thiazo- -1-2-yl)-N'-(3-iodophenyl)urea
[0537] 1 g (3.25 mmol) of
4-nitrophenyl-5-isopropyl-1,3-thiazol-2-ylcarbam- -ate and 0.39 ml
(3.25 mmol) of 3-iodoaniline were suspended under argon in 25 ml of
acetonitrile. After 2 hours at 70.degree. C. the resulting solution
was cooled, giving rise 0.923 g of the title compound,
recrystallized from a mixture of diethylether/pentane 1/1.
[0538] m.p. 160-162.degree. C.
[0539] .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.05 (m, 1H, CH.sub.3CHCH.sub.3); 7.03
(d, 1H, J=0.8, H thiazole); 7.07 (t, 1H, J=8.0, H-5'-phenyl); 7.35
(m, 2H, H-4',6'-phenyl); 8.00 (t, 1H, J=1.8, 1.8, H-2'-phenyl);
9.06 (bs, 1H, NH); 10.50 (bs, 1H, NH).
[0540] ESI (+)-MS: m/z 388 (100, (M+H).sup.+).
[0541] By analogous procedure but employing
2-[(2-propynylamino)methyl]ben- zenesulfonamide,
2-{[{[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}(2-pro-
pynyl)amino]methyl}benzenesulfonamide can be prepared m.p.
90-92.degree. C.
[0542] .sup.1H-NMR (400 MHZ-DMSO) .delta.ppm: 1.19 (d, 6H, J=6.8,
CH.sub.3CHCH.sub.3); 2.93 (m, 1H, CH.ident.C--); 3.13 (m, 1H,
CH.sub.3CHCH.sub.3); 4.18, 5.08 (2 m, 4H,
CH.sub.2Ph+CH.sub.2C.ident.C); 6.89 (m, 1H, H-thiazole); 7.22 (m,
1H, H-3'-phenyl); 7.41, 7.53 (2m, 2H, H-5', H-4'-phenyl); 7.86 (m,
1H, H-6'-phenyl); 11.90 (bs, 1H, NH). ESI(+)-MS; m/z 415 (100,
(M+Na).sup.+); m/z 393 (50, (M+H).sup.+.
[0543] By analogous procedure but employing
1H-benzimidazol-6-amine,
N-(1H-benzimidazol-5-yl)N'-(5-iosopropyl-1,3-thiazol-2-yl)urea can
be obtained.
[0544] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.27 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.09 (m, 1H, CH.sub.3CHCH.sub.3); 7.01
(s, 1H, H-thiazole); 7.13 (d, 1H, H-6'-benzimidazole); 7.49 (d, 1H,
H-7'-benzimidazole); 7.81 (s, 1H, H-4'-benzimidazole); 8.03 (s, 1H,
H-2'-benzimidazole).
[0545] ESI(+)-MS; m/z 302 (100, (M+H).sup.+).
[0546] By analogous procedure but employing 1H-indole-6-amine,
N-(1H-indol-6-yl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea can be
prepared.
[0547] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.06 (m, 1H, CH.sub.3CHCH.sub.3); 7.03
(bs, 1H, H thiazole); 6.33 (m, 1H, H-3'-indole); 6.84 (d, 1H,
J=8.3, H-5'-indole); 7.23 (t, 1H, J=2.4, 2.4, H-2'-indole); 7.42
(d, 1H, J=8.3, H-4'-indole); 7.77 (s, 1H, H-7'-indole); 8.82 (s,
1H, NH); 10.18 (bs, 1H, NH); 10.95 (s, 1H, NH-indole).
[0548] ESI (+)-MS: m/z 301 (100, (M+H).sup.+).
[0549] By analogous procedure but employing 1H-indole-5-amine,
N-(1H-indol-5-yl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea can be
prepared.
[0550] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.06 (m, 1H, CH.sub.3CHCH.sub.3); 7.02
(s, 1H, H thiazole); 6.35 (m, 1H, H-3'-indole); 7.05 (dd, 1H,
J=2.0, J=8.5, H-6'-indole); 7.30 (m, 2H, H-2', H-7'-indole); 7.67
(d, 1H, J=2.0, H-4'-indole); 8.68 (s, 1H, NH); 10.15 (s, 1H, NH);
10.98 (s, 1H, NH-indole).
[0551] ESI (+)-MS: m/z 301 (100, (M+H).sup.+).
[0552] By analogous procedure but employing
imidazo[1,2-a]pyridin-2-ylmeth- -anamide, N-(imidazo
[1,2-a]pyridin-2-yl-methyl)-N'-(5-isopropyl-1,3-thiaz- ol-2-yl)urea
can be prepared.
[0553] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.04 (m, 1H, CH.sub.3CHCH.sub.3); 4.40
(d, 2H, J=5.6, CH.sub.2); 6.96 (d, 1H, J=1.2, H thiazole); 6.84
(dt, 1H, J=2.2, 6.8, H-6'-imidazopyridine); 7.20 (m, 1H,
H-5'-imidazopyridine); 7.47 (m, 1H, H-7'-imidazopyridine); 7.78 (s,
1H, H-3'-imidazopyridine); 8.49 (m, 1H, H-4'-imidazopyridine); 7.01
(t, 1H, J=5.4, NH--CH.sub.2); 10.23 (bs, 1H, NH--CO).
[0554] ESI(+)-MS: m/z 316 (100, (M+H).sup.+); m/z 338 (85,
(M+Na).sup.+).
[0555] By analogous procedure but employing
1-methyl-2-[(2-aminophenoxy)me- thyl]1H-imidazole,
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-{2-[(1-methyl-1H-im-
-idazol-2-yl)methoxy]phenyl}urea can be prepared.
[0556] .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.05 (m, 1H, CH.sub.3CHCH.sub.3); 3.70
(s, 3H, N--CH.sub.3); 5.21 (s, 2H, CH.sub.2); 6.92 (bs, 1H, H
thiazole); 6.90-8.20 (m, 6H, imidazole+phenyl); 8.10 (bs, 1H, NH);
10.96 (s, 1H, NH).
[0557] ESI(+)-MS: m/z 372 (95, (M+H).sup.+); m/z 410 (100,
(M+K).sup.+).
[0558] By analogous procedure but employing 2-(2-aminophenoxy)
acetamide,
N-(5-isopropyl-1,3thiazol-2-yl)-N'-(2-phenoxyacetamido)urea can be
prepared.
[0559] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=7.0, CH.sub.3CHCH.sub.3); 3.07 (m, 1H, CH.sub.3CHCH.sub.3); 4.50
(s, 2H, CH.sub.2); 7.05 (d, 1H, J=1.0, H thiazole); 6.50-7.00 (m,
3H, phenyl); 8.10 (m, 1H, phenyl), 7.55 (s, 2H, NH.sub.2), 8.67
(bs, 1H, NH); 10.86 (s, 1H, NH).
[0560] ESI(+)-MS: m/z 335 (50, (M+H).sup.+); m/z 373 (100,
(M+K).sup.+).
[0561] By analogous procedure but employing
(2S)-2-amino-2-phenylethanamid- -e,
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(S)-phenylglicinamido]urea can
be prepared.
[0562] .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.19 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.01 (m, 1H, CH.sub.3CHCH.sub.3); 5.26
(d, 1H, J=7.7 CH); 6.95 (s, 1H, H-thiazole); 7.20-7.60 (m, 6H,
NH--CH+phenyl); 7.20-7.80 (s, 2H, NH.sub.2), 10.26 (bs, 1H,
NH).
[0563] ESI(+)-MS: m/z 319 (25, (M+H).sup.+); m/z 357 (100,
(M+K).sup.+);
[0564] By analogous procedure but employing
(2R)-2-amino-2-phenylethanamid- -e,
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(R)-phenylglicinamido]urea can
be prepared.
[0565] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.19 (d, 6H,
J=7.0, CH.sub.3CHCH.sub.3); 3.01 (m, 1H, CH.sub.3CHCH.sub.3); 5.26
(d, 1H, J=7.6 CH); 6.95 (d, 1H, J=1.3, H thiazole); 7.20-7.50 (m,
6H, NH--CH+phenyl); 7.21-7.79 (s, 2H, NH.sub.2), 10.20 (bs, 1H,
NH).
[0566] ESI(+)-MS; m/z 319 (100, (M+H).sup.+); m/z 357 (65,
(M+K).sup.+).
[0567] By analogous procedure but employing 2-aminophenol,
N-(2-hydroxyphenyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea can be
prepared. m.p. 204-206.degree. C.
[0568] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.06 (m, 1H, CH.sub.3CHCH.sub.3); 7.02
(s, 1H, H-thiazole); 6.74 (m, 1H, H-5'-phenyl); 6.82 (m, 2H, H-3',
H-4'-phenyl); 7.98 (d, 1H, J=7.6, H-6'-phenyl); 8.60 (bs, 1H, NH);
10.0 (bs, 1H, NH); 10.80 (bs, 1H, OH). ESI(+)-MS; m/z 278 (100,
(M+H).sup.+).
[0569] By analogous procedure but employing 3-aminophenol,
N-(3-hydroxyphenyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea can be
prepared. m.p. 185-187.degree. C.
[0570] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.05 (m, 1H, CH.sub.3CHCH.sub.3); 7.03
(m, 3H, H-thiazole+H-2', H-5'-phenyl); 6.39 (d, 2H, J=8.0,
H-4'-phenyl); 6.77 (d, 2H, J=8.0, H-6'-phenyl); 8.81 (s, 1H, NH);
9.37 (s, 1H, NH). ESI(+)-MS: m/z 278 (100, (M+H).sup.+).
[0571] By analogous procedure but employing 4-aminophenol,
N-(4-hydroxyphenyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea can be
prepared. m.p. 130-132.degree. C.
[0572] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.05 (m, 1H, CH.sub.3CHCH.sub.3); 7.00
(s, 1H, H-thiazole); 6.68 (d, 2H, J=8.8, H-3', H-5'-phenyl); 7.21
(d, 2H, J=8.8, H-2', H-6'-phenyl); 8.60 (s, 1H, NH); 9.14 (s, 1H,
NH); 10.18 (bs, 1H, OH). ESI(+)-MS: m/z 278 (100, (M+H).sup.+).
[0573] By analogous procedure but employing
(2R)-2-amino-2-phenyl-1-ethano- -l,
N-[(1S)-2-hydroxy-1-phenylethyl[-N'-(5-isopropyl-1,3-thiazol-2-yl)urea
can be prepared.
[0574] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.20 (d, 6H,
J=7.0, CH.sub.3CHCH.sub.3); 3.01 (m, 1H, CH.sub.3CHCH.sub.3); 3.60
(s, 2H, CH.sub.2); 4.73 (m, 1H, CH); 5.00 (t, 1H, J=5.1, 5.1, OH)
6.95 (d, 1H, J=1.1, H thiazole); 7.10-7.40 (m, 6H, NH--CH+phenyl);
10.15 (s, 1H, NH). ESI(+)-MS: m/z 306 (100, (M+H).sup.+).
[0575] By analogous procedure but employing
(2S)-2-amino-2-phenyl-1-ethano- -1,
N-[(1R)-2-hydroxy-1-phenylethyl]-N'-(5-isopropyl-1,3-thiazol-2-yl)urea
can be prepared.
[0576] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.19 (d, 6H,
J=6.9, CH.sub.3CHCH.sub.3); 3.01 (m, 1H, CH.sub.3CHCH.sub.3); 3.59
(s, 2H, CH.sub.2); 4.73 (m, 1H, CH); 5.02 (t, 1H, J=5.1, 5.1, OH)
6.95 (d, 1H, J=0.7, H thiazole); 7.20-7.40 (m, 6H, NH--CH+phenyl);
10.17 (s, 1H, NH). ESI(+)-MS: m/z 306 (100, (M+H).sup.+).
EXAMPLE 8
[0577] Preparation of a Compound of Formula (I):
N-[3-(3-hydroxy-1-butynyl-
-)phenyl]-N'-(5-isopropyl-1,3-thiazol-2-yl)urea
[0578] To a solution of 0.2 g (0.56 mmol) of
N-(5-isopropyl-1,3-thiazol-2-- yl)-N'-(3-iodophenyl)urea in 3 ml of
anhydrous N,N-dimethylformamide 0.6 ml of tetramethylguanidine,
0.088 ml (1.126 mmol) of D,L-1-butyn-3-ol, 19 mg (0.027 mmol) of
bis(triphenyiphosphine) palladium(II)dihydrochioride and 5.8 mg
(0.03 mmol) of rameous iodide under argon were added successively.
After 5 hours water was added and the mixture extracted with
ethylacetate. The organic layer was washed with brine, dried over
sodium sulfate and evaporated, giving 0.116 g of the title compound
as a yellowish solid. m.p. 71-73.degree. C.
[0579] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=6.9, CH.sub.3CHCH.sub.3); 3.06 (m, 1H, CH.sub.3CHCH.sub.3); 1.37
(s, 3H, J=6.6CH.sub.3); 4.57 (t, 1H, CH); 5.43 (d, 1H, J=5.1, OH)
7.03 9s, 1H, H thiazole); 7.02 (d, 1H, J=8.0, H-4'-phenyl); 7.27
(t, 1H, J=8.0, 8.0, H-5'-phenyl); 7.34 (d, 1H, J=8.0, H-6'-phenyl);
7.65 (s, 1H, H-2'phenyl); 8.02 (s, 1H, NH); 10.40 (bs, 1H, NH).
ESI(+)-MS: m/z 330 (100, (M+H).sup.+).
[0580] By analogous procedure and by starting from
N,N-dimethyl-2-propyl-1- -amine,
N-{3-[3-(dimethylamino)-1-propynyl]phenyl}-N'-(5-isopropyl-1,3-thi-
-azol-2-yl)urea can be prepared;
[0581] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.05 (m, 1H, CH.sub.3CHCH.sub.3); 2.23
(s, 2H, N(CH.sub.3).sub.2); 3.44 (s, 2H, CH.sub.2); 7.03 (s, 1H,
H-thiazole); 7.05 (d, 1H, J=7.8, H-4'-phenyl); 7.27 (t, 1H, J=7.8,
7.8, H-5'-phenyl); 7.36 (d, 1H, J=7.8, H-6'-phenyl); 7.64 (s, 1H,
H-2'-phenyl); 9.04 (bs, 1H, NH); 10.45 (bs, 1H, NH). ESI(+)-MS: m/z
343 (100, (M+H).sup.+).
[0582] By analogous procedure and by starting from
3-methoxy-l-propyne,
N-[3-(3-methoxy-1-propynyl]phenyl]-N'-(5-isopropyl-1,3-thiazol-2-yl)urea
can be prepared;
[0583] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.05 (m, 1H, CH.sub.3CHCH.sub.3); 3.32
(s, 3H, CH.sub.3); 4.31 (s, 2H, CH.sub.2); 7.03 (s, 1H, H-thiazole)
7.08 (d, 1H, J=8.3, H-4'-phenyl); 7.29 (t, 1H, J=8.3, 8.3,
H-5'-phenyl); 7.39 (d, 1H, J=8.3, H-6'-phenyl); 7.67 (s, 1H,
H-2'-phenyl); 9.03 (s, 1H, NH); 10.40 (bs, 1H, NH). ESI(+)-MS; m/z
330 (100, (M+H).sup.+).
EXAMPLE 9
[0584] Preparation of a Compound of Formula (I):
N-(5-isopropyl-1,3-thiazo- -1-2-yl)-N'-(3-aminophenyl)urea
[0585] A mixture of 1.55 g (5.05 mmol) of
(5-isopropyl-1,3-thiazol-2-yl)-N- -'-(3-nitrophenyl) urea prepared
as described in example 5 and 0.98 g ((17.7 inimol) of iron dust
with 2.02 ml (35.35 mmol) of glacial acetic acid in 50 ml of
ethanol was stirred at reflux under argon atmosphere. After 5 hours
1.5 l of water was added and the product extracted with
ethylacetate. The organic layer was washed with brine, dried over
sodium sulfate and evaporated. The residue was finally purified by
chromatography on a silica gel column (chloroform/methanol 47/3)
giving 0.84 g of the title compound as a white solid. m.p.
113-115.degree. C.
[0586] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.05 (m, 1H, CH.sub.3CHCH.sub.3); 5.07
(s, 2H, NH.sub.2); 7.02 (s, 1H, H-thiazole); 6.20 (dd, 1H, J=2.0,
7.8, H-4'-phenyl); 6.52 (dd, 1H, J=1.5, 8.3, H-6'-phenyl); 6.76
(bs, 1H, H-2'-phenyl); 6.89 (t, 1H, J-8.3, 8.3, H5'-phenyl); 8.61
(s, 1H, NH); 10.13 (bs, 1H, NH). ESI(+)-MS: m/z 277 (100,
(M+H).sup.+).
[0587] By analogous procedure and by starting respectively from
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-nitrophenyl)urea and
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-nitrophenyl)urea, the
following compounds can be prepared:
[0588] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-aminophenyl)urea;
[0589] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-aminophenyl)urea;
[0590] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.22 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.04 (m, 1H, CH.sub.3CHCH.sub.3); 4.83
(s, 2H, NH.sub.2); 6.99 (s, 1H, H-thiazole); 6.50 (d, 2H, J=8.7,
H-3', H-5'-phenyl); 7.05 (d, 2H, J=8.7, H-2', H-6'-phenyl); 8.42
(s, 1H , NH); 10.09 (bs, 1H, NH). ESI(+)-MS: m/z 277 (100,
(M+H).sup.+).
[0591] Again by analogous procedure, and by starting respectively
from 6-nitro-1H-indole and from 6-nitro-1H-benzimidazole,
1H-indol-6-amine and 1H-benzimidazol-6-amine can be prepared.
EXAMPLE 10
[0592] Preparation of a Compound of Formula (I):
N-[4-({[(5-isopropyl-1,3--
thiazol-2-yl)amino]phenyl]methanesulfonamide
[0593] 0.2 g (0.724 mmol) of
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-aminop- -henyl)urea were
dissolved in 10 ml of absolute ethanol and 0.2 g (1.95 mmol) of
potassium hydrogen carbonate and 124.3 mg (1.0855 mmol) of
methanesulfonylchloride were added successively. The mixture was
maintained at 80.degree. C. under argon for 7 hours and then
evaporated. The residue was partitioned between water and
dichloromethane. The organic layer was then dried over sodium
sulfate and afforded, after concentration and cooling, 104 mg of
the title compound as a white solid. m.p. 246-248.degree. C.
[0594] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.06 (m, 1H, CH.sub.3CHCH.sub.3); 2.97
(s, 3H, CH.sub.3); 7.03 (s, 1H, H-thiazole); 6.84 (d, 1H, J=6.8,
H-6'-phenyl); 7.19 (m, 2H, H-4', H-5'-phenyl); 7.39 (s, 1H,
H-2'-phenyl); 9.00 (s, 1H, NH); 9.72 (bs, 1H, NH); 10.18 (bs, 1H,
NHSO.sub.2). ESI(+)-MS; m/z 355 (100, (M+H).sup.+).
EXAMPLE 11
[0595] Preparation of a Compound of Formula (I):
2-[3-({[5-isopropyl-1,3-t- -hiazol-2-yl) amino]carbonyl}amino)
anilino]acetamide
[0596] To a solution of 0.2 g (0.724 mmol) of
N-(5-isopropyl-1,3-thiazol-2- -yl)-N'-(3-aminophenyl)urea in 2 ml
of N,N-dimethylformamide, 100 mg (0.724 mmol) of 2-bromoacetamide
and 108.6 mg (1.95 mmol) of potassium hydrogencarbonate were added
successively. The mixture was maintained 8 hours at 40.degree. C.
under argon, then poured into water and extracted with
dichloromethane. The organic layer was then washed with brine,
dried over sodium sulfate and concentrated to give, after cooling,
160 mg of the title compound. m.p. 133-135.degree. C.
[0597] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.06 (m, 1H, CH.sub.3CHCH.sub.3); 3.54
(s, 2H, J=5.4, CH.sub.3); 7.02 (s, 1H, H-thiazole); 5.88 (m, 1H,
NH--CH.sub.2) 6.21 (d, 1H, J=7.8, H-4'-phenyl); 6.65 (d, 1H, J=7.8,
H-6'-phenyl); 6.69 (s, 1H, H-2'-phenyl); 6.98 (t, 1H, J=7.8, 7.8,
H-5'-phenyl); 8.71 (s, 1H, NH); 10.11 (s, 1H, NH); 7.08, 7.29 (s,
2H, NH.sub.2). ESI(+)-MS; m/z 334 (100, (M+H).sup.+).
EXAMPLE 12
[0598] Preparation of (2R)-2-amino-2-phenylethanamide
[0599] 3.025 g (15 mmol) of (2R)-2-amino-2-phenylethanoate
hydrochloride were suspended in 45 ml of dioxane and 45 ml of
aqueous ammonium hydrate were added. After 8 hours at room
temperature under stirring the solvent was evaporated and the
residue redissolved with chloroform and washed with water. The
organic layer was concentrated to afford 1.7 g of the title
compound as a white solid.
[0600] By analogous procedure and by starting from
(2S)-2-amino-2-phenylet- -hanoate, (2S)-2-amino-2-phenylethanamide
can be prepared.
EXAMPLE 13
[0601] Preparation of
1-methyl-2-[(2-nitrophenoxy)methyl]-1H-imidazole
[0602] A solution of 1.92 g (11.97 mmol) of o-nitrophenol sodium
salt, 3.8 g (35.9 mmol) of sodium carbonate, 2 g (11.97 mmol) of
1-methyl-2-chloromethylimidazole hydrochloride in 30 ml of
N,N-dimethylformamide were heated at 50.degree. C. for 2 hours. The
mixture was then poured into water and extracted with ethylacetate.
The organic layer was washed with brine, dried over sodium sulfate.
and evaporated, affording 1.17 g of the title compound,
recrystallized from diethylether. m.p. 172-174.degree. C.
[0603] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 3.67 (d, 3H,
CH.sub.3); 5.34 (s, 2H, OCH.sub.2); 6.86 (s, 1H, H-4-imidazole);
7.13 (m, 1H, H-6-phenyl); 7.19 (s, 1H, H-5-imidazole); 7.60 (m, 1H,
H-3 phenyl). EST(+)MS: m/z 234 (100, (M+H).sup.+).
[0604] By analogous procedure and by starting from
2-chloroacetamide, 2-(2-nitrophenoxy)acetamide can be prepared.
m.p. 190-192.degree. C.
[0605] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 4.65 (s, 2H,
CH.sub.2); 7.14 (ddd, 1H, J=1.0, 7.5, 7.9, H-4); 7.22 (dd, 1H,
J=1.0, 8.7); H-6); 7.32, 7.47 (2 bs, 2H, CONH.sub.2); 7.64 (ddd,
J=1.5, 7.5, 8.7, H-5); 7.90 (dd, 1H, J=1.5, 7.9, H-3). ESI(+)MS:
m/z 197 (100, (M+H).sup.+).
EXAMPLE 14
[0606] Preparation of
1-methyl-2-[(2-aminophenoxy)methyl]-1H-imidazole
[0607] A solution of 1.13 g of
1-methyl-2-[(2-nitrophenoxy)methyl]-1H-imid- -azole in 70 ml of
methanol with 0.14 g of palladium on charcoal 10% was hydrogenated
at 50 psi for 6 hours at room temperature. The catalyst was then
separated by filtration and the solvent evaporated. The residue was
finally purified by chromatography on a silica gel column (eluent:
chloroformmethanol 48/2) giving rise 0.856 g of the title compound
as a red oil.
[0608] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 3.72 (s, 3H,
CH.sub.3); 3.80 (bs, 2H, NH.sub.2); 5.15 (s, 2H, H-3+H-4-phenyl);
6.81 (m, 1H, H-5-phenyl); 6.90 (s, 1H, H-4-imidazole); 7.02 (m, 2H,
H-6-phenyl+H-5-imidazole). ESI(+)MS: m/z 204 (100,
(M+H).sup.+).
[0609] By analogous procedure and by starting from
2-(2-nitrophenoxy)aceta- -mide, 2-(2aminophenoxy)acetamnide can be
prepared. m.p. 114-116.degree. C.
[0610] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 4.30 (s, 2H,
CH.sub.2CO); 5.03 (s, 2H, NH.sub.2); 6.45 (m, 1H, H-5); 6.61 (m,
1H, H-3); 6.67 (m, 1H, H-4); 6.72 (m, 1H, H-6); 7.45 (s, 1H, CONH);
7.73 (s, 1H, CONH.sub.2). ESI(+)MS: m/z 167 (100, (M+H).sup.+).
EXAMPLE 15
[0611] Preparation of
2-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-isoindole-1,- -3(2H)-dione
4 g (0.024 mol) of 2-(chloromethyl)imidazo[1,2a]pyridine were
dissolved in 140 ml of N,N-dimethylformamide and 4.81 g (0.026 mol)
of potassium ftalimide were added portionwise. The mixture was
heated at 60.degree. C. for 20 hours. The precipitate was filtered,
washed with water, diethylether and finally tetrahydrofuran,
affording 4.8 g of the title compound. m.p. 230-232.degree. C.
[0612] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 4.88 (s, 2H,
CH.sub.2); 6.82 (m, 1H, H-6-imidazopyridine); 7.17 (m, 1H,
H-5-imidazopyridine); 7.44 (m, 1H, H-7-imidazopyridine); 7.88 (m,
4H, H-phenyl); 8.42 (m, 1H, H-4-imidazopyridine). ESI(+)MS: m/z 278
(100, (M+H).sup.+).
EXAMPLE 16
[0613] Preparation of imidazo[1,2-a]pyridin-2-ylmethanamine
[0614] A solution of 1.37 g (4.94 mmol) of
2-(imidazo[1,2-a]pyridin-2-ylme- -thyl)-1H-isoindole-1,3(2H)-dione
in a 14 ml of hydrazine hydrate 98% and 1 ml of ethanol. Was
stirred at room temperature for an hour. The mixture was then
poured into 25 ml of sodium hydroxide 35% and extracted with
dichloromethane. The organic layer was dried over anhydrous sodium
sulfate and evaporated to give 0.426 g of the title compound
crystallized from diethylether. m.p. 91-93.degree. C.
[0615] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.98 (s, 2H,
NH.sub.2); 3.78 (s, 2H, CH.sub.2); 6.80 (m, 1H, H-5); 7.15 (m, 1H,
H-5); 7.41 (m, 1H, H-7); 7.73 (m, 1H, H-3); 8.46 (m, 1H, H-4).
ESI(+)MS: m/z 148 (100, (M+H).sup.+).
EXAMPLE 17
[0616] Preparation of the Polymer Supported Compound (VIII)
[0617] A solution of 8.72 g (69.1 mmol) of 4-mercaptophenol in 20
ml of dry N,N-dimethylformamide was added dropwise to a solution of
7.76 g (69.1 mmol) of potassium t-butoxyde in 120 ml of the same
solvent, under argon atmosphere, at 5.degree. C., over a period of
20 minutes. 25 g (19.75 mmol) of the Merrifield resin (VII)
(Novabiochem loading 0.79 mmol/g) was added to the solution and the
temperature was kept to 60.degree. C. The mixture was gently
stirred at 60.degree. C. for 18 hours and at 22.degree. C. for 24
hours. The resin was then filtered, washed with
N,N-dimethylformamide, dichloromethane, methanol and evaporated.
The loading of 4-mercaptophenol on the resin was calculated from
the percentage of sulfur determined via microanalysis: S 2.64%;
loading 0.755 mmol S/g. The presence of OH group was confirmed via
DRIFTS (broad strong band 3180-3520 nn).
EXAMPLE 18
[0618] Preparation of the Polymer Supported Compound (IX)
[0619] 7.98 g (39.6 mmol) of 4-nitrophenylchloroformate and 4.35 ml
(39.6 mmol) of N-methylmorpholine were added to 24 g (19.8 mmol) of
the polymer supported compound (VIII) swelled in 200 ml of
dichloromethane under argon atmosphere. The mixture was stirred at
22.degree. C. for 22 hours. The obtained compound (IX) was
filtered, washed with dichloromethane, methanol and evaporated
under vacuum. The loading of 4-nitro-phenylchloroformate on the
resin was calculated from the percentage of sulfur determined via
microanalysis: S 2.34%; loading 0.731 mmol S/g. The disappearance
of the OH band (broad strong band 3400 nm) and the appearance of
carbonate group were monitored via DRIFTS (strong band 1785
nm).
EXAMPLE 19
[0620] Preparation of a Polymer Supported Compounds (X)
[0621] A solution of 2-amino-5-isopropyl-1,3-thiazole (39.6 mmol)
in 12.5 ml of dichloromethane was added to the polymer supported
compound (IX) (19.8 mmol) swelled in 200 ml of dichloromethane
under argon atmosphere. The mixture was stirred at 22.degree. C.
for 22 hours. The obtained compound (X) was filtered, washed with
dichloromethane, methanol and evaporated under vacuum. The loading
of 2-amino-5-isopropyl-1,3-thiazole on the resin was calculated
from the percentage of sulfur determined via microanalysis: S
4.21%; loading 0.724 minol S/g. The presence of carbamate group was
confirmed via DRIFTS (strong band 1742 nm).
EXAMPLE 20
[0622] Preparation via Parallel Synthesis of the Compounds of
Formula (I)
[0623] The amines (V) (0.236 mmol) and N,N-diisopropylethylamine
(0.236 mmol) were added to the polymer supported compounds (X)
(0.118 mmol) swelled in 3 ml of toluene in the Argonaut Quest 210
apparatus vessels. 128 mg (4 eq) of N,N-diisopropylethylamine resin
bounded (PS-DIEA loading 3.68 mmol/g) was used whenever the amines
were in the salified form. The reactions were stirred for 22 hours
at 60.degree. C., then the reaction mixtures were filtered and the
resin washed with dichloromethane. The liquid phase, recovered in
Climax test tubes, was evaporated under nitrogen flux at 35.degree.
C. using Liebisch Termochem Metal-block thermostat. The obtained
crude products were triturated with diethylether-dichloromethane
and the resulting solids were filtered on frit equipped syringes
(Alltech extract-clean filter tubes 1.5 ml, Alltech Teflon frits
for 1.5 ml tubes). The products were finally dried under
vacuum.
[0624] Employing this procedure and using the suitable amine the
following compounds can be prepared:
[0625] N-(5-isopropyl-1,3-thiazol-2-yl)-4-morpholine
carboxamide;
[0626]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-methylphenyl)urea;
[0627]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-fluorophenyl)urea;
[0628] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-cyanophenyl)urea;
[0629] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-cyanophenyl)urea;
[0630]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,6-dimethylphenyl)urea;
[0631]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-fluorobenzyl)urea;
[0632]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-acetylphenyl)urea;
[0633] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=7.0, CH.sub.3CHCH.sub.3); 3.06 (m, 1H, CH.sub.3CHCH.sub.3); 2.55
(s, 3H, COCH.sub.3); 7.32 (t, 1H, J=7.6, H-5'-phenyl); 7.44 (t, 1H,
J=7.9, H-5'-phenyl); 7.5-7.8 (m, 2H, H-4', H-6'-phenyl); 8.08 (s,
1H, H-2'-phenyl); 7.04 (s, 1H, H-thiazole); 9.2 (bs, 1H,
CONH-phenyl); 10.5 (bs, 1H, NHCONHPh);
[0634]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-acetylphenyl)urea;
[0635]
3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzoic
acid;
[0636]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-isopropylphenyl)urea;
[0637]
3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzamide
[0638] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.05 (ept, 1H, J=6.8,
CH.sub.3CHCH.sub.3); 7.32 J=7.6, H-5'-phenyl); 7.35 (t, 1H, J=1.5,
H-2'-phenyl); 7.49 (d, 1H, J=7.6, H-6'-phenyl); 7.62 (dd, 1H,
J=7.6, 1.5, H-4'-phenyl); 7.04 (s, 1H, H-thiazole); 9.64 (s, 1H,
CONH-phenyl); 10.36 (s, 1H, NHCONHPh);
[0639]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-methoxybenzyl)urea;
[0640] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-butylphenyl)urea;
[0641]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-trifluoromethylphenyl)urea;
[0642] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-bromophenyl)urea;
[0643]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-cyclohexyphenyl)urea;
[0644]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-phenoxyphenyl)urea
[0645] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=7.0, CH.sub.3CHCH.sub.3); 3.05 (m, 1H, CH.sub.3CHCH.sub.3); 6.96
(m, 4H, H-3', H-5'-phenyl, H-2', H-6'-phenyl); 7.02 (s, 1H,
H-thiazole); 7.08 (m, 1H, H-4'-phenoxy); 7.35 (m, 2H, H-3',
H-5'-phenoxy); 7.47 (m, 2H, H-2', H-6'-phenyl); 8.95 (bs, 1H,
CONH-phenyl); 10.3 (bs, 1H, NHCONH);
[0646]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-benzyloxphenyl)urea;
[0647]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,5-dimethylphenyl)urea
[0648] .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.05 (ept, 1H, J=6.8,
CH.sub.3CHCH.sub.3); 2.22 (s, 6H, 2CH.sub.3); 6.65-7.06 (m, 3H,
H-phenyl); 7.02 (s, 1H, H-thiazole); 6.71 (s, 1H, H-phenyl); 6.72
(s, 1H, H-phenyl); 8.75 (bs, 1H, CONH-phenyl); 10.3 (bs, 1H,
NHCONH). ESI(+)-MS: m/z 362 (100,(M+H).sup.+);
[0649]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,3-dimethylphenyl)urea;
[0650]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-methoxy[1,1'-biphenyl]-4-yl)-
- urea;
[0651]
N-(5-isopropyl-1,3-thiazol-2-yl)-3,4-dihydro-2(1H)-isoquinoline
carboxamide;
[0652] N-benzyl-N'-(5-isopropyl-1,3-thiazol-2-yl)-N-methylurea;
[0653]
N-(5-isopropyl-1,3-thiazol-2-yl)-6,7-dimethoxy-3,4-dihydro-2(1H)-is-
-oquinoline carboxamide
[0654] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.4, CH.sub.3CHCH.sub.3); 2.99 (ept, 1H, J=6.8,
CH.sub.3CHCH.sub.3); 2.7 (t, 2H, J=5.5, CH.sub.2NCH.sub.2CH.sub.2);
3.68 (t, 2H, J=5,5, CH.sub.2NCH.sub.2CH.sub.2); 3.69 (s, 3H,
OCH.sub.3); 3.71 (s, 3H, OCH.sub.3); 4.55 (s, 2H,
CH.sub.2NCH.sub.2CH.sub.2); 6.97 (s, 1H, H-thiazole); 6.71 (s, 1H,
H-phenyl); 6.72 (s, 1H, H-phenyl); 10.7 (bs, 1H, NH). ESI(+)-MS:
m/z 362 (100, (M+H).sup.+).
[0655]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(3-chloro-4-methyl)-phenyl]ure-
- a;
[0656]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(3-chloro-6-methyl)phenyl]urea-
-;
[0657]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,5-dimethoxyphenyl)urea
[0658] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=7.0, CH.sub.3CHCH.sub.3); 3.07 (m, 1H, J=7.0,
CH.sub.3CHCH.sub.3); 3.68, 3.80 (two s 6H, 2-OCH.sub.3); 7.04 (d,
J=1.0, 1H, H-thiazole); 6.53 (dd, 1H, J=3.0, 8.9, H-4'-phenyl);
6.93 (d, 1H, J=8.9, H-3'-phenyl); 7.79 (d, 1H, J=3.0, H-6'-phenyl);
8.7 (bs, 1H, NHPh); 10.9 (bs, 1H, NHCONHPh).
[0659]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,4-dimethoxyphenyl)urea
[0660] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=7.0, CH.sub.3CHCH.sub.3); 3.05 (ept, 1H, J=7.0,
CH.sub.3CHCH.sub.3); 3.7 (s, 3H, OCH.sub.3); 3.73 (s, 3H,
OCH.sub.3); 7.02 (s, 1H, H-thiazole); 6.8-7.2 (m, 3H, H-phenyl);
8.76 (s, 1H, NHCONHPh); 10.2 (s, 1H, NHCONHPh);
[0661]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(2-methoxy-5-chloro)phenyl]ure-
-a;
[0662]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-((2-chloro-4-methoxyphenyl)urea-
-;
[0663]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,5-dichlorophenyl)urea;
[0664] N-[(1,1
'-biphenyl)-2-yl]-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0665] N-ethyl-N'-(5-isopropyl-1,3-thiazol-2-yl)-N-phenylurea;
[0666]
N-[4-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-2-metho-
xyphenyl]acetamide;
[0667]
2-({[(5-isopropyl-1,3-thiazol-2-yl)arnino]carbonyl}amino)-N-phenylb-
enzamide;
[0668]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-morpholinophenyl)urea;
[0669] N-[4-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)
phenyl]-N-methyl acetamide
[0670] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.22 (d, 6H,
J=6.6, CH.sub.3CHCH.sub.3); 3.08 (m, 1H, CH.sub.3CHCH.sub.3); 1.73
(s, 3H, NCOCH.sub.3); 7.03 (s, 1H, H-thiazole); 3.09 (s, 3H,
CH.sub.3NCOCH.sub.3); 7.23 (d, 2H, J=8.1, H-6', H-4'-phenyl); 7.51
(d, 2H, J=8.1, H-5', H-3'-phenyl); 9.1 (bs, 1H, NHCONHPh); 10.4
(bs, 1H, NHCONHPh);
[0671]
N-(2-{[cyclophexyl(methyl)amino]methyl}phenyl)-N-(5-isopropyl-1,3-t-
hiazol-2-yl)urea;
[0672]
N-[3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-4-metho-
xyphenyl]acetamide;
[0673]
N-(5-isopropyl-1,3-thiazol-2-yl)-4-(4-methoxyphenyl)-1-piperazine
carboxamide;
[0674] N-(2-furylmethyl-N'-(5-isopropyl-1,3-thiazol-2-yl)urea
[0675] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 2.99 (ept, 1H, J=6.8,
CH.sub.3CHCH.sub.3); 4.32 (d, 2H, J=5.6, NHCH.sub.2); 6.26 (d, 1H,
J=3, H-5'-furyl); 6.4 (d, 1H, J=3, H-4'-furyl); 6.98 (s, 1H,
H-thiazole); 6.93 (t, 1H, NHCH.sub.2); 7.59 (s, 1H, H-3'-furyl);
10.19 (bs, 1H, NHCO). ESI(+)-MS: m/z 266 (100, (M+H).sup.+);
[0676]
N-(4-fluorophenyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0677]
N-(2-methoxybenzyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0678]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[2-(1-methyl-1H-pyrrol-2-yl)eth-
yl]urea;
[0679]
N-(3,4-dimethoxybenzyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea
[0680] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=7.0, CH.sub.3CHCH.sub.3); 3.01 (ept, 1H, J=7.0,
CH.sub.3CHCH.sub.3); 3.69 (s, 3H, OCH.sub.3); 3.72 (s, 3H,
OCH.sub.3); 4.22 (d, 2H, J=5.0, NHCH.sub.2Ph); 6.8-6.9 (m, 3H,
H-phenyl); 6.96 (s, 1H, H-thiazole);
[0681]
N-(5-isopropyl-1,3-thiazol-2-yl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4-
-5]decane-8-carboxamide
[0682] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.03 (ept, 1H, J=6.8,
CH.sub.3CHCH.sub.3); 1.62 (d, 2H, J=13.6, H-3'eq,
H-5'-eq-piperidine); 2.4 (td, 2H, J=13.6, 5.1, H-3'ax,
H-5'ax-piperidine); 3.46 (bt, 2H, J=10.4, H-6'ax,
H-2'ax-piperidine); 4.14 (bd, 2H, J=10.4, H-6'eq,
H-2'eq-piperidine); 4.58 (s, 2H, CONHCH.sub.2NPh); 6.6-6.7 (m, 3H,
H-2', H-6', H-4'-phenyl); 7.14 (t, 2H, J=7.5, H-3', H-5'-phenyl);
6.98 (bs, 1H, H-thiazole); 8.75 (bs, 1H, CONHCH.sub.2NPh); 10.85
(bs, 1H, thiazole-NHCON);
[0683]
N-(5-isopropyl-1,3-thiazol-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane-8--
carboxamide;
[0684]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[2-(1-piperidinyl)ethyl]urea;
[0685]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[2-(1-morpholinyl)ethyl]urea;
[0686]
4-(4-fluorophenyl)-N-(5-isopropyl-1,3-thiazol-2-yl)-1-piperazine
carboxamide;
[0687]
N-[4-(4-chlorophenyl)-3-ethyl-5-isoxazolyl]-N'-(5-isopropyl-1,3-thi-
-azol-2-yl)urea;
[0688]
N-[(4-fluorophenyl)(hydroxy)methyl]-N-(5-isopropyl-1,3-thiazol-2-yl-
-)-1-piperidine carboxamide;
[0689]
N-(3-ethynylphenyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0690]
N-(2-methoxy-3-fluorophenyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0691]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-oxo-1-piperidinyl)urea;
[0692]
N-(3-acetylaminophenyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0693]
N-[3-(2-furyl)-1H-pyrazol-5yl]-N'-(5-isopropyl-1,3-thiazol-2-yl)ure-
-a
[0694]
N-{4-[ethyl(isopropyl)amino]phenyl}-N'-(5-isopropyl-1,3-thiazol-2-y-
l)urea;
[0695]
N-(1,3-benzodioxol-5-yl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0696]
5-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-1-phenyl-1-
H-pyrazole-4-carboxamide;
[0697]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-pyridinylmethyl)urea;
[0698] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-pyrazinyl)urea;
[0699]
n-(5-isopropyl-1,3-thiazol-2-yl)-N'-(5-phenyl-1,3,4-oxadiazol-2-yl)-
-urea;
[0700]
N-(5-isopropyl-1,3-thiazol-2-yl)-4-(2-oxo-2,3-dihydro-1H-benzimidaz-
-ol-1-yl)-1-piperidine carboxamide
[0701] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.23 (d, 6H,
J=7.0, CH.sub.3CHCH.sub.3); 3.01 (ept, 1H, J=7.0,
CH.sub.3CHCH.sub.3); 1.69 (bd, 2H, J=9.8, H-3'eq,
H-5'-eq-piperidine); 2.21 (m, 2H, H-3'ax, H-5'ax-piperidine); 3.46
(bt, 2H, J=12.4, H-2'ax, H-6'eq-piperidine); 4.14 (m, 3H, H-2'eq,
H-6'eq, H-4'ax-piperidine); & 9-7.2 (m, 4H, aromatics); 6.98
(s, 1H, H-thiazole); 10.8 (bs, 2H, NHCONH);
[0702]
N-(1,3-benzothiazol-6-yl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0703] .sup.1H-NMR (400 MHz- DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.05 (ept, 1H, J=6.8,
CH.sub.3CHCH.sub.3); 7.5 (dd, 1H, J=8.8, 1.9, H-5'-benzothiazole);
7.98 (d, 1H, J=8.8, H-4'-benzothiazole); 8.38, (d, 1H, J=1.9,
H-7'-benzothiazole); 9.22 (s, 2H, H-2'-benzothiazole+NHCONHPh);
7.04 (s, 1H, H-thiazole); 10.41 (s, 1H, NHCONHPh);
[0704]
N-(1,3-dimethyl-1H-pyrazol-5-yl)-N'-(5-isopropyl-1,3-thiazol-2-yl)u-
-rea;
[0705]
N-(3-phenyl-1-methyl-1H-pyrazol-5yl)-N'-(5-isopropyl-1,3-thiazol-2--
yl)urea;
[0706] N-(5-isopropyl-1,3-thiazol-2-yl)-3-hydroxy-1-piperidine
carboxamide;
[0707]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-methyl-1,3-dioxo-2,3-dihydro-
-1H-isoindol-5-yl)urea;
[0708] N-(5-isopropyl-1,3-thiazol-2-yl)-4-benzyl-1-piperazine
carboxamide;
[0709] N-(5-isopropyl-1,3-thiazol-2-yl)-4-methyl-1-piperazine
carboxamide;
[0710] 4-hydroxy-N-(5-isopropyl-1,3-thiazol-2-yl)-1-piperidine
carboxamide;
[0711]
N-(5-isopropyl-1,3-thiazol-2-yl)-3-azabicyclo[3.2.2]nonane-3-carbox-
amide;
[0712]
N-(5-isopropyl-1,3-thiazol-2-yl)-4-(4-acetylphenyl)-1-piperazine
carboxamide;
[0713] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=7.0, CH.sub.3CHCH.sub.3); 2.99 (ept, 1H, J=7.0, CHCH.sub.3); 2.44
(s, 3H, CH.sub.3COPh); 3.29 (bt, 4, CH.sub.2-2',6'-piperazine);
3.63 (bt, 4H, CH.sub.2-3',5'-piperazine); 6.97 (d, 2H, J=9.2,
H-3',5'-phenyl); 7.8 (d, 2H, J=9.2, H-2',6'-phenyl) 6.97 (s, 1H,
H-thiazole); 10.95 (bs, 1H, NHCON);
[0714]
4-[bis(4-fluorophenyl)-N-(5-isopropyl-1,3-thiazol-2-yl)-1-piperazin-
-e carboxamide;
[0715]
N-(5-isopropyl-1,3-thiazol-2-yl)-4-oxo-2,3,4,5-tetrahydro-1-1,5-ben-
zodiazepine-1-carboxamide;
[0716] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(5
,6,7,8-tetrahydro-1-naphtale- n-yl)urea;
[0717]
N-(4-phenyl-2-thiazolyl)-N'-(5-isopropyl-1,3-thiazol-2-yl)urea;
[0718]
4-(4-fluorobenzoyl)-N-(5-isopropyl-1,3-thiazol-2-yl)-1-piperidine
carboxamide;
[0719]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-1,3-dihydro-2-benzofuran-5-yl)u-
-rea;
[0720]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-pyrimidinyl)-1-piperazine
carboxamide;
[0721] N-(5-isopropyl-1,3-thiazol-2-yl)-3-oxo-3,4-dihydro-1
(2H)-quinoxalin-e;
[0722]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(1H-indazol-6-yl)urea
[0723] .sup.1H-NMR (500 MHz-DMSO-d.sub.6) .delta.ppm: 1.25 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.07 (m, 1H, CH.sub.3CHCH.sub.3); 6.94
(d, 1H, J=8.4, H-5'-indazole); 7.65 (d, 1H, J=8.4, H-4'-indazole);
7.94 (m, 2H, H-3', H-7'-indazole); 7.04 (s, 1H, H-thiazole); 9.12
(bs, 1H, CONH-indazole); 10.30 (bs, 1H, NH-thiazole); 12.87 (bs,
1H, NH-indazole). ESI(+)-MS: m/z 302 (100, (M+H).sup.+).
[0724] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-chlorobenzyl)urea
[0725] .sup.1H-NMR (500 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.9, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 4.38
(d, 2H, J=5.9, CH.sub.2); 7.3-7.44 (m, 4, phenyl); 6.97 (d, 1H,
J=0.9, H-thiazole); 7.10 (bs, 1H, NHCH.sub.2); 10.32 (bs, 1H,
NH-thiazole); ESI(+)-MS: m/z 310 (100, (M+H).sup.+).
[0726]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,4-dichlorobenzyl)urea;
[0727] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-fluorobenzyl)urea
[0728] .sup.1H-NMR (500 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 4.32
(d, 2H, J=6.1, CH.sub.2); 6.97 (d, 1H, J=0.9, H-thiazole); 7.04-7.4
(m, 5H, phenyl+NHCH.sub.2); 10.30 (bs, 1H, NH-thiazole). ESI(+)-MS:
m/z 294 (100, (M+H).sup.+);
[0729]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,4-dichlorobenzyl)urea
[0730] .sup.1H-NMR (500 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.7, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 4.30
(d, 2H , J=6.1, CH.sub.2); 7.28 (dd, 1H, J=2.0, 8.2, H-6'-phenyl);
7.52 (d, 1H, J=2.0, H-2'-phenyl); 7.58 (d, 1H, J=8.2, H-5'-phenyl);
6.97 (d, 1H, J=0.9, H-thiazole); 7.12 (bs, 1H, NHCH.sub.2); 10.41
(bs, 1H, NH-thiazole). ESI(+)-MS: m/z 143 (100,
isopropylaminothiazole+H).sup.+); m/z 344 (65, (M+H).sup.+).
[0731]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,4-difluorobenzyl)urea
[0732] .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.7, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 4.30
(d, 2H, J=6.0, CH.sub.3); 6.97 (d, 1H, J=0.9, H-thiazole); 7.0-7.4
(m, 4H, phenyl+NHCH.sub.2); 10.20 (bs, 1H, NH-thiazole). ESI(+)-MS:
m/z 312 (100, (M+H).sup.+);
[0733]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,5-difluorobenzyl)urea
[0734] .sup.1H-NMR (500 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.9, CH.sub.3CHCH.sub.3); 3.02 (m, 1H, CH.sub.3CHCH.sub.3); 4.35
(d, 2H, J=5.8, CH.sub.2); 7.08 (m, 2H, H-3', H-5'-phenyl); 7.39 (m,
1H, H-4'-phenyl); 6.95 (d, 1H, J=0.9, H-thiazole); 7.04 (bs, 1H,
NHCH.sub.2); 10.08 (bs, 1H, NH-thiazole). ESI(+)-MS: m/z 312 (100,
(M+H).sup.+).
[0735]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-2,6-difluorobenzyl)urea;
[0736]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(4-hydroxy-3-methoxy)benzyl]ur-
-ea;
[0737]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(5-melthyl-2-furyl)urea
[0738] .sup.1H-NMR-(500 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 2.21
(s, 3H, CH.sub.3); 4.23 (d, 2H, J=5.8, CH.sub.3); 5.97, 6.11 (2s,
2H, furane); 6.96 (d, 1H, J=1.0, H-thiazole); 6.91 (bs, 1H,
NHCH.sub.2); 10.14 (bs, 1H, NH-thiazole). ESI(+)-MS: m/z 280 (100,
(M+H).sup.+).
[0739]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-methylsulfonylbenzyl)urea;
[0740] N-[(1R,
2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-N'-(5-isopropyl-1,-
-3-thiazol-2-yl)urea;
[0741] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-chlorobenzyl)urea
[0742] .sup.1H-NMR (500 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 4.29
(d, 2H, J=6.1, CH.sub.2); 7.3, 7.37 (2d, 4H, J=8.5, phenyl); 6.97
(d, 1H, J=0.9, H-thiazole); 7.06 (bs, 1H, NHCH.sub.2); 10.30 (bs,
1H, NH-thiazole). ESI(+)-MS: m/z 310 (100, (M+H).sup.+).
[0743]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-pyridinylmethyl)urea;
[0744]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,5-dimethoxybenzyl)urea;
[0745] .sup.1H-NMR (500 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 4.24
(d, 2H, J=5.9, CH.sub.2); 3.71 (s, 6H, 2 OCH.sub.3) 6.37 (s, 1H,
H-4'-phenyl); 6.44 (s, 2H, H-2', H-6'-phenyl); 6.97 (s, 1H,
H-thiazole); 6.99 (bs, 1H, NHCH.sub.2); 10.22 (bs, 1H,
NH-thiazole). ESI(+)-MS: m/z 336 (100, (M+H).sup.+).
[0746]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-pyridinylmethyl)urea;
[0747]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-trifluorobenzyl)urea;
[0748]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,4,5-trimethoxybenzyl)urea;
[0749] .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 4.24
(d, 2H, J=5.9, CH.sub.2); 3.60, 3.65 (3s, 9H, 3 OCH.sub.3); 6.60
(s, 2H, phenyl); 6.97 (s, 1H, H-thiazole); 6.99 (bs, 1H,
NHCH.sub.2); 10.20 (bs, 1H, NH-thiazole). ESI(+)-MS: m/z 366 (100,
(M+H).sup.+); m/z 181 (100,
(CH.sub.3O).sub.3--C.sub.7H.sub.4.sup.+);
[0750]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,4-dimethoxybenzyl)urea
[0751] .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 4.24
(d, 2H, J=5.9, CH.sub.2); 3.70, 3.78 (2s, 6H, 2 OCH.sub.3); 6.48
(dd, 1H, H-5'-phenyl); (d, 1H, H-3'-phenyl); 7.05 (d, 1H,
H-6'-phenyl); 6.97 (s, 1H, H-thiazole); 6.80 (bs, 1H, NHCH.sub.2);
10.08 (bs, 1H, NH-thiazole). ESI(+)-MS: m/z 336 (100,
(M+H).sup.+);
[0752]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-dimethylaminobenzyl)urea;
[0753]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,5-dimethoxybenzyl)urea;
[0754]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(2-chloro-6-phenoxy)benzyl]ure-
-a;
[0755] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(1R,
2S)-2-hydroxy-2,3-dihydro- -1H-inden-1-yl]urea;
[0756]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[(3-hydroxy-4-methyl)phenyl]ure-
-a;
[0757]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[4-(1H-benzimidazol-2-yl)phenyl-
-]urea;
[0758]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-phenyl-1H-pyrazol-5-yl)urea;
[0759]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-methyl-6-quinolinyl)urea
[0760] .sup.1H-NMR (500 MHz-DMSO-d6) .delta.ppm: 1.25 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.07 (m, 1H, CH.sub.3CHCH.sub.3); 2.61
(s, 3H, CH.sub.3); 7.05 (s, 1H, H-thiazole); 7.36 (d, 1H, J=8.4,
H-3'-quinoline); 7.65 (dd, 1H, J=2.0, 9.0, H-7'-quinoline); 7.85
(d, 1H, J=9.0, H-8'-quinoline); 8.14 (m, 2H, H-4', H-5'-quinoline);
9.22 (bs, 1H, NHCONH-quinoline); 10.40 (bs, 1H, NH-thiazole).
ESI(+)MS: m/z 185 (100,
(MH--CH.sub.3).sub.2--CH-amino-thiazole).sup.+); 327 (75,
(M+H).sup.+);
[0761]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-[4-(cynanomethyl)phenyl]urea
[0762] 1-NMR (500 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H, J=6.9,
CH.sub.3CHCH.sub.3); 3.05 (m, 1H, CH.sub.3CHCH.sub.3); 7.03 (s, 1H,
H-thiazole); 3.94 (s, 2H, CH.sub.2); 7.27 (d, 2H, H-3',
H-5'-phenyl); 7.48 (d, 2H, J=8.5, H-2', H-6'-phenyl); 9.01 (bs, 1H,
NH-phenyl); 10.30 (bs, 1H, NH-thiazole). ESI(+)MS: m/z 301 (100,
(M+H).sup.+);
[0763] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2-quinolinyl)urea
[0764] .sup.1H-NMR (500 MHz-DMSO-d.sub.6) .delta.ppm: 1.27 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.13 (m, 1H, CH.sub.3CHCH.sub.3); 7.17
(s, 1H, H-thiazole); 7.44 (m, 1H, H-3'-quinoline); 7.50 (m, 1H,
H-6'-quinoline); 7.75 (m, 1H, H-7'-quinoline); 7.82 (m, 1H,
H-8'-quinoline); 7.90 (m, 1H, H-5'-quinoline); 8.34 (m, 1H,
H-4'-quinoline); 10.45 (bs, 1H, NHCONH-quinoline); 13.02 (bs, 1H,
NHCON). ESI(+)MS: m/z 313 (100, (M+H).sup.+).
[0765]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(1-oxo-2,3-dihydro-1H-inden-5-y-
l)urea;
[0766]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3-oxo-1,3-dihydro-2-benzofuran-
-5-yl)urea
[0767] .sup.1-NMR (500 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.06 (m, 1H, CH.sub.3CHCH.sub.3); 7.04
(s, 1H, H-thiazole); 5.35 (s, 1H, CH.sub.2); 7.58 (d, 1H, J=8.4,
H-5'-phenyl); 7.71 (d, 1H, J=8.4, H-6'-phenyl); 8.08 (s, 1H,
H-2'-phenyl); 9.34 (bs, 1NHCONHPh); 10.50 (bs, 1H, NHCON).
ESI(+)MS: m/z 318 (100, (M+H).sup.+).
[0768]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(5-oxo-5,6,7,8-tetrahydro-2-nap-
talenyl)urea;
[0769]
methyl-3-(<[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)--
4-methylbenzoate
[0770] .sup.1H-NMR (300 MHz-DMSO-d6) .delta.ppm: 1.25 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.10 (m, 1H, CH.sub.3CHCH.sub.3); 2.30
(s, 3H, CH.sub.3-phenyl); 3.80 (s, 3H, CH.sub.3O); 7.05 (s, 1H,
H-thiazole); 7.30 (d, 1H, H-5'-phenyl); 7.58 (dd, 1H, H-6'-phenyl);
8.55 (m, 2H, H-2'-phenyl+NHPh); 10.80 (bs, 1H, NH-thiazole). ESI(+)
MS: m/z 334 (100, (M+H).sup.+);
[0771]
methyl-4(<[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)-3-
-methylbenzoate
[0772] .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 2.25 (s, 3H,
CH.sub.3-phenyl); 3.83 (s, 3H, CH.sub.3O); 7.03 (s, 1H,
H-thiazole); 7.30 (d, 1H, H-3'-phenyl); 7.53 (dd, 1H, H-4'-phenyl);
8.50 (m, 2H, H-6'-phenyl+NHPh); 10.70 (bs, 1H, NH-thiazole).
ESI(+)MS: m/z 334 (100, (M+H).sup.+);
[0773]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(4-imidazo[1,2-a]pyridin-2-yl-p-
-henyl)urea
[0774] .sup.1-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H.
J=6.8, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 7.03
(s, 1H, H-thiazole); 6.84, 7.20 (2m, 2H, H-5',
H-6"-imidazopyridine): 7.50, 7.90 (2m, 5H, H-2', H-3', H-5',
H-6'-phenyl+H-7'-imidazopyridine); 8.30 (s, 1H,
H-3'-imidazopyridine); 8.50 (d, 1H, H-4'-imidazopyridine); 9.00
(bs, 1H, NHCONPh) 10.40 (bs, 1H, NHCON). ESI(+)MS: m/z 236 (100,
(MH--CH.sub.3).sub.2--CH-amino-thiazole).sup.+); m/z 378 (85,
(M+H).sup.+);
[0775]
ethyl-4-(<[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)be-
-nzoate
[0776] .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.20 (d, 6H,
CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 7.00 (s, 1H,
H-thiazole); 1.15 (t, 3H, CH.sub.3); 3.58 (s, 2H, CH.sub.2-phenyl);
4.06 (q, 2H, CH.sub.2O); 7.16, 7.38 (2d, 4H, phenyl); 8.90 (bs, 1H,
NHCONHPh); 10.30 (bs, 1H, NHCON). ESI(+)MS: m/z 348 (100,
(M+H).sup.+);
[0777]
(2R)-1-benzyl-2-(<[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}-
-amino)propanamide;
[0778]
2-hydroxy-5-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}benzoic
acid
[0779]
2-chloro-5-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)be-
nzoic acid;
[0780] .sup.1H-NMR (400 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.04 (m, 1H, CH.sub.3CHCH.sub.3); 7.02
(s, 1H, H-thiazole); 7.35 (d, 1H, J=8.8, H-5'-phenyl); 7.55 (dd,
1H, H-6'-phenyl); 7.88 (bs, 1H, H-2'-phenyl); 9.75 (bs, 1H,
NHCONPh); 11.00 (bs, 1H, NHCON). ESI(+)MS: m/z 340 (100,
(M+H).sup.+);
[0781]
3-({[(5-isopropyl-1,3-thiazol-2-yl)amino]carbonyl}amino)benzoic
acid
[0782] .sup.1H-NMR (500 MHz-DMSO-d.sub.6) .delta.ppm: 1.24 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 7.04
(s, 1H, H-thiazole); 7.40 (dd, 1H, J=7.9, H-5'-phenyl); 7.58, 7.63
(2d, 2H, J=7.9, H-4', H-6'-phenyl); 8.13 (s, 1H, H-2'-phenyl); 9.28
(s, 1H, NHCONPh); 10.50 (bs, 1H, NHCON). ESI(+)MS: m/z 306 (100,
(M+H).sup.+);
[0783]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(5-methyl-3-isoxazolyl)urea;
[0784]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,6-dimethoxyphenyl)urea;
[0785]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,3-dimethoxybenzyl)urea
[0786] .sup.1H-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.21 (d, 6H,
J=6.8, CH.sub.3CHCH.sub.3); 3.03 (m, 1H, CH.sub.3CHCH.sub.3); 4.32
(s, 2H, J=6.1, CH.sub.2); 3.72, 3.75 (2s, 6H, 2 OCH.sub.3); 6.8-7.0
(m, 3H, phenyl); 6.97 (s, 1H, H-thiazole); 6.90 (bs, 1H,
NHCH.sub.2); 10.20 (bs, 1H, NH-thiazole). ESI(+)-MS: m/z 336 (100,
(M+H).sup.+);
[0787]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(3,4-difluorobenzyl)urea;
[0788]
N-(5-isopropyl-1,3-thiazol-2-yl)-N'-(2,4-dimethylphenyl)urea;
[0789] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-butylurea
[0790] .sup.1-NMR (300 MHz-DMSO-d.sub.6) .delta.ppm: 1.20 (d, 6H,
CH.sub.3CHCH.sub.3); 3.00 (m, 1H, CH.sub.3CHCH.sub.3); 0.85 (t, 3H,
CH.sub.3); 1.20-1.40 (m, 4H, CH.sub.2--CH.sub.2); 3.10 (m, 2H,
CH.sub.2--NH); 6.94 (d, 1H, J=1.0, H-thiazole); 6.49 (t, 1H,
NHCH.sub.2); 10.5 (bs, 1H, NH-thiazole). ESI(+)-MS: m/z 242 (100,
(M+H).sup.+);
[0791] N-(5-isopropyl-1,3-thiazol-2-yl)-N'-benzoylurea;
[0792]
N-(5-methyl-1,3-thiazol-2-yl)-N'-(2,6-dimethylphenyl)urea;
[0793] N-(5-methyl-1,3-thiazol-2-yl)-N'-benzylurea;
[0794] N-(5-methyl-1,3-thiazol-2-yl)-N'-butylurea;
[0795] N-(5-methyl-1,3-thiazol-2-yl)-4-morpholinecarboxamide;
[0796] N-(5-methyl-1,3-thiazol-2-yl)-N'-phenylurea;
[0797] N-(5-methyl-1,3-thiazol-2-yl)N'-(4-methoxybenzylurea;
[0798] N-(5-methyl-1,3-thiazol-2-yl)-N'-(4-fluoropheyl)urea;
[0799]
N-[(1-ethyl-2-pyrrolidinyl)methyl]-N'-(5-methyl-1,3-thiazol-2-yl)ur-
-ea;
[0800]
N-(5-methyl-1,3-thiazol-2-yl)-N'-(5-hydroxy-1H-pyrazol-3-yl)urea;
[0801] N-(5-methyl-1,3-thiazol-2-yl)-N'-(3-pyridinyl)urea;
[0802] N-(4-fluorophenyl)-N'-(5-methyl-1,3-thiazol-2-yl)urea.
[0803] All compounds were characterized by mass spectrometry (MS).
LC-MS confirmed that in each case the principle component had a
molecular ion corresponding to the expected product. The compounds
showed an HPLC area % ranging from 70 to 100.
[0804] HPLC Analysis:
[0805] Instrument: Beckman System Gold Cromatographer (127 Solvent
module, 168 Detector, 507e Autosampler)
[0806] Mobile A: H.sub.2O/CH.sub.3CN (90/10)+0.1% TFA.
[0807] Mobile B: H.sub.2O/CH.sub.3CN (10/90)+0.075% TFA.
[0808] Flow rate: 1.5 ml/mm.
[0809] Sample volume: 20 cml.
[0810] Column: Supelco.TM., Discovery RPAmide C16, 5 .mu.m.
(50.times.4.6)mm
[0811] Temp: 25.degree. C.
[0812] Gradient:
1 Time (min) % A % B 0 0 100 6.5 0 100 7 100 0 10 100 0
[0813] Detection: diode array UV 254 nm.
[0814] All the compounds were analyzed by M/S spectrometry (ESI)
using a LCQ Finnigan Mass Spectrometer. 37 randomly chosen
compounds were analyzed by H.sup.1-NMR. The spectra were run on a
Varian XL 400 Spectrometer.
* * * * *