U.S. patent application number 10/169805 was filed with the patent office on 2003-08-14 for novel thiourea derivatives and the pharmaceutical compositions containing the same.
Invention is credited to Choi, Jin Kyu, Jeong, Yeon Su, Joo, Yung Hyup, Kim, Hee Doo, Kim, Jin Kwan, Kim, Sun Young, Koh, Hyun Ju, Lee, Jee Woo, Lee, Yong Sil, Lim, Kyung Min, Moh, Joo Hyun, Oh, Uh Taek, Oh, Young Im, Park, Hyeung Geun, Park, Ok Hui, Park, Young Ho, Suh, Young Ger, Yi, Jung Bum.
Application Number | 20030153596 10/169805 |
Document ID | / |
Family ID | 36643340 |
Filed Date | 2003-08-14 |
United States Patent
Application |
20030153596 |
Kind Code |
A1 |
Suh, Young Ger ; et
al. |
August 14, 2003 |
Novel thiourea derivatives and the pharmaceutical compositions
containing the same
Abstract
The present invention relates to novel thiourca derivatives as a
modulator for vanilloid receptor (VR) and the phar- maceutical
compositions containing the same. As diseases associated with the
activity of vanilloid receptor, pain acute pain, chronic pain,
neuropathic pain, post-operative pain, migraine, arthralgia,
neuropathies, nerve injury, diabetic neuropathy, neurodegeneration,
neurotic skin disorder, stroke, urinary bladder hypersensitiveness,
irritable bowel syndrome, a respiratory disorder such as asthma or
chronic obstructive pulmonary disease, irritation of skin, eye or
mucous membrane, fervescence, stomach-duodenal ulcer, inflam-
matory bowel disease and inflammatory diseases can be enumerated.
The present invention provides a pharmaceutical composition for
prevention or treatment of these diseases.
Inventors: |
Suh, Young Ger; (Kyunggi-do,
KR) ; Oh, Uh Taek; (Kyunggi-do, KR) ; Kim, Hee
Doo; (Seoul, KR) ; Lee, Jee Woo; (Seoul,
KR) ; Park, Hyeung Geun; (Seoul, KR) ; Park,
Ok Hui; (Chungchongnam-do, KR) ; Lee, Yong Sil;
(Seoul, KR) ; Park, Young Ho; (Seoul, KR) ;
Joo, Yung Hyup; (Seoul, KR) ; Choi, Jin Kyu;
(Kyunggi-do, KR) ; Lim, Kyung Min; (Kyunggi-do,
KR) ; Kim, Sun Young; (Kyunggi-do, KR) ; Kim,
Jin Kwan; (Seoul, KR) ; Koh, Hyun Ju; (Seoul,
KR) ; Moh, Joo Hyun; (Kyunggi-do, KR) ; Jeong,
Yeon Su; (Kyunggi-do, KR) ; Yi, Jung Bum;
(Kyunggi-do, KR) ; Oh, Young Im; (Kyunggi-do,
KR) |
Correspondence
Address: |
Finnegan Henderson
Farabow Garrett & Dunner
1300 I Street N W
Washington
DC
20005-3315
US
|
Family ID: |
36643340 |
Appl. No.: |
10/169805 |
Filed: |
July 9, 2002 |
PCT Filed: |
August 20, 2001 |
PCT NO: |
PCT/KR01/01407 |
Current U.S.
Class: |
514/311 ;
514/357; 514/400; 514/406; 514/428; 514/480; 514/481; 514/580;
514/595; 514/609; 546/176; 546/330; 546/331; 546/332; 548/238;
548/335.5; 548/375.1; 548/561 |
Current CPC
Class: |
C07D 295/13 20130101;
A61P 25/00 20180101; A61P 29/00 20180101; C07D 209/14 20130101;
C07D 311/58 20130101; C07C 335/20 20130101; C07D 333/20 20130101;
C07D 217/06 20130101; C07D 213/61 20130101; C07D 241/24 20130101;
C07C 311/08 20130101; C07D 317/58 20130101; A61P 27/02 20180101;
C07C 335/14 20130101; C07D 239/42 20130101; C07D 333/42 20130101;
A61P 3/10 20180101; C07C 333/20 20130101; C07D 231/56 20130101;
C07D 241/12 20130101; A61P 1/04 20180101; A61P 11/00 20180101; C07D
277/28 20130101; C07D 295/215 20130101; C07D 295/32 20130101; C07D
207/416 20130101; C07C 2602/10 20170501; A61P 11/06 20180101; A61P
9/00 20180101; A61P 17/00 20180101; C07C 335/12 20130101; C07D
207/42 20130101; C07C 2601/14 20170501; C07D 213/76 20130101; A61P
25/18 20180101; C07D 207/323 20130101; A61P 13/10 20180101; C07C
335/26 20130101; C07C 311/47 20130101; C07D 235/14 20130101; C07D
233/64 20130101; C07D 209/08 20130101; C07D 213/40 20130101; C07D
307/52 20130101; A61P 25/06 20180101; C07D 231/14 20130101 |
Class at
Publication: |
514/311 ;
514/400; 514/357; 514/406; 514/428; 514/480; 514/481; 514/580;
514/595; 514/609; 546/176; 546/330; 546/331; 546/332; 548/238;
548/335.5; 548/375.1; 548/561 |
International
Class: |
A61K 031/47; A61K
031/44; A01N 043/40; A61K 031/415; A61K 031/4172 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 21, 2000 |
KR |
2000/48385 |
Claims
1. A compound of the following formula (I): 322or a
pharmaceutically acceptable salt thereof, wherein: X represents S,
O or --NCN; Y represents single bond, NR.sup.3, O or S; R.sup.1
represents 323pyridinylmethyl, pyrrolylmethyl, oxazolyhuethyl,
pyrazolylnethyl, imidazolylnethyl, anthracenylnethyl,
naphthylmethyl, quinolinylmethyl, alkoxycarbonyl or
alkylcarbonyloxy (wherein, m is 0, 1, 2, 3 or 4; R.sup.4 and
R.sup.5 are independentyl hydrogen, lower alkyl having 1 to 5
carbon atoms, hydroxy, methanesulfanylamino, lower alkoxy having 1
to 5 carbon atoms, methoxyalkoxy, methoxyalkoxyalkyl,
alkoxycarbonyloxy, benzyloxy, acetoxymethyl, propinoyloxymethyl,
butoxyalkyl, trimethylacetoxy, trimethylacetoxymethyl or halogen;
and R.sup.6 and R.sup.7 are independently hydrogen, lower alkyl
having 1 to 5 carbon atoms); R.sup.2 represents
R.sup.8--(CH.sub.2).sub.n--{wherein, n is 0, 1, 2, 3 or 4; R.sup.8
is benzoyl, imidazolyl, indolyl, indazolyl, thiazolyl, pyrazolyl,
oxazolyl, isoxazolyl, benzimidazolyl, chromonyl or benzothiazolyl
substituted or unsubstituted with lower alkyl having 1 to 5 carbon
atoms, nitro, amino, cyano, methanesulfonylamino, formyl or
halogen, or 324(wherein, R.sup.9 is hydrogen, halogen, lower alkyl
having 1 to 5 carbon atoms, lower alkoxy having 1 to 5 carbon
atoms, hydroxy, nitro, cyano, --NHSO.sub.2R.sup.2,
--S(O).sub.pR.sup.12, --NR.sup.13R.sup.14, carboxyl; R.sup.10 is
hydrogen, nitro, NHSO.sub.2R.sup.12, S(O).sub.pR.sup.12 or
NR.sup.13R.sup.14; R.sup.11 is hydrogen or cyano; R.sup.12 is lower
alkyl having 1 to 5 carbon atoms, methylphenyl, NR.sup.13R.sup.14,
trifluoromethyl or alkenyl; R.sup.13 and R.sup.14 are independently
hydrogen or lower alkyl having 1 to 5 carbon atoms; and p is 0 or
2.); or 325(wherein, Z is O, S, NH or --NCH.sub.3; R.sup.15 is
hydrogen, halogen, lower alkyl having 1 to 5 carbon atoms, nitro,
cyano, --NHSO.sub.2R.sup.12, --S(O).sub.pR.sup.12,
N,N-dimethylaminomethyl or alkoxycarbonylamino; and p and R.sup.12
have the same meanings as defined in R.sup.9); 326(wherein, W is O,
S, NH, NR.sup.16, --N(SO.sub.2CH.sub.3)-- or --CH.sub.2--; and
R.sup.16 is pyridinyl or pyrimidinyl substituted or unsubstituted
with lower alkyl having 1 to 5 carbon atoms, nitro,
methanesulfonylamino or halogen; or benzyl or phenethyl substituted
or unsubstitued with lower alkyl having 1 to 5 carbon atoms,
alkoxy, hydroxy, nitro, methanesulfonylamino or halogen); or
327(wherein, R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.21
are independently hydrogen, halogen, lower alkyl having 1 to 5
carbon atoms, alkoxy, methylenedioxy, methanesulfonylaminomethyl,
alkoxycarbonyl, hydroxy, sulfamoyl, aminoalkoxy,
alkoxycarbonylamno, --NHCH.sub.2CO.sub.2H,
alkoxyalkylcarbonylamino, alkoxycarbonylalkylamino- , nitro,
formyl, acetyl, formnylarnino, acetoxyamino, cyano,
--OSO.sub.2CH.sub.3, --NHSO.sub.2R.sup.12,
--N(SO.sub.2R.sup.12)CH.sub.3, --N(SO.sub.2R.sup.12).sub.2,
--S(O).sub.pR.sup.12, --NR.sup.13R.sup.14, thiocarbamnoyl,
--C(.dbd.O)NHNH.sub.2, --C(.dbd.O)NHOH, --C(.dbd.O)NHOCH.sub.3,
--PO(.dbd.O)(OCH.sub.3).sub.2, carboxyl, NHBoc,
--NHC(.dbd.O)SCH.sub.3 or guanidine; R.sup.22 and R.sup.23 are
independently hydrogen, halogen, alkoxy or hydroxy; and p,
R.sup.12, R.sup.13 and R.sup.14 have the same meanings as defined
in R.sup.9); or hydroxyphenylalkyl or
(methanesulfonylaminophenyl)alkyl}; and R.sup.3 represents
hydrogen, alkyl or cycloalkyl having 1 to 8 carbon atoms, lower
alkylphenyl having 1 to 5 carbon atoms, pyridinylethyl,
bisphenylmethyl; or phenylalkyl substituted with lower alkyl having
1 to 5 carbon atoms, halogen or methanesulfonylamino.
2. A compound or a pharmaceutically acceptable salt thereof
according to claim 1, wherein, X represents S, O or --NCN; Y
represents N.sup.3 or O; R.sup.1 represents 328(wherein, m is 0, 1
or 2; and R.sup.4 and R.sup.5 are independently hydrogen, lower
alkyl having 1 to 4 carbon atoms, hydroxy, methanesulfonylamino,
lower alkoxy having 1 to 5 carbon atoms, methoxyalkoxy,
methoxyalkoxyalkyl, benzyloxy, acetoxymethyl,
trimethylacetoxymethyl or halogen); R.sup.2 represents
R.sup.8--(CH.sub.2).sub.n--{wherein, n is 0, 1, 2 or 3; R.sup.8 is
benzoyl, imidazolyl, indolyl, indazolyl, thiazolyl, pyrazolyl,
oxazolyl, benzimidazolyl or chromonyl substituted or unsubstituted
with lower alkyl having 1 to 5 carbon atoms, nitro, amino, cyano,
methanesulfonylamino, formyl or halogen, or 329(wherein, R.sup.9 is
hydrogen, halogen, lower alkyl having 1 to 4 carbon atoms, lower
alkoxy having 1 to 4 carbon atoms, nitro, cyano,
--NHSO.sub.2R.sup.12, --NR.sup.13R.sup.14 or carboxyl; R.sup.10 is
hydrogen, nitro, NHSO.sub.2R.sup.12 or --NR.sup.13R.sup.14;
R.sup.11 is hydrogen or cyano; R.sup.12 is lower alkyl having 1 to
4 carbon atoms, methylphenyl, --NR.sup.13R.sup.14 or
trifluoromethyl; R.sup.13 and R.sup.14 are independently hydrogen
or lower alkyl having 1 to 4 carbon atoms; and p is 0 or 2);
330(wherein, Z is O, S, NH or --NCH.sub.3; R.sup.1 is hydrogen,
lower alkyl having 1 to 4 carbon atoms, nitro, cyano or
NHSO.sub.2R.sup.12; and R.sup.12 has the same meanings as defined
in R.sup.9); or 331(wherein, W is O, S, NH, NR.sup.16 or
--CH.sub.2--; and R.sup.16 is pyridinyl or pyrirnidinyl substituted
or unsubstituted with lower alkyl having 1 to 4 carbon atoms, nitro
or methanesulfonylamino; or benzyl or phenethyl substituted or
unsubstituted with lower alkyl having 1 to 4 carbon atoms, alkoxy,
hydroxy or methanesulfonylamino); 332(wherein, R.sup.17, R.sup.18,
R.sup.19, R.sup.20 and R.sup.21 are independently hydrogen,
halogen, lower alkyl having 1 to 5 carbon atoms, alkoxy,
methylenedioxy, methanesulfonylaminomethyl, alkoxycarbonyl,
hydroxy, sulfamoyl, alkoxycarbonylamino, --NHCH.sub.2CO.sub.2H,
allcoxyalkylcarbonylamino, alkoxycarbonylalkylamino, nitro, formyl,
acetyl, fonnylamino, acetoxyamino, cyano, --OSO.sub.2CH.sub.3,
--NHSO.sub.2R.sup.12, --N(SO.sub.2R.sup.12)CH.sub.3,
--N(SO.sub.2R.sup.12).sub.2, --S(O).sub.pR.sup.12,
NR.sup.13R.sup.14, thiocarbamoyl, --C(.dbd.O)NHNH.sub.2,
--C(.dbd.O)NHOH, --C(.dbd.O)NHOCH.sub.3, carboxyl, NHBoc,
--NHC(.dbd.O)SCH.sub.3, guanidine; R.sup.22 and R.sup.23 are
independently hydrogen, alkoxy or hydroxy; and p, R.sup.12,
R.sup.13 and R.sup.14 have the same meanings as defined in
R.sup.9); or hydroxyphenylalkyl or
(methanesulfonylaminophenyl)alkyl}; and R.sup.3 represents
hydrogen, alkyl having 1 to 4 carbon atoms, lower alkylphenyl
having 1 to 3 carbon atoms, pyridinylethyl or bisphenylmethyl; or
phenylalkyl substituted with lower alkyl having 1 to 4 carbon
atoms, halogen or methanesulfonylamino.
3. A compound or a pharmaceutically acceptable salt thereof
according to claim 2, wherein, X represents S, O or --NCN; Y
represents NR.sup.3 or O; R.sup.1 represents 333(wherein, m is 1 or
2; and R.sup.4 and RW are independently hydrogen, t-butyl, hydroxy,
methanesulfonylamino, lower alkoxy having 1 to 5 carbon atoms,
methoxymethoxy, methoxyethoxy, benzyloxy, acetoxymethyl,
trimethylacetoxymethyl or halogen); R.sup.2 represents
R.sup.8--(CH.sub.2).sub.n--{wherein, n is 1, 2 or 3; R.sup.8 is
benzoyl, imidazolyl, indolyl, indazolyl, thiazolyl, pyrazolyl or
benzimidazolyl substituted or unsubstituted with methyl, nitro or
halogen; or 334(wherein, R.sup.9 is hydrogen, halogen, methyl,
nitro or methanesulfonylamino; R.sup.10 is hydrogen or nitro; alid
R.sup.11 is hydrogen or cyano); 335(wherein, Z is O, S, NH or
--NCH.sub.3; and R.sup.15 is hydrogen, methyl, nitro, cyano or
methanesulfonylamino); 336(wherein, W is O, S, NH, NR.sup.16 or
--CH.sub.2--; and R.sup.16 is pyridinyl, pyrirnidinyl; or benzyl or
phenethyl substituted or unsubstituted with methyl, methoxy or
hydroxy); or 337(wherein, R.sup.17, R.sup.18, R.sup.19, R.sup.20
and R.sup.21 are independently hydrogen, halogen, lower alkyl
having 1 to 4 carbon atoms, methoxy, methylenedioxy,
methanesulfonylaminomethyl, methoxycarbonyl, hydroxy, sulfamoyl,
alkoxycarbonylamino, --NHCH.sub.2CO.sub.2H,
methoxymethylcarbonylamino, alkoxycarbonylalkylamino, nitro,
acetyl, formylamino, acetoxyamino, cyano, --OSO.sub.2CH.sub.3,
--NHSO.sub.2R.sup.12, --N(SO.sub.2R.sup.12)CH.sub.3,
--N(SO.sub.2R.sup.12).sub.2, --S(O).sub.pR.sup.12,
NR.sup.13R.sup.14, thiocarbamoyl, --C(.dbd.O)NHNH.sub.2,
--C(.dbd.O)NHOH, --C(.dbd.O)NHOCH.sub.3, carboxyl, NHBoc,
--NHC(.dbd.O)SCH.sub.3, guanidine; R.sup.22 and R.sup.23 are
independently hydrogen, methoxy or hydroxy; and p, R.sup.12,
R.sup.13 and R.sup.14 are the same meanings as defmed in R.sup.9);
or hydroxyphenylalkyl or (methanesulfonylarinophenyl)- alkyl}; and
R.sup.3 represents hydrogen, methyl, isopropyl, isobutyl,
cyclohexyl, benzyl, phenethyl or bisphenylmethyl; or phenylalkyl
substituted with t-butyl, halogen or methanesulfonylamuno.
4. A compound or a pharmaceutically acceptable salt thereof
according to claim 1, wherein the fomula (I) represents
1-(4-t-butylbenzyl)-3-[2-(1-me- thyl 1H-pyrrol-2-yl)ethyl]thiourea;
1-(4-t-butylbenzyl)-3-(4-amino-2,5-dif- luorobenzyl)thiourea;
1-(4-t-butylbenzyl)-3-(4-sulfamoylbenzyl)thiourea;
1-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfonylaminobenzyl)thiourea;
1-phenethyl-3-(3-fluoro-4-methanesulfonylaninobenzyl)thiourea;
1-(4-t-butylbenzyl)-3-(3-chloro-4-methanesulfonylaniinobenzyl)thiourea;
1-(4-t-butylbenzyl)-3-(3-methoxycarboxy1-4-methanesulfonylaminobenzyl)thi-
ourea;
1-(4-t-butylbenzyl)-3-(3-carboxy1-4-methanesulfonylaminobenzyl)thio-
urea;
1-(4-t-butylbenzyl)-3-((3-N-hydroxyaminocarbony1-4-methanesulfonylam-
ino)benzyl)thiourea;
1-(4-t-butylbenzyl)-3-(3-methoxycarboxylbenzyl)thiour- ea;
1-(4-t-butylbenzyl)-3-(3-carboxylbenzyl)thiourea;
1-(4-t-butylbenzyl)-3-(2,3,5
,6-tetrafluoro-4-methanesulfonylaminobenzyl)- thiourea;
1-(4-t-butylbenzyl)-3-(2,5-difluoro-4-methanesulfonylaminobenzyl-
)thiourea;
1-(4-t-butylbenzyl)-3-[(3-methanesulfonylamino-6-pyridinyl)meth-
yl]thiourea;
1-(4-t-butylbenzyl)-3-(2,6-dichloro-5-methanesulfonylaminoben-
zyl)thiourea;
1-(4-t-butylbenzyl)-3-(4-methanesulfonylaminophenethyl)thiou- rea;
1-(4-t-butylbenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;
1-(4-t-butylbenzyl)-3-[2,6-difluoro-3-(N-methanesulfonylanino)benzyl]thio-
urea;
1-(4-t-butylbenzyl)-3-[3-(N-methanesulfonylamino)benzyl]thiourea;
1-(4-t-butyl-2-methoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;
1-(4-t-butyl-2-ethoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;
1-(4-t-butyl-2-propoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;
1-(4-t-butyl-2-butoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;
1-(4-t-butyl-2-isopropoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea-
;
1-(4-t-butyl-2-isobutoxybenzyl)-3-(4-methanesulfotiylaminobenzyl)thioure-
a;
1-(4-t-butyl-2-neopentoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiour-
ea;
1-(4-t-butyl-2-methoxymethoxybenzyl)-3-(4-methanesulfonylaninobenzyl)t-
hiourea;
1-(4-t-butyl-2-methoxyethoxybenzyl)-3-(4-methanesulfonylaminobenz-
yl)thiourea;
1-(4-t-butyl-2-benzyloxybenzyl)-3-(4-methanesulfonylaminobenz-
yl)thiourea;
1-(2-acetoxymethyl-4-t-butylbenzyl)-3-(4-methanesulfonylamino-
benzyl)thiourea;
1-(4-t-butylbenzyl)-3-[2-(4-rnethylthiazol-5-yl)ethyl]thi- ourea;
1-(4-t-butylbenzyl)-3-((2-chloro-5-pyridinyl)methyl)thiourea;
1-(4-t-butylbenzyl)-3-(2-pyridin-2-ylethyl)thiourea;
1-(4-t-butylbenzyl)-3-(2,5-difluorobenzyl)tbiourea;
1-(4-t-butylbenzyl)-3-(3-fluorophenethyl)thiourea;
1-(4-t-butylbenzyl)-3-(4-sulfamoylphenethyl)thiourea;
1-(4-t-butylbenzyl)-3-(4-morpholinylethyl)thiourea;
1-(4-t-butylbenzyl)-3-[2-(1H-irnidazo1-4-yl)ethyl]thiourea;
1-(4-t-butylbenzyl)-3-[2-thiophen-2-ethyl]thiourea;
1-(4-t-butylbenzyl)-3-(4-methanesulfonylamino- 1-methyl-
1H-pyrrol-2-yl)tbiourea;
1-benzy1-1-(3-(4-hydroxy-3-methoxyphenyl)propyl)-
-3-phenethylthiourea; 1-(3-(4-hydroxy-3-methoxyphenyl)propyl)-
1-phenethyl-3-phenethylthiourea; 1-bisphenylmethyl-
1-(3-(4-hydroxy-3-methoxyphenyl)propyl)-3-phenethylthiourea; or
N"-cyano-N-(4-t-butylbenzyl)-N'-(4-methanesulfonylaminobenzyl)guanidine.
5. A compound or a pharmaceutically acceptable salt thereof
according to claim 1, wherein the fomula (1) represents
1-(4-t-butylbenzyl)-3-(3-fluor-
o-4-methanesulfonylaminobenzyl)thiourea;
1-(4-t-butylbenzyt)-3-(3-chloro-4-
-methanesulfonylaminobenzyl)thiourea;
1-(4-t-butylbenzyl)-3-(3-methoxycarb-
oxy1-4-methanesulfonylaminobenzyl)thiourea;
1-(4-t-butylbenzyl)-3-(4-metha- nesulfonylarninobenzyl)thiourea; or
1-(4-t-butyl-2-isobutoxybenzyl)-3-(4-m-
ethanesulfonylamnino)thiourea.
6. A pharmaceutical composition comprising the compound according
to claim 1 or a pharmaceutically acceptable salt thereof as an
active ingredient together with a pharmaceutically acceptable
carrier.
7. A pharmaceutical composition according to claim 6, wherein the
compound according to claim 1 or a -pharmaceutically acceptable
salts thereof as an active ingredient together with an
pharmaceutically acceptable carrier is present in an effective
amount for preventing or treating pain, acute pain, chronic pain,
neuropathic pain, post-operative pain, migraine, arthralgia,
neuropathies, nerve injury, diabetic neuropathy, neurodegeneration,
neurotic skin disorder, stroke, urinary bladder hypersensitiveness,
irritable bowel syndrome, a respiratory disorder such as asthma or
chronic obstructive pulmonary disease, irritation of skin, eye or
mucous membrane, stomach-duaodenal ulcer, inflammatory bowel
disease or inflammatory diseases.
8. A method for preventing or treating pain, acute pain, chronic
pain, nieuropathic pain, post-operative pain, migraine, arthralgia,
neuropathfies, nerve injury, diabetic neuropathy,
neurodegeneration, neurotic skin disorder, stroke, urinary bladder
hypersensitiveness, irritable bowel syndrome, a respiratory
disorder such as asthma or chronic obstructive pulmonary disease)
irritation of skin, eye or mucous membrane, stomach-duodenal ulcer,
inflammatory bowel disease or inflammatory diseases, wherein the
method comprises administering a therapeutically effective amount
of the compound selected from the group consisting of compounds of
formula I or a pharmaceutically acceptable salt thereof.
9. Use of a compound selected from the group consisting of compound
of formula I or a pharmaceutically acceptable salt thereof as an
antagonist of vanilloid receptor.
10. Use of a compound selected from the group consisting of
compound of formula I or a pharmaceutically acceptable salt thereof
as an agonist of vanilloid receptor.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel thiourea derivatives
and the pharmaceutical compositions containing the same, and
particularly, to novel thiourea compounds as a modulator for
vanilloid receptor (VR) and the pharmaceutical compositions
thereof. Here, the modulator means the thing that can be bonded to
the receptor to act as an antagonist or an agonist.
BACKGROUND ART
[0002] As diseases associated with the activity of vanilloid
receptor, pain, acute pain, chronic pain, neuropathic pain,
post-operative pain, migraine, arttralgia, neuropathies, nerve
injury, diabetic neuropathy, neurodegeneration, neurotic skin
disorder, stroke, urinary bladder hypersensitiveness, irritable
bowel syndrome, a respiratory disorder such as asthma or chronic
obstructive pulnonary disease, irritation of skin, eye or mucous
membrane, fervescence, stomach-duodenal ulcer, inflammatory bowel
disease and inflammatory diseases can be enumerated. The present
invention provides pharmaceutical compositions for prevention or
treatment of these diseases. Yet, the diseases described above are
only for enumeration, not to limit the scope of clinical
application of vanilloid receptor modulator.
[0003] Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a main
pungent component in hot peppers. Hot peppers have been used, for a
long time, not only as a spice but also as traditional medicine in
the treatment of gastric disorders and when applied locally, for
the relief of pain and inflammation (Szallasi and Blumberg, 1999,
Pharm, Rev. 51, ppl59-211). Capsaicin has a wide spectrum of
biological actions, and not only exhibits effects on the
cardiovascular and respiratory systems but also induces pain and
irritancy on local application. Capsaicin, however, after such
induction of pain, induces desensitization, both to capsaicin
itself and also to other noxious stimuli to make the pain stopped.
Based on this property, capsaicin and its analogues such as
olvanil, nuvanil, DA-5018, SDZ-249482, resiniferatoxin are either
used as analgesic agent, therapeutic agent for incontinentia urinae
or skin disorder, or under development (riggleworth and Walpole,
1998, Drugs of the Future 23, pp 531-538).
[0004] Transmissions of mechanical, thermal and chemical noxious
stimuli are mainly occurred by primary afferent nerve fibers of
fine unmyclinated nerve (C-fiber) and thin myclinated nerve
(A-fiber), and main reaction site of capsaicin and its analog
called vanilloid is present at the nerve fiber transmitting the
noxious stimuli. Capsaicin acts at the receptor existing on these
neurons to induce potent stimuli by causing potent inflow of
mono-and di-valent cations such as calcium and sodium, then
exhibits potent analgesic effect by blocking the nervous fimction
(Wood et al., 1988, J. Neurosci, 8, pp3208-3220). Vanilloid
receptor (VR-1) has been recently cloned and its existence becomes
clear(Caterina et al., 1997, Nature 389, pp816-824). It was
clarified that this receptor transmits not only stimuli by
capsaicin anlogues(vanilloid) but also various noxious stimuli such
as proton and thermal stimuli (Tominaga et al., 1998, Neuron 21,
pp531-543). Based on this, it is considered that vanilloid receptor
finctions as a integrative modulator against various noxious
stimuli and carries out critical role in transmissions of pain and
noxious stimuli. Recently, knock-out mouse in which gene encoding
for vanilloid receptor was deleted was prepared (Caterina et al.,
2000, Science 288, pp306-313; Davis et al., 2000, Nature 405,
ppl83-187). Compared to normal mice, the mouse was found out to
exhibit much reduced reaction to thermal stimuli and thermal pain,
while exhibiting no difference in general behavior, reconfirming
the importance of the receptor in transmission of noxious signal.
However, except proton, no other endogenous ligand, not exogenous
ligand such as capsaicin, actually involved in transmission of
noxious stimuli at vanilloid receptor was known. It is considered
that leucotriene metabolite represented by
12-hydroperoxyeicosatetraenoic acid (12-BPETE) (Hwang et al., 2000,
PNAS 11, pp61.sup.55-6160) and arachidonic aicd derivatives such as
anandamide (Zygmunt et al., 2000, Trends Phannocol. Sci. 21,
pp.sup.43-44) act as the most likely endogenous ligand for the
receptor and proton acts as a cofactor with receptor-stimulating
activity, rather than as a direct ligand.
[0005] As such, a capsaicin-sensitive sensory nerve cell and a
vanilloid receptor existing in the cell are distributed over the
entire body and play basic function in transmission of noxious
stimuli and pain, further act as crucial factor in expression of
neurogenic inflammation, thereby to have close relation with the
cause of neuropathies, nerve injury, stroke, asthma, chronic
obstructive pulmonary diseases, urinary bladder hypersensitiveness,
irritable bowel syndrome, inflammatory bowel disease, fervescence,
skin disorder and inflammatory disease. Lately, their correlation
even with neuropathic disease is suggested (WO 99/00125). Recently,
attention has focused to the role of afferent sensory nerve
responding to capsaicin in gastrointestinal injury, and it was
proposed that the afferent nerve might have a dual character that
it exhibits protective action against gastric damage by improving
gastric microcirculation through releasing peripheral neuropeptide
such as CGRP (calcitonin gene-related peptide), while inducing
gastric injury by stimulating sympathetic nervous system (Ren et
al., 2000, Dig. Dis. Sci. 45, pp830-836). It is determined that
vanilloid receptor modulator has very high potential to be used for
prevention or treatment of the said various diseases by modulating
the activity of the vanilloid receptor conducting such varied
functions.
[0006] As described above, there has been widely studied for
clinical application of vainiloid receptor agonist, and it is
understood that there is a possibility that the agonist derived
from the present studies will be developed for clinical
application. Though it may be, theoretically, anticipated that
antagonist for this receptor would exhibit substantial degree of
inhibitory action against pain and neurogenic inflammation, it was
found out that the competitive antagonist for this receptor,
capsazepine, almost the only one known until now, failed to exhibit
significant analgesic and anti-inflammatory effects (Perkins and
Campbell, 1992, Br. J. Pharmacol. 107, pp329-333). Therefore, not
much progress was made on this field. However, recently, there has
been a report on significant results for analgesic action of
capsazepine in animal studies (Kwak et al., 1998, Neurosci. 86,
pp619-626; Santos and calixto, 1997, Neurosci. Lett. 235, pp73-76),
in particular, the inventors of the present invention clearly
demonstrated through animal studies the analgesic and
anti-inflanmmatory effects of the strong vanilloid receptor
antagonists which were identified through experiments in our
laboratory, and based on this, strongly suggest the development
potential of vanilloid receptor antagonist as an analgesic,
anti-infla matory and anti-ulcerous agent. Yet, though the
vanilloid receptor antagonist or agonist derived from the present
studies will mainly act based on the antagonistic or agonistic
activity of itself, even a possibility that it could exhibit the
pharmacological activity through transformation into agonist or
antagonist via metabolism after absorption into body is not to be
excluded.
[0007] The present invention is to provide novel compounds which
are acted as a modulator for vanilloid receptor and exhibit
excellent analgesic, anti-inflammatory and anti-ulcer effects, and
pharmaceutical compositions containing the same.
DISCLOSURE OF THE INVENTION
[0008] In order to attain the above objects, the present invention
provides a novel compound of the following formula (I): 1
[0009] wherein,
[0010] X represents S, O or --NCN;
[0011] Y represents single bond, NRW, O or S;
[0012] R.sup.1 represents 2
[0013] pyridinyhnethyl, pyrrolylmethyl, oxazolylmethyl,
pyrazolylmethyl, imidazolylrnethyl, anthracenylmethyl,
naphthylmethyl, quinolinylmethyl, alkoxycarbonyl or
alkylcarbonyloxy (wherein, m is 0, 1, 2, 3 or 4; R.sup.4 and
R.sup.5 are independentyl hydrogen, lower alkyl having I to 5
carbon atoms, hydroxy, methanesulfonylamino, lower alkoxy having 1
to 5 carbon atoms, methoxyalkoxy, methoxyalkoxyalkyl,
alkoxycarbonyloxy, benzyloxy, acetoxymethyl, propinoyloxymethyl,
butoxyallcl, trimethylacetoxy, trimethylacetoxymethyl or halogen;
and R.sup.6 and R.sup.7 are independently hydrogen, lower alkyl
having 1 to 5 carbon atoms);
[0014] R.sup.2 represents R.sup.8--(CH.sub.2).sub.n--
[0015] {wherein, n is 0, 1, 2, 3 or 4; R.sup.8 is benzoyl,
imidazolyl, indolyl, indazolyl, thiazolyl, pyrazolyl, oxazolyl,
isoxazolyl, benzimidazolyl, chromonyl or benzothiazolyl substituted
or unsubstituted with lower alkyl having 1 to 5 carbon atoms,
nitro, amino, cyano, methanesulfonylamino, formyl or halogen, or
3
[0016] (wherein, R.sup.9 is hydrogen, halogen, lower alkyl having 1
to 5 carbon atoms, lower alkoxy having 1 to 5 carbon atoms,
hydroxy, nitro, cyano, --NHSO.sub.2R.sup.2, --S(O).sub.pR.sup.12,
NR.sup.13R.sup.14, carboxyl; R.sup.10 is hydrogen, nitro,
NHSO.sub.2R.sup.2, S(O).sub.pR.sup.12 or NR.sup.13R.sup.14;
R.sup.11 is hydrogen or cyano; R.sup.12 is lower alkyl having 1 to
5 carbon atoms, methylphenyl, NR.sup.13R.sup.14, tifluoromethyl or
alkenyl; R.sup.13 and R.sup.14 are independently hydrogen or lower
alkyl having 1 to 5 carbon atoms; and p is 0 or 2.); or or 4
[0017] (wherein, Z is 0, S, NH or --NCH.sub.3; R.sup.15 is
hydrogen, halogen, lower alkyl having 1 to 5 carbon atoms, nitro,
cyano, --NHSO.sub.2R.sup.12, --S(O).sub.pR.sup.12,
N,N-dimethylaminomethyl or alkoxycarbonylamino; and p and R.sup.12
have the same meanings as defined in R.sup.9); 5
[0018] (wherein, W is O, S, NH, NR.sup.16, --N(SO.sub.2CH.sub.3)--
or --CH.sub.2--; and R.sup.16 is pyridinyl or pyrimidinyl
substituted or unsubstituted with lower alkyl having 1 to 5 carbon
atoms, nitro, methancsulfonylamino or halogen; or benzyl or
phenethyl substituted or unsubstitued with lower alkyl having 1 to
5 carbon atoms, alkoxy, hydroxy, nitro, methanesulfonylamnino or
halogen); 6
[0019] (wherein, R.sup.17, R.sup.18, R.sup.19, R.sup.20 and
R.sup.21 are independently hydrogen, halogen, lower alkyl having 1
to 5 carbon atoms, alkoxy, methylenedioxy,
methanesulfonylaminomethyl, alkoxycarbonyl, hydroxy, sulfamoyl,
amninoalkoxy, alkoxycarbonylamino, --NHCH.sub.2CO.sub.2H,
alkoxyalkylcarbonylammo, alkoxycarbonylalkylarnino- , nitro,
formyl, acetyl, formylamino, acetoxyamino, cyano,
--OSO.sub.2CH.sub.3, --NHSO.sub.2R.sup.12,
--N(SO.sub.2R.sup.12)CH.sub.3, --N(SO.sub.2R.sup.12).sub.2,
--S(O).sub.pR.sup.12, --NR.sup.13R.sup.14, thiocarbamoyl,
--C(.dbd.O)NHNH.sub.2, --C(.dbd.O)NHOH, --C(.dbd.O)NHOCH.sub.3,
--PO(.dbd.O)(OCH.sub.3).sub.2, carboxyl, NHBoc,
--NHC(.dbd.O)SCH.sub.3 or guanidine; R.sup.22 and R.sup.23 are
independently hydrogen, halogen, alkoxy or hydroxy; and p,
R.sup.12, R.sup.13 and R.sup.14 have the same meanings as defined
in R.sup.9);
[0020] or hydroxyphenylalkyl or (methanesulfonylaminophenyl)alkyl};
and
[0021] R.sup.3 represents hydrogen, alkyl or cycloalkyl having 1 to
8 carbon atoms, lower alkylphenyl having 1 to 5 carbon atoms,
pyridinylethyl, bisphenylmethyl; or phenylallcyl substituted with
lower allcyl having 1 to 5 carbon atoms, halogen or
methanesulfonylamino.
[0022] Preferably, in the above formula (I),
[0023] X represents S, O or --NCN;
[0024] Y represents NR.sup.3 or 0;
[0025] R.sup.1 represents 7
[0026] (wherein, m is 0, 1 or 2; and R.sup.4 and R.sup.5 are
independently hydrogen, lower alkyl having 1 to 4 carbon atoms,
hydroxy, methanesulfonylamino, lower alkoxy having 1 to 5 carbon
atoms, methoxyalkoxy, methoxyalkoxyalkyl, benzyloxy, acetoxymethyl,
trimethylacetoxymethyl or halogen);
[0027] R.sup.2 represents R.sup.8--(CH.sub.2).sub.n--
[0028] {wherein, n is 0, 1, 2 or 3; and R.sup.8 is benzoyl,
imidazolyl, indolyl, indazolyl, thiazolyl, pyrazolyl, oxazolyl,
benzinidazolyl or chromonyl substituted or unsubstituted with lower
alkyl having 1 to 5 carbon atoms, nitro, amino, cyano,
methanesulfonylamino, formyl or halogen, or 8
[0029] (wherein, R.sup.9 is hydrogen, halogen, lower alkyl having 1
to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, nitro,
cyano, --NHSO.sub.2R.sup.12, --NR.sup.13R.sup.14 or carboxyl;
Rk.degree. is hydrogen, nitro, NHSO.sub.2R.sup.12 or
--NR.sup.13R.sup.14; R.sup.11 is hydrogen or cyano; R.sup.12 is
lower alkyl having 1 to 4 carbon atoms, methylphenyl,
--NR.sup.13R.sup.14 or trifluoromethyl; R.sup.13 and R.sup.14 are
independently hydrogen or lower alkyl having 1 to 4 carbon atoms;
and p is 0 or 2); 9
[0030] (wherein, Z is O, S, NH or --NCH.sub.3; R.sup.15 is
hydrogen, lower alkyl having 1 to 4 carbon atoms, nitro, cyano or
NHSO.sub.2R.sup.12; and R.sup.12 has the same meanings as defined
in R.sup.9); or 10
[0031] (wherein, W is O, S, NH, NR.sup.16 or --CH.sub.2--; and
R.sup.16 is pyridinyl or pyrimidinyl substituted or unsubstituted
with lower alkyl having 1 to 4 carbon atoms, nitro or
methanesulfonylamino; or benzyl or phenethyl substituted or
unsubstituted with lower alkyl having 1 to 4 carbon atoms, alkoxy,
hydroxy or methanesulfonylamino);
[0032] or 11
[0033] (wherein, R.sup.17, R.sup.18, R.sup.19, R.sup.20 and
R.sup.21 are independently hydrogen, halogen, lower alkyl having 1
to 5 carbon atoms, alkoxy, methylenedioxy,
methanesulfonylaminomethyl, alkoxycarbonyl, hydroxy, sulfamoyl,
alkoxycarbonyl amino, --NHCH.sub.2CO.sub.2H,
alkoxyalkylcarbonylaminno, alkoxycarbonylalkylamino, nitro, fonnyl,
acetyl, fonnylamino, acetoxyamnino, cyano, --OSO.sub.2CH.sub.3,
--NHSO.sub.2R.sup.12, --N(SO.sub.2R.sup.12)CH.sub.3,
--N(SO.sub.2R.sup.12).sub.2, --S(O).sub.pR.sup.2,
NR.sup.13R.sup.14, thiocarbamoyl, --C(.dbd.O)NHNH.sub.2,
--C(.dbd.O)NHOH, --C(.dbd.O)NHOCH.sub.3, carboxyl, NHBoc,
--NHC(.dbd.O)SCH.sub.3, guanidine; R.sup.22 and R.sup.23 are
independently hydrogen, alkoxy or hydroxy; and p, R.sup.12,
R.sup.13 and R.sup.14 have the same meanings as defined in
R.sup.9);
[0034] or hydroxyphenylalkyl or (methanesulfonylaminophenyl)alkyl};
and
[0035] R.sup.3 represents hydrogen, alkyl having 1 to 4 carbon
atoms, lower alkcylphenyl having 1 to 3 carbon atoms,
pyridinylethyl or bisphenylmethyl; or phenylalkyl substituted with
lower alkyl having 1 to 4 carbon atoms, halogen or
methanesulfonylamino.
[0036] More preferably, in the above formula (I), X represents S, O
or --NCN;
[0037] Y represents NR.sup.3 or O;
[0038] R.sup.1 represents 12
[0039] (wherein, m is 1 or 2; and R.sup.4 and R.sup.5 are
independently hydrogen, t-butyl, hydroxy, methanesulfonylamino,
lower alkoxy having 1 to 5 carbon atoms, methoxymethoxy,
methoxyethoxy, benzyloxy, acetoxymethyl, trimethylacetoxymethyl or
halogen);
[0040] R.sup.2 represents R.sup.8--(CH.sub.2).sub.n--{wherein, n is
1, 2 or 3; R.sup.8 is benzoyl, imidazolyl, indolyl, indazolyl,
thiazolyl, pyrazolyl or benzimidazolyl substituted or unsubstituted
with methyl, nitro or halogen;
[0041] or 13
[0042] (wherein, R.sup.9 is hydrogen, halogen, methyl, nitro or
methanesulfonylamino; R.sup.10 is hydrogen or nitro; and R.sup.11
is hydrogen or cyano);
[0043] or 14
[0044] (wherein, Z is O, S, NH or --NCH.sub.3; and R.sup.15 is
hydrogen, methyl, nitro, cyano or methanesulfonylamino);
[0045] or 15
[0046] (wherein, W is O, S, NH, NR.sup.16 or --CH.sub.2--; and
R.sup.16 is pyridinyl, pyrimnidinyl; or benzyl or phenethyl
substituted or unsubstituted with methyl, methoxy or hydroxy);
[0047] or 16
[0048] (wherein, R.sup.17, R.sup.18, R.sup.19, R.sup.20 and
R.sup.21 are independently hydrogen, halogen, lower alkyl having 1
to 4 carbon atoms, methoxy, methylenedioxy,
methanesulfonylaminomethyl, methoxycarbonyli hydroxy, sulfamoyl,
alkoxycarbonylamino, --NHCH2CO.sub.2H, methoxymethylcarbonylamino,
alkoxycarbonylalkylamino, nitro, acetyl, fonnylamino, acetoxyamino,
cyano, --OSO.sub.2CH.sub.3, --NHSO.sub.2R.sup.12,
--N(SOR.sup.12)CH.sub.3, --N(SO.sub.2R.sup.12).sub.- 2,
--S(O).sub.pR.sup.12, NR.sup.13R.sup.14, thiocarbamoyl,
--C(.dbd.O)NHNH.sub.2, --C(.dbd.O)NHOH, --C(.dbd.O)NHOCH.sub.3,
carboxyl, NHBoc, --NHC(.dbd.O)SCH.sub.3, guanidine; R.sup.22 and
R.sup.23 are independently hydrogen, methoxy or hydroxy; and p,
R.sup.12, R.sup.13 and R.sup.14 have the samne meanings as defined
in R.sup.9);
[0049] or hydroxyphenylalkyl or (methanesulfonylaminophenyl)alkyl};
and
[0050] R.sup.3 represents hydrogen, methyl, isopropyl, isobutyl,
cyclohexyl, benzyl, phenethyl or bisphenylmethyl; or phienylalkyl
substituted with t-butyl, halogen or methanesulfonylamino.
[0051] Preferable examples of the compounds of formula (I)
according to the present invention are as follows:
[0052]
1-(4-t-butylbeiizyl)-3-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]thiourea;
[0053]
1-(4-t-butylbenzyl)-3-(4-amino-2,5-difluorobenzyl)thiourea;
[0054] 1-(4-t-butylbenzyl)-3-(4-sulfamoylbenzyl)thiourea;
[0055]
1-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfonylamiobenzyl)thioure-
a;
[0056]
1-phenethyl-3-(3-fluoro-4-methanesulfonylaminobenzyl)thiourea;
[0057]
1-(4-t-butylbenzyl)-3-(3-chloro-4-methanesulfonylaminobenzyl)thiour-
ea;
[0058]
1-(4-t-butylbenzyl)-3-(3-methoxycarboxyl-4-methanesulfonylaminobenz-
yl)thiourea;
[0059]
1-(4-t-butylbenzyl)-3-(3-carboxyl-4-methanesulfonylamninobenzyl)thi-
ourea;
[0060]
1-(4-t-butylbenzyl)-3-((3-N-hydroxyaminocarbonyl-4-methanesulfonyla-
mino)benzyl)thiourea;
[0061] 1-(4-t-butylbenzyl)-3-(3-methoxycarboxylbenzyl)thiourea;
[0062] 1-(4-t-butylbenzyl)-3-(3-carboxylbenzyl)tiourea;
[0063]
1-(4-t-butylbenzyl)-3-(2,3,5,6-tetrafluoro-4-methainesulfonylaminob-
enzyl)thiourea;
[0064]
1-(4-t-butylbenzyl)-3-(2,5-dfluoro-4-methanesulfonylaminobenzyl)thi-
ourea;
[0065]
1-(4-t-butylbenzyl)-3-(3-methanesulfonylamino-6-pyridinyl)methylthi-
ourea;
[0066]
1-(4-t-butylbenzyl)-3-(2,6-dic1loro-5-methanesulfonylaminobenzyl)th-
iourea;
[0067]
1-(4-t-butylbenzyl)-3-(4-methanesuffonylaminophenethyl)thiourea;
[0068]
1-(4-t-butylbenzyl)-3-(4-inethanesulfonylaminobenzyl)thiourea;
[0069]
1-(4-t-butylbenzyl)-3-[2,6-difluoro-3-(N-methanesulfonylaniino)benz-
yl]thiourea;
[0070]
1-(4-t-butylbenzyl)-3-[3-(N-methanesulfonylamino)benzyl]thiourea;
[0071]
1-(4-t-butyl-2-methoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiou-
rea;
[0072]
1-(4-t-butyl-2-ethoxybenzyl)-3-(4-methanesulfonylaimnobenzyl)thiour-
ea;
[0073]
1-(4-t-butyl-2-propoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiou-
rea;
[0074]
1-(4-t-butyl-2-butoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiour-
ea;
[0075]
1-(4-t-butyl-2-isopropoxybenzyl)-3-(4-methanesulfonylaminobenzyl)th-
iourea;
[0076]
1-(4-t-butyl-2-isobutoxybenzyl)-3-(4-methanesulfonylamifnobenzyl)th-
iourea;
[0077]
1-(4-t-butyl-2-neopentoxybenzyl)-3-(4-methanesulfonylaminobenzyl)th-
iourea;
[0078]
1-(4-t-butyl-2-methoxymethoxybenzyl)-3-(4-methatiesulfonylaminobenz-
yl)thiourea;
[0079]
1-(4-t-butyl-2-methoxyethoxybenzyl)-3-(4-methanesulfonylaminobenzyl-
)thiourea;
[0080]
1-(4-t-butyl-2-benzyloxybenzyl)-3-(4-methanesulfonylaminobenzyl)thi-
ourea;
[0081]
1-(2-acetoxymethyl-4-t-butylbenzyl)-3-(4-methanesulfonylaminobenzyl-
)thiourea;
[0082]
1-(4-t-butylbenzyl)-3-[2-(4-methylthiazol-5-yl)ethyl]thiourea;
[0083]
1-(4-t-butylbenzyl)-3-((2-chloro-5-pyridinyl)methyl)thiourea;
[0084] 1-(4-t-butylbenzyl)-3-(2-pyridin-2-ylethyl)thiourea;
[0085] 1-(4-t-butylbenzyl)-3-(2,5-difluorobenzyl)thiourea;
[0086] 1-(4-t-butylbenzyl)-3-(3-fluorophenethyl)thiourea;
[0087] 1-(4-t-butylbenzyl)-3-(4-sulfamoylphenethyl)thiourea;
[0088] 1-(4-t-butylbenzyl)-3-(4-morpholinylethyl)thiourea;
[0089]
1-(4-t-butylbeiizyl)-3-[2-(lH-imidazol-4-yl)ethyl]thiourea;
[0090] 1-(4-t-butylbenzyl)-3-[2-thiophen-2-ethyl]thiourea;
[0091]
1-(4-t-butylbenzyl)-3-(4-methanesulfonylamino-1-methyl-1H-pyrrol-2--
yl)thiourea;
[0092]
1-benzyl-1-(3-(4-hydroxy-3-methoxyphenyl)propyl)-3-phenethylthioure-
a;
[0093] 1-(3-(4-hydroxy-3-methoxyphenyl)propyl)-
I-phenethyl-3-phenethylthi- ourea;
[0094] 1-bisphenylmethyl-
I-(3-(4-hydroxy-3-methoxyphenyl)propyl)-3-phenet- hylthiourea;
or
[0095]
N"-cyano-N-(4-t-butylbenzyl)-N'-(4-methanesulfonylaninobenzyl)guani-
dine.
[0096] More preferable examples of the compounds of formula (I)
according to the present invention are follows:
[0097]
1-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfonylaminobenzy)thioure-
a;
[0098]
1-(4-t-butylbenzyl)-3-(3-chloro-4-methanesulfonylaminobenzyl)thiour-
ea;
[0099]
1-(4-t-butylbenzyl)-3-(3-methoxycarboxyl-4-methanesulfonylaminobenz-
yi)thiourea;
[0100]
1-(4-t-butylbenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;
or
[0101]
1-(4-t-butyl-2-isobutoxybenzyl)-3-(4-methanesulfonylamino)thiourea.
[0102] The compounds according to the present invention can
chemically be synthesized by the following reaction schemes.
However, these are given only for illusion of the invention and not
intended to limit them. 17
[0103] As depicted in the above Scheme 1, the nitrile compound 1-1
or 1-3 is reduced with lithium aluminium hydride or hydrogen to
afford an arnine 1-2 or 1-4, and then suitable isothiocyanate or
isocyanate is reacted therewith to prepare thiourea or urea
compound 1-5.about.13. 18
[0104] As depicted in the above Scheme 2, pipsyl chloride is
treated with ammonia solution to afford compound 2-2 and the
nitrile compound 2-3 is obtained therefrom using palladium
catalyst. The compound 2-3 is subjected to catalytic reduction
using palladium and concentrated hydrochloric acid to prepare amine
compound 2-4, and compounds 2-5, 2-6 and 2-7 are synthesized
therefrom according to the procedure as described in Scheme 1.
19
[0105] As depicted in the above Scheme 3, 2-fluoro-4-iodo
phenylamine compound 3-1 is mesylated, and cyano group is
introduced thereinto in the presence of palladium catalyst. And the
compound 3-3 is reduced to afford primary amine compound 3-4. The
obtained intermediate is reacted with isocyanate or isothiocyanate
to synthesize compounds 3-5.about.3-7. And their derivatives such
as compound 3-8.about.3-10 (Example 16.about.18) and 4-6.about.4-13
(Example 24 31) are synthesized according to the similar procedure
as the synthetic method of the compounds 3-5.about.3-7. 20
[0106] As depicted in the above Scheme 4, the compound 4-1 obtained
according to the procedure as described in Example 19 is reacted
with oxalyl chloride to give acid chloride, and then the acid
chloride is subjected to various reaction to yield compounds
4-2.about.4-5. 21
[0107] As depicted in the above Scheme 5, amine compound 5-1 is
mesylated and the obtained compound 5-2 is hydrogenated to afford
amine compound 5-3, and then 4-t-butylbenzylisothiocyanate is
reacted therewith to synthesize compound 5-4.about.5-9. 22
[0108] As depicted in the above Scheme 6, the amine group of
4-nitrobenzylamine hydrochloride compound 6-1 is protected. Nitro
group thereof is reduced to give amino group and then
methylchlorothiol formate is reacted therewith to prepare compound
6-3, followed by reacting 4-t-butylbenzylisothiocyanate therewith
to obtain compound 6-5. 23
[0109] As depicted in the above Scheme 7, guanidine group and cyano
group are introduced into 4-iodoaniline 7-1 to prepare compound
7-3, and the compound 7-3 is reduced in the presence of palldium
catalyst to give amine compound 7-4. The compound 7-4 is reacted
with 4-t-butylbenzylisothiocyanate, followed by deprotection to
synthesize compound 7-6. 24
[0110] As depicted in the above Scheme 8, 4-aminobenzylamine is
selectively protected with t-butoxycarbonyl group (Boc) to prepare
compound 8-1 and methanesulfonyl chloride is reacted with NH2 group
thereof to yield compound 8-2. Boc group is removed therefrom in
acidic condition, and then
2-(1-methyl-1H-pyrrol-2-yl)ethylisocyanate is reacted therewith to
yield compound 8-4. 25
[0111] Compounds 9a.about.9h are synthesized by reacting
4-t-butylbenzylisothiocyanate with corresponding benzylamine
derivatives, respectively. 26
[0112] As depicted in the above Scheme 10, hydroxy group of
2-hydroxy-4-nitrobenzaldehyde is protected with TBDPS, and then
oxime 10-1 is prepared therefrom. The compound 10-1 is reduced with
hydrogen in the presence of palladium catalyst and protected with
Boc group to afford compounds 10-2 and 10-3. The compond 10-2 is
reacted with t-butylbenzylisothiocyanate, and then TBDPS is removed
therefrom to synthesize compound 10-4. Two protecting groups of
compound 10-3 are removed using trifluoroacetic acid and the
deprotected compound is protected with Boc group in the presence of
triethylamine to synthesize compound 10-5. TBDPS and Boc group are
removed from the compound 10-5 and t-butylbenizylisothiocyanate is
reacted therewith in the presence of triethylamine to give compound
10-6. 27
[0113] As depicted in the above Scheme 11,
2,6-difluoro-3-nitrobenzonitril- e is reduced and then proteced
with Boc group to prepare compound 11-1. The amino group of the
compound 11-1 is mesylated, and after removing of the Boc group
therefrom, the mesylated compound is reacted with
4-t-butylbenzylisothiocyanate to give compound 11-2. 28
[0114] As depicted in the above Scheme 12, the carbonyl group of
nitrobenzaldehyde is converted into oxime group, and the oxime
group and nitro group are reduced with hydrogen in the presence of
Pd/C catalyst to prepare amine compound 12-1. The amine compound
12-1 is selectively protected and mesylated to afford compound
12-2. Boc group is removed from compound 12-2, and, in the presence
of triethylamine, t-butylbenzylisothiocyanate compound is reacted
therewith to synthesize compound 12-3a.about.12-3 g. 29
[0115] As depicted in the above Scheme 13,
4-t-butyl-2-hydroxybenzonitrile 13-1 as a starting material is
0-alkylated and reduced to prepare amine compound 13-3.
4-Methanesulfonaminobenzylisothiocyanate is reacted therewith to
yield thiourea compound 13-4a.about.13-4k. And compound 13-1 is
reacted with 0-triflate, and subsequently with carbon monoxide in
the presence of palladium acetate catalyst to yield ester 13-6. The
ester 13-6 is reduced, and then reacted with
4-methanesulfonaminobenzylisothioc- yanate to prepare alcohol
compound 13-8. The prepared compound 13-8 is sbjected to
condensation reaction with acid to yield the corresponding
tlliourea compound 13-9a and 13-9b. 30
[0116] As depicted in the above Scheme 14, respective compounds
14-1 and 14-4 are obtained from 4-(methylthio)benzylalcohol and
4-methylthiazol-5-ethanol, respectively, under Mitsunobu condition,
or obtained by introducing mesyl group into
4-(methylthio)benzylalcohol and 4-methylthiazol-5-ethanol,
respectively, followed by reacting potassium phthalimide therewith.
Phthalimide group is removed from compounds 14-1 and 14-4 with
hydrazine to give amine compounds 14-2 and 14-5, respectively. The
obtained amine compounds 14-2 and 14-5 are separately reacted with
one equivalent of 4-t-butylbenzylisothiocyanate to the objective
thiourea compounds 14-3 and 14-6, respectively.
2-Chloro-5-chloromethylpyridine is reacted with potassium
phtlialimide to yield compound 14-7, and then compound 14-9 is
synthesized according to the same procedure as the synthetic method
of the compounds 14-3 and 14-6. 31
[0117] Thiomorpholine is reacted with 2-(bromoethyl)phthalimide in
the presence of base to yield compound 15-1. Phthaloyl group of the
compound 15-1 is treated with hydrazine to prepare amine compound
15-2 and 4-t-butylbenzylisothiocyanate is reacted therewith to
afford the objective compound 15-3. 32
[0118] As depicted in the above Scheme 16, compound A and
isothiocyanate compound B of the above formula are reacted with
each other in the presence of suitable solvent (dichloromethane,
acetonitrile, ethylacetate, dimethylformamide) using suitable
condition (triethylamine) to yield thiourea compound C (Example 76
122). 33
[0119] As depicted in the above Scheme 17, pyrrolecarboxaldehyde
and 5-nitro-2-thiophenaldehyde are respectively converted to
oximes, and the oximes are reduced to prepare primary amine
hydrochloride. The prepared intermediates are reacted with
isothiocyanates to give compounds 17-1.about.17-4, respectively.
34
[0120] As depicted in the above Scheme 18, ethyl-2-methyl
nicotinate 18-1 is reduced to prepare alcohol, and then amine is
introduced thereinto. The prepared intennediate is reacted with
4-t-butylbenzylisothiocyanate to yield compound 18-5. 35
[0121] As depicted in the above Scheme 19, 5-nitro-1H-indazole is
reduced to prepare amine, and then isothiocyanate is reacted
therewith to afford compounds 19-1 and 19-2. 36
[0122] As depicted in the above Scheme 20,
2-fluoro-4-hydroxybenzonitrile is reduced with sodium borohydride
in the presence of nickel catalyst, and proctected with Boc group
to prepare protected amine compounds 20-1a and 20-1b. Phenol group
of compound 20-1a is mesylated, and Boc group is removed therefrom,
followed by reacting with t-butylbenzylisothiocyanate to give
compound 20-2a. And compound 20-2b is obtained from compound 20-1b,
according to the similar procedure as the synthetic method of
compound 20-2a. 37
[0123] depicted in the above Scheme 21, 2-aminopicoline is reacted
with pivaloyl chloride to yield compound 21-1. The compound 21-1 is
brominated with NBS to prepare compound 21-2 and potassium
phthalimide is reacted therewith to obtain compound 21-3 protected
with phthaloyl group. Pivaloyl group is removed from compound 21-3
in the presence of concentrated sulfuiric acid, and
methanesulfonylchloride is reacted therewith to prepare compound
21-5. The prepared compound 21-5 is treated with hydrazine and
reacted with 4-t-butylbenzylisothiocyanate to yield compound 21-7.
38
[0124] Nitro group is selectivlely introduced into
pyrrolecarboxaldehyde under nitric acid/acetic anhydride condition
and the compound 22-1 was reduced with borane to prepare alcohol
22-2. The prepared compound 22-2 is reacted with
4-t-butylbenzylisothiocyanate in the presence of sodium hydride to
yield compound 22-3. And pyrrolecarboxaldehyde is reacted with
hydroxylamine hydrochloride in the presence of
1-methyl-2-pyrrolidinone (NMP) as a solvent to produce nitrile
compound 22-4 and nitro goup is introduced thereinto under the
similar condition as above. The nitro goup is reduced and mesylated
to give compound 22-7. The nitrite group of the compound 22-7 is
reduced in the presence of palladium/carbon and
4-t-butylbenzylisothiocyanate is reacted therewith to synthesize
compound 22-9. 39
[0125] As depicted in the above Scheme 23, 4-nitrobenzylamine
hydrochloride is converted to methanesulfonyl derivatives 23-1.
Nitro group of the compound 23-1 is reduced with tin (II) chloride
and 4-t-butylbenzylisothiocyanate is reacted therewith to give
compound 23-2. 40
[0126] As depicted in the above Scheme 24, amine compound D is
reacted with isothiocyanate compound B in suitiable solvent to
yield thiourea compound E (Example 136.about.141). 41
[0127] As depicted in the above Scheme 25, benzaldehyde,
phenylacetaldehyde and cinnamaldehyde derivatives are subjected to
reductive amination with alkylamine to prepare the corresponding
sencondary amines, respectively, and phenethylisothiocyanates are
reacted therewith to obtain compounds 25-1.about.25-26 (Example
142.about.167, respectively). 42
[0128] As depicted in the above Scheme 26, 2-fluoro-4-iodo
methanesulfonylbenzylamine 3-2 is subjected to cross coupling using
palladium to prepare compound 26-1 and the compound 26-1 is
hydrogenated in the presence of palladium/carbon to give compound
26-2. The compound 26-2 is reacted with 4-t-butylbenzylamine to
sythesize amide compound 26-3. 43
[0129] 4-t-butylbenzoylchloride is reacted with
3-fluoro-4-methanesulfonyl- aminobenzylamine hydrochloride (3-4) to
yield amide compound 27. 44
[0130] As depicted in the above Scheme 28,
3-fluoro-4-methanesulfonylamino- benzyl amine hydrochloride 3-4 is
reacted with 4-t-butylbenzyl bromide and carbon disulfide in the
presence of cesium carbonate to yield compound 28. 45
[0131] As depicted in the above Scheme 29, 4-t-butylbenzylamine is
reacted with triphosgene to prepare isocyanate, and
3-fluorophenethylamine is reacted therewith to afford compound 29.
46
[0132] As depicted in the above Scheme 30, 2-fluorobenzoyl chloride
is reacted successively with KSCN and 4-t-butylbenzylamine to
obtain final compound 30. 47
[0133] As depicted in the above Scheme 31, cyanoguanidine compounds
are synthesized by two methods. As one method, 4-t-butylbenzylamine
is reacted with dimethyl N-cyanodithioiminocarbonate or diphenyl
cyanocarbonimidate, and then amine is reacted therewith to yield
final compounds 31-1.about.31-6 (Example 173.about.178). And
thiourea compound is reacted with lead cyanamide to give compounds
31-7.about.31-9 (Example 179.about.181). 48
[0134] As depicted in the above Scheme 32, tetralone is converted
to oxime and the oxime is reduced with nickel catalyst and sodium
borohydride to prepare amine compounds 32-1, 32-3 and 32-5. These
compounds are reacted with various benzylisothiocyanates to give
compounds 32-2, 32-4 and 32-6.about.32-10. And methoxy group of
compounds 32-3 and 32-5 are treated with hydrobromic acid to form
hydroxy group and the resulting compound are reacted with various
benzylisothiocyanates in the presence of triethylamine to yield
compounds 32-11 and 32-12. 49
[0135] As depicted in the above Scheme 33, 2-amino-3-formylchromone
33-1 or 3,5-dimethylpyrazole-1-methanol 33-3 is, repectively,
reacted with 4-t-butylbenzylisothiocyanate in the presence of base
to give compounds 33-2 or 33-4. 50
[0136] As depicted in the above Scheme 34, 4-t-butylbenzaldehyde is
reacted with phosphonate to prepare compound 34-2, and the compound
34-2 is reduced and hydrolyzed to give 4-t-butylhydrocinnamic aicd
34-4. The obtained compound is reacted with compound 3-4 which is
prepared according to the procedure as described in Example 13, to
synthesize final compound 34-5. 51
[0137] As depicted in the above Scheme 35,
N-t-butyloxycarbonyl-p-aminoben- zylamine 8-1 is reacted with
sulfamoyl chloride in basic condition to prepare compound 35-1. The
prepared compound 35-1 is deprotected with trifluoroacetic acid to
afford amine, and 4-t-butylbenzylisothiocyanate is subjected to
condensation reaction therewith to yield thiourea compounds 35-2a,
35-2b and 35-2c. 3-Nitro-4-aminobenzonitrile is mesylated to give
compound 35-4, and then nitrile group of the compound 35-4 is
reduced with borane to afford amine. 4-t-Butylbenzylisothiocyanat-
e is subjected to condensation reaction therewith to synthesize
thiourea compound 35-5. 52
[0138] As depicted in the above Scheme 36, oxime 36-2, prepared
from 4-aminoacetophenone as a starting material, is reduced to
yield compound 36-3. Isothiocyanates are reacted therewith to give
compounds 36-4 and 36-5. And compound 36-1 is reduced with
methylamine to afford benzylamine derivatives, and
4-t-butylbenzylisothiocyanate is reacted therewith to synthesize
compound 36-6.
[0139] The compound of formula (I) according to the present
invention can be provided as a pharmaceutical composition
containing pharmaceutically acceptable carriers, adjuvants, or
diluents. For instance, the compounds of the present invention can
be dissolved in oils, propylene glycol or other solvents which are
commonly used to produce an injection. Suitable examples of the
carriers include physiological saline, polyethylene glycol,
ethanol, vegetable oils, isopropyl myristate, etc., but are not
limited to them. For topical administration, the compounds of the
present invention can be formulated in the form of ointment or
cream.
[0140] The pharmaceutical composition containing the compound of
the present invention as an active ingredient can be used for
preventing or treating pain, acute pain, chronic pain, neuropathic
pain, post-operative pain, migraine, arthralgia, neuropathies,
nerve injury, diabetic neuropathy, neurodegeneration, neurotic skin
disorder, stroke, urinary bladder hypersensitiveness, irritable
bowel syndrome, a respiratory disorder such as astluna or chronic
obstructive pulmonary disease, irritation of skin, eye or mucous
membrane, fervescence, stomach-duodenal ulcer, inflammatory bowel
disease and inflammatory diseases.
[0141] Hereinafter, the formulating methods and kinds of excipients
will be described, but the present invention is not limited to
them.
[0142] The compound according to the present invention may also be
used in the forms of pharmaceutically acceptable salts thereof, for
example, alkali metals salts such as sodium salts, potassium salts
and the like; alkali earth metals salts such as calcium salts,
magnesium salts and the like; amines such as triethanolamine or
ammonium salts, and may be used either alone or in combination or
in admixture with other pharmaceutically active compounds.
[0143] The compounds of the present invention may be formulated
into injections by dissolving, suspending or emulsifying in
water-soluble solvent such as saline and 5% dextrose, or in
water-insoluble solvents such as vegetable oils, synthetic fatty
acid glyceride, higher fatty acid esters and propylene glycol. The
formulations of the invention may include any of conventional
additives such as dissolving agents, isotonic agents, suspending
agents, emulsifiers, stabilizers and preservatives.
[0144] The preferable dose level of the compounds according to the
present invention depends upon a variety of factors including the
condition and body weight of the patient, severity of the
particular disease, dosage form, and route and period of
administration, but may appropriately be chosen by those skilled in
the art. The compounds of the present invention are preferably
administered in an amount ranging from 0.001 to 100 mg/kg of body
weight per day, and more preferably from 0.01 to 30 mg/kg of body
weight per day. Doses may be administered once a day, or several
times a day with each divided portions. The compounds of the
present invention are used in a pharmaceutical composition in an
amount of 0.0001.about.10% by weight, and preferably 0.001.about.1%
by weight, based on the total amount of the composition.
[0145] The pharmaceutical composition of the present invention can
be administered to a mammalian subject such as rat, mouse, domestic
animals, human being and the like via various routes. The methods
of administration which may easily be expected include oral and
rectal administration; intravenous, intramuscular, subcutaneous,
intrauterine, duramatral and intracerebroventricular
injections.
BEST MODE FOR CARRYING OUT THE INVENTION
[0146] The present invention is more specifically explained by the
following examples. However, it should be understood that the
present invention is not limited to these examples in any
manner.
EXAMPLE 1
[0147] Synthesis of 1-(1H-indol-5-ylmethyl)-3-phenethylthiourea
(1-5) 53
[0148] Step 1: synthesis of (1H-indol-5-yl)methylamine
[0149] To an ice cold suspension of aluminium chloride (126mg) in
ether (1.5 ml) was added a suspension of lithium aluminium hydride
(55 mg) in ether (1.5 ml), followed by stirring for 5 min. A
solution of 5-cyanoindole (103 mg) in ether (5 ml) was added
dropwise thereto. The mixture was stirred at room temperature for 6
hours, followed by adding aqueous Rochel solution thereto and then
stirring for 5 hours. The resulting mixture was basified with 1M
aqueous sodium hydroxide solution, extracted twice with ethyl
acetate (50 ml), washed with saturated aqueous sodium chlroride
solution, dried over magnesium sulfate and then filtered to yield
(1H-indol-5-yl)methylamine (93 mg, 88%).
[0150]
[0151] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.46(d, 1H,
J=l.OHz), 7.29(d, 1H, J=8.3 Hz), 7.14(d, 1H, J=3.2 Hz), 7.02(dd,
1H, J=1.7, 8.3 Hz), 6.34(dd, 1H, J=0.7, 3.2 Hz), 3.89(s, 211)
[0152] Step 2: synthesis of
1-(1H-indol-5-yhmethyl)-3-phenethylthiourea (1-5)
[0153] (1H-indol-5-yl)methylamine (8.5 mg) prepared in Step 1 was
dissolved in dimethylformamide (100 .mu.l) and the solution was
diluted with dichloromethane (1 ml). To the diluted solution was
added phenethylisothiocyanate (40 .mu.l) and the mixture was
stirred at room temperature for 2 hours. The resulting mixture was
concentrated under reduced pressure and the obtained residue was
chromatographed on a silica gel column eluting with ethyl
acetate/hexane (2/3) to yield
1-(1H-indol-5-ylmethyl)-3-phenethylthiourea (15 mg, 83%).
[0154] 1H NMR(300 MHz, CDCl.sub.3): .delta. 8.17(s, 1H), 7.53(s,
1H), 7.28(d, 1H, J=8.3 Hz), 7.11-7.19(m, 5H), 6.98-7.04(m, 2H),
6.46(t, 1H, J=2.2 Hz), 6.03(s, 11), 5.59(s, 1H), 4.44(s, 2H),
3.66(m, 2H), 2.77(t, 2H, J=6.8 Hz)
EXAMPLE 2
[0155] Synthesis of 1-(1H-indol-5-ylmethyl)-3-phenethylurea (1-6)
54
[0156] (1H-indol-5-yl)methylamine (12.5 mg) was reacted with
phenethylisocyanate (30 g) according to the similar procedure as
described in step 2 of Example 1, to give
1-(1H-indol-5-ylmethyl)-3-phene- thylurea (1-6) (19 mg, 76%). 1H
NMR(300 MHz, CDCl.sub.3): .delta. 8.16(s, 111), 7.44(s, 1H),
7.27(d, 1H, J=8.3 Hz), 7.02-7.21(m, 7H), 6.43-6.45(m, 1H), 4.48(t,
1H), 4.31(d, 2H, J=5.6 Hz), 4.22(m, 1H), 3.37(q, 2H, J=6.8 Hz),
2.71(t, 2H, J=6.8 Hz)
EXAMPLE 3
[0157] Synthesis of
1-(4-t-butylbenzyl)-3-(1H-indol-5-ylmethyl)thiourea (1-7) 55
[0158] Step 1: synthesis of 4-t-butylbenzylisotbiocyanate
[0159] Di-2-pyridyl thionocarbonate (45 mg) was dissolved in
methylenechloride (2 ml) and to the solution were added
4-t-butylbenzylamine (29 mg) and triethylamine (20 .mu.l), followed
by stirring at room temperature for 2 hours. The reaction solution
was concentrated under reduced pressure and the obtained residue
was chromatographed on a silica gel column eluting with ethyl
acetate/hexane (1/10) to yield 4-t-butylbenzylisothiocyanate (26
mg, 71%).
[0160] .sup.1H NMR(30OMHz, CDCl.sub.3): .delta. 7.39(d, 2H, J=8.5
Hz), 7.23(d, 2H, J=8.3 Hz), 4.65(s, 2H), 1.30(s, 9H)
[0161] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-(1H-indol-5-ylmethyl)thi- ourea (1-7)
[0162] (1H-indol-5-yl)methylamine (15 mg) was reacted with
4-t-butylbenzylisothiocyanate (20 mg) according to the similar
procedure as described in Step 2 of Example 1, to synthesize
1-(4-t-buylbenzyl)-3-(1H-indol-5-ylmethyl)thiourea (1-7) (21 mg,
70%).
[0163] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 8.33(s, 1H),
7.48(s, 1H), 7.19-7.33(m, 4H), 7.03-7.10(m, 4H), 6.47(t, 1H),
6.18(s, 1H), 6.06(s, 1R), 4.58(d, 2H, J=13 Hz), 1.26(s, 9H)
EXAMPLE 4
[0164] Synthesis of
1-(4-t-butylbenzyl)-3-(4-methanesulfonylbenzyl)thioure- a (1-8)
56
[0165] Lithium aluminum hydride (0.38 g) was dissolved in anhydrous
ether (20 ml). The solution was cooled to 0.degree. C. and
4-(methylsulfonyl)benzonitrile (1.81 g) was slowly added dropwise
thereto. The mixture was stirred for 3 hours while allowed to
slowly warm up to room temperature and the reaction was quenched
with 20% aqueous sodium hydroxide solution and water. The water
layer was washed with ether, and then the ether layer was mixed
with the organic layer. The combined organic layer was dried over
anhydrous magnesium sulfate and concentrated. The residue was
purified by column-chromatography (acetone) to yield a liquid (0.3
g).
[0166] The obtained liquid was dissolved in dichloromethane (10 ml)
and 4-t-butylbenzylisothiocyanate (0.33 g) was added thereto,
followed by stirring at room temperature for 19 hours. The reaction
mixture was concentrated and then purified by column-chromatography
(hexane/ethyl acetate =1/1) to yield compound 1-8 (0.02 g) as a
white solid.
[0167] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.85-7.81(m, 2H),
7.41-7.30(m, 4H), 7.27-7.23(m, 2H), 6.25(brs, 1H), 6.05(brs, 1H),
4.88(d, 2H, S=6 Hz), 4.60-4.55(m, 211), 3.01(s, 3H), 1.31(s,
9H)
EXAMPLE 5
[0168] Synthesis of
1-(4-t-butylbenzyl)-3-[2-(1-methyl-1H-pyrro1-2-yl)ethy- l]thiourea
(1-9) 57
[0169] Step 1: Synthesis of (1-methyl-1H-pyrro1-2-yl)ethylamine
[0170] 1-methyl-2-pyrroleacetonitrile (2 g) was slowly added
dropwise to a suspension of lithium aluminium hydride (695 mg) in
ether (100 ml) while the temperature was adjusted to -78.degree. C.
The miture was stirred for 1 hour, and then stirred for 3 hours at
room temperature. After confirming the completion of the reaction
using TLC, 15% aqueous sodium hydroxide solution (10 ml) and water
(20 ml) were added dropwise and the resulting mixture was stirred
for 1 hour. The reaction mixture was extracted three times with
ether. The organic layer was washed with saturated aqueous sodium
chloride solution and concentrated under reduced pressure to yield
amine compound. The amine compound, which was not purified, was
used in the following reaction.
[0171] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-[2-(1-methyl-1H-pyrro1-2- -yl)ethyl]thiourea
(1-9)
[0172] Amine (250 mg) prepared in Step 1 and
4-t-butylbenzylisothiocyanate (420 mg) were dissolved in ethyl
acetate (20 ml) and the solution was stirred at room temperature
for 12 hours. The resulting mixture was concentrated under reduced
pressure to remove the solvent and the residue was purified by
column-chromatography (ethyl acetate/hexane={fraction (1/3)}) to
yield compound 1-9 (498 mg, 75%) as a liquid.
[0173] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.0 7.37(d, 2H),
7.19(d, 2H), 6.54(m, 1H), 6.01(m, 1H), 5.83(s, 1H), 4.46(brs, 2H),
3.72(brs, 2H), 2.841(t, 2H, J=6.9 Hz), 1.31(s, 9H)
EXAMPLE 6
[0174] Synthesis of
1-(4-amino-3,5-dichlorobenzyl)-3-(4-t-butylbenzyl)thio- urea (1-10)
58
[0175] 4-amino-3,5-dichlorobenzomitrile (260 mg) was dissolved in
methanol (20 ml) and a small amount of concentrated hydrochloric
acid and 5% palladium/carbon catalyst was added thereto. After the
mixture was stirred for 15 hours, the reaction mixture was filtered
through celite and concentrated. The obtained mixture was dissolved
in dichloromethane (10 ml), and 4-t-butylbenzylisothiocyanate (200
mg) and triethylamine (2 ml) was added thereto, followed by
stirring at room temperature for 15 hours. The resulting mixture
was extracted with water and dichloromethane, and the residue was
purified by column-chromatography (hexane/ethyl acetate=1/1) to
yield compound 1-10 (72 mg, 13%, as a liquid. 1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.40-7.00(m, 6H), 5.92(brs, 2H), 4.58(m, 2H),
4.45(m, 2H), 3.71(brs, 2H), 1.31(s, 9H)
EXAMPLE 7
[0176] Synthesis of
1-(4-t-butylbenzyl)-3-(pyrazin-2-y1-methyl)thiourea (1-11) 59
[0177] Pyrazinecarbonitrile (500 mg) and 10% palladiui/carbon (450
mg) were dissolved in anhydrous methanol (30 ml) and the mixture
was stirred under hydrogen atmosphere for 12 hours.
[0178] The resulting mixture was filtered, and then the filtrate
was concentrated under reduced pressure. The obained compound (200
mg) and 4-t-butylbenzylisothiocyanate (330 mg) were dissolved in
ethyl acetate (30 ml). The solution was stirred for 12 hours and
then concentrated. The resulting residue was purified by
colunmn-chromatography (ethyl acetate/hexne=3/1) to yield the
compound 1-11 (271 mg, 53%).
[0179] 1H NMR (300 MHz, CDCl.sub.3) .delta. 8.51(s, 1H), 8.41(s,
1H), 8.16(s, 1H), 7.38(m, 2H), 7.29(m, 2H), 5.10(s, 21), 4.86(d,
2H, J=2.25 Hz), 1.33(s, 9H)
EXAMPLE 8
[0180] Synthesis of
1-(4-t-butylbenzyl)-3-(3-cyanopyrazin-2-ylmethyl)thiou- rea (1-12)
60
[0181] 2,3-pyrazinedicarbonitrile (200 mg) and 10% palladium/carbon
(200 mg) were dissolved in anhydrous methanol (30 ml) and the
rirxture was stirred under hydrogen atmosphere for 12 hours. The
resulting mixture was filtered, and then the filtrate was dried
under reduced pressure to give an amine. The obtained amine (150
mg) and 4-t-butylbenzylisothiocyanate (180 mg) were dissolved in
ethyl acetate (30 ml). The solution was stirred for 12 hours to
complete the reaction and purified by colum-chromatography (ethyl
acetate/hexane=3/1) to yield the compond 1-12 (77 mg, 25%) as a
white solid.
[0182] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.0 8.76(m, 1H),
8.67(m, 1H), 7.38(m, 41), 5.38(s, 2H), 4.98(d, 2H, J=2.7 Hz),
1.32(s, 9H)
EXAMPLE 9
[0183] Synthesis of
1-(4-amino-2,5-difluorobenzyl)-3-(4-t-butylbenzyl)thio- urea (1-13)
61
[0184] Step 1: Synthesis of 4-amino-2,5-difluorobenzylamine
[0185] 4-amnino-2,5-difluorobenzonitrile (400 mg) and Raney nickel
Catalyst were added to methanol (20 ml) and the mixture was stirred
under hydrogen atmosphere at room temperature for 18 hours. After
confirmiing the completion of the reaction, the resulting mixture
was filtered through celite and the filtrate was concentrated under
reduced pressure. The following procedure was carried out, using
the concentrate which was not purified.
[0186] Step 2: Sythesis of
1-(4-amino-2,5-difluorobenzyl)-3-(4-t-butylbenz- yl)thiourea
(1-13)
[0187] The compound (330 mg) obtained in Step 1 and
4-t-butylbenzylisothiocyanate (428 mg) were dissolved in ethyl
acetate (40 ml) and the solution was stirred at room temperature
for 6 hours. The mixture was concentrated under reduced pressure
and the residue was purified by column-chromatography (ethyl
acetate/hexane=1/3) to yield the compound 1-13 (190 mg, 25%).
[0188] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.37(m, 2H),
7.22(m, 2H), 6.95(m, 1H), 6.43(m, 1H), 6.08(brs, 1H), 5.90(brs,
1H), 4.59(s, 2H), 4.57(s, 2H), 3.83(s, 2H), 1.31(s, 9H)
EXAMPLE 10
[0189] Synthesis of 1-phenethyl-3-(4-sulfamoylbenzyl)thiourea (2-5)
62
[0190] Step 1: Synthesis of 4-iodo-1-sulfamoylbenzene (2-2)
[0191] Pipsylchloride (100 mg) was dissolved in 28% ammonia
solution (4 ml) and the solution was stirred at room temperature
for 1 hours. The resulting mixture was extracted with ethyl acetate
(20 ml), washed with water and saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was
chromatographed on column eluting with ethyl acetate/hexane (1/2)
to yield the compound 2-2 (89 mg, 100%/0).
[0192] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.91(td, 1H,
J=9.OHz), 7.63(td, 1H, J=9.OHz)
[0193] Step 2: Synthesis of 4-cyano-1-sulfamoylbenzene (2-3)
[0194] The compound 2-2 (58 mg) prepared in Step 1 was dissolved in
dimethylformamide (2 ml) and to the solution were added zinc
cyanide [Zn(CN).sub.2] (58 mg) and tetrakistriphenylphosphine
palladium (10 mg), followed by stirring at 80.degree. C. for 12
hours. The resulting mixture was basified with aqueous sodium
bicarbonate solution, diluted with ethyl acetate (30 ml), washed
with water and saturated aqueous sodium chloride solution, dried
over anhydrous magnesium sulfate, and then concentrated under
reduced pressure. The obtained residue was chromatographed on
silica gel column eluting with ethyl acetate/hexane (1/2) to yield
the compound 2-3 (30 mg, 80%).
[0195] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.92-7.96 (m,
211), 7.69-7.73 (m, 2H), 6.47 (s, 2H)
[0196] Step 3: Sythesis of 4-sulfamoylaminobenzene (2-4)
[0197] The compound 2-3 (52 mg) prepared in Step 2 was dissolved in
methanol (2 ml) and to the solution were added a catalytic amount
of 10% palladium/carbon and concentrated hydrochloric acid (10
.mu.l), followed by stirring under hydrogen gas atmosphere at room
temperature for 1 hour. The resulting mixture was diluted in ether,
filtered through celite, neutralized with 1N aqueous sodium
hyroxide solution, and then washed with water and saturate aqueous
sodium chloride solution. The obtained residue was dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure to yield the compound 2-4 (26 mg, 50%).
[0198] .sup.1H-NMR(300 MHz, CD.sub.3OD): .delta. 7.77 (dd, 2H,
J=1.7, 6.6 Hz), 7.41 (d, 2H, J=8.5 Hz), 3.80 (s, 2H)
[0199] Step 4: Synthesis of
1-phenethyl-3-(4-sulfamoylbenzyl)thiourea (2-5)
[0200] The compound 2-4 (10 mg) prepared in Step 3 was dissolved in
dimethylformamide (100 le). The solution was diluted with
dichloromethane (2 ml) and to the solution was added
phenethylisothiocyanate (1.0 ml), followed by stirring at room
temperature for 2 hours. The reaction solution was concentrated
under reduced pressure and the obtained residue was chromatographed
on a column eluting with ethyl acetate/hexane (1/1) to yield the
compound 2-5 (11 mg, 59%).
[0201] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.82-7.85 (m, 2H),
7.42 (d, 2H, J=8.5 Hz), 7.16-7.30 (m, 5H), 4.78 (br s, 2H), 3.72
(br s, 2H), 2.88 (t, 2H, J=7.1 Hz)
EXAMPLE 11
[0202] Synthesis of 1-phenethyl-3-(4-sulfamoylbenzyl)urea (2-6)
63
[0203] Compound 2-6 (13 mg, 79%) was synthesized according to the
same procedure as described in Step 4 of Example 10 except that
compound 2-4 (9 mg) was reacted with phenethylisocyanate (100
ut).
[0204] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.82-7.84 (m, 2H),
7.39 (d, 2H, J=8.3 Hz), 7.15-7.32 (m, 51), 4.35 (s, 2H)
EXAMPLE 12
[0205] Synthesis of
1-(4-t-butylbenzyl)-3-(4-sulfamoylbenzyl)thiourea (2-7) 64
[0206] Compound 2-7 (7 mg, 96%) was synthesized according to the
same procedure as described in Step 4 of Example 10 except that
compound 2-4 (7 mg) and 4-t-butylbenzylisothiocyanate (10 mg) were
used as reactants.
[0207] .sup.1H NMR(300 MHz, acetone-d.sub.6): .delta. 7.81 (d, 2H,
J=8.3 Hz), 7.48 (d, 2H, J=8.3 Hz), 7.36 (dd, 2H, J=1.7, 6.3 Hz),
7.26 (d, 2H, J=8.3 Hz), 4.91 (br s, 2H), 4.75 (br s, 2H), 1.29 (s,
9H)
EXAMPLE 13
[0208] Synthesis of
1-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfonylamino-
benzyl)thiourea (3-5) 65
[0209] Step 1: Synthesis of
2-fluoro-4-iodo-1-methanesulfonylaminobenzene (3-2)
[0210] 2-fluoro-4-iodophenylamine (1.50 g) was dissolved in
dichloromethane (40 ml) and to the solution were added pyridine
(1.02 ml) and methanesulfonylchloride (700 .mu.l). The mixture was
stirred at room temperature for 1 hour and 1.5 N aqueous
hydrochloric acid was added thereto to quench the reaction. The
resulting mixture was extracted with dichloromethane, dried over
anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The obtained residue was column-chromatographed (ethyl
acetate/hexane=1/1) to yield the compound 3-2 (1.89 g, 95%).
[0211] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.47(dd, 2H,
J=1.2, 1.7 Hz) 7.30(t, 1H, J=8.3 Hz) 6.51(s, 1H) 3.01(s, 3H)
[0212] Step 2: Synthesis of
4-cyano-2-fluoromethanesulfonylaniinobenzene (3-3)
[0213] The compound 3-2 (1.81 g) prepared in Step 1 was dissolved
in dimethylformamide (10 ml) and to the solution were added zinc
(11) cyanide (845 mg) and tetrakistriphenylphosphine palladium (187
mg), followed by stirring at 80-90.degree. C. for 1.5 hours. The
resulting mixture was diluted with ethyl acetate (20 ml), washed
with water and saturated aqueous sodium chloride solution, and then
dried over anhydrous magnesium sulfate. The remaining liquid was
concentrated under reduced pressure and the obtained residue was
chromatographed on column eluting with ethyl acetate/hexane
({fraction (1/2)}) to yield the compoind 3-3 (1.03 g, 80%). 1H
NMR(300 MHz, CDCl.sub.3): .delta. 7.65(t, 1H, J-8.OHz) 7.41(d, 1H,
J=9.8 Hz) 7.37(dd, 1H, J=9.5, 1.7 Hz) 6.83(s, 1H) 3.07(s, 3H)
[0214] Step 3: Sythesis of 3-fluoro-4-methanesulfonaminobenzylamine
hydrochloride (3-4)
[0215] The compound 3-3 (1.03 g) prepared in Step 2 was dissolved
in methanol (20 ml) and to the solution were added a catalytic
amount of 10% palladium/carbon and concentrated hydrochloric acid
(3 ml), followed by stirring at room temperature under hydrogen gas
atmosphere for 1 hour. The resulting mixture was diluted in ether,
filtered through celite, concentrated under reduced pressure, and
then washed with ethyl acetate to yield the compound 3-4 (1.13 g,
92%).
[0216] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.57(t, 1H, J=8.3
Hz) 7.33(dd, 1H, J=9.8, 1.8 Hz) 7.27(d, 1H,J=8.5 Hz) 4.11(s, 2H)
3.02(s, 3H)
[0217] Step 4: Synthesis of
1-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfo-
nylaminobenzyl)tbiourea (3-5)
[0218] Compound 3-4 (1.13 g) prepared in Step 3 was dissolved in
dimethylformamide (6 ml) and the solution were diluted in
dichloromethane (35 ml). To the diluted solution was added
4-t-butylbenzylisothiocyanate (1.09 g) and triethylamine (1.2 ml)
in order, and then the mixture was stirred at room temperature for
2 hours. The resulting mixture was concentrated under reduced
pressure, diluted with ethyl acetate (20 ml), and then washed with
water and saturatated aqueous sodium chloride solution. The residue
was dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The obtained residue was purified by
chromatography on column eluting with ethyl acetate/hexane
({fraction (2/3)}) to yield the compound 3-5 (1.23 g, 65%).
[0219] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.41(t, 1H, J=8.2
Hz) 7.34(d, 2H, J=8.OHz) 7.20(d, 2H, J=8.OHz) 7.01(d, 1H, J-11.9
Hz) 6.97(d, 1H, J=9.8 Hz) 6.69(brs, 1H) 4.68(s, 2H) 4.54(s, 2H)
2.97(s, 3H) 1.28(s, 9H)
EXAMPLE 14
[0220] Synthesis of
1-phenethyl-3-(3-fluoro-4-methanesulfonaminobenzyl)ure- a (3-6)
66
[0221] Compound 3-6 (17 mg, 36%) was synthesized according to the
same procedure as desribed in Step 4 of Example 13 .except that
compound 3-4 (28 mg) was reacted with phenethylisocyanate (38
gt).
[0222] .sup.1H NMR(300 MHz, CD.sub.3OD): 8 7.40(t, 1H, J=8.2 Hz)
7.28-7.06(m, 7H) 4.69(s, 2H, CH2) 3.87 (t, 2H) 2.98(s, 3H) 2.87(t,
2H, J=7.1 Hz)
EXAMPLE 15
[0223] Synthesis of
1-phenethyl-3-(3-fluoro-4-methanesulfonylaminobenzyl)t- hiourea
(3-7) 67
[0224] Compound 3-7 (8.3 mg, 24%) was synthesized according to the
same procedure as desribed in Step 4 of Example 13 except that
compound 3-4 (20 mg) and phenethylisothiocyanate (27 .mu.l) were
used as reactants.
[0225] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.40(t, 1H, J=8.2
Hz) 7.29-7.14(m, 5H) 7.10-7.03(m, 2H) 4.26(s, 2H) 3.36 (t, 2H)
2.95(s, 3H) 2.76(t, 2H, J=7.1 Hz)
[0226] Compounds 3-8, 3-9 and 3-10 were synthesized according to
the similar procedure as described in the Example 13, and NMR data
thereof are shown below.
1 68 Compounds Examples No. R.sup.a R.sup.b Spectra data 16 3-8
NHSO.sub.2Me CH.sub.3 .sup.1H NMR(300MHz, CD.sub.3OD): .delta.
7.32(d, 2H), J=8.0Hz) 7.30(d, 1H, J=8.3Hz) 7.17(d, 2H, J=8.3Hz)
7.10(s, 1H) 7.04(d, 1H, J=8.0Hz) 6.37(brs, 1H) 4.59(s, 2H) 4.55(s,
2H) 2.97(s, 3H) 2.25(s, 3H) 1.28(s, 9H) 17 3-9 NHSO.sub.2Me Cl
.sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.50(d, 1H, J=8.3Hz)
7.37(d, 2H, J=8.3Hz) 7.35(d, 1H, J=2.0Hz) 7.23(d, 2H, J=8.3Hz)
7.13(d, 1H, J=7.1Hz) 6.92(brs, 1H) 4.69(s, 2H) 4.58(s, 2H) 2.978(s,
3H) 1.30(s, 9H) 18 3-10 NHSO.sub.2Me CO.sub.2Me .sup.1H NMR(400MHz,
CDCl.sub.3): .delta. 10.38(brs, 1H) 7.99(s, 1H) 7.57(d, 1H,
J=8.5Hz) 7.41(d, 1H, J=8.4Hz) 7.36(d, 2H, J=8.0Hz) 7.23(d, 2H,
J=8.0Hz) 4.71(s, 2H) 4.62(s, 2H) 3.93(s, 3H) 2.84(s, 3H) 1.31(s,
9H) 69 70 71
EXAMPLE 19
[0227] Synthesis of
1-(4-t-butylbenzyl)-3-(3-carboxy1-4-methanesulfonylami-
nobenzyl)thiourea (4-1) 72
[0228] Compond 3-10 (1.08 g) prepared according to the procedure as
described in Example 13 was dissolved in acetone (20 ml) and to the
solution was added 2.5 M aqueous lithium hydroxide solution (15
ml). The mixture was stirred at room temperature for 5 hours and
the solvent was removed therefrom. The residue was dissolved in
ethyl acetate and then extracted to yield the compound 4-1 (980 mg,
94%/).
[0229] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 8.07(d, 1H, J=2.2
Hz) 7.63(d, 1H, J=8.5 Hz) 7.51(d, 1H) 7.34(d, 2H, J=8.5 Hz) 7.20(d,
2H, J=8.OHz) 4.73(s, 2H) 4.66(s, 2H) 3.03(s, 3H) 1.29(s, 9H)
EXAMPLE 20
[0230] Synthesis of
1-(4-t-butylbenzyl)-3-((3-N-methoxyaminocarbony1-4-met-
hanesulfonylamino)benz yl)thiourea (4-2) 73
[0231] Compound 4-1 (50 mg) prepared according to the procedure as
described in Example 19 was dissolved in benzene (2 ml) and to the
solution was added dropwise oxalyl chloride (100 .mu.l), followed
by refluxing for 2 hours. The resulting nixture was concentrated
under reduced pressure, and to the concentrate was added
methoxylamine (92 mg). The mixture was dissolved in pyridine (2
ml), and the solution was stirred at room temperature for 24 hours
and then concentrated under reduced pressure. To the concentrate
was added ethyl ether, and the mixture was filtered and
concentrated under reduced pressure. The obtained residue was
chromatogrphed on column eluting ethyl acetate to yield the
compound 4-2 (16 mg, 30%).
[0232] .sup.1H NMR(300Mlz, CDCl.sub.3): .delta. 10.14(s, 111)
9.38(s, 11) 7.55(m, 3H) 7.32(m, 4H) 5.04(s, 2H) 5.01(s, 21) 3.82(s,
3H) 3.00(s, 3H) 1.25(s, 91)
[0233] Compound 4-3 was synthesized according to the similar
procedure as described in the Example 20, and NMR data thereof are
shown below.
2 74 Example Compound No. R' R" Spectral data 21 4-3 NHSO.sub.2Me
CONHOH .sup.1H NMR(300MHz, CD.sub.3OD): .delta. 8.09(d, 1H,
J=2.0Hz) 7.51(d, 1H, J=8.3Hz) 7.44(dd, 1H, J=2.2, 8.6Hz) 7.31(m,
4H) 5.05(s, 4H) 2.92(s, 3H) 1.27(s, 9H)
[0234] 75
EXAMPLE 22
[0235] Synthesis of
1-(4-t-butylbenzyl)-3-(3-hydrazido-4-methanesulfonylam-
inobenzyl)thiourea (4-4) 76
[0236] Compound 4-1 (76 mg) prepared according to the procedure as
described in Example 19 was dissolved in benzene (3 ml) and to the
solution was added dropwise oxalyl chloride (200 .mu.l), followed
by refluxing for 3 hours. The resulting mixture was concentrated
under reduced pressure and to the concentrate was added hydrazine
(55 mg). The mixture was dissolved in tetrahydrofuran (3 ml), and
the solution was stirred at 0.degree. C. for 2 hours and then
concentrated under reduced pressure. The obtained residue was
chromatogrphed on silica gel column (ethyl acetate/hexane=1/1) to
yield the compound 4-4 (5 mg, 6%).
[0237] .sup.1H NMR(300 MHz, DMSO-d.sub.6): .delta. 10.9(s, 1H),
10.2(s, 1H), 7.75(s, 1H), 7.64(d, 1H), 7.55(d, 1H), 7.41(s, 4H),
5.04(s, 2H), 5.00(s, 2H), 3.14(s, 3H), 1.20(s, 9H)
EXAMPLE 23
[0238] Synthesis of
1-(4-t-butylbenzyl)-3-(3-cyano-4-methanesulfonylaminob-
enzyl)thiourea (4-5) 77
[0239] Compound 4-1 (50 mg) prepared according to the procedure as
described in Example 19 was dissolved in benzene (3 ml) and to the
solution was added dropwise oxalyl chloride (100 ul), followed by
refluxing for 3 hours. The resulting mixture was concentrated under
reduced pressure and to the concentrate was added sulfamide (106
mg). The mixture was dissolved in sulfolane (2 ml) and the solution
was refluxed at 120.degree. C. for 3 hours. To the reaction mixture
was added 1 N-aqueous sodium hydroxide solution to quench the
reaction. The resulting mixture was extracted with ether, washed
several times with water, dried over anhydrous magnesium sulfate,
and then concentrated under reduced pressure. The obtained residue
was column-chromatogrphed (ethyl acetate/hexane=1/1) to yield the
compound 4-5 (8 mg, 16%).
[0240] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 10.8(s, 1H),
7.65(m, 2H), 7.58(m, 1H), 7.33(d, 4H), 5.05(s, 4H), 3.01(s, 3H),
1.24(s, 9H)
[0241] Compounds 4-6- 4-13 were synthesized according to the
similar procedure as described in the Example 13, and NMR data
thereof are shown below.
3 78 Example Compound No. R.sup.c R.sup.d Spectral data 24 4-6
NHCO.sub.2Me F .sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.97(t,
1H), 7.35(d, 2H), 7.68(d, 2H), 6.95(d, 2H), 6.82(s, 1H), 4.62(s,
2H), 4.46(s, 2H), 3.76(s, 3H), 1.26(s, 9H) 25 4-7 NHCOCH.sub.2OMe F
.sup.1H NMR(300MHz, CDCl.sub.3): .delta. 8.49(s, 1H), 8.07(t, 1H,
J=8.0Hz), 7.36(d, 2H, J=8.0Hz) 7.23(d, 2H, J=8.0Hz), 7.03(d, 1H,
J=11.2Hz), 6.93(d, 1H, J=8.3Hz) 6.66(brs, 1H) 4.67(s, 2H), 4.62(s,
2H), 3.49(s, 3H), 1.32(s, 9H) 26 4-8 NHCO.sub.2Et F .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 7.95(s, 1H) 7.33(d, 2H, J=8.0Hz)
7.17(d, 2H, J=8.0Hz) 6.94(d, 2H) 6.77(s, 1H), 4.60(s, 2H) 4.55(s,
2H), 4.19(q, 2H, J=7.2Hz), 1.27(m, 12H) 27 4-9 NHCH.sub.2CO.sub.2Et
F .sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.31(d, 2H, J=8.5Hz),
7.15(d, 2H, J=8.3Hz), 6.86(s, 1H), 6.83(s, 1H), 6.46(t, 1H),
J=8.4Hz), 6.10(d, 1H), 4.53(s, 2H), 4.48(s, 2H), 4.20(q, 2H,
J=7.1Hz), 3.75(s, 2H), 1.27(m, 12H) 28 4-10 NHCH.sub.2CO.sub.2Me F
.sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.39(d, 2H, J=8.3Hz),
7.23(d, 2H, J=8.3Hz), 6.93(s, 1H), 6.90(s, 1H), 6.52(t, 1H),
J=8.4Hz), 6.36(s, 1H), 4.60(s, 2H), 4.53(s, 2H), 3.83(s, 2H),
3.74(s, 3H), 1.34(s, 9H) 29 4-11 NHCH.sub.2CO.sub.2H F .sup.1H
NMR(300MHz, CD.sub.3OD): .delta. 7.32(d, 2H, J=8.5Hz), 7.18(d, 2H,
J=8.3Hz), 6.90(m, 2H), 6.56(t, 1H, J=8.6Hz), 4.65(s, 2H), 4.55(s,
2H), 3.70(s, 2H), 1.28(s, 9H) 30 4-12 H CO.sub.2Me .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 7.95-7.98(d, 2H, J=7.3Hz),
7.30-7.51(m, 4H), 7.20-7.25(d, 2H, J=8.3Hz), 4.75-4.79(d, 2H,
J=5.4Hz), 4.61-4.64(d, 2H, J=4.4Hz), 3.92(s, 3H), 1.33(s, 9H) 31
4-13 H CO.sub.2H .sup.1H NMR(300MHz, CD.sub.3OD): .delta.
7.97-7.98(s, 1H), 7.88-7.91(d, 1H, J=7.6Hz), 7.32-7.53(m, 4H,),
7.18-7.22(d, 2H, J=8.0Hz), 4.79(s, 2H), 4.67(s, 2H), 1.28(s, 9H) 79
80 81 82 83 84 85 86
EXAMPLE 32
[0242] Synthesis of
1-(4-t-butylbenl)-3-(2,3,5,6-tetrafluoro-4-methanesulf-
onylaminobenzylithiourea (5-4) 87
[0243] Step 1: Synthesis of
4-cyano-2,3,5,6-tetrafluoro-1-methanesulfonyla- minobenzene
[0244] 4-amino-2,3,4,5-tetrafluoronitrile (105 mg) was dissolved in
tetrahydrofuran (4 ml) and the solution was cooled to 0.degree. C.
To the solution was added dropwise 1.6 M n-butyl lithium and the
mixtrure was stirred for 10 minutes, followed by adding dropwise
methanesulfonyl chloride (100 .mu.l). After 1 hour, the reaction
was quenched with 1.5 N aqueous hydrochloric acid. The resulting
mixture was extracted with ethyl acetate, and then concentrated
under reduced pressure. The obtained residue was chromatographed on
column eluting with ethyl acetate/hexane (1/1) to yield
4-cyano-2,3,5,6-tetrafluoro-1-methanesulfonylaminobenzene (20 mg,
10%). .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 6.84(brs, 1H)
3.08(s, 3H)
[0245] Step 2: Synthesis of
2,3,5,6-tetrafluoro-4-methanesulfonylaminobenz- ylamine
hydrochloride
[0246] 4-cyano-2,3,5,6-tetrafluoro-1-methanesulfonylaminobenzene
(11 mg) prepared in Step 1 was dissolved in methanol (5 ml) and to
the solution were added a catalytic amount of 10% palladium/carbon
and concentrated hydrochloric acid (300 .mu.l), followed by
stirring at room temperature under hydrogen gas atmosphere for 1
hour. The resulting mixture was diluted in ether, filtered through
celite, concentrated under reduced pressure, and then washed with
ethyl acetate to yield
2,3,5,6-tetrafluoro-4-methanesulfonylaminobenzylamine hydrochloride
(7.0 mg, 59%).
[0247] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 4.32(s, 2H)
3.18(s, 3H)
[0248] Step 3: Synthesis of
1-(4-t-butylbenzyl)-3-(2,3,5,6-tetrafluoro-4-m-
ethanesulfonylaminobenzyl)thiourea (5-4)
[0249] 2,3,5,6-tetrafluoro-4-methanesulfonylaminobenzylamine
hydrochloride (20 mg) prepared in Step 2 was dissolved in
dimethylformamide (800 .mu.l), and the solution was diluted with
dichloromethane (6 ml). To the diluted solution were added
t-butylbenzylisothiocyanate (20 mg) and triethylamine (200 .mu.l),
and the mixture was stirred at room temperature for 2 hours. The
mixture was concentrated under reduced pressure, diluted with ethyl
acetate (20 ml), and then washed with water and saturated aqueous
sodium chloride solution. The resulting mixture was dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure, and the obtained residue was chromatographed on column
eluting ethyl acetate/hexane ({fraction (2/3)}) to yield the
compound 5-4 (28 mg, 91%).
[0250] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.34(dd, 2H,
J-1.8, 6.5 Hz) 7.20(d, 2H, J=8.3 Hz) 4.87(s, 2H) .sup.4..sup.63(s,
2H) 3.13(s, 3H) 1.29(s, 9H)
EXAMPLE 33
[0251] Synthesis of
1-(4-t-butylbenzyl)-3-(2,5-difluoro-4-methanesulfonyla-
minobenzyl)tlhiourea (5-5) 88
[0252] Step 1: Synthesis of
2,5-difluoro-4-cyano-1-methanesulfonylaminoben- zene
[0253] To an ice-cold solution of 4-amino-2,5-difluorobenzonitrile
(1.0 g) in anhydrous tetrahydrofuran (50 ml) was slowly added
n-butyl lithium (2.6 ml) through an injector with stirring,
followed by stirring 30 minutes. To the mixture was slowly added
methanesulfonyl chloride (550 .mu.l), followed by stirring at room
temperature for 24 hours. After confirming the completion of the
reaction using TLC, the resulting mixture was concentrated under
reduced pressure, diluted with 1 N aqueous hydrochloric acid (100
ml), extracted with dichloromethane (50 ml x3). The combined
organic layer was dried over magnesium sulfate, filtered, and then
concectrated under reduced pressure. The obtained residue was
purified by column-chromatography (ethyl acetate/hexane 2/3) to
yield 2,5-difluoro-4-cyano-1-methanesulfonylaminobenzene (1.2 g,
79.6%).
[0254] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.54(m, 1H),
7.40(m, 1H), 7.01(brs, 1H), 3.18(s, 3H)
[0255] Step 2: Sythesis of 2,5-difluoro-4-methanesulfonaminobenzyl
hydrochloride
[0256] 2,5-difluoro-4-cyano-1-methanesulfonylaminobenzene (250 mg),
a catalytic amount of 10% palladium/carbon catalyst and methanol
(20 ml) were added to a reactor. The reactor was filled with
hydrogen gas while the mixture was stirred. Concentrated
hydrochloric acid (250 .mu.l) was slowly added thereto through an
injector, followed by stirring for 18 hours. The reaction mixture
was filtered through celite and the filtrate was concentrated under
reduced pressure to afford a compound (250 mg, 85%) as a solid. The
obtained compound was washed with ether, and the following
procedure was carried out using the washed compound.
[0257] Step 3: Synthesis of
1-(4-t-butylbenzyl)-3-(2,5-difluoro-4-methanes-
ulfonaminebenzyl)thiourea (5-5)
[0258] 2,5-difluoro-4-methanesulfonaminobenzyl hydrochloride (250
mg) prepared by Step 2 was dissolved in dimethylformamide (5 ml)
and to the solution was added triethylamine (128 .mu.l) with
stirring, followed by stirring for 30 minutes. To the mixture was
added t-butylbenzylisothiocya- nate (189 mg), followed by stirring
for 6 hours. After the completion of the reaction, the resulting
mixture was diluted with water (30 ml), and extracted with ethyl
acetate (30 ml.times.3). The organic layer was dried over magnesium
sulfate, filtered, and then concentrated under reduced pressure.
The obtained residue was purified by colunm-chromatography (ethyl
acetate/hexane={fraction (1/2)}) to yield the compound 5-5 (264 mg,
52.4%).
[0259] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.36(m, 2H),
7.31(m, 111), 7.23(m, 2H), 7.17(m, 11), 6.69(brs, 1Il), 6.31(brs,
1R), 6.04(brs, 1H), 4.77(d, 2H, J=5.7 Hz), 4.53(d, 2H, J=4.8 Hz),
3.04(s, 3H), 1.31(s, 9H)
EXAMPLE 34
[0260] Synthesis of
1-(4-t-butylbenzyl)-3-[(5-methanesulfonylaminopyridin--
2-yl)methyl]thiourea (5-6) 89
[0261] Step 1: Synthesis of
3-methanesulfonylamino-6-cyanopyridine
[0262] 5-Amino-2-cyanopyridine (5 g) was dissolved in pyridine (30
ml). The solution was cooled to 0.degree. C. and to the solution
was added dropwise methanesulfonyl chloride (3.6 ml), followed by
stirring at room temperature for 17 hours. The resulting mixture
was concentrated under reduced pressure, extracted with water and
dichloromethane, and then dried. The obtained residue was purified
by column-chromatography (hexane/ethyl acetate=2/1) to yield an
orange colored solid (6.4 g, 77%).
[0263] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 8.47-8.46(m, 1H),
7.84-7.69(m, 2H), 6.89(brs, 1H, 3.16(s,3H)
[0264] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-[(5-methanesulfonylamino-
pyridin-2-yl)methyl]thiourea (5-6)
[0265] The compound (1.97 g) prepared in Step 1 was dissolved in
methanol (50 ml) and to the solution were added concentrated
hydrochloric acid (2 ml) and a catalytic amount of 5%
palladium/carbon, followed by stirring under hydrogen atmosphere
for 21 hours. The mixture was filtered through celite and the
filtrate was concentrated under reduced pressure to obtain foamy
compound (3 g). Part (135 mg) of the obtained compound was
dissolved in dimethylformamide (5 ml) and to the solution were
added triethylamine (101 mg) and 4-t-butylbenzylisothiocyanate (100
mg), followed by stirring at room temperature for 20 hours. The
mixture was concentrated under reduced pressure, extracted with
water and dichloromethane, and then purified by
column-chromatography (ethyl acetate) to yield the compound 5-6 (98
mg, 48%) as a brown liquid.
[0266] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 8.33-8.31(m, 1H),
.sup.7..sup.66-.sup.7..sup.62(m, 1H), 7.40-7.26(m, 5H), 6.99(brs,
1H), 6.76(brs, 1H), 4.77-4.60(m, 4H), 3.04(s, 3H), 1.32(s,9H)
EXAMPLE 35
[0267] Synthesis of
1-(4-t-butylbenzyl)-3-(3,5-dichloro-4-methanesulfonyla-
minobenzyl)thiourea (5-7) 90
[0268] 4-Amino-3,5-dichlorobenzonitrile (1 g) was dissolved in
acetonitrile (50 ml) and to the solution were added triethylamine
(890 .mu.l) and methanesulfonyl chloride (670 mg), followed by
refluxing for 8 hours. The mixture was extracted with water and
dichloromethane, dried, concentrated, and then purified by
column-chromatography (hexane/ethyl acetate=4/1) to obtain a
compound (80 mg) as a liquid. The obtained compound was dissolved
in methanol (10 ml), and then the solution was stirred for 15 hours
in the presence of a small amount of concentrated hydrochloric acid
and 5% palladium/carbon catalyst to hydrogenate the compound. The
reaction solution was filtered through celite and concentrated. The
concentrate was dissolved in dichloromethane (5 ml) and to the
solution were added 4-t-butylbenzylisothiocyanate (54 mg) and
triethylamiine (500 .mu.l), followed by stirring at room
temperature for 15 hours. The resulting mixture was extracted with
water and dichloromethane, and then purified by
column-chromatography (hexane/ethyl acetate=2/1) to yield the
compound 5-7 (38 mg) as a liquid. 1H NMR(300 MHz, CDCl.sub.3):
.delta. 7.42-7.23(r, 6H), 6.23(brs, 1H), 5.87(brs, 11),
4.85-4.82(ni, 211), 4.58-4.56(m, 2H), 3.57(s, 3H), 1.31(s,9H)
EXAMPLE 36
[0269] Synthesis of
1-(4-t-butylbenzyl)-3-(4-methanesulfonylaminophenethyl- )thiourea
(5-8) 91
[0270] Step 1: Synthesis of 4-methanesulfonylaminobenzyl
cyanide
[0271] To an ice-cold solution of 4-aminobenzyl cyanide (1 g) in
dichloromethane (30 ml) were added dropwise triethylamine (1.58 ml)
and methanesulfonyl chloride (700 .mu.l), followed by stirring at
room temperature for 12 hours. After confirming the completion of
the reacion using TLC, to the mixture was added 1 N aqueous
hydrochloric acid (50 ml). The resulting mixture was extracted with
dichloromethane (30 ml.times.3), washed with saturated aqueous
sodium chloride solution, dried over magnesium sulfate, and then
filtered.
[0272] The filtrate was concentrated under reduced pressure and the
obtained residue was purified by column-chromatography (ethyl
acetate/hexane=2/3) to yield 4-methanesulfonylarninobenzyl cyanide
(1.35 g, 85%).
[0273] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.7.34(d, 2H, J=8.4
Hz), 7.24(d, 2H, J=8.7 Hz), 6.51(bs, 1H), 3.74(s, 2H), 3.03(s,
3H)
[0274] Step 2: Synthesis of 4-methanesulfonaminophenethylamine
[0275] 4-Methanesulfonylbenzyl cyanide (200 mg) and Raney nickel
(catalytic amount) were added to methanol (15 ml) and the mixture
was stirred for 6 hours with the reactor filled with hydrogen gas.
After confirming the completion of the reaction, the resulting
mixture was filtered through celite and the filtrate was
concentrated under reduced pressure. The following procedure was
carried out using the concentrate which was not purified.
[0276] Step 3: Synthesis of
1-(4-t-butylbenzyl)-3-(4-methanesulfonylaminop- henethyl)thiourea
(5-8)
[0277] 4-Methaiiesulfonaniinophenethylamine (200 mg) prepared in
Step 2 and 4-t-butylbenzylisothiocyanate (190 mg) were dissolved in
ethyl acetate (30 ml) and the solution was subjected to reaction
for 6 hours. After the completion of the reaction, the resulting
mixture was concentrated under reduced pressure and the obtained
residue was purified by column-chromatography (ethyl
acetate/hexane={fraction (1/2)}) to yield the compound 5-8 (210 mg,
53%). 1H NMR(300 MHz, CDCl.sub.3): .delta. 7.38(d, 2H, J=8.4 Hz),
7.21(d, 2H, J=8.4 Hz), 7.14(s, 4H), 6.56(s, 1H), 6.05(brs, 1H),
5.69(brs, 1H), 4.51(brs, 2H), 3.72(d, 2H, J=4.8 Hz), 2.99(s, 3H),
2.86(t, 2H, J=6.9 Hz), 1.32(s, 9E[)
EXAMPLE 37
[0278] Synthesis of
1-(4-t-butylbenzyl)-3-(2-methanesulfonylamiinophenethy- l)thiourea
(5-9) 92
[0279] Step 1: Synthesis of
(2-methanesulfoliylaniinophenyl)acetonitrile
[0280] To an ice-cold solution of 2-aminophenylacetonitrile (500
mg) in dichloromethane (20 ml) were added triethylamine (330 .mu.l)
and methanesulfonyl chloride (530 .mu.l) and the mixture was
stirred for 16 hours, under argon gas atmosphere. After confirming
the completion of the reaction using TLC, the resulting mixture was
diluted with 1 N aqueous hydrochloric acid solution (30 ml), and
extracted with dichloromethane (50 ml.times.3). The organic layer
was washed with brine, dried over magnesium sulfate, and then
filtered. The filtrate was concentrated under reduced pressure and
the obtained residue was purified by column-chromatography (ethyl
acetate/hexane={fraction (1/2)}) to yield
(2-methanesulfonylaminophenyl)acetonitrile (573 mg, 72%).
[0281] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.7.56(m, 1H),
7.37(m, 311), 6.55(brs, 11), 3.99(s, 2H), 3.06(s, 3H)
[0282] Step 2: Synthesis of
2-methanesulfonylaminophenethylamine
[0283] (2-Methanesulfonylaminophenyl)acetonitrile (300 mg) was
mixed with 10% palladium/carbon (catalytic amount) in methanol (20
ml) and the mixture was stirred under hydrogen gas atmosphesre for
48 hours. After confirming the completion of the reaction using
TLC, the resulting mixture was filtered through celite and the
filtrate was concentrated under reduced pressure. The following
procedure was carried out using the concectrate which was not
purified.
[0284] Step 3: Sythesis of
1-(4-t-butylbenzyl)-3-(2-methanesulfonylaminoph- enethyl)thiourea
(5-9)
[0285] 2-Methanesulfonylaniinophenethylamine (200 mg) prepared in
Step 2 and t-butylbenzeneisothiocyanate (192 mg) were dissolved in
ethyl acetate (20 ml) and the solution was stirred for 6 hours.
After confirming the completion of the reaction, the resulting
mixture was concentrated under reduced pressure and the concetrate
was purified by column-chromatography (ethyl acetate/hexane=2/3) to
yield the compound 5-9 (165 mg, 42%).
[0286] 1H NMR(300 MHz, CDCl.sub.3): .delta.7.28(m, 8H), 6.38(brs,
1H), 4.74(s, 1H), 4.72(s, 1H), 3.79(m, 2H), 3.14(m, 4H), 3.01(s,
3H), 1.31(s, 9H)
EXAMPLE 38
[0287] Synthesis of
1-(4-t-butylbenzyl)-3-(4-methanesulfanylcarbonylaminob-
enzyl)thiourea (6-5) 93
[0288] Step 1: Synthesis of (4-nitrobenzyl)carbamic acid t-butyl
ester (6-2)
[0289] 4-Nitrobenzylamine hydrochloride (110 mg) was dissolved in
dichloromethane (2 ml) and to the solution were added
dimethylaminopyridine (14 mg) and di-t-butyl dicarbonate (382 mg),
followed by adding triethylamine (200 .mu.l) thereto and stirring
at room temperature for 3 hours. After the completion of the
reaction, the resulting mixture was concentrated under reduced
pressure and the obtained residue was chromatographed on column
eluting with ethyl acetate/hexane ({fraction (1/3)}) to yield the
compound 6-2 (88.3 mg, 66%).
[0290] 1H NMR(300 MHz, CDCl.sub.3): .delta. 8.18 (d, 2H, J=8.5 Hz),
7.43 (d, 2H, J=8.8 Hz) 4.40 (d, 2H, J=6.3 Hz), 1.45 (s, 9H)
[0291] Step 2: Synthesis of
(4-methylsulfanylcarbonylaminobenzyl)carbamic acid t-butyl ester
(6-3)
[0292] The compound 6-2 (88.3 mg) prepared in Step 1 was dissolved
in methanol (2 ml) and to the solution was added catalytic amount
of 10% palladium/carbon, followed by stirring at room temperature
under hydrogen gas atmosphere for 30 minutes. The resulting mixture
was diluted with ether, and filtered through celite. The filtrate
was concentrated under reduced pressure to yield compound (76 mg).
The obtained compound, which was not purified, was dissolved in
dichloromethane (1 ml) and to the solution were added
methylchlorothiolformate (100 .mu.l) and pyridine (49 .mu.l). After
stirring the mixture at room temperature for 1 hour, the resulting
mixture was extracted with dichloromethane, dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure.
The obtained residue was column-chromnatographed (ethyl
acetate/hexane=1/1) to yield the compound 6-3 (22 mg, 22%).
[0293] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.36 (d, 1H, J=8.5
Hz), 7.20-7.25 (m, 211), 7.03 (d, 1H, J=8.3 Hz), 4.25 (s, 2H), 2.40
(s, 3H), 1.44 (s, 9H)
[0294] Step 3: Synthesis of
4-methylsulfanylcarbonylaminobenzylamine hydrochloride (6-4)
[0295] The compound 6-3 (22 mg) prepared in Step 2 was dissolved in
ethyl acetate (1 ml) and to the solution was added 5 N aqueous
hydrochloric acid (1 ml). The mixture was stirred at 60.degree. C.
for 1 hour and concentrated under reduced pressure to yield the
compound 6-4 (15 mg, 100%).
[0296] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.65 (d, 1H,
J=8.5Iz), 7.57 (d, 1H, J=8.3 Hz), 7.49 (d, 1H, J=8.5 Hz), 7.38 (d,
1H, J=8.8 Hz), 4.05(s, 2H) 2.35(s, 3H)
[0297] Step 4: Synthesis of
1-(4-t-butylbenzyl)-3-(4-methylsulfanylcarbony-
laminobenzyl)thiourea (6-5)
[0298] The compound 6-4 (15 mg) prepared in Step 3 was diluted in
dichloromethane (1 ml) and to the solution were added
4-t-butylisothiocyanate (20 mg) and triethylamine (100 .mu.l),
followed by stirring at room temperature for 1 hour. The resulting
mixture was concentrated under reduced pressure and the obtained
residue was chromatographed on column eluting with
ethylacetate/hexane ({fraction (1/3)}) to yield the compound 6-5
(20 mg, 83%).
[0299] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.16-7.35 (m, 8H),
4.56 (br, 4H), 2.35 (s, 3H), 1.26 (s, 9H)
EXAMPLE 39
[0300] Synthesis of
1-(4-t-butylbenzyl)-3-(4-guanidinobenzyl)thiourea (7-6) 94
[0301] Step 1: Synthesis of
4-(1,3-bis(t-butoxycarbonyl)-2-guanidino)pheny- liodide (7-2)
[0302] 4-lodoaniline 7-1 (100 mg) was dissolved in
dimethylformarnide (2 ml) and to the solution were added
1,3-bis(t-butoxycarbonyl)-2-methyl-2-t- hiopseudourea (200 mg),
mercury (II) chloride (186 mg) and triethylarnine (200 td),
followed by stirring for 1 hour. Aftrer the completion of the
reaction, the resulting mixture was concentrated under reduced
pressure at the temperature not more than 50.degree. C. and the
obtained residue was chromatographed eluting with ethyl
acetate/hexane ({fraction (1/3)}) to yield the compound 7-2 (137
mg, 66%/).
[0303] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 11.60 (br, 1H)
10.33 (br, 1H), 7.58-7.63 (d, 2H, J=8.8 Hz), 7.35-7.38 (d, 2H,
J=8.8 Hz), 1.51 (s, 9H), 1.48 (s, 9H)
[0304] Step 2: Synthesis of
4-[1,3-bis(t-butoxycarbonyl)-2-guanidino]benzo- nitrile (7-3)
[0305] The compound 7-2 (137 mg) prepared in Step 1 was dissolved
in dimethylformamide (2 ml) and to the solution were added zinc
(II) cyanide (40 mg) and tetrakistriphenylphosphine palladium (14
mg), followed by stirring at 80.degree. C. for 1 hour. The reaction
was quenched with water. The resulting mixture was extracted with
ethyl acetate, and the organic phase was dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure.
The obtained residue was chromatographed on column eluting with
ethyl acetate/hexane ({fraction (1/3)}) to yield the compound 7-3
(95 mg, 89%).
[0306] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 11.58 (br, 1H)
10.62 (br, 11), 7.76-7.79 (d, 2H, J=8.8 Hz), 7.58-7.61 (dd, 2H,
J=2.0, 6.8 Hz), 1.52 (s, 9H), 1.50 (s, 9H)
[0307] Step 3: Synthesis of 1-(4-t-butylbenzyl)-3-[4- {
1,3-bis(t-butoxycarbonyl)-2-guanidino}benzyl]thiourea (7-5)
[0308] The compound 7-3 (20 mg) prepared in Step 2 was dissolved in
methanol (2 ml) and to the solution was added catalytic amount of
palladium/carbon, followed by stirring at room temperature under
hydrogen gas atmosphere for 30 minutes. The resulting mixture was
diluted with ether, filtered through celite, and then concentrated
under reduced pressure to give the compound 7-4. The compound 7-4
was diluted with dichloromethane (3 ml). To the solution was added
4-t-butylbenzylisothioc- yanate (40 mg) and the mixture was stirred
at room temperature for 1 hour. The resulting mixture was
concentrated under reduced pressure and the obtained residue was
chromatographed eluting with ethyl acetate/hexane ({fraction
(1/3)}) to yield the compound 7-5 (35 mg, 95%).
[0309] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.18-7.49 (m, 8H),
4.66-4.69 (br, 4H), 1.56 (s, 9H), 1.45 (s, 91), 1.29 (s, 9H)
[0310] Step 4: Synthesis of
1-(4-t-butylbenzyl)-3-(4-guanidinobenzyl)thiou- rea (7-6)
[0311] The compound 7-5 (35 mg) prepared in Step 3 was dissolved in
ethyl acetate (1.0 ml) and to the solution was added 5 N aqueous
hydrochloric acid (1 ml). The mixture was stirred at 60.degree. C.
for 1 hour and concentrated under reduced pressure to yield the
compound 7-6 (18 mg, 100%).
[0312] .sup.1H NMR(300 MHz, acetone-d.sub.6): .delta. 7.07-7.37 (m,
8H), 4.73(s, 2H), 4.66 (s, 2H), 1.17 (s, 9H)
EXAMPLE 40
[0313] Synthesis of
1-[2-(1-methyl-I-pyrro1-2-yl)ethyl]-3-(4-methanesuffon-
ylaminobenzyl)thiourea (8-4) 95
[0314] Step 1: Syntheis of (4-aminobenzyl)carbanic acid t-butyl
ester (8-1)
[0315] 4-Aminobenzylamine (1.02 g) was dissolved in anhydrous
tetrahydrofuran (10 ml) and to the solution was added
di-t-butyldicarbonate (2.002 g), followed by stirring at room
temperature for 2 hours. The resulting mixture was concentrated
under reduced pressure to remove the solvent. The obtained residue
was purified by column-chromatography (ethyl
acetate/hexane={fraction (2/3)}) to yield the compound 8-1 (1.78 g,
96%) as a yellow solid.
[0316] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.7.09-7.05 (m, 2H),
6.6-6.62 (m, 2H), 4.70 (brs, 1H), 4.18(d, 2H, J=5.7 Hz), 3.64(brs,
2H), 1.45 (s, 911)
[0317] Step 2: Synthesis of (4-methanesulfonylaminobenzyl)carbamic
acid t-butyl ester (8-2)
[0318] Compound 8-1 (1 g) was dissolved in anhydrous
dichloromethane and the solution was cooled to 0.degree. C. To the
solution was added triethylamine (630 .mu.l) and methanesulfonyl
chloride (350 .mu.l) in order and the mixture was stirred at room
temperature for 24 hours. After confirming the completion of the
reaction using TLC, the resulting mixture was neutralized with
hydrochloric acid solution, diluted with water, and then extracted
three times with dichloromethane. The extracted organic layer was
washed with water and saturated aqueous sodium chloride solution,
dried over magnesium sulfate, and then dried under reduced
pressure. The obtained residue was purified by
coluimn-chromatography (hexane/ethyl acetate=2/1) to yield the
compound 8-2 (1.28 g, 95%) as a white solid.
[0319] .sup.1H NMR (300MIz, CDCl.sub.3): .delta. 7.1-7.3 (m, 4H),
6.77 (s, 11), 4.88 (brs, 1H), 4.28 (d, 2H), 2.99 (s, 3I1), 1.46 (s,
9H)
[0320] Step 3: Synthesis of 4-methanesulfonylaimnobenzylammonium
trifluoroacetate (8-3)
[0321] (4-Methanesulfonylaminobenzyl)carbamic acid t-butyl ester
8-2 (500 mg) was dissolved in anhydrous dichloromethane (30 ml) and
the solution was cooled to 0C, followed by slowly adding
trifluoroacetic acid (5 ml) thereto. The mixture was stirred at
0.degree. C. for 1 hour and 30 minutes and then, after confirming
the completion of the reaction using TLC, concentrated under
reduced pressure to yield an orange colored residue. The residue
was washed with ether and filtered to yield the compound 8-3 (420
mg, 80%) as a pink solid.
[0322] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 8.14 (brs, 3M),
7.39 (d, 2H), 7.22 (d, 2H), 3.97 (s, 2H), 2.99 (s, 3H)
[0323] Step 4: Synthesis of
1-[2-(1-methyl-1H-pyrro1-2-yl)ethyl]-3-(4-meth-
anesulfonylaminobenzyl)thiourea (8-4)
[0324] Compound 8-3 (500 mg) was dissolved in dimethylformamide (2
ml) and to the solution was added triethylamine (230 fd), followed
by stirring for 1 hour. To the mixture was added
2-(2-isothiocyanatoethyl)-1-methyl-1- H-pyrrole (280 mg), followed
by adding ethyl acetate (10 ml) thereto. The mixture was stirred
for 12 hours, filtered under reduced pressure, and then purified by
column-chromatography (ethyl acetate/hexane=4/1) to yield the
compound 8-4 (146 mg, 25%) as a red solid.
[0325] .sup.1H NMR (300 MHz, CH.sub.3COCH.sub.3-d.sub.6): .delta.
7.32(m, 4H), 7.16(m, 1H), 6.42(d, 1H, J=2.1 Hz), 6.02(d, 1H, J=1.95
Hz), 4.76(m, 2H), 3.89(m, 2H), 3.81(m, 21), 3.01(m, 2H), 2.96(s,
3H)
EXAMPLE 41
[0326] Synthesis of 1-(4-anidnobenzyl)-3-(4-t-butylbenzyl)thiourea
(9a) 96
[0327] 4-t-Butylbenzylisothiocyanate (100 mg) was dissolved in
dichloromethane (3 ml) and then cooled to 0.degree. C. To the
solution was added 4-nitrobenzylamine (75 mg), followed by stirring
at room temperature for 6 hours. After the completion of the
reaction, dichloromethane was evaporated therefrom under reduced
pressure and the residue was dissolved in methanol (3 ml). To the
solution was added catalytic amount of 5% platinum/carbon and the
mixture was subjected to hydrogenation reacton under atmospheric
pressure. After the completion of the reaction, the methanol was
evaporated under reduced pressure and the obtained residue was
column-chromatographed (hexane/ethyl acetate=1/1) to yield the
compound 9a (137 mg, 85%) as a white solid.
[0328] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 6.70-7.40(m, 81),
6.00-6.40(br, 2H), 4.55(br, 2H), 4.45(br, 2H), 1.28(s, 9H)
[0329] MS (1E) m/e 327 [M+]
EXAMPLE 42
[0330] Synthesis of
1-(4-acetylaminobenzyl)-3-(4-t-butylbenzyl)thiourea (9b) 97
[0331] Compound 9a (100 mg) and triethylamine (50 mg) were
dissolved in dichloromethane (3 ml) and cooled to 0.degree. C. To
the solution was added anhydrous acetic acid (35 mg). After the
completion of the reaction, dichloromethane was evaporated under
reduced pressure and the obtained residue was
column-chromatographed (hexane/ethyl acetate=1/1) to yield the
compound 9b (107 mg, 95%) as a white solid.
[0332] 1H NMR (300 MHz, DMSO-d.sub.6): .delta. 8.31(s, 1H),
7.87(br, 2H), 7.50(d, 2H, J=8.40 Hz), 7.32(d, 2H, J=8.25 Hz),
7.1.sup.6-7.17(m, 4H), 4.59(br, 4H), 2.01(s, 3H), 1.25(s, 9H)
[0333] MS (El) m/e 369 [M+]
EXAMPLE 43
[0334] Synthesis of
1-(4-(N,N-dimethanesulfonyl)aminobenzyl)-3-(4-t-butylb-
enzyl)thiourea (9c) 98
[0335] 4-t-Butylbenzylisothiocyanate (100 mg) was dissolved in
dichloromethane (3 ml) and cooled to 0.degree. C. To the solution
was added (N,N-dimethylsulfony1-4-amino)benzylamine (136 mg),
followed by stirring at room temperature for 6 hours. After the
completion of the reaction, dichloromethane was evaporated under
reduced pressure and the obtained residue was
column-chromatographed (hexane/ethyl acetate=1/1) to yield the
compound 9c (184 mg, 75%) as a white solid.
[0336] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.00-7.35(m, 8H),
6.30(br, 21), 4.66(s, 2H), 4.49(s, 2H), 3.26(s, 6H), 1.22(s, 9H);
MS (El) ni/e 469 [M+]
4 9 99 Examples Compounds No. R.sup.D R.sup.E Spectral data 44 9d
H-- .sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.37(d, 2H),
CH.sub.3SO.sub.2-- 7.1-7.3(m, 6H), 6.39(s, 1H), 5.99(brs, 1H),
4.66(d, 2H), 4.56(m, 2H), 3.00(s, 3H), 1.31(s, 9H) MS(EI) m/e
405[M+] 45 9e H-- .sup.1H NMR(300MHz, DMSO-d.sub.6): .delta.
7.90(br, 1H), CF.sub.3SO.sub.2-- 7.25(m, 8H), 4.50-4.70(br, 4H),
1.25(s, 9H) MS(EI) m/e 459[M+] 46 9f --H .sup.1H NMR(300MHz,
CDCl.sub.3): .delta. 8.20-8.40(br, --CHO 2H), 8.05(s, 1H),
6.80-7.30(m, 8H), 4.52(br, 4H), 1.19(s, 9H) MS(EI) m/e 355[M+] 47
9g --H .sup.1H NMR(300MHz, DMSO-d.sub.6): .delta. 9.64(s, 1H),
--C(.dbd.S)NH.sub.2 7,86(br, 2H), 7.20-7.40(m, 8H), 4.61(br, 4H),
1.26(s, 9H) MS(EI) m/e 386[M+] 48 9h --H .sup.1H NMR(300MHz,
DMSO-d.sub.6): .delta. 9.56(s, 1H), --CO.sub.2Et 7.81(br, 2H),
7.15-7.45(m, 8H), 4.58(br, 4H), 4.10(q, 2H, J=7.05Hz), 1.25(s, 9H),
1.23(t, 3H), J=7.05Hz) MS(EI) m/e 399[M+] 100 101 102 103 104
EXAMPLE 49
[0337] Synthesis of
1-(4-t-butylbenzyl)-3-12-hydroxy-4-(N-t-butoxycarbonyl-
)amiuobenzyl]thiourea 105
[0338] 2-Hydroxy-4-nitrobenzaldehyde (1.67 g),
t-butyldiphenylsilylchlorid- e (TBDPSCI) (2.65 g) and imidazole
(681 mg) were dissolved in dichloromethane (100 ml) and the
solution was stirred at room temperature for 18 hours. The
precipitate was filtered off and the filtrate was concentrated
under reduced pressure. The obtained residue was purified by
column-chromatography (hexane/ethyl acetate=3/1) to yield the
compound 10-1 (4.00 g, 99%). The compound 10-1 (3.00 g) was reduced
in the presence of palladium/carbon catalyst to yield an amine. The
amine was dissolved in tetrahydrofuran (15 ml) and to the solution
was added Boc.sub.2O (950 mg), followed by stirring at room
temperature for 18 hours. To the mixture were added water (20 ml)
and ethyl acetate (10 ml). From the mixture, an organic layer was
separated and an aqueous layer was extracted with ethyl acetate (10
ml x2). The combined organic layer was washed with brine, dried
over magnesium sulfate and then concentrated under reduced
pressure. The obtained residue was purified by
column-chromatography (hexane/ethyl acetate=3/1) to yield the
compound 10-2 (380 mg, 20%) and 10-3 (764 mg, 41%). The compound
10-2 was dissolved in ethyl acetate (10 ml) and to the solution was
added t-butylbenzylisothiocyanate (150 mg), followed by stirring at
room temperature for 18 hours. The resulting mixture was
concentrated under reduced pressure and the obtained residue was
purified by column-chromatography (hexane/ethyl acetate=3/1) to
yield thiourea compound (300 mg, 56%). The compound (300 mg) was
dissolved in THF (5.0 ml) and to the solution was added
tetrabutylanumonium fluoride (131 mg), followed by stirring at room
temperature for 45 minutes. The reaction was quenched with
saturated sodium bicarbonate and an aqueous solution layer was
extracted with ethyl acetate (10 ml.times.2). The combined organic
layer was washed with saturated aqueous sodium chloride solution,
dried over magnesium sulfate, and then concentrated under reduced
pressure. The obtained residue was purified by
column-chromatography (hexane/ethyl acetate=1/1) to yield the
compound 10-4 (52 mg, 27%).
[0339] 1H NMR (30OMfz, CDCl.sub.3): .delta. 7.35(d, J=8.4 Hz, 2H),
7.20(d, J=8.4 Hz, 2H), 7.07(dd, J=2.7, 8.4 Hz, 1H), 6.94(d, J=8.4
Hz, 1H), 6.89(d, J=2.7 Hz, 1H), 6.01(bs, 1H), 5.19(bs, I11),
4.83(d, J=5.7 Hz, 211), 4.15(d, J=6.6 Hz, 2H), 1.44(s, 9H), 1.30(s,
9H)
EXAMPLE 50
[0340] Synthesis of
1-(4-t-butylbenzyl)-3-[2-hydroxy-4-methanesulfonylamin-
obenzyl]thiourea (10-6) 106
[0341] Step 1: Synthesis of
2-(N-t-butyloxycarbonylamino)methyl-4-methanes-
ulfonylamino-l1-t-butyldiphenylsilylo xybenzene (10-5)
[0342] The compound 10-3 (700 mg) prepared by Example 49 was
dissolved in dichloromethane (10 ml) and the solution was cooled to
0C, followed by adding trifluoroacetic acid (2.0 ml) thereto. The
mixture was stirred for 2 hours and concentrated under reduced
pressure. The obtained residue (186 mg) was dissolved in TBF (2.0
ml) and to the solution was added triethylamine (90 .mu.l),
followed by stirring for 12 hours. To the solution was added
Boc.sub.2O (68 mg) and the mixture was stirred at room temperature
for 10 hours. To the resulting mixture were added water (10 ml) and
ethyl acetate (10 ml). The organic layer was separated and the
aqueous layer was extracted with ethyl acetate (10 ml.times.2). The
combined organic layer was washed with saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and then
concentrated under reduced pressure. The obtained residue was
purified by column-chromatography (hexane/ethyl acetate={fraction
(1/2)}) to yield an alkylamine intermediate (100 mg, 69%),
protected with Boc group. The intermediate and triethylamnine (40
ye) were dissolved in dichloromethane (2.0 ml) and the solution was
cooled to 0.degree. C. To the solution was added methanesulfonyl
chloride (20 i) and the mixture was stirred at room temperature for
2 hours. The water was added thereto to quench the reaction. An
organic layer was separated, dried over magnesium sulfate, and then
concentrated under reduced pressure. The obtained residue was
purified by column-chromatography (hexane/ethyl acetate=3/2) to
yield the compound 10-5 (69 mg, 60%).
[0343] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.68(m, 4H),
7.40(m, 6H), 7.12(d, J=3.0 Hz, 1H), 6.73(dd, J=3.0, 8.7 Hz, 1H),
6.40(d, J=8.7 Hz, 1H), 6.04(s, 1H), 4.94(bs, 1H), 4.46(d, J=5.4ffz,
2H), 2.90(s, 3H), 1.48(s, 9H), 1.I1 (s, 9H).
[0344] Step 2: Synthesis of
[0345]
1-(4-t-butylbenzyl)-3-[2-hydroxy-4-methanesulfonylaminobenzyl]thiou-
rea (10-6)
[0346] Compound 10-5 (90 mg) was dissolved in TBF (2.0 ml) and to
the solution was added tetrabutylanunoniumfluoride (200 .mu.l),
followed by stirring at room temperature for 45 rminutes. The
reaction was quenched with saturated aqueous sodium bicarbonate
solution and the aqueous layer was extracted with ethyl acetate (10
ml.times.2). The combined organic layer was washed with saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
then concentrated under reduced pressure. The obtained residue was
purified by column-chromatography (hexane/ethyl acetate=1/1) to
yield a phenol compound (38 mg, 71%). The compound was dissolved in
dichloromethane (3.0 ml) and the solution was cooled to 0.degree.
C. To the solution was added trifluoroacetic acid (500 .mu.l), and
the mixture was stirred for 2 hours and concentrated under reduced
pressure. The concentrate was dissolved in ethyl acetate (2.0 ml)
and to the solution was added triethylarnine (16 .mu.l), followed
by stirring for 1 hour. To the solution was slowly added a solution
of t-butylbenzylisothiocyanate (25 mg) in ethyl acetate (1.0 ml),
and the mixture was stirred at room temperature for 18 hours and
concentrated under reduced pressure. The obtained residue was
purified by column-chromatography (hexane/ethyl acetate={fraction
(1/3)}) to yield the compound 10-6 (37 mg, 73%).
[0347] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.35(d, J=8.1 Hz,
2H), 7.19(d, J=8.1 Hz, 2H), 7.06(d, J=2.4 Hz, 1H), 7.00(dd, J=2.4,
8.4 Hz, 1H), 6.89(d, J=8.4 Hz, 11), 6.31(bs, 1H), 6.23(bs, 1H),
4.80(d, J=6.3 Hz, 2H), 4.49(bs, 2H), 2.94(s, 3H), 1.30(s, 9H)
EXAMPLE 51
[0348] Synthesis of
1-(4-t-butylbenzyl)-3-(2,6-difluoro-3-methanesulfonyla-
minobenzyl)thiourea (11-2) 107
[0349] Step 1: Synthesis of
2,4-difluoro-3-[N-(t-butoxycarbonylamino)methy- l]aniline
(11-1)
[0350] 2,6-Difluoro-3-nitrobenzonitrile (921 mg) and 10%
palladium/carbon (200 mg) were mixed in methanol (15 ml) and to the
mixture was added c-HCl (900 .mu.l), followed by stirring under
hydrogen atmosphere for 1 day. The mixture was diluted with ethyl
acetate (30 ml) and filtered through celite pad. The filtrate was
neutralized with 1 N aqueous sodium hydroxide solution and the
organic layer was separated. The aqueous layer was extracted with
ethyl acetate (10 ml.times.2). The combined organic layer was
washed with saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and then concentrated under reduced pressure.
The residue was purified by column-chromatography (methanol/ethyl
acetate=2/1) to yield an amine salt (580 mg, 50%). The obtained
amine salt was dissolved in tetrahydrofuran (5.0 ml) and to the
solution was added triethylamine (700 .mu.l), followed by stirring
at room temperature for 12 hours. To the solution was added
Boc.sub.2O (548 mg) and the mixture was stirred at room temperature
for 10 hours. To the resulting mixture were added water (10 ml) and
ethyl acetate (10 ml) and then the organic layer was separated. The
aqueous layer was extrated with ethyl acetate (10 ml.times.2). The
combined organic layer was washed with saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and then
concentrated under reduced pressure. The obtained residue was
purified by column-chromatography (hexane/ethyl acetate=1/1) to
yield intermediate material 11-1 (531 mg, 82%) protected with
Boc.
[0351] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.0 6.67(m, 2H),
4.86(bs, 1U, 4.39(d, J=4.8 Hz, 2H), 3.59(bs, 2H), 1.44(s, 9H)
[0352] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-(2,6-difluoro-3-methanes-
ulfonylaminobenzyl)thiourea (11-2)
[0353] Compound 11-1 (531 mg) was mesylated and treated with
trifluoroacetic acid to remove Boc group therefrom.
4-t-butylbenzylisothiocyanate was reacted therewith to yield the
compound 11-2 (145 mg, 16%).
[0354] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.50(dt, J=5.7,
9.0 Hz, 1H), 7.38(d, J-8.1 Hz, 2H), 7.22(d, J=8.1 Hz, 2H), 6.90(dt,
J=1.8, 9.0 Hz, 1H), 6.41(bs, 1H), 6.14(bs, 1H), 6.02(bs, 1H),
4.79(d, J=5.7 Hz, 211), 4.55(bs, 2H), 3.00(s, 3H), 1.32(s, 9H)
EXAMPLE 52
[0355] Synthesis of
1-(4-t-butylbenzyl)-3-(3-methanesulfonylaminobenzyl)th- iourea
(12-3b) 108
[0356] Step 1: Synthesis of 3-aminomethyl-phenylamine (12-1b)
[0357] 3-Nitrobenzaldehyde (1.51 g) and hydroxylamine hydrochhride
(1.29 g) were dissolved in methanol (100 ml), and to the solution
was slowly added pyridine (2.37 g) at room temperature, followed by
stirring for 18 hours. The resulting mixture was concentrated under
reduced pressure. The residue was dissolved in ethyl acetate (30
ml), washed with water (10 ml.times.2) and saturated aqueous copper
sulfate solution (10 ml), dried over magnesium sulfate,
concentrated under reduced pressure, and then the residue was
purified by column-chromatography (hexane/ethyl acetate=3/1) to
yield oxime (1.66 g). The obtained oxime was dissolved in methanol
(20 ml) and to the solution was added 10% palladium/carbon (414
mg), followed by stirring at room temperature under hydrogen
atmosphere for 3 days. The reaction mixture was filtered to remove
the precipitate and the filtrate was concentrated under reduced
pressure to yield the compound 12-1b (643 mg, 53%).
[0358] .sup.1H NMR(300 MHz, DMSO-d6): .delta. 7.08(t, J=8.1 Hz,
1H), 6.66(m, 2H), 6.55(d, J=8.1 Hz, 1H), 2.40 (bs, 2H)
[0359] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-(3-methanesulfonylaminob- enzyl)thiourea
(12-3b)
[0360] Compound 12-1b (643 mg) was dissolved in tetrahydrofuran
(6.0 ml) and to the solution was slowly added Boc.sub.2O (1.26 g)
at room temperature, followed by stirring for 18 hours. The
resulting mixture was concentrated under reduced pressure and the
obtained residue was purified by column-chromatography
(hexane/ethyl acetate=2/1) to yield an intermediate compound (622
mg) protected with Boc group. The intermediate compound and
triethylamine (500 .mu.l) were dissolved in dichloromethane (20 ml)
and the solution was cooled to 0.degree. C. To the solution was
added methanesulfonyl chloride (300 .mu.l) and the mixture was
stirred at room temperature for 50 minutes. The water was added
thereto to quench the reaction. The organic layer was separated,
dried over magnesium sulfate, concentrated under reduced pressure,
and then the residue was purified by column-chromatography
(hexane/ethylacetate=1/1) to yield the compound 12-2b (871 mg,
47%). The compound 12-2b was dissolved in dichloromethane (15 ml)
and the solution was cooled to 0C, followed by adding
trifluoroacetic acid (3.0 ml) thereto and stirring for 2 hours. The
resulting mixture was concentrated under reduced pressure and the
residue was dissolved in ethyl acetate (10 ml), followed by adding
triethylamine (140 .mu.l) thereto and stirring for 1 hour. To the
solution was slowly added a solution of t-butylbenzylisothiocyanate
(421 mg) in ethyl acetate (2 ml) and the mixture was stirred at
room temperature for 18 hours. The resulting mixture was
concentrated under reduced pressure and the obtained residue was
purified by column-chromatography (hexane/ethyl aceate=1/1) to
yield the compound 12-3b (385 mg, 95%).
[0361] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.7.33(d, J=8.4 Hz,
2H), 7.25(t, J=8.1 Hz, 1H), 7.18(d,J=8.4 Hz, 2H), 7.13(m, 2H),
7.03(d, J=7.5 Hz, 1H), 6.31(bs, 2H), 4.66(d, J=5.1 Hz, (d, J=4.8
Hz, 2H), 2.95(s, 3H), 1.29(s, 9H).
[0362] Compounds 12-3a and 12-3c - 12-3 g of Example 53 Example 59
were synthesized according to the synthesizing procedure as
described above.
5 12-3 109 Compounds R.sup.F = Examples No. R.sup.G = Spectral data
53 12-3a H .sup.1H NMR(300MHz, CDCl.sub.3): .delta. 8.13(bs, 1H),
7.46(d, 2-NHMs J=8.1Hz, 1H), 7.31(m, 2H), 7.31(d, J=8.4Hz, 2H),
7.17(d, J=5.4Hz, 1H), 7.16(d, J=8.4Hz, 2H), 6.34(m, 2H), 4.87(d,
J=6.0Hz, 2H), 4.47(bs, 2H), 2.99(s, 3H), 1.28(s, 9H). 54 12-3c H
.sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.62(d, J=7.5Hz,
2-NMs.sub.2 1H), 7.47(t, J=7.5Hz, 1H), 7.40(t, J=8.4Hz, 1H),
7.34(d, J=8.4Hz, 3H), 7.17(d, J=8.4Hz, 2H), 6.49(bs, 3.43(s, 6H),
1.29(s, 9H). 55 12-3d H .sup.1H NMR(300MHz, CDCl.sub.3):
.delta.7.43(d, J=7.2Hz, 1H), 3-NMs.sub.2 7.38(m, 1H), 7.38(d,
J=8.4Hz, 2H), 7.31(m, 1H), 7.29(m, 1H), 7.22(d, J=8.4Hz, 2H),
6.16(bs, 1H), 6.04(bs, 1H), 4.78(d, J=5.7Hz, 2H), 4.57(bs, 2H),
3.40(s, 6H), 1.30(s, 9H). 56 12-3e 4-F .sup.1H NMR(300MHz,
CDCl.sub.3): .delta.7.46(d, J=8.1Hz, 1H), 3-NHMs 7.47(d, J=8.4Hz,
2H), 7.22(d, J=8.4Hz, 2H), 7.08(d, J=8.1Hz, 2H), 6.50(bs, 1H),
6.12(bs, 1H), 5.97(bs, 1H), 4.71(d, J=5.4Hz, 2H), 4.57(d, J=4.8Hz,
2H), 3.03(s, 3H), 1.31(s, 9H). 57 12-3f 4-F .sup.1H NMR(300MHz,
CDCl.sub.3): .delta.7.37(d, J=8.4Hz, 2H), 3-NMs.sub.2 7.36(m, 2H),
7.24(d, J=8.4Hz, 2H), 7.15(d, J=9.3Hz, 1H), 6.20(bs, 1H), 6.04(bs,
1H), 4.74(d, J=5.4Hz, 2H), 4.55(d, J=5.1Hz, 2H), 3.43(s, 6H),
1.31(s, 9H). 58 12-3g 6-F .sup.1H NMR(300MHz, CDCl.sub.3):
.delta.7.36(d, J=8.1Hz, 2H), 3-NHMs 7.28(dd, J=2.4, 6.4Hz, 1H),
7.21(d, J=8.1Hz, 2H), 7.08(m, 1H), 7.00(t, J=9.2Hz, 1H), 6.88(bs,
1H), 6.34(bs, 1H), 6.18(bs, 1H), 4.76(d, J=5.7Hz, 2H), 4.55(d,
J=4.5Hz, 2H), 2.97(s, 3H), 1.30(s, 9H). 110 111 112 113 114 115
EXAMPLE 59
[0363] Synthesis of
1-(4-t-buty1-2-methoxybenzyl)-3-(4-methanesulfonylamin-
obenzyl)thiourea (13-4a) 116
[0364] Step 1: Synthesis of 4-t-buty1-2-methoxybenzonitrile
(13-2a)
[0365] 4-t-Butyl-2-hydroxybenzonitrile (1.16 g) and potassium
carbonate (376 mg) were dissolved in dimethylformamide (4 ml) and
to the solution was added dropwise iodomethane (226 fd), followed
by stirring at 50.degree. C. for 2 hours. The resulting mixture was
filtered to remove the remaining potassium carbonate and
concentrated under reduced pressure. The obtained residue was
purified by column-chromatography (hexane/ethyl acetate=10/1) to
yield the compound 13-2a (167 mg, 97%).
[0366] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.7.45(d, 1H,
J-8.OHz), 7.01(dd, 1H, J=1.7, 8.2 Hz), 6.94(d, 1H, J-1.5 Hz),
3.92(s, 3H), 1.31(s, 9H)
[0367] Step 2: Synthesis of 4-t-butyl-2-methoxybenzylamine
(13-3a)
[0368] Lithium aluminium hydride (50 mg) was suspended in ether (2
ml) and the suspension was cooled to 0.degree. C. To the suspension
was added dropwise a solution of the compound 13-2a (167 mg)
prepared by Step 1 in ether (2 ml) and the mixture was refluxed for
2 hours. After the completion of the reaction, the reaction
solution was basified with 5 N aqueous sodium hydroxide solution.
Then, aqueous Rochel solution was added thereto and stirred for 1
hour, at room temperature. Then, resulting mixture was extracted
with ether (50 ml.times.3) and concentrated under reduced pressure
to yield the compound 13-3a (120 mg, 71%). The following Step 3 was
proceeded using the compound 13-3a which was not purified.
[0369] Step 3: Synthesis of
1-(4-t-butyl-2-methoxybenzyl)-3-(4-methanesulf-
onylainiobenzyl)thiourea (13-4a)
[0370] The compound 13-3a (132 mg) prepared according to the same
procedure as described in Step 2 was dissolved in dichloromethane
(5 ml) and to the solution were added triethylamine (143 .mu.l) and
4-methanesulfonaminobenzylisothiocyanate (165 mg) in order,
followed by stirring at room temperature for 3 hours. The reaction
solution was evaporated under reduced pressure and the obtained
residue was purified by column-chromatography (hexane/ethyl
acetate=2/1) to yield the compound 13-4a (190 mg, 70%),
[0371] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.7.11-7.32(m, 5H),
6.96(d, 1H, J=7.0 Hz), 6.82(s, 1H), 4.67(s, 2H), 4.45(s, 2H),
3.62(s, 3H), 3.00(s, 3H), 1.2(s, 9H); MS (FAB) m/e
436[M.sup.++1]
[0372] Compounds of Example 60 69 are shown in the Scheme 13. In
Step 1 of the Examples, compounds 13-2b - 13-2k were synthesized
according to the similar procedure as described in Step 1 of
Example 59, and properties and spectral data thereof are shown in
below table. And in Step 2 of the respective examples, amines were
synthesized according to the similar procedure as described in Step
2 of Example 59, and the following Step 3 were proceeded using the
obtained amine compounds which was not purified. In the Example 60
69, the final compounds 13-4b 134k were synthesized according to
the similar procedure as described in Step 3 of Example 59 except
that amines prepared by Step 2 were used, and properties and
spectral data thereof are shown in below table.
6 13-2b.about.13-2k 117 Examples- step Compounds R.sup.H Spectral
data 60-1 13-2b ethyl H NMR(300MHz, CDCl.sub.3): .delta.7.45(d, 1H,
J=8.1Hz), 6.98(dd, 1H, 8.1Hz), 6.92(d, 1H, 1.5Hz), 4.15(q, 2H,
J=6.8Hz), 1.46(t, 3H, J=7.1Hz), 1.30(s, 9H); MS (FAB) m/e 450[M+1]
61-1 13-2c n-propyl .sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.45(d,
1H, J=8.3Hz), 6.98(dd, H, J=1.7, 8.2Hz), 6.91(d, 1H, J=1.7Hz), 4.02
(t, 2H, J=6.6Hz), 1.78-1.92(m, 2H), 1.30(s, 9H), 1.07(t, 3H, 7.3Hz)
62-1 13-2d n-butyl .sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.44(d,
1H, J=8.0Hz), 6.98(dd, 1H, J=1.7, 8.0Hz), 6.92(d, 1H, J=1.5Hz),
4.04(t, 2H, J=3.4Hz), 1.70-1.88(m, 2H), 1.40-1.62(m, 2H), 1.30(s,
9H), 0.97(t, 3H, J=7.3Hz) 63-1 13-2e n-pentyl .sup.1H NMR(300MHz,
CDCl.sub.3): .delta.7.44(d, 1H, J=8.0Hz), 6.98(dd, 1H, J=1.7,
8.0Hz), 6.91(d, 1H, J=1.7Hz), 4.05(t, 2H, J=6.6Hz), 1.84(m, 2H,
J=6.8Hz), 1.34-1.53(m, 4H), 1.30(s, 9H); 0.92(t, 3H, J=7.1Hz) 64-1
13-2f isopropyl .sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.44(d, H,
J=8.0Hz), 6.97(dd, 1H, J=1.7, 8.0Hz), 6.94(d, 1H, J=1.7Hz), 4.65(m,
1H, J=5.9Hz), 1.38(d, 6H, J=6.1Hz), 1.29(s, 9H) 65-1 13-2g isobutyl
.sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.45(d, 1H, J=8.3Hz),
6.8(dd, 1H, J=1.7, 8.0Hz), 6.90(d, 1H, J=1.5Hz), 3.81 (d, 2H,
J=6.4Hz, 2.08-2.20(m, 1H), 1.30(s, 9H), 1.06(d, 6H, J=6.8Hz) 66-1
13-2h neo-pentyl .sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.45(d,
1H, J=8.0Hz), 6.98(dd, 1H, J=1.7, 8.0Hz), 6.89(d, 1H, 1.7Hz), 3.68
(s, 2H), 1.30(s, 9H), 1.08(s, 9H) 67-1 13-2i MOM .sup.1H
NMR(400MHz, CDCl.sub.3): .delta.7.51(d, 1H, J=8.1Hz), 7.19(dd, 1H,
J=1.5, 5.2Hz), 7.10(d, 1H, J=1.6Hz), 5.31(s, 2H), 3.56(s, 3H),
1.34(s, 9H) 68-1 13-2j methoxyet- .sup.1H NMR(300MHz, CDCl.sub.3):
.delta.7.45(d, 1H, J=7.8Hz), hoxymethyl 7.02(d, 1H, J=1.7Hz),
6.99(dd, 1H, J=1.7, 3.0Hz), 4.23(t, 2H, J=4.6Hz), 3.80(t, 2H,
J=4.5Hz), 3.47 (s, 3H), 1.29(s, 9H) 69-1 13-2k benzyl .sup.1H
NMR(300MHz, CDCl.sub.3): .delta.7.50-7.27(m, 6H), 7.02(d, 1H,
J=0.7Hz), 6.98(dd, 1H, J=1.7, 5.3Hz), 5.21(s, 2H), 1.25(s, 9H),
3.47(s, 3H)
[0373]
7 13-4b.about.13-4k 118 Examples- step Compounds R.sup.H Spectral
data 60-3 13-4b ethyl .sup.1H NMR(300MHz, CDCl.sub.3):
.delta.7.01-7.10(m, 5H), 6.91 (d, 1H, J=7.6Hz), 6.77(s, 1H),
4.64(s, 2H), 4.42(s, 2H), 3.87(q, 2H, J=7.1Hz), 2.94(s, 3H),
1.15-1.24 (m, 12H); MS(FAB) m/e 450[M.sup.++1] 61-3 13-4c n-propyl
.sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.06(m, 5H), 6.95(dd, 1H,
J=1.7, 7.9Hz), 6.1(d, 1H, J=1.5Hz), 4.68(s, 2H), 4.44(s, 2H),
3.80(t, 2H, J=6.6Hz), 2.98(s, 3H), 1.52-1.74(m, 2H), 1.29(s, 9H),
0.95(t, 3H, J=7.6Hz); MS(FAB) m/e 464[M.sup.++1] 62-3 13-4d n-butyl
.sup.1NMR(300MHz, CDCl.sub.3): .delta.7.08-7.33(m, 5H), 6.96 (d,
1H, J=7.8Hz), 6.83(s, 1H), 4.68(s, 2H), 4.47(s, 2H), 3.85(t, 2H,
J=6.8Hz), 2.98(m, 3H), 1.39-1.80 4H), 1.29(s, 9H), 0.91(t, 3H,
J=7.3Hz); MS(FAB) m/e 478[M.sup.++1] 63-3 13-4e n-pentyl .sup.1H
NMR(300MHz, CDCl.sub.3): .delta..05-7.35(m, 5H), 6.75-7.00(m, 2H),
4.61(s, 2H), 2.96(s, 3H), 1.55-1.70(m, 2H), 1.10-1.48(m, 13H),
0.92(t, 3H, J=7.1Hz); MS(FAB) m/e 492[M.sup.++1] 64-3 13-4f
isopropyl .sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.06-7.37(m, 5H),
6.95(dd, H, J=1.7, 7.8Hz), 4.69(s, 2H), 4.33-4.60(m, 3H), 2.97(s,
3H), 1.29(s, 9H), 1.23(d, 6H, J=6.1Hz); MS(FAB) m/e 464[M.sup.++1]
65-3 13-4g isobutyl .sup.1H NMR(300MHz, CDCl.sub.3):
.delta.7.06-7.33(m, 5H), 6.95(d, 1H, J=8.0Hz), 6.81(d, 1H,
J=1.7Hz), 4.68(s, 2H), 4.48(s, 2H), 3.62(d, 2H, J=6.3Hz), 2.98(s,
3H), 1.30(s, 9H), 0.96(d, 6H, J=6.8Hz); MS(FAB) m/e 478[M.sup.++1]
66-3 13-4h neo-pentyl .sup.1H NMR(300MHz, CDCl.sub.3):
.delta.7.04-7.21(m, 5H), 6.95(d, 1H, J=1.8Hz), 6.82(d, 1H,
J=1.7Hz), 4.68(s, 2H), 4.53(s, 2H), 3.54(s, 2H), 2.97(s, 3H),
1.30(s, 9H), 0.99(s, 9H); MS(FAB) m/e 492[M.sup.++1] 67-3 13-4i MOM
.sup.1H NMR(300MHz, CDCl.sub.3): .delta.6.96-7.30(m, 7H), 5.06 (s,
2H), 4.66(s, 2H), 4.51(s, 2H), 3.39(s, 3H), 2.98 (s, 3H), 1.28(s,
9H); MS(FAB) m/e 466[M.sup.++1] 68-3 13-4j methoxy- .sup.1H
NMR(300MHz, CDCl.sub.3): .delta.7.10-7.37(m, 5H), ethoxy- 6.98(d,
1H, J=7.8Hz), 6.85(s, 1H), 4.68(s, 2H), 4.61(s, methyl 2H),
4.00-4.15(m, 2H), 3.60-3.75(m, 2H), 3.30(s, 3H), 2.97(s, 3H),
1.28(s, 9H); MS(FAB) m/e 480 [M.sup.++1] 69-3 13-4k benzyl .sup.1H
NMR(400MHz, CDCl.sub.3): .delta.7.50-6.95(m, 12H), 5.01(s, 2H),
4.68-4.40(m, 4H), 3.00(s, 3H), 1.33 (s, 9H); MS(FAB) m/e
512[M.sup.++1] 119 120 121 122 123 124 125 126 127 128
EXAMPLE 70
[0374] Synthesis of
1-(2-acetoxymethyl-4-t-butylbenzyl)-3-(4-methanesulfon-
ylaminobenzene)thiourea (13-9a) 129
[0375] Step 1: Synthesis of
4-t-butyl-2-trifluoromethanesulfonyloxybenzoni- tile (13-5)
[0376] 4-t-butyl-2-hydroxybenzonitrile (800 mg) was dissolved in
dichloromethane
[0377] (16 ml) and cooled to 0.degree. C. To the solution were
added triethylamine (663 Yu) and trifluoromethanesulfonic anhydride
(764 .mu.l) in order, followed by stiring for 1 hour. The reaction
solution was evaporated under reduced pressure and the obtained
residue was purified by column-chromatography (hexane/ethyl
aceate=10/1) to yield the compound 13-5 (1.30 g, 93%).
[0378] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.7.67(d, 1H,
J=8.OHz), 7.49(dd, 1H, J=1.7, 8.3 Hz), 7.43(d, 1H, J=1.5 Hz),
1.34(s, 9H)
[0379] Step 2: Synthesis of methyl 5-t-butyl-2-cyanobenzoate
(13-6)
[0380] The compound 13-5 (1.30 g) prepared according to the same
procedure as described in Step 1 was mixed with palladium acetate
(28 mg) and 1,1'-bis(diphenylphosphino)ferrocene (141 mg), and the
atmosphere of the reactor was brought into an atmosphere of carbon
monoxide. To the mixture was added dimethylsulfoxide (25 ml) to
dissolve the mixture. To the solution was added triethylamine (1.77
ml) and methanol (3.42 ml) successively with stirring and the
mixture was stirred at 50.degree. C. for 4 hours. The resulting
mixture was filtered to remove the catalyst and the filtrate was
evaporated under reduced prssure. The obtained residue was purified
by column-cbromatography (hexane/ethyl acetate=20/1) to yield the
compound 13-6 (400 mg, 44%).
[0381] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.8.13(d, 1H, J=2.0
Hz), 7.72(d, 1H, J=8.1 Hz), 7.64(dd, 1H, J=2.2, 8.2 Hz), 3.99(s,
3H), 1.34(s, 9H)
[0382] Step 3: Synthesis of (2-aminomethyl-5-t-butylphenyl)methanol
(13-7)
[0383] Lithium aluminium hydride (105 mg) was supended in ether (3
ml) and the suspension was cooled to 0.degree. C. To the suspension
was added dropwise a solution of the compound 13-6 (140 mg)
prepared by Step 2 in ether (4 ml) and the mixture was refluxed for
2 hours. After the completion of the reaction, the reaction mixture
was basified with 5 N aqueous sodium hydroxide solution, followed
by adding aqueous Rochel solution thereto and then stirring for 1
hour. Then, the resulting mixture was extracted with ether (50
ml.times.3) and concentrated under reduced pressure to yield the
compound 13-7 (320 mg, 90%). The following Step 4 was proceeded
using the compound 13-7 which was not purified
[0384] Step 4: Synthesis of
1-(4-t-butyl-2-hydroxymethylbenzyl)-3-(4-metha-
nesulfonylaminobenzyl)thiourea (13-8)
[0385] The compound 13-7a (320 mg) prepared according to the same
procedure as described in Step 3 was dissolved in dichloromethane
(7 ml) and to the solution were added triethylamine (231 .mu.l) and
4-methanesulfonaminobenzylisothiocyanate (401 mg) successively,
followed by stirring at room temperature for 3 hours. The reaction
solution was evaporated under reduced pressure and the obtained
residue was purified by column-chromatography (hexane/ethyl
acetate=1/1) to yield the compound 13-8 (460 mg, 64%).
[0386] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.7.38-7.00 (m, 7H),
4.75-4.60(m, 4H), 4.50(s, 2H), 2.92(s, 3H), 1.25(s, 9H)
[0387] Step 5: Synthesis of
1-(2-acetoxymethyl-4-t-butylbenzyl)-3-(4-metha-
nesulfonylaninobenzenc)thiourea (13-9a)
[0388] 1,3-Dicyclohexylcarbodiimide (68 mg) was dissolved in
dichloromethane (1 ml), and the solution was stirred and cooled to
0.degree. C. To the solution were added dropwise a mixed solution
of the compound 13-8 (130 mg) prepared according to the same
procedure as described in Step 4 and 4-(dimethylamino)pyridine (4
mg) in dichloromethane (3 ml), followed by adding acetic acid (34
.mu.l) thereto. The mixture was stirred at room temperature for 12
hours and concentrated under reduced pressure. The obtained residue
was purified by column-chromatograpohy (hexane/ethyl acetate 3/2)
to yield the compound 13-9a (52 mg, 37%).
[0389] .sup.1H NMR(300 MHz, CDCl.sub.3) .delta.7.40-7.06(m, 7H),
5.10(s, 2H), 4.68(s, 4H), 2.30(s, 3H1), 2.01(s, 3H), 1.30(s, 9H);
MS (FAB) m/e 478 [MW+1]
EXAMPLE 71
[0390] Synthesis of
1-(2-trimethylacetoxymethyl-4-t-butylbenzyl)-3-(4-meth-
anesulfonylaminobenzene) thiourea (13-9b) 130
[0391] Compound 13-9b (110 mg, 71%) was synthesized by reacting
compound 13-8 (130 mg) with trimethylacetic acid (45 mg) according
to the similar procedure as described in Step 5 of Example 70.
[0392] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.7.43-7.07(m, 7R),
5.10(s, 2H), 4.72(s, 2H), 4.66(s, 2H), 2.97(s, 3H), 1.29(s, 9H),
1.12(s, 9); MS (FAB) ni/e 520 [M+1]
EXAMPLE 72
[0393] Synthesis of
1-(4-t-butylbenzyl)-3-(4-methylthiobenzyl)thiourea (14-3) 131
[0394] Step 1: Synthesis of
2-(4-methylthiobenzyl)isoindol-1,3-dione (14-1)
[0395] (4-methyltliio)benzylalcohol (1.54 g) was dissolved in
anhydrous tetrahydrofuran (10 ml) and to the solution were added
phthalimide (1.47 g) and triphenylphosphine (2.62 g). To the
mixture was slowly added dropwise a solution of
diisopropylazodicarboxylate CHAD) (2.02 g) in anhydrous
tetrahydrofuran (4 ml), while the mixture was stirred at room
temperature. After 18 hours, the reaction mixture was concentrated
and the residue was purified by column-chromatography
(hexane/etlhyl acetate=5/1) to yield a white solid (2.00 g,
71%).
[0396] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.86-7.68(m, 4H),
7.38-7.35(m, 2H), 7.22-7.18(m, 2H), 4.79(s, 2H), 2.44(s, 3H)
[0397] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-(4-methylthiobenzyl)thio- urea (14-3)
[0398] 2-(4-methylthiobenzyl)isoindol-1,3-dione (14-1) (1.67 g) was
dissolved in ethanol (10 ml) and to the solution was added
hydrazine hydrate (300 mg), followed by refluxing. After 24 hours,
the resulting mixture was diluted with dichloromethane (50 ml) and
washed with 2 N hydrochloric acid solution. An organic layer was
washed with aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, concentrated under reduced pressure. The residue
was purified by colunin-chromatography to obtain a liquid (0.8 g).
The obtained liquid mixture (400 mg) was dissolved in
dichloromethane (20 ml) and to the solution was added
4-t-butylbenzylisothiocyanate (0.54 g), followed by stirring at
room temperature for 24 hours. The reaction mixture was
concentrated and the residue was purified by column-chromatography
(dichloromethane) to yield the compound 14-3 (0.52 g, 56%) as a
white solid.
[0399] 1H NMR(300 MHz, CDCl.sub.3): .delta. 7.37-7.15(m, 8H1),
6.00(brs, 2H), 4.60-4.50(m, 4H), 2.47(s, 3H), 1.31(s, 9H)
EXAMPLE 73
[0400] Synthesis of
1-(4-t-butylbenzyl)-3-[2-(4-methylthiazol-5-yl)ethyl]t- hiourea
(14-6) 14-6) 132
[0401] Step 1: Synthesis of
5-(2-methylsulfonyloxyethyl)-4-methylthiazole
[0402] 2-(4-methylthiazol-5-yl)ethanol (5.01 g) was dissolved in
dichloromethane (100 ml) and to the solution was added
triethylamine (5.06 g), followed by adjusting the temperature of
reactor to 0.degree. C. To the obtained solution was added dropwise
methanesulfonyl chloride (4.58 g), and the mixture was stirred for
21 hours while allowed to warm up to room temperature. The reaction
solution was washed with water, concentrated under reduced
pressure, and then purified by column-chromatography (hexane/ethyl
acetate {fraction (1/3)}) to yield
5-(2-methylsulfonyloxyethyl)-4-methylthiazolei (5.18 g, 67%) as a
pale yellow liquid.
[0403] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 8.63(s, 1H),
4.37(t, 3H, J=6 Hz), 3.23(t, 3H, J=6 Hz), 2.97(s, 3H), 2.43(s,
311)
[0404] Step 2: Synthesis of
2-[2-(4-methylthiazol-5-yl)ethyl]isoindol-1,3-- dione (14-4)
[0405] 5-(2-methylsulfonyloxyethyl)-4-methylthiazole (4.17 g) was
dissolved in dimethylformamide (20 ml) and to the solution was
added potassium phthalimide (3.84 g), followed by stirring at
70.degree. C. for 5 hours. The mixture was concentrated under
reduced pressure and water was added thereto to form precipitate.
The resulting mixture was filtered to collect the precipitate. The
obtained precipitate was dissolved in dichloromethane. The solution
was dried over anhydrous magnesium sulfate, concentrated, and then
crystallized (dichloromethane/petroleum ether) to yield the
compound 14-4 (3.77 g, 74%) as a pale yellow solid.
[0406] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 8.57(s, 1H),
7.86-7.70(m, 4H), 3.91(t, 3H, 3 Hz), 3.18(t, 3H, J=6 Hz), 2.38(s,
3H)
[0407] Step 3: Synthesis of
1-(4-t-butylbenzyl)-3-[2-(4-methylthiazol-5-yl- )ethyl]thiourea
(14-6)
[0408] 2-[2-(4-methylthiazol-5-yl)ethyl]isoindol-1,3-dione (3 g)
was dissolved in a mixture of methanol (10 ml) and tetrahydrofaran
(10 ml) and to the solution was added dropwise hydrazine hydrate
(610 mg), followed by stirring for 20 hours. To the obtained
solution was added 2 N aqueous hydrochloric acid solution (6 ml),
and the mixture was stirred for 3 hours and concentrated under
reduced pressure to obtain reaction mixture (3.5 g) as a yellow
solid. The obtained mixture (140 mg) was dissolved in
dimethylformamide (5 ml) and to the solution were added
4-t-butylbenzylisothiocyanate (0.2 g) and a small amount of
triethylamine, followed by stirring at room temperature for 21
hours. The resulting mixture was diluted with dichloromethane,
washed with water, dried, concentrated under reduced pressure, and
then purified by colurn-chromatography (hexane/ethyl acetate=1/1)
to yield the compound 14-6 (0.07 g) as a liquid.
[0409] .sup.1H NMR(300MFz, CDCl.sub.3): .delta. 8.53(s,l1H),
7.38-7.18(m, 4H), 6.25(brs, 1H), 5.77(brs, 1H), 4.49(s,2H),
3.78-3.73(m, 2H), 3.08(t, 2H, J=6 Hz), 2.36(s, 3H), 1.31(s, 9H)
EXAMPLE 74
[0410] Synthesis of
1-(4t-butylbenzyl)-3-((2-chloro-5-pyridinyl)methyl)thi- ourea
(14-9) 133
[0411] Step 1: Synthesis of
((2-chloro-5-pyridinyl)methyl)isoindol-1 ,3-dione (14-7)
[0412] 2-chloro-5-chloromethylpyridine (5 g) was dissolved in
dimethylformamide (60 ml) and to the solution was added phthalimide
(6.29 g), followed by stirring at room temperature for 17 hours.
The solvent of the reaction solution was removed under reduced
pressure and the residue was extracted with water and
dichloromethane to yield a white solid (6.2 g, 74%). 1H NMR(300
MHz, CDCl.sub.3): .delta. 8.50-8.49(m, 1H), 7.88-7.72(m, 5H),
7.30-7.26(m, 1H), 4.83(s, 2H), 2.44(s, 3H)
[0413] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-((2-chloro-5-pyridinyl)m- ethyl)thiourea
(14-9)
[0414] ((2-chloro-5-pyridinyl)methyl)isoindol-1,3-dione (4.7 g) was
dissolved in methanol (100 ml) and to the solution was added
hydrazine hydrate (7.7 ml), followed by stirring at room
temperature for 2 hours. The reaction slolution was extracted with
water and dichloromethane and concentrated under reduced pressure
to obtain a liquid (1.4 g). The obtained liquid mixture (66 mg) was
dissolved in dichloromethane (5 ml) and to the solution was added
4-t-butylbenzylisothiocyanate (95 mg), followed by stirring at room
temperature for 24 hours. The reaction mixture was concentrated and
purified by coliun-chromatography (hexane/etlhyl acetate=2/1) to
yield the compound 14-9 (45 mg, 28%/0) as a white solid.
[0415] .sup.1H NMR(30OMffz, CDCl.sub.3): .delta. 8.16-8.15(m, 1H),
7.61-7.57(m, 1H), 7.38-7.18(m, 4H), 6.48(brs, 2H), 6.21(brs, 2H),
4.74(d, 2H, J=5.7 Hz), 4.54(d,2H, J=4.5 Hz), 1.29(s, 9H)
EXAMPLE 75
[0416] Synthesis of
1-(4-t-butylbenzyl)-3-(2-(thiomorpholin-4-yl)ethyl)thi- ourea
(15-3) 134
[0417] Step 1: Synthesis of
2-(2-thiomorpholin-4-yl)ethyl)isoindol-1,3-dio- ne (15-1)
[0418] Thiomorpholine (3.75 g) was dissolved in acetone (100 ml)
and to the solution were added anhydrous potassium carbonate (5.52
g) and 2-(bromoethyl)phthalimide (9.22 g), followed by refluxing
for 26 hours. The obtained mixture was filtered, concentrated, and
then dissolved in dichloromethane. The solution was washed with
water, dried, concentrated under reduced pressrure, and then
purified by colurnn-chromatography (hexane/ethyl acetate=1/1) to
yield the compound 15-1 (2 g, 20%) as a yellow solid.
[0419] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.87-7.70(m, 4H),
3.80(t, 2H, J=6.6 Hz), 2.79-2.57(m, 1OH)
[0420] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-(2-(thiomorpholin-4-yl)e- thyl)thiourea
(15-3)
[0421] 2-(2-thiomorpholin-4-ylethyl)isoindol-1,3-dione 15-1 (2.76
g) was dissolved in a mixture of methanol (20 ml) and
tetrahydrofaran (20 ml) and to the solution was added dropwise
hydrazine hydrate (550 mg), followed by stirring for 21 hours. To
the obtained solution was added 2 N aqueous hydrochloric acid
solution (6 ml), and the mixture was stirred for 3 hours and then
concentrated under reduced pressure. To the concentrate was added
water (15 ml) and the undissolved material was filtered off.
[0422] The filtrate was concentrated to obtain reaction mixture
(1.62 g) as a solid. The obtained mixture (150 mg) was dissolved in
dimethylformamide (5 ml) and to the solution was added
4-t-butylbenzylisothiocyanate (210 mg) and a small amount of
triethylamine, followed by stirring at room temperature for 23
hours. The resulting mixture was diluted with dichloromethane,
washed with water, and concentrated under reduced pressure. The
residue was purified by column-chromatography (hexane/ethyl
acetate={fraction (1/3)}) to the compound 15-3 (0.12 g) as awhite
solid.
[0423] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.42-7.26(m, 4H),
6.32(brs, 1H), 4.60(s,2H), 3.40(s, 2H1), 2.62-2.20(m, 10H), 1.32(s,
9H)
EXAMPLE 76
[0424] Synthesis of
1-(furan-2-ylmethyl)-3-(4-methoxybenzyl)thiourea (16-1) 135
[0425] Furan-2-ylmethylamine (190 mg) was dissolved in
dimethylformamide (5 ml) and to the solution were added
triethylamine (200 mg) and 4-methoxybenzylisothiocyanate (360 mg),
followed by stirring at room temperature for 24 hours. Then, the
resulting mixture was diluted with ethyl acetate, washed with
water, dried, and concentrated under reduced pressure. The residue
was purified by column-chrornatography (hexane/ethyl acetate=1/1)
to yield the compound 16-1 (0.5 g, 90%) as a liquid.
[0426] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.33-7.32(m, 1H),
7.23-7.19(m, 2H), 6.89-6.85(m, 211), 6.32-6.23(m, 2H),
6.20(brs,1H), 6.05(brs,1H), 4.67-4.64(m, 2H), 4.55-4.53(m, 2H),
3.80(s, 3H)
EXAMPLE 77
[0427] Synthesis of
1-(4-t-butylbenzyl)-3-(furan-2-ylmethyl)thiourea (16-2) 136
[0428] Furan-2-yhnethylamine (0.58 g) was dissolved in
dichloromethane (50 ml) and to the solution was added
4-t-butylbenzylisothiocyanate (1.23 g), followed by stirring at
room temperature for 8 hours. Then, the resulting mixture was
diluted with ethyl acetate, washed with water, dried, and
concentrated under reduced pressure. The residue was purified by
columin-chromatography (dichloromethane) to yield the compound 16-2
(1.57 g, 87%) as a liquid.
[0429] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.37-7.20(m, 5H),
6.31-6.29(m, 1H), 6.21-6.19(m, 1H), 6.10(brs,1H), 4.65-4.63(m, 2H),
4.58-4.50(m, 2M), 1.30(s, 9H)
EXAMPLE 78.about.EXAMPLE 121
[0430] Compounds of Example 78 Example 121 are shown in the Scheme
16. The compounds were syntesized according to the similar
procedure as described in Example 76 or Example 77, and properties
and spectral data are shown in below table.
8 137 138 139 Examples Compounds R = Types Spectral data 78 16-3
140 B .sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.34-7.18(m, 6H),
6.31-6.28(m, 1H), 6.21-6.20(m, 1H), 5.92(brs, 2H), 4.60-4.50(m,
2H), 3.75-3.65(m, 2H), 2.91(t, 2H, J=6.6Hz) 79 16-4 141 A .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 8.41-8.39(m, 1H), 7.70-7.64(m,
1H), 7.38-7.17(m, 6H), 4.73(m, 2H), 4.64(m, 2H), 1.31(s, 9H) 80
16-5 142 B .sup.1H NMR(300MHz, CDCl.sub.3): .delta. 8.41-8.38(m,
1H), 7.72-7.66(m, 1H), 7.34-7.05(m, 9H), 4.69(m, 2H), 3.77(m, 2H),
2.96(t, 2H, J=6.9Hz) 81 16-6 143 A .sup.1H NMR(300MHz, CDCl.sub.3):
.delta. 8.52-8.48(m, 2H), 7.63-7.59(m, 1H), 7.39-7.35(m, 2H),
7.24-7.20(m, 3H), 6.22(brs, 1H), 5.95(brs, 1H), 4.79-4.76(m, 2H),
4.57-4.55(m, 2H), 1.31(s, 9H) 82 16-7 144 A .sup.1H NMR(300MHz,
CDCl.sub.3): .delta. 8.51-8.49(m, 2H), 7.40-7.37(m, 2H),
7.25-7.21(m, 2H), 7.10-7.07(m, 2H), 6.30(brs, 1H), 6.00(brs, 1H),
4.80-4.77(m, 2H), 4.58-4.56(m, 2H), 1.31(s, 9H) 83 16-8 145 A
.sup.1H NMR(300MHz, CDCl.sub.3): .delta. 8.16-8.14(m, 1H),
7.62-7.55(m, 1H), 7.37-7.22(m, 4H), 7.16-7.05(m, 2H), 4.54(m, 2H),
3.91(m, 2H), 3.04(t, 2H, J=6Hz), 1.32(s, 9H) 84 16-9 146 B .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 8.41-8.38(m, 1H), 7.66-7.60(m,
1H), 7.33-7.13(m, 7H), 6.31(br, 2H), 3.87(m, 2H), 3.66(m, 2H),
3.04(t, 2H, J=6Hz), 2.92(t, 2H, J=6.9Hz), 85 16-10 147 A .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 7.37-7.19(m, 6H), 7.12-6.99(m,
2H), 6.11(brs, 1H), 6.01(brs, 1H), 4.75-4.73(m, 2H), 4.57-4.55(m,
2H), 1.31(s, 9H) 148 149 150 151 152 153 154 155
[0431]
9 Examples Compounds R = Types Spectral data 86 16-11 156 A .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 7.38-6.88(m, 8H), 6.14(brs, 1H),
5.96(brs, 1H), 4.70-4.67(m, 2H), 4.57-4.55(m, 2H), 1.31(s, 9H) 87
16-12 157 A .sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.37-7.33(m,
2H), 7.20-7.16(m, 4H), 7.01-6.95(m, 2H), 6.07(brs, 1H), 6.00(brs,
1H), 4.63-4.54(m, 4H), 1.31(s, 9H) 88 16-13 158 A .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 7.39-7.35(m, 2H), 7.23-7.19(m,
2H), 7.10-6.90(m, 4H), 6.08(brs, 1H), 5.85(brs, 1H), 4.69-4.66(m,
2H), 4.56-4.53(m, 2H), 1.31(s, 9H) 89 16-14 159 A .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 7.40-7.37(m, 2H), 7.24-7.21(m,
3H), 6.73-6.66(m, 2H), 6.24(brs, 1H), 5.90(brs, 1H), 4.74-4.71(m,
2H), 4.56-4.54(m, 2H), 1.31(s, 9H) 90 16-15 160 A .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 7.39-7.36(m, 2H), 7.24-7.22(m,
2H), 7.02-6.94(m, 3H), 6.16(brs, 1H), 5.92(brs, 1H), 4.78-4.76(m,
2H), 4.56-4.54(m, 2H), 1.31(s, 9H) 91 16-16 161 A .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 7.38-7.20(m, 5H), 6.90-6.74(m,
2H), 6.10(brs, 1H), 5.91(brs, 1H), 4.75-4.72(m, 2H), 4.55-4.50(m,
2H), 1.31(s, 9H) 92 16-17 162 A .sup.1H NMR(300MHz, CDCl.sub.3):
.delta. 7.38-7.34(m, 2H), 7.27-7.20(m, 3H), 6.91-6.85(m, 2H),
6.05(brs, 1H), 6.02(brs, 1H), 4.71-4.70(m, 2H), 4.61-4.60(m, 2H),
1.31(s, 9H) 163 164 165 166 167 168 169
[0432]
10 Examples Compounds R = Types Spectral data 93 16-18 170 A
.sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.39-7.35(m, 2H),
7.25-7.20(m, 3H), 7.15-7.05(m, 1H), 6.95-6.85(m, 1H), 6.16(brs,
1H), 5.88(brs, 1H), 4.80-4.78(m, 2H), 4.53-4.51(m, 2H), 1.31(s, 9H)
94 16-19 171 A .sup.1H NMR(300MHz, CDCl.sub.3): .delta.
7.39-7.35(m, 2H), 7.25-7.06(m, 3H), 6.86-6.78(m, 1H), 6.14(brs,
1H), 5.95(brs, 1H), 4.79-4.76(m, 2H), 4.56-4.50(m, 2H), 1.31(s, 9H)
95 16-20 172 A .sup.1H NMR(300MHz, CDCl.sub.3): .delta.
7.39-7.35(m, 2H), 7.26-6.98(m, 6H), 5.97(brs, 1H), 5.68(brs, 1H),
4.51-4.49(m, 2H), 3.75-3.74(m, 2H), 2.94(t, 2H, J=6.6Hz), 1.32(s,
9H) 96 16-21 173 A .sup.1H NMR(300MHz, CDCl.sub.3): .delta.
7.38-7.19(m, 6H), 6.92-6.84(m, 2H), 6.03(brs, 1H), 5.59(brs, 1H),
4.46(m, 2H), 3.78(m, 2H), 2.89(t, 2H, J=6.6Hz), 1.32(s, 9H) 97
16-22 174 A .sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.38-6.92(m,
8H), 5.94(brs, 1H), 5.58(brs, 1H), 4.46(m, 2H), 3.73(m, 2H),
2.85(t, 2H, J=6Hz), 1.32(s, 9H) 98 16-23 175 A .sup.1H NMR(300MHz,
CDCl.sub.3): .delta. 7.40-7.35(m, 2H), 7.19-7.16(m, 2H),
7.10-6.83(m, 3H), 6.08(brs, 1H), 5.58(brs, 1H), 4.47-4.44(m, 2H),
3.77-3.70(m, 2H), 2.84(t, 2H, J=6.9Hz), 1.31(s, 9H) 176 177 178 179
180 181
[0433]
11 Examples Compounds R = Types Spectral data 99 16-24 182 A
.sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.38-7.34(m, 2H).
7.19-7.16(m, 2H), 7.08-7.04(m, 2H), 6.84-6.80(m, 2H), 5.90(brs,
1H), 5.62(brs. 1H), 4.48-4.46(m, 2H), 3.79(s, 3H), 3.70-3.68(m,
2H), 2.81(t, 2H, J=6.6Hz), 1.31(s, 9H) 100 16-25 183 A .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 7.37-7.33(m, 2H), 7.22-7.15(m,
3H), 6.79-6.71(m, 3H), 5.93(brs, 1H), 5.64(brs, 1H). 4.47-4.45(m,
2H), 3.79(s, 3H), 3.78-3.72(m, 2H). 2.85(t, 2H, J=6.6Hz), 1.31(s,
9H) 101 16-26 184 A .sup.1H NMR(300MHz, CDCl.sub.3): .delta.
7.39-7.35(m, 2H), 7.25-7.18(m, 3H), 7.10-7.07(m. 1H), 6.92-6.87(m,
1H), 6.82-6.79(m, 1H). 6.23(brs, 1H), 6.04(brs, 1H), 4.60-4.59(m,
2H), 3.61(s, 3H), 3.61-3.50(m, 2H), 2.89(t, 2H, J=6.9Hz), 1.32 (s,
9H) 102 16-27 185 A .sup.1H NMR(300MHz, CDCl.sub.3): .delta.
7.36-7.33(m, 2H), 7.18-7.15(m, 2H), 6.79-6.75(m, 1H), 6.69-6.66(m,
2H), 6.03(brs, 1H), 5.77(brs, 1H), 4.48-4.46(m, 2H), 3.84(s, 3H),
3.83(s, 3H), 3.72-3.70(m, 2H), 2.81(t, 2H, J=6.9Hz), 1.30(s, 9H)
103 16-28 186 A .sup.1H NMR(300MHz, CDCl.sub.3): .delta.
7.37-7.33(m, 2H), 7.20-7.17(m, 2H), 6.48(s, 2H), 6.00(brs, 2H),
4.60-4.55(m, 4H), 3.82-3.79(m, 9H), 1.30(s, 9H) 187 188 189 190
191
[0434]
12 Examples Compounds R = Types Spectral deta 104 16-29 192 A
.sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.83-7.79(m, 2H),
7.39-7.18(m, 6H), 6.13(brs, 1H), 5.71(brs, 1H), 4.85(s, 2H),
4.50(m, 2H), 3.80-3.75(m, 2H), 2.97(t, 2H, J=7.2Hz), 1.31(s, 9H)
105 16-30 193 A .sup.1H NMR(300MHz, CDCl.sub.3): .delta.
7.40-7.35(m, 2H), 7.20-7.16(m, 2H), 6.78-6.75(m, 1H), 6.66-6.65(m,
1H), 6.58-6.54(m, 1H), 5.94(brs, 1H), 5.67(brs, 1H), 4.48-4.46(m,
2H), 3.65-3.64(m, 2H), 2.74(t, 2H, J=6.6Hz), 1.31(s, 9H) 106 16-31
194 C .sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.56(brs, 1H),
7.41-7.25(m, 4H), 6.63(brs, 1H), 4.86(d, 2H, J=6Hz), 3.90-3.86(m,
2H), 3.63-3.55(m, 2H), 2.98-2.93(m, 2H), 2.67-2.60(m, 2H), 1.33(s,
9H) 107 16-32 195 A .sup.1H NMR(300MHz, CDCl.sub.3): .delta.
7.29-7.32 (m, 2H), 7.21(d, 2H, J=8.0Hz), 6.39(brs, 1H), 4.55(brs,
2H), 2.86-2.94(m, 6H), 2.42(t, 2H, J=5.4Hz), 2.29(t, 2H, J=4.7Hz),
1.24(s, 9H) 108 16-33 196 B .sup.1H NMR(300MHz, CDCl.sub.3):
.delta. 7.34-7.20(m, 5H), 6.29(s, 1H), 3.80-3.70(m, 2H),
3.60-3.50(m, 4H), 3.40-3.30(m, 2H), 2.96(t, 2H, J=6.9Hz),
2.51-2.35(m, 6H) 109 16-34 197 A .sup.1H NMR(300MHz, CDCl.sub.3):
.delta. 7.40-7.26(m, 4H), 6.40(brs, 1H), 4.63(m, 2H), 3.50-3.30(m,
6H), 2.52-2.36(m, 6H), 1.31(s, 9H) 110 16-35 198 A .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 7.37-7.26(m, 4H), 6.40(brs, 1H),
4.68(m, 2H), 3.34(m, 2H), 2.42(t, 2H, J=5.1Hz), 2.30(m, 4H),
1.60(m, 2H), 1.30(s, 9H), 1.29-1.09(m, 4H) 111 16-36 199 A .sup.1H
NMR(300MHz, CD.sub.3OD): .delta. 7.57(d, 1H, J=1.0Hz), 7.32-7.36(m,
2H), 7.21(d, 1H, J=8.6Hz), 4.63(brs, 2H), 3.72(brs, 2H), 2.83(t,
2H, J=7.1Hz), 1.29(s, 9H) 112 16-37 200 A .sup.1H NMR(300MHz,
CDCl.sub.3): .delta. 7.97(brs, 1H), 7.59-7.56(m, 1H), 7.38-7.09(m,
8H), 6.96(brs, 1H), 5.85(brs, 1H), 5.72(brs, 1H), 4.40(m, 2H),
3.79(m, 2H), 3.04(t, 2H, J=6.6Hz), 1.30(s, 9H) 201 202 203 204 205
206 207 208 209
[0435]
13 Examples Compounds R = Types Spectral deta 113 16-38 210 B
.sup.1H NMR(300MHz, CDCl.sub.3): .delta. 8.03(brs, 1H),
7.60-7.05(m, 9H), 5.67(brs, 1H), 5.51(brs, 1H), 3.68(m, 2H),
3.54(m, 2H), 3.03(t, 2H, J=6.6Hz), 2.75(t, 2H, J=6.6Hz) 114 16-39
211 A .sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.52-7.15(m,
2.67(brs, 2H), 1.25(s, 3H) 115 16-40 212 A .sup.1H NMR(300MHz,
CDCl.sub.3): .delta. 8.70(brs, 1H), 8.14-8.09(m, 1H), 7.38-7.20(m,
5H), 6.42-6.30(m, 2H), 5.91(brs, 1H), 4.58(m, 2H), 3.79-3.66(m,
4H), 1.30(s, 9H) 116 16-41 213 A .sup.1H-NMR(300MHz, CDCl.sub.3):
.delta. 7.37-7.47 (m, 2H), 7.21-7.24(d, 2H, J=8.3Hz), 6.70-6.78 (m,
3H), 5.98(s, 2H), 4.57-4.60(br, 4H), 1.35 (s, 9H) 117 16-42 214 A
.sup.1H-NMR(300MHz, acetone-d.sub.6,): .delta. 7.50(s, 1H),
7.32(dd, 2H, J=1.9, 6.3Hz), 7.22(d, 2H, J=8.5Hz), 7.05(s, 1H),
6.86(s, 1H), 4.66(brs, 2H), 4.01(t, 2H, J=7.1Hz), 3.50(t, 2H,
J=6.6Hz), 1.99-2.08(m, 2H), 1.24(s, 9H) 118 16-43 215 A
.sup.1H-NMR(300MHz, CDCl.sub.3): .delta. 7.32-7.35(m, 2H),
7.11-7.18(m, 3H), 6.88(dd, 1H, J=3.4, 5.1Hz), 6.74(d, 1H, J=2.9Hz),
6.09(brs, 1H), 5.75(brs, 1H), 4.44(brs, 2H), 4.08(t, 2H, J 7.3Hz),
3.07(t, 2H. J=6.6Hz), 1.29 (s, 9H) 119 16-44 216 A
.sup.1H-NMR(300MHz, CDCl.sub.3): .delta. 7.36-7.39(m, 2H),
7.21-7.26(m, 3H), 6.94-6.96(m, 2H), 6.24(brs, 1H), 6.04(brs, 1H),
4.88(d, 2H, J=4.8Hz), 4.57(brs, 2H), 1.33(s, 9H) 120 16-45 217 A
.sup.1H NMR(CDCl.sub.3) .delta. 7.37(m, 2H), 7.23(m, 2H), 4.45(bs,
2H), 3.50(m, 2H), 2.73(m, 2H), 2.50(bs, 1H), 2.21(s, 3H). 2.13(m,
1H), 1.88(m, 3H), 1.68(m, 4H), 1.30(s, 9H) 218 219 220 221 222 223
224 225
EXAMPLE 121
[0436] Synthesis of 1-(4-t-butylbenzyl)-3-(2-pyridinyl)thiourea
(16-46) 226
[0437] 2-aminopyridine (86 mg) was dissolved in acetonitrile (10
ml) and to the solution were added 4-t-butylbelizylisothiocyanate
(190 mg) and triethylamine (140 .mu.l), followed by refluxing for
27 hours. The resulting mixture was extracted with water and
dichloromethane, dried, concentrated under reduced pressure, and
then crystallized (dichloromethane/petroleum ether) to yield the
compound (90 mg, 33%) as a white solid.
[0438] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 11.99(brs, 1H),
8.13-8.11(m, 1H), 7.67-7.61(m, 1H), 7.41-7.27(m, 4H), 6.96-6.92(m,
1H), 6.68-6.64(m, 1H), 4.99-4.96 (m, 21), 1.32(s, 9H)
EXAMPLE 122
[0439] Synthesis of
1-(4-t-butylbenzyl)-3-((2-hydroxy-1-methyl-2-phenyl)et-
hyl)thiourea (16-47) 227
[0440] Phenylpropanolamine hydrochloride (100 mg) was dissolved in
dimethylformamide (5 ml) and to the solution was added
triethylamine (80 .mu.l), followed by stirring for 30 minutes. To
the obtained reaction mixture was added
t-butylbenzeneisothiocyanate (135 mg), and the mixture was stirred
for 4 hours, diluted with water (20 ml), extracted with
dichloromethane (30 ml.times.3), dried over magnesium sulfate, and
then flitered. The filtrate was concentrated under reduced pressure
and the obtained residue was purified by column-chromatography
(ethyl acetate/hexane={fraction (1/3)}) to yield the compound 16-47
(159 mg, 83.7%).
[0441] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.7.32(m, 9H),
6.65(brs, 1H), 5.69(d, 1H, J=7.8 Hz), 4.92(s, 1H), 4.57(s, 2H),
2.66(s, 1H), 1.58(s, 1H), 1.31(s, 9H), 0.98(d, 3H, J=6.9 Hz)
EXAMPLE 123
[0442] Synthesis of
1-(4-t-butylbenzyl)-3-(1H-pyrro1-2-ylmethyl)thiourea (17-1) 228
[0443] Step 1: Synthesis of 1H-pyrro1-2-carboxaldehyde oxime
[0444] Pyrrole-3-carboxaldehyde (120.4 mg) was dissolved in
methanol (4 ml) and to the solution were added hydroxylamine
hydrochloride (106 mg) and sodium acetate (127 mg), followed by
stirring for 1 hour. The resulting mixture was extracted with ethyl
acetate, and then dried over anhydrous magnesium sulfate. The
filtrate was concentrated under reduced pressure, and then
column-chromatographed (ethyl acetate/hexane={fraction (1/3)}) to
yield the compound (122 mg, 100 %).
[0445] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.19(s, 1H), 6.92
(t, 1H, J=2.1 Hz), 6.52 (q, 1H, J=3.7 Hz), 6.15 (q, 1H, J=3.7
Hz)
[0446] Step 2: Synthesis of (1H-pyrrol-2-yl)methylamine
hydrochloride
[0447] 1H-pyrrol-2-carboxaldehyde oxime (60 mg) prepared according
to the same procedure as described in Step 1 was dissolved in
methanol (2 ml) and to the solution were added a catalytic amount
of 10% palladium/carbon and concentrated hydrochloric acid (100
.mu.l), followed by stirring at room temperature under hydrogen gas
atmosphere for 1 hour. The resulting mixture was diluted with
ether, and then filtered through celite. The filtrate was
concentrated under reduced pressure to yield
(1H-pyrrol-2-yl)methylarnine hydrochloride (60 mg, 100%).
[0448] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 6.78 (q, 1H, J=4.2
Hz), 6.23 (s, 1H), 6.10 (q, 1H, J=5.9 Hz), 4.08 (s, 2H)
[0449] Step 3: Sythesis of
1-(4-t-butylbenzyl)-3-(1H-pyrrol-2-ylmethyl)thi- ourea (17-1)
[0450] (1H-pyrrol-2-yl)methylamine hydrochloride (60 mg) prepared
according to the same procedure as described in Step 2 was
dissolved in dichloromethane (2 ml) and to the solution was added
4-t-butylbenzylisothiocyanate (155 mg), followed by stirring at
room temperature for 1 hour. The resulting mixture was concentrated
under reduced pressure and the obtained residue was
column-chromatographed (ethyl acetate/hexane={fraction (1/3)}) to
yield the compound 17-1 (120 mg, 65%).
[0451] .sup.1H-NMR(300 MHz, CD.sub.3OD): .delta. 7.23-7.35 (t, 2H,
J=7.4 Hz), 7.18-7.21 (d, 2H, J=8.5 Hz), 6.65 (d, 1H, J=2.2 Hz),
5.97-5.98 (d, 2H, Jo 2.0 Hz), 4.61 (br, 4H), 1.29 (s, 9H)
EXAMPLE 124
[0452] Synthesis of
1-(4-t-butylbenzyl)-3-(1-methyl-1H-pyrrol-2-yl)methylt- hiourea
(17-2) 229
[0453] Step 1: Synthesis of methyl-IH-pyrrol-2-carboxaldehyde
oxime
[0454] Methyl-2-pyrrolecarboxaldehyde (5 g), hydroxylanine
hydrochloride (9.55 g) and sodium acetate (11.28 g) were dissolved
in methanol (100 ml) and the solution was refluxed for 12 hours.
Afire confirmng the completion of the reaction using TLC, the
resulting mixture was purified by colunm-chromatography (ethyl
acetate/hexane=3/1) to yield the compound (5.01 g, 88%) as a brown
solid.
[0455] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.40(s, 1H),
7.31(m, 1H), 6.70(m, 1H), 6.23(m, 1H), 3.74(s, 3H)
[0456] Step 2: Synthesis of
(1-methyl-1H-pyrrol-2-yl)methylamine
[0457] Sodium borohydride (310 mg) was dried under vacuum and
anhydrous tetrahydrofuran (30 ml) was added thereto through an
injector, followed by adjusting the temperature down to -15.degree.
C. To the mixture at -15.degree. C. was added a solution of
methyl-1H-pyrrol-2-carboxaldehyde oxime (500 mg) and nickel (II)
chloride hexahydrate (catalytic amount) in anhydrous methanol (30
ml) and the mixture was stirred, followed by stirring at room
temperature for 12 hours. After confiring the completion of the
reaction, the resulting mixture was filtered and the obtained brown
oil was purified by column-chromatography (ethyl acetate) to yield
(1-mehtyl-1H-pyrrol-2-yl)methylamine (275 mg, 62%) as solid.
[0458] 1H NMR (300 MHz, CDCl.sub.3): .delta. 6.63(m, 1H), 6.11(m,
2H), 3.94(m, 2H), 3.72(brs, 2H), 3.64(s, 3H)
[0459] Step 3: Synthesis of
1-(4-t-butylbenzyl)-3-(1-methyl-IH-pyrrol-2-yl- )methylthiourea
(17-2)
[0460] (1-methyl-1H-pyrrol-2-yl)rnethylarnine (65 mg) and
4-t-butylbenzylisothiocyanate (120 mg) were dissolved in ethyl
acetate (30 ml) and the solution was stirred for 12 hours. After
the completion of the reaction, the resulting mixture was purified
by column-chromatography (ethyl acetate/hexane={fraction (1/3)}) to
yield the compound 17-2 (140 mg, 75%)
[0461] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.36(m, 211),
7.19(m, 2H), 6.58(m, 1H), 6.18(brs, 1H), 6.01(m, 2H), 5.69(brs,
1H), 4.63(d, 2H, J=2.1 Hz), 4.52(d, 2H, J-2.4 Hz), 3.52(s, 3H),
1.31(s, 9H)
EXAMPLE 125
[0462] Synthesis of
1-(1-methyl-1H-pyrrol-2-ylmethyl)-3-phenethylthiourea (17-3)
230
[0463] (1-methyl-1H-pyrrol-2-yl)methylamine (65 mg) and
(2-isothiocyanatoethyl)benzene (100 mg) were dissolved in ethyl
acetate (20 ml) and the solution was stirred for 12 hours. After
the completion of the reaction, the resulting mixture was purified
by column-chromatography (ethyl acetate/hexane={fraction (1/3)}) to
yield the compound 17-3 (97 mg, 60%) as a brown liquid.
[0464] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.25(m, 5H),
6.60(m, 1H), 6.02(m, 1H), 5.97(s, 1H), 4.51(brs, 2H), 3.69(brs,
2H), 2.87(t, 2H, J=6.9 Hz)
EXAMPLE 126
[0465] Synthesis of
1-(4-t-butylbenzyl)-3-(5-nitrothiophen-2-ylmethyI)thio- urea (17-4)
231
[0466] Step 1: Synthesis of 5-nitrothiophen-2-carboxaldehyde
oxime
[0467] 5-Nitrothiophen-2-carboxaldehyde oxime (yield: 85%, pale
yellow solid) was synthesized according to the similar procedure as
described in Step 1 of Example 124 except that
5-nitrothiophen-2-carboxaldehyde was usded as a starting
material.
[0468] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.21(s, 1H),
7.91(d, 1H, S=2.1 Hz), 7.85(d, 1H, J=2.25 Hz), 7.76(s, 1H), 7.26(s,
1H), 7.11(d, 1H, J=2.1 Hz)
[0469] Step 2: Synthesis of (5-nitrothiophen-2-yl)methylanine
[0470] Sodium borohydride (132 mg) was dried under vacuum and then
anhydrous tetrahydrofiuran (30 ml) was added thereto through an
injector, followed by adjusting the temperature down to -15.degree.
C. To the mixture at -15.degree. C. was added a solution of
5-nitrothiophen-2-carbo- xaldehyde oxime (200 mg; synthesized in
Step 1) and nickel chloride (II) hexahydrate (catalytic amount) in
anhydrous methanol (20 ml), and the mixture was stirred for 12
hours. After confir g the completion of the reaction, the resulting
mixture was filtered to obtain the compound as a brown liquid.
[0471] Step 3: Synthesis of
1-(4-t-butylbenzyl)-3-(5-nitrotbiophen-2-ylmet- hyl)thiourea
(17-4)
[0472] The compound 17-4 (yield: 40%, yellow solid) was synthesized
by reacting the compound prepared in Step 2 with
4-t-butylbenzylisothiocyana- te according to the similar procedure
as described in Step 3 of Example 124.
[0473] .sup.1H NMR (309 MHz, CDCl.sub.3): .delta. 7.71(d, 1H,
J=1.95 Hz), 7.37(m, 2H), 7.23(m, 2H), 6.85(d, 1H, J=1.95 Hz),
6.59(brs, 1H), 6.30(brs, 11), 4.96(d, 2H, 33 Hz), 4.55(brs, 2H),
1.29(s, 9H)
EXAMPLE 127
[0474] Synthesis of
1-(4-t-butylbenzyl)-3-(2-methyl-pyridin-3-ylmethyl)thi- ourea
(18-5) 232
[0475] Step 1: Synthesis of(2-methylpyridin-3-yl)methanol
(18-2)
[0476] Ethyl 2-methylnicotinate 18-1 (257 mg) was mixed with
dichloromethane (4 ml) and to the mixture at -78.degree. C. was
added dropwise 1 M diisobutyl aluminium hydride (4 ml), followed by
stirring for 1 hour. The reaction was quenched with methanol and to
the mixture was added aqueous Rochel solution (20 ml), followed by
stirring for 2 hours. The resulting mixture was extracted with
dichloromethane, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was
column-cbromatographed (ethyl acetate/hexane=1/1) to yield the
compound 18-2 (166 mg, 87%).
[0477] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 8.34 (d, 1H, J=3.4
Hz), 7.74 (d, 1H, J=7.6 Hz), 7.15 (dd, 1H, J=5.1 Hz, J=7.8 Hz),
4.70 (s, 21), 3.21 (br, 1H), 2.51 (s, 3H)
[0478] Step 2: Synthesis of
(2-methylpyridin-3-yl)methylariinophthalimide (18-3)
[0479] Compound 18-2 (166 mg) prepared in Step 1 was dissolved in
tetrahydrofuran (4 ml) and to the solution were added phthalimide
(401 mg) and triphenylphospbine (716 mg), followed by adding
diethylazodicarbonate (0.24 ml) thereto and stirring for 30
minutes. After the completion of the reaction, the resulting
mixture was concentrated under reduced pressure and the obtained
residue was column-chromatographed (ethyl acetate/hexane=1/1) to
yield the compound 18-3 (300 mg, 88%).
[0480] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 8.40 (dd, 1H,
J=1.7 Hz, J=3.2), 7.87-7.83 (m, 2H), 7.76-7.72 (m, 2H), 7.61 (d,
1H, J=6.6 Hz), 7.10 (dd, 1H, J 4.9 Hz, J=7.8 Hz) 4.80 (s, 2H), 2.72
(s, 3H)
[0481] Step 3: Synthesis of
1-(4-t-butylbenzyl)-3-(2-methylpyridin-3-ylmet- hyl)thiourea
(18-5)
[0482] The compound 18-3 (19 mg) prepared in Step 2 was dissolved
in ethanol and to the solution was added a drop of methylamine.
After stirring the mixture at 55.degree. C. for 30 hours,
t-butylbenzylisothiocyanate (62 mg) was added thereto, and the
mixture was stirred at room temperature for 1 hour. The resulting
mixture was concentrated under reduced pressure and the obtained
residue was column-chromatographed
(methanol/dichloromethane={fraction (1/10)}) to yield the compound
18-5 (26.2 mg, 100%).
[0483] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 8.56-8.55 (m, 11),
8.37-8.30 (m, 1H), 7.75-7.67(m, 1H), 7.40-7.10 (m, 4H), 4.74 (s,
2H), 4.44 (s, 2H), 3.05 (s, 3H), 1.30 (s, 9H)
EXAMPLE 128
[0484] Synthesis of 1-(1H-indazol-5-yl)-3-phenethylthiourea (19-1)
233
[0485] Step 1: Synthesis of 5-amuio-1H-indazole
[0486] 5-Nitro-1H-indazole (20 mg) was dissolved in methanol (1 ml)
and to the solution was added a catalytic amount of
palladium/carbon, followed by stirring at room temperature under
hydrogen gas atmosphere for 30 minutes. The resulting mixture was
diluted with ether, filtered through celite, and then concentrated
under reduced pressure to yield 5-amino-1H-indazole (16 mg,
100%).
[0487] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.78 (s, 1H), 7.32
(d, 1H, J=8.7 Hz), 7.01-6.95 (m, 2H)
[0488] Step 2: Synthesis of 1-(1H-indazol-5-yl)-3-phenethylthiourea
(19-1)
[0489] 5-Amino-1H-indazole (9 mg) prepared according to the same
procedure as described in Step 1 was dissolved in dichloromethane
(1 ml) and the solution was stirred at room temperature for 3
hours. The resulting mixture was concentrated under reduced
pressure and the obtained residue was column-chromatographed
eluting with ethyl acetate/hexane ({fraction (1/2)}) to yield the
compound 19-1 (10 mg, 60%).
[0490] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.99 (d, 1H, J=1.0
Hz), 7.51-7.47 (m, 2H), 7.27-7.13 (m, 6H), 3.78 (t, 2H, J=6.8 Hz),
2.90 (t, 2H, J=7.3 Hz)
EXAMPLE 129
[0491] Synthesis of 1-(4-t-butylbenzyl)-3-(1H-indazolyl)thiourea
(19-2) 234
[0492] Compound 19-2 (25 mg, 65%) was synthesized using
5-amino-1H-indazole (15 mg) and t-butylbenzylisothiocyanate (30 mg)
according to the similar procedure as described in Step 2 of
Exmaple 128.
[0493] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.99(s, 1H), 7.65
(s, I), 7.50 (d, 1H, J-- 8.8 Hz), 7.33-7.21 (m, 5H), 4.73 (brs,
2H), 1.27 (s, 9H)
EXAMPLE 130
[0494] Synthesis of
1-(4-t-butylbenzy1)-3-(2-fluoro-4-methanesulfonyloxybe-
nzyl)thiourea (20-2a) 235
[0495] Step 1: Synthesis of
3-fluoro-4-(N-t-butyloxycarbonylaminomethyl)ph- enol (20-1a) and
3-fluoro-4-(N-t-butyloxycarbonylainomethyl)phenol
t-butyloxycarbonyl ether (20-1b)
[0496] 2-Fluoro-4-hydroxybenzonitrile (686 mg), nickel chloride
(I1) (1.18 g) and Boc.sub.2O (2.18 mg) were dissolved in methanol
(40 ml) and the solution was cooled to 0.degree. C. To the solution
was slowly added sodium borohydride (1.32 g), and the mixture was
stirred at 0.degree. C. for 10 minutes and then at room temperature
for 24 hours. The resulting mixture was concentrated under reduced
pressure and to the concentrate were added ethyl acetate (60 ml)
and sodium borohydride (300 mg), followed by filtering. The
filtrate was extracted twice with ethyl acetate. The total filtrate
was concentrated under reduced pressure, and then purified by
column-chromatography (hexane/ethyl acetate=3/1) to yield the
compound 20-1a (134 mg, 11 I/o) and 20-1b (710 mg, 42%). 20-1a:
[0497] .sup.1H NMR (300 MHz, CDCl.sub.3) 6 7.11(t, J=8.2 Hz, 1H),
6.62(bs, 1H), 6.61(d, J=9.6 Hz, 2H), 4.91(bs, 1H), 4.24(d, J=4.8
Hz, 2H), 1.46(s, 9H) 20-1b:
[0498] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.0 7.37(t, J=8.3 Hz,
11), 6.93(m, 2H), 4.88(bs, 11), 4.32(d, J=5.7 Hz, 2H), 1.55(s, 9H),
1.44(s, 9H)
[0499] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-(2-fluoro-4-methanesulfo-
nyloxybenzyl)thiourea (20-2a)
[0500] Compound 20-1a (134 mg) prepared in Step 1 was dissolved in
dichloromethane (2 ml) and to the solution at 0.degree. C. were
added dropwise methanesulfonyl chloride (44 Al) and pyridine (45
.mu.l), followed by stirring at room temperature for 24 hours. The
resulting mixture was concentrated under reduced pressure and the
obtained residue was purified by column-chromatography
(hexane/ethyl acetate=3/1) to obtain methanesulfonyl compound (55
mg, 31%). The obtained compound was dissolved in dichlorormethane
(2.0 ml) and the solution was cooled to 0.degree. C., followed by
adding trifluoroacetic acid (100 .mu.l) thereto and stirring for 2
hours. The resulting mixture was concentrated under reduced
pressure and dissolved in dimethylformamide (5.0 ml). To the
solution was added triethylamine (30 .mu.l) and the mixure was
stirred for 1 hour. To the obtained solution was added
4-t-butylbenzylisothiocyan- ate (40 mg) and the mixture was stirred
at room temperature for 18 hours. The resulting mixture was
concentrated under reduced pressure and the obtained residue was
purified by colum-chromatography (hexane/ethyl acetate=2/1) to
yield the compound 20-2a (61 mg, 85%).
[0501] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.43(t, J=8.7 Hz,
1H), 7.37(d, J=8.1 Hz, 2H), 7.22(d, J=8.1 Hz, 2H), 7.02(m, 2H),
6.20(bs, 1H), 6.00(bs, 1H), 4.79(d, J=5.4 Hz, 211), 4.53(d,
J=4.2ffz, 211), 3.16(s, 311), 1.31(s, 9H).
EXAMPLE 131
[0502] Synthesis of
1-(4-t-butylbenzyl)-3-(2-fluoro-4-hydroxy)thiourea (20-2b) 236
[0503] The compound 20-1b (710 mg) prepared in Step 1 of Example
130 was dissolved in dichloromethane (10 ml) and the solution was
cooled to 0.degree. C., followed by adding trifluoroacetic acid
(1.0 ml) thereto and stirring for 2 hours. The resulting mixture
was concentrated under reduced pressure and part (211 mg) of the
obtained residue was dissolved in dimethylformamide (5.0 ml). To
the solution was added triethylamine (120 Ag) and the mixture was
stirred for 1 hour. To the obtained solution was slowly added
4-t-butylbenzylisothiocyanate (170 mg) and the mixture was stirred
at room temperature for 18 hours. The resulting mixture was
concentrated under reduced pressure and purified by
colurn-nchromatography (hexane/ethyl acetate 1/1) to yield the
compound 20-2b (196 mg, 68%).
[0504] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.35(d, J=8.4 Hz,
2H), 7.20(d, J=8.4 Hz, 2H), 7.13(t, J=8.4 Hz, 1H), 6.54(m? 2H),
6.08(bs, 1H), 6.02(bs, 1H), 5.75(bs, 1H), 4.59(m, 4H), 1.31(s,
9H)
EXAMPLE 132
[0505] Synthesis of
1-(4-t-butylbenzyl)-3-[(6-methanesulfonylanopyridin-2--
yl)methyl]thiourea (21-7) 237
[0506] Step 1: Synthesis of
2,2-dimethyl-N-(6-methyl-2-pyridinyl)propaneam- ide (21-1)
[0507] 2-amino-6-picoline (26 g) was dissolved in dichloromethane
(280 ml) and the reactor was cooled to 0.degree. C., followed by
adding triethylamine (30. g) thereto. To the obtained solution was
slowly added dropwise a solution of trimethylacetylchloride (31.8
g) in dichloromethane (20 ml) and the mixture was stirred at room
temperature for 3 hours. The resulting mixture was filtered, washed
with water, dried over anhydrous magnesium sulfate, concentrated
under reduced pressure and then crystallized
(dichloromethane/petroleum ether) to yield a pale yellow solid (38
g, 82%).
[0508] Step 2: Synthesis of
N-[6-(bromomethyl)-2-pyridinyl]-2,2-dimethylpr- opaneamide
(21-2)
[0509] 2,2-dimethyl-N-(6-methyl-2-pyridinyl)propaneanide (21-1) (32
g) and N-bromosuccinimide (29.6 g) were added to carbon
tetrachloride (300 ml) and to the mixture was added AIBN (15 mg),
followed by reluxing for 20 hours under light emitted by 500 W
lamp. The resulting mixture was cooled to room temperature,
filtered, and concentrated under reduced pressure. The residue was
purified by column-chromatography (hexane/ethyl acetate=10/1) to
yield the compound 21-2 (1.94 g, 5%) as a pure white solid.
[0510] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 8.20-8.17(m, 1H),
8.00(brs, 1H), 7.72-7.66(m, 1H), 7.16-7.13(m, 1H), 4.42(s, 2H),
1.34(s, 9H)
[0511] Step 3: Synthesis of
N-[6-{(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-
methyl}-2-pyridinyl]-2,2-dimethylprop aneamide (21-3)
[0512] N-[6-(bromomethyl)-2-pyridinyl]-2,2-dimnethylpropaneamide
(21-2) (1.9 g) was dissolved in dimethylformamide (20 ml) and to
the solution was added potassium phthalimide (1.43 g), followed by
stirring at room temperature for 24 hours. The resulting mixture
was concentrated under reduced pressure and extrated with water and
dichloromethane. An organic layer was concentrated under reduced
pressure to yield the compound 21-3 (2.27 g, 96%) as a bright
yellow solid. I
[0513] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 8.15-8.12(m, 1H),
7.92-7.74(m, 4H), 7.66-7.60(m, 1H), 7.00-6.97(m, 1H), 4.90(s, 2M,
1.29(s, 9H)
[0514] Step 4: Synthesis of
2-[(2-amino-6-pyridinyl)methyl]-1H-isoindol-1,- 3(2H)-dione
(21-4)
[0515] N-[6-{(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl}
-2-pyridinyl]-2,2-dimethylpropaneamide 21-3 was dissolved in
ethanol (20 ml) and to the solution was added concentrated sulfaric
acid (2 ml), followed by refluxing for 6 hours. The obtained
solution was basified with ammonia solution, extracted with
dichloromethane, and then dried over anhydrous magnesium sulfate.
The residue was concentrated under reduced pressure and purified by
column-chromatography (hexane/ethyl acetate=1/1) to yield the
compound 21-4 (400 mg, 23%) as a pale yellow solid.
[0516] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.90-7.71(m, 41),
7.38-7.32(m, 1H), 6.59-6.56(m, 1H), 6.37-6.33(m, 1H), 4.83(s, 2H),
4.36(brs, 2H)
[0517] Step 5: Synthesis of
2-[(2-methanesulfonylamino-6-pyridinyl)methyl]- -1H-isoindol-1,3
(2H)-dione (21-5)
[0518] The compound 21-4 (200 mg) prepared in Step 4 was dissolved
in dichloromethane (10 ml) and to the solution were added
triethylamine (130 .mu.l) and methanesulfonyl chloride (67 a),
followed by stirring at room temperature for 24 hours. The
resulting mixture was extracted with water and dichloromethane,
dried, concentrated under reduced pressure, and then crystallized
(dichloromethane/petroleum ether) to yield the compound 21-5 (260
mg, 99%) as a white solid.
[0519] Step 6: Synthesis of
1-(4-t-butylbenzyl)-3-[(2-methanesulfonylamino-
-6-pyridinyl)methyi]thiourea (21-7)
[0520] The compound 21-5 (220 mg) prepared in Step 5 was dissolved
in methanol (5 ml) and to the solution was added hydrazine hydrate
(270 u), followed by stirring at room temperature for 2 hours. The
obtained reaction solution was concentrated under reduced pressure
to obtain the compound 21-6. The compound 21-6 (690 mg) was
dissolved in dimethylfornamide (20 ml) and to the solution was
added 4-t-butylbenzylisothiocya-nate (370 mg), followed by stirring
at 100.degree. C. for 7 hours. The reaction mixture was
concentrated and purified by column-chromatography hexaneletliyl
acetate={fraction (1/2)}) to yield the compound 21-7 (58 mg, 23%)
as a green foamy solid.
[0521] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.69-7.63(m, 1H),
7.42-7.38(m, 2H), 7.31-7.25(m, 3H), 7.04-6.65(m, 3H), 4.76-4.60(m,
4H), 3.07(s, 3H), 1.31(s,9H)
EXAMPLE 133
[0522] Synthesis of (4-t-butylbenzyl)thiocarbainic acid
(1-methyl-4-nitro-1-pyrrol-2-yl)methyl ester (22-3) 238
[0523] Step 1: Synthesis of
N-methyl-4-nitro-pyrrol-2-carboxaldehyde (22-1)
[0524] N-methylpyrrol-2-carboxaldehyde (5 g) was dissolved in
anhydrous acetic acid (50 ml), and to an ice-cold of the solution
was slowly added dropwise nitric acid (1.84 ml) with stirring. The
mixture was stirred at this temperature for I hour, and then at
room temperature for 18 hours. After confiing the completion of the
reaction, to the mixture was added an ice-water (200 ml), followed
by slowly adding solid sodium hydroxide (20 g) thereto and stirring
for 1 hour. The obtained mixture was extracted with ether (150
ml.times.3). The obtained organic layer was washed with aqueous
sodium bicarbonate solution and saturated aqueous sodium chloride
solution, dried over sodium sulfate, and then filtered. The
filtrate was concentrated under reduced pressure and purified by
column-chromatography (ethyl acetatelhexane={fraction (1/4)}) to
yield the compound 22-1 (3.5 g, 49.6%).
[0525] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.9.63(s, 1H),
7.68(s, 1H), 7.43(s, 1H), 4.03(s, 3H)
[0526] Step 2: Synthesis of
2-hydroxymethyl-N-methyl-4-nitro-pyrrole (22-2)
[0527] Compound 22-1 (550 mg) was dissolved in anhydrous
tetrahydrofuiran (30 ml) and cooled to 0.degree. C. To the solution
was slowly added dropwise 1M borane-tetrahydrofaran (3.25 ml),
followed by refluxing at 80.degree. C. for 3 hours. After the
completion of the reaction, the solvent was evaporated under
reduced pressure to be removed, and then the residue was purified
by column-chromatography (ethyl acetate/hexane=2/1) to yield the
compound 22-2 (500 mg, 90%).
[0528] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.51(s, 1H),
6.65(s, 1H), 4.59(s, 2H), 3.75(s, 3H)
[0529] Step 3: Synthesis of (4-t-butylbenzyl)thiocarbamic acid
(1-methyl-4-nitro-1H-pyrrol-2-yl)methyl ester (22-3)
[0530] Compond 22-2 (100 mg) was dissolved in anhydrous
tetrahydrofuran (15 ml) and cooled to 0.degree. C. To the solution
was slowly added sodium hydride (190 mg) with stirring, followed by
stirring for 30 minutes. To the mixture was added
t-butylbenzylisothiocyanate (130 mg), followed by stirring for 6
hours. The solvent was evaporated under reduced pressure to be
removed, and then the residue was diluted with water (20 ml). The
obtained mixture was extracted with ethyl acetate (20 ml.times.3),
dried over magnesium sulfate, and then filtered. The filtrate was
evaporated under reduced pressure and the obtained residue was
purified by column-chromatography (ethyl acetate/hexane={fraction
(1/3)}) to yield the compound 22-3 (130 mg, 56.2%).
[0531] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.7.51(m, 1H),
7.31(m, 3H), 7.10(m, 1H), 6.83(m, 1H), 6.47(brs, 1H), 5.44(s, 2H),
4.71(d, 2H, 35.7 Hz), 3.68(s, 3H), 1.31(s, 9H)
EXAMPLE 134
[0532] Synthesis of
1-(4-t-butylbenzyl)-3-(4-methanesulfonylamino-1-methyl-
-1H-pyrrol-2-yl)thiourea (22-9) 239
[0533] Step 1: Synthesis of 2-cyano-N-methylpyrrole (22-4)
[0534] N-methyl-2-pyrrolcarboxaldehyde (5 g) and hydroxylamine
hydrochloride (3.82 g) were mixed in 1-methyl-2-pyrrolidinone (50
ml) and the mixture was refluxed at 110.degree. C. for 2 hours.
After confiring the completion of the reaction, to the reaction
mixture was slowly added an ice-water (200 ml) and the resulting
mixure was extracted with ethyl acetate (150 ml.times.3), washed
with brine, dried over sodium sulfate, and then filtered. The
filtrate was concentrated under reduced pressure and the obtained
residue was purified by column-chromatography (ethyl
acetate/hexane={fraction (1/4)}) to yield the compound 22-4 (3.5 g,
72%).
[0535] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 6.79(m, 2H),
6.16(m, 1H), 3.78(s, 3H)
[0536] Step 2: Synthesis of 4-nitro-2-cyano-N-methylpyrrole
(22-5)
[0537] Compound 22-4 (1 g) was dissolved in anhydrous acetic acid
(100 ml), and cooled to 0.degree. C. To the solution was slowly
added dropwise nitric acid (380 .mu.l) with stirring, followed by
stirring at the same temperature for 1 hour and subsequently at
room temperature for 18 hours. After confirming the completion of
the reaction, to the mixture was added an ice-water (200 ml),
followed by slowly adding solid sodium hydroxide (20 g) thereto and
stirring for 1 hour. The obtained mixture was extracted with ether
(50 ml.times.3). The obtained organic layer was washed with aqueous
sodium bicarbonate solution and saturated aqueous sodium chloride
solution, dried over sodium sulfate, and then filtered. The
filtrate was concentrated under reduced pressure and purified by
column-chromatography (ethyl acetate/hexane={fraction (1/3)}) to
yield the compound 22-5 (1.05 g, 73.7%).
[0538] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.65(s, 11T),
7.32(s, 1H), 3.88(s, 3H)
[0539] Step 3: Synthesis of 2-cyano-4-amino-N-methylpyrrole
(22-6)
[0540] Compound 22-5 (500 mg) and 10% palladium/carbon (50 mg) were
poured into the reactor and dissolved in methanol (10 ml), and then
reacted under hydrogen gas atmosphere for 2 hours. After confinning
the completion of the reaction, the resulting mixture was filtered
through celite, and the filtrate was concentrated under reduced
pressure and purified by columu-chromatography (ethyl
acetate/hexane=3/1) to yield the compound 22-6 (310 mg, 77.4%).
[0541] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.6.36(d, 1H, 12.1
Hz), 6.30(d, 1H, J=4.2 Hz), 3.66(s, 3H)
[0542] Step 4: Synthesis of
4-methanesulfonylamino-2-cyano-N-methylpyrrole (22-7)
[0543] Compound 22-6 (310 mg) was dissolved in dichloromethane (30
ml) and cooled to 0.degree. C. To the solution were added
triethylamine (430 .mu.l) and methanesulfonyl chloride (210 .mu.l)
successively through an injector, followed by stirring at room
temperature for 24 hours. The resulting mixture was diluted with 1
N aqueous hydrochloric acid, and an organic layer was dried over
magnesium sulfate and filtered. The filtrate was concentrated under
reduced pressure and the obtained residue was purified by
column-chromatography (ethyl aceate/hexane=1/1) to yield the
compound 22-7 (400 mg, 78.5%)
[0544] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 6.78(d, 1H, J=1.8
Hz), 6.53(d, 1H, J=1.8 Hz), 5.95(brs, 1H), 3.92(s, 3H), 2.97(s,
3H)
[0545] Step 5: Synthesis of
(4-methanesulfonylamino-1-methyl-1H-pyrrol-2-y- l)methylamine
(22-8)
[0546] Compound 22-7 (150 mg) and 10% palladiuni/carbon (catalytic
amount), together with methanol (10 ml), were poured into reactor
and the reactor was filled with hydrogen gas, followed by stirring
at room temperature for 24 hours. After the completion of the
reaction, the resulting mixture was filtered through celite and
concentrated under reduced pressure. The following procedure was
carried out using the obtained residue which was not purified.
[0547] Step 6: Synthesis of
1-(4-t-butylbenzyl)-3-(4-methanesulfonylamino--
1-methyl-1H-pyrrol-2-yl)thiourea (22-9)
[0548] The compound 22-8 (95 mg) prepared in Step 5 and
4-t-butylbenzylisothiocyanate (96 mg) were added to ethyl acetate
(20 ml) and the mixture was stirred for 16 hours. The resulting
mixture was concentrated under reduced pressure and the obtained
residue was purified by column-chromatography (ethyl
acetate/hexane=3/2) to yield the compound 22-9 (105 mg, 55%).
[0549] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.7.37(d, 2H, J=8.1
Hz), 7.22(d, 2H, J=8.1 Hz), 6.61(d, 1H, J=1.8 Hz), 5.95(d, 1H,
J=2.1 Hz), 6.26(brs, 1H), 5.87(brs, 1H), 5.77(brs, 1H), 4.64(d, 2H,
J=4.8 Hz), 4.54(d, 2H, J=3.9 Hz), 3.48(s, 3H), 2.91(s, 3H), 1.31(s,
9H)
EXAMPLE 135
[0550] Synthesis of
1-(4-t-butylbenzyl)-3-[(4-methanesulfonylaminomethyl)p-
henyl]thiourea (23-2) 240
[0551] Step 1: Synthesis of
(4-methanesulfonylaminomethyl)-1-nitrobenzene (23-1)
[0552] 4-nitrobenzylamine hydrochloride (3.77 g) was dissolved in
dichloromethane (20 ml) and to the solution at 0.degree. C. was
added triethylamine (6.14 ml), followed by adding dropwise
methanesulfonyl chloride (1.7 ml) thereto and stirring at room
temperature for 23 hours. Afier the completion of the reaction, the
resulting mixture was extracted with water and dichloromethane,
concentrated under reduced pressure, and then crystallized
(dichloromethane/petroleum ether) to yield an ocherous solid (1.2
g, 26%).
[0553] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-[(4-methanesulfonylarnin-
omethyl)phenyl]thiourea (23-2)
[0554] The compound 23-1 prepared in Step 1 was dissolved in ethyl
acetate (30 ml) and to the solution was added tin (II) chloride
dihydrate (6.1 g), followed by refluxing at 50.degree. C. for 2
hours. After allowed to cool down to room temperature, the
resulting mixture was basified with saturated aqueous sodium
bicarbonate solution, washed with water and brine, dried, and then
concentrated under reduced pressure to obtain a yellow solid (610
mg, 59%). The obtained compound (107 mg), which was not purified,
was dissolved in acetonitrile (10 ml) and to the solution were
added triethylamine (100 .mu.l) and 4-t-butylbenzylisothiocyanate
(110 mg), followed by refluxing for 24 hours. The resultant mixture
was concentrated under reduced pressure and purified by
column-chromatography (hexane/ethyl acetate={fraction (1/2)}) to
yield the compound 23-2 (73 mg, 34%) as a solid.
[0555] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.84(brs, 1H),
7.46-7.18(m, 8H), 6.26(brs, 1H), 5.00-4.81(m, 3H), 4.31-4.28(m,
2H), 2.92(s, 3H), 1.29(s,911)
EXAMPLE 136.about.EXAMPLE 141
[0556] Compounds of Example 136.about.Example 141, which are shown
in the Scheme 24, were synthesized according to the similar
procedure as described in Example 76 or Example 77, and properties
and spectral data thereof are shown in below table.
14 241 Examples Compounds R = Types Spectral deta 136 24-1 242 A
.sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.39-7.26(m, 9H),
5.55(brs, 1H), 4.81(d, 2H, J=4.8Hz), 3.83-3.79(m, 4H), 3.53(s, 2H),
2.51-2.47(m, 4H), 1.32(s, 9H) 137 24-2 243 B .sup.1H NMR(300MHz,
CDCl.sub.3): .delta. 7.33-7.19(m, 10H), 5.40(brs, 1H), 3.97-3.90(m,
2H), 3.72-3.69(m, 4H), 3.52(s, 2H), 2.94(t, 2H, J=6.9Hz),
2.46-2.42(m, 4H), 1.32(s, 9H) 138 24-3 244 A .sup.1H NMR(300MHz,
CDCl.sub.3): .delta. 8.34-8.32(m, 1H), 7.40-7.26(m, 5H), 6.55(t,
1H, J=4.5Hz), 5.57(brs, 1H), 4.85(d, 2H, J=4.2Hz), 3.96-3.94(m,
8H), 1.32(s, 9H) 139 24-4 245 A .sup.1H NMR(300MHz, CDCl.sub.3):
.delta. 8.19-8.16(m, 1H), 7.53-7.26(m, 5H), 6.68-6.56(m, 2H),
5.58(brs, 1H), 4.85(d, 2H, J=4.8Hz), 4.04-4.00(m, 4H), 3.74-3.70(m,
4H), 1.32(s, 9H) 140 24-5 246 A .sup.1H-NMR(300MHz, CDCl.sub.3):
.delta. 9.15(s, 1H), 9.10(m, 1H), 7.95(s, 1H), 7.34(d, 2H,
J=8.6Hz), 7.25(d, 2H, J=8.6Hz), 4.84(d, 2H, J=5.6Hz), 1.25(s, 9H)
141 24-6 247 A .sup.1H NMR(CDCl.sub.3): .delta. 7.35(m, 2H),
7.18(m, 4H), 5.62(bs, 1H), 4.92(s, 2H), 4.87(d, 2H, J=2.25Hz),
3.98(m, 2H), 2.94(m, 2H), 1.32(s, 9H) 248 249 250 251 252 253
EXAMPLE 142
[0557] Synthesis of
1-benzy1-1-l4-hydroxy-3-methoxybenzyl)-3-phenethylthio- urea (25-1)
254
[0558] Vaniline (200 mg) and benzylamine (129 mg) were dissolved in
methanol (3 ml) and the solution was stirred for 30 minutes. To the
solution was added a catalytic amount of 10% platinum/carbon to be
subjected to the hydrogenation reaction (I atm) . After the
completion of the reaction, the resulting mixture was filtered and
evaporated under reduced pressure to remove methanol. The obtained
residue was dissolved in dichloromethane (3 ml) and to the solution
was added phenethylisothiocyanate (196 mg, 1.2 mmol), followed by
stirring at room temperature for 5 hours. Then, dichloromethane was
evaporated under reduced pressure and the obtained residue was
column-chromatographed (hexane/ethyl acetate=1/1) to yield the
compound 25-1 (400 mg, 82%) as a white solid.
[0559] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.25 (m, 10H),
6.94 (m, 311), 6.69(m, 2H), 5.69(s, 111), 5.51(t, 11, J=4.68 Hz),
4.88(s, 2H), 4.75(s, 2H), 3.89(m, 2H), 3.75(s, 3I1), 2.78(t, 2H,
J=6.57 Hz): MS (El) m/e 406 [M+]
EXAMPLE 143.about.EXAMPLE 167
[0560] Compounds 25-2.about.25-26 of Example 143- Example 167,
which are shown in the Scheme 25, were synthesized according to the
similar procedure as described in Example 142, and properties and
spectral data thereof are shown in below table.
15 255 Compounds R.sup.M, R.sup.N, Examples No. R.sup.P, m Spectral
data 143 25-2 R.sup.M = --OH .sup.1H NMR(300MHz, CDCl.sub.3):
.delta. 7.20(m, 1H), 6.82(d, R.sup.N = --OCH.sub.3 1H, J=8.04Hz),
6.66(s, 1H), 6.58(d, 1H, J=8.04Hz) R.sup.P = --(CH.sub.2).sub.2Ph
5.59(s, 1H), 5.30(t, 1H), 4.59(s, 2H), 3.88(m, 4H), m = 1 3.81(s,
3H), 2.84(m, 6H); MS(EI) m/e 420[M.sup.+] 144 25-3 R.sup.M = --OH
.sup.1H NMR(300Mhz, CDCl.sub.3): .delta. 7.20(m, 10H), R.sup.N =
--OCH.sub.3 6.83(d, 1H, J=8.04Hz), 6.72(s, 1H), 6.57(d, 1H,
J=8.04Hz) 5.58(s, 2H), 5.21(t, 1H, J=4.62Hz), m = 1 2.82(t, 2H,
J=7.68Hz) 2.51(t, 2H, J=8.55Hz) MS(EI) m/e 434[M.sup.+] 145 25-4
R.sup.M = --OH .sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.19(m,
10H), 6.70(m, R.sup.N = --OCH.sub.3 3H), 5.58(s, 1H) 4.69(s, 2H),
3.79(s, 3H), 3.87(m, R.sup.P = --(CH.sub.2).sub.4Ph 2H), 3.38(m,
2H), 2.84(t, 2H, J=6.6Hz), 2.58(t, 2H, m = 1 J=7.7Hz), 1.55(m, 4H);
MS(EI) m/e 448[M.sup.+] 146 25-5 R.sup.M = --OH .sup.1H NMR(300MHz,
CDCl.sub.3): .delta.7.20(m, 5H), 6.74(m, R.sup.N = --OCH.sub.3 3H),
5.63(s, 1H) 5.36(t, 1H), 4.77(s, 2H), 3.94(m, R.sup.P =
--C.sub.8H.sub.17 2H), 3.85(s, 3H), 3.49(t, 2H, J=7.8Hz), 2.89(t,
2H, m = 1 J=6.57Hz), 1.48(t, 2H), 1.28(m, 2H), 0.90(t, 3H) MS(EI)
m/e 428[M.sup.+] 256 257 258 259
[0561]
16 Compounds R.sup.M, R.sup.N, Examples No. R.sup.P, m Spectral
data 147 25-6 R.sup.M = --OH .sup.1H NMR(300MHz, CDCl.sub.3):
.delta. 6.86(m, 8H), 5.75(s, R.sup.N = --OCH.sub.3 1H), 5.59(s, 1H)
5.35(s, 1H), 4.32(s, 2H), 3.80(s, 3H), R.sup.P = -isopropyl 3.85(m,
3H), 2.74(t, 2H, J=6.71Hz), 1.18(d, 6H); MS m = 1 (EI) m/e
358[M.sup.+] 148 25-7 R.sup.M = --OH .sup.1H NMR(300MHz,
CDCl.sub.3): .delta. 7.07(m, 5H), 6.67(m, R.sup.N = --OCH.sub.3
3H), 5.56(s, 2H) 5.34(m, 4H), 4.37(s, 2H), 3.86(m, R.sup.P =
-cyclohexyl 2H), 3.79(s, 3H), 2.74(t, 2H, J=6.71Hz), 1.43(m, m = 1
10H); MS(EI) m/e 398[M.sup.+] 149 25-8 R.sup.M = --OH .sup.1H
NMR(300MHz, CDCl.sub.3): .delta.7.08(m, 10H), 6.46(m, R.sup.N =
--OH 3H), 6.38(s, 1H) 3.70(t, 2H, J=7.23Hz), 3.42(t, 2H, R.sup.P =
--(CH.sub.2).sub.3Ph J=7.61Hz), 2.78(t, 2H, J=7.32Hz), 1.70(m, 2H);
MS m = 1 (EI) m/e 420[M.sup.+] 150 25-9 R.sup.M = --OH .sup.1H
NMR(300MHz, CDCl.sub.3): .delta.7.21(m, 10H), 6.82(d, R.sup.N =
--OCH.sub.3 1H, J=8.04Hz), 6.64(s, 1H) 6.56(d, 1H, J=7.56Hz),
R.sup.P = --(CH.sub.2).sub.2Ph 5.53(s, 1H), 5.10(m, 1H), 3.87(s,
3H), 3.82(d, 2H, m = 2 J=5.13Hz), 3.63(d, 2H, J=5.13Hz), 2.80(m,
6H); MS (EI) m/e 434[M.sup.+] 151 25-10 R.sup.M = --OH .sup.1H
NMR(300MHz, CDCl.sub.3): .delta.7.28(m, 5H), 6.70(m, R.sup.N =
--OCH.sub.3 3H), 5.56(m, 2H) 5.20(m, 1H), 3.95(m, 2H), 3.88(s,
R.sup.P = -isopropyl 3H), 3.45(m, 1H), 2.94(t, 2H), 2.69(t, 2H,
J=7.53Hz), m = 2 1.18(d, 2H, J=6.57Hz) MS(EI) m/e 372[M.sup.+] 152
25-11 R.sup.M =--OH .sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.18(m,
10H), 6.66(m, R.sup.N = --OCH.sub.3 3H), 5.47(s, 1H) 5.20(m, 1H),
4.77(s, 2H), 3.83(s, R.sup.P = -benzyl 3H), 3.83(m, 2H), 3.54(t,
2H, J=7.68Hz), 2.79(t, 2H, m = 3 J=6.825Hz), 2.46(t, 2H, J=744Hz),
1.82(m, 2H); MS (EI)m/e 434[M.sup.+] 153 25-12 R.sup.M = --OH
.sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.20(m, 10H), 6.69(m,
R.sup.N = --OCH.sub.3 3H), 5.51(s, 1H) 5.07(t, 2H, J=7.30Hz),
3.85(m, 5H), R.sup.P = --(CH.sub.2).sub.2Ph 3.71(t, 2H, J=7.68Hz),
3.33(t, 2H, J=7.80Hz), m = 3 2.84(m, 4H), 2.47(t, 2H, J=7.30Hz),
1.79(m, 2H); MS(EI) m/e448[M.sup.+] 260 261 262 263 264 265 266
[0562]
17 Compounds R.sup.M, R.sup.N, Examples No. R.sup.P, m Spectral
data 154 25-13 R.sup.M = --OH .sup.1H NMR(300MHz, CDCl.sub.3):
.delta.7.22(m, 5H), 6.73(m, R.sup.N = --OCH.sub.3 3H), 5.55(s, 1H)
5.04(t, 1H, J=4.96Hz), 3.88(s, 3H), R.sup.P = --(CH.sub.2)Ph
3.83(m, 2H), 3.48(m, 4H), 3.88(t, 2H, J=6.80Hz), m = 3 2.56(t, 2H,
J=7.58Hz), 2.51(t, 2H, J=7.45Hz), 1.85(m, 4H); MS(EI) m/e
462[M.sup.+] 155 25-14 R.sup.M = --OH .sup.1H NMR(300MHz,
CDCl.sub.3): .delta.7.23(m, 5H), 6.74(m, R.sup.N --OCH.sub.3 3H),
3.84(m, 5H) 3.61(m, 2H), 3.27(m, 2H), 2.87(m, R.sup.P = --H 2H),
2.59(t, 2H, J=7.94Hz), 2.83(n,, 2H); MS(EI) m = 3 m/e 344[M.sup.+]
156 25-15 R.sup.M = --OH .sup.1H NMR(300MHz, CDCl.sub.3):
.delta.7.23(m, 5H), 6.70(m, R.sup.N = --OCH.sub.3 3H), 5.28(s, 2H)
3.86(m, 5H), 3.64(m, 2H), 3.02(s, R.sup.P = --CH.sub.3 3H), 2.92(t,
2H, J=6.69Hz), 2.52(t, 2H, J=7.43Hz), m = 3 1.84(m, 2H); MS(EI) m/e
358[M.sup.+] 157 25-16 R.sup.M = --OH .sup.1H NMR(300MHz,
CDCl.sub.3): .delta.7.28(m, 5H), 6.73(m, R.sup.N = --OCH.sub.3 3H),
5.50(s, 1H) 5.12(m, 1H), 3.91(m, 5H), 3.55(t, R.sup.P =
--C.sub.8H.sub.17 2H, J=7.34Hz), 2.93(m, 2H), 2.53(t, 2H,
J=7.50Hz), m = 3 1.87(m, 2H), 1.44(m, 2H), 1.25(m, 10H), 0.91(m,
3H); MS(EI) m/e 456[M.sup.+] 158 25-17 R.sup.M = --OH .sup.1H
NMR(300MHz, CDCl.sub.3): .delta.7.21(m, 5H), 6.70(m, R.sup.N =
--OCH.sub.3 3H), 3.88(m, 5H) 5.59(m, 2H), 5.25(m, 2H), 3.H(m,
R.sup.P = -isobutyl 4H), 2.75(m, 1H), 2.56(m, 2H), 1.83(m, 2H),
0.86(m, m = 3 2H), 0.79(d, 6H) MS(EI) m/e 400[M.sup.+] 159 25-18
R.sup.M = --OH .sup.1H NMR(300MHz, CDCl.sub.3): 67.26(m, 5H),
6.67(m, R.sup.N = --OCH.sub.3 3H), 5.53(s, m, 2H) 5.02(t, 1H),
3.85(m, 2H), 3.80(m, R.sup.P = -isopropyl 2H) 3.09(t, 2H,
J=8.28Hz), 2.85(t, 2H, J=6.81Hz), m = 3 2.45(t, 2H, J=6.95Hz),
2.72(m, 2H), 1.09(d, 6H); MS (EI) m/e 386[M.sup.+] 160 25-19
R.sup.M = --OH .sup.1H NMR(300MHz, CDCl.sub.3): 67.23(m, 5H),
6.65(xn, R.sup.N = --OCH.sub.3 3H), 5.50(s, 1H) 4.93(m, 2H),
3.85(s, 3H), 3.83(m, R.sup.P = -cyclo- 2H), 3.13(t, 2H, J=7.8Hz),
2.83(t, 2H, J=6.82Hz), hexyl 2.42(t, 2H, J=7.07Hz), 1.65(m, 9H),
1.18(m, 5H); m = 3 MS(EI) m/e 426[M.sup.+] 161 25-20 R.sup.M = --OH
.sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.64(s, 1H), 7.23(m,
R.sup.N = OCH.sub.3 15H), 6.52(m, 3H) 5.48(s, 1H), 5.25(t, 1H,
J=5.0O R.sup.P = --CH(Ph).sub.2 Hz), 3.85(m, 5H), 3.33(t, 2H,
J=8.30Hz), 2.83(t, 2H, m = 3 J=6.823Hz), 2.07(t, 2H, J=4.49Hz),
1.26(m, 2H); MS(EI) m/e 510[M.sup.+] 267 268 269 270 271 272 273
274
[0563]
18 Compounds R.sup.M, R.sup.N, Examples No. R.sup.P, m Spectral
data 162 25-21 R.sup.M = --OH .sup.1H NMR(300MHz, CDCl.sub.3):
.delta.7.17(m, 9H), 6.68(m, R.sup.N = -p-t-butylb 5H), 3.61(m, 2H),
2.81(t, 2H, J=6.83Hz), 2.50(t, 2H, enzyl J=7.44Hz), 1.88(m, 2H),
1.31(s, 9H); MS(EI) m/e m = 3 490[M+] 163 25-22 R.sup.M = --OH
.sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.28(m, 5H), 6.73(m,
R.sup.N = --OH 3H), 6.45(t, 2H, J=8.04Hz) 3.80(m, 4H), 3.05(m,
R.sup.P = -isopropyl 4H), 2.88(m, 2H), 2.54(m, 1H), 2.39(t, 2H,
J=6.83 m = 3 Hz), 1.71(m, 4H), 1.11(d, 6H) MS(EI) m/e 372[M.sup.+]
164 25-23 R.sup.M = --OCH.sub.3 .sup.1H NMR(300MHz, CDCl.sub.3):
.delta.7.23(m, 5H), 6.69(m, R.sup.N = --OCH.sub.3 3H), 5.31(s, 1H)
3.85(m, 5H), 3.H(t, 2H, J=7.32), R.sup.P = -isopropyl 2.85(t, 2H,
J=6.71Hz), 2.46(t, 2H, J=6.83Hz), m = 3 1.75(m, 2H), 1.90(m, 1H),
1.09(d, 6H, J=3.32Hz); MS(EI) m/e 400[M.sup.+] 165 25-24 R.sup.M =
--OH .sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.14(m, 5H), 6.77(m,
R.sup.N = --H 4H), 3.77(m, 7H) 3.10(m, 2H), 2.88(m, 1H), 0.83(m,
R.sup.P = -isopropyl 10H); MS(EI) m/e 356[M.sup.+] m = 3 166 25-25
R.sup.M = --H .sup.1H NMR(300MHz, CDCl.sub.3): .delta.7.23(m, 5H),
6.69(m, R.sup.N = OCH.sub.3 3H), 5.32(m, 1H) 3.77(m, 5H), 3.11(t,
2H, J=7.07 R.sup.P = ---isopropyl Hz) 2.87(t, 2H, J=6.60Hz),
2.49(t, 2H, J=7.20Hz), m = 3 2.73(m, 2H), 1.91(m, 1H), 1.08(d, 6H,
J=6.84Hz); MS(EI) m/e 370[M.sup.+] 167 25-26 R.sup.M = --H .sup.1H
NMR(300MHz, CDCl.sub.3): .delta.7.21(m, 10H), 5.48(m, R.sup.N = --H
1H), 5.038(m, 1H) 3.83(m, 2H), 3.11(t, 2H, J=8.30 R.sup.P =
-isopropyl Hz), 2.89(t, 2H, J=6.83Hz), 2.54(t, 2H, J=7.19Hz), m = 3
1.78(m, 2H), 1.11(d, 2H, J=6.81Hz); MS(EI) m/e 340[M.sup.+] 275 276
277 278 279 280
EXAMPLE 168
[0564] Synthesis of
N-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfonylamino-
phenyl)propionamide (26-3) 281
[0565] Step 1: Synthesis of
(3-fluoro-4-methanesulfonylamino)cinmamic acid methyl ester
(26-1)
[0566] 2-fluoro-4-iodomethanesulfonylaminobenzene 3-2 (200 mg) was
dissolved in dimethylformaamide (16 ml) and to the solution were
added palladium acetate (7.2 mg),
[0567] 1,1'-bis(diphenylphosphino)ferrocene (20 mg), triethylamine
(200 A) and methylacrylate (550 mg), followed by stirring at
60.degree. C. for a day. The reaction mixture was cooled to room
temperature, diluted with dichloromethane (40 ml) and then washed
with water and aqueous hydrochloric acid solution. The obtained
mixture was dried over anhydrous magnesium sulfate, concentrated
under reduced pressure, and then column-chromatographed (ethyl
acetate/hexane 1/1) to yield the compound 26-1 (214 mg, 70%).
[0568] .sup.1H NMR(300MElz, CDCl.sub.3 +CD.sub.3OD): .delta.
7.62(d, 1H, J=16.3 Hz), 7.55(t, 1H, J=8.3 Hz), 7.46(dd, 1H, J-2.0,
11.7 Hz), 7.41(dd, 1H, J=2.0, 8.3 Hz), 6.50(d, 1H, J=15.8 Hz),
3.77(s, 3H), 3.03(s, 3H)
[0569] Step 2: Synthesis of methyl
[0570] 3-(3-fluoro-4-methanesulfonylaminophcnyl)propionate (26-2)
The compound 26-1 (78 mg) prepared according to the same procedure
as described in Step 1 was dissolved in methanol (10 ml) and to the
solution was added a catalytic amount of 10% palladium/carbon,
followed by stirring at room temperature under hydrogen atmosphere
for 2 hours. The resulting mixture was diluted with ether, filtered
through celite, and then concentrated under reduced pressure to
yield the compound 26-2 (68 mg, 86%).
[0571] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.45(t, 1H, J-8.2
Hz), 6.98(d, 2H), 6.46(s, 1H), 3.66(s, 3H), 3.00(s, 3H), 2.91(t,
2H, J=7.6 Hz), 2.60(t, 2H, J=7.6 Hz)
[0572] Step 3: Synthesis of N-(4-t-butylbenzyl)
3-(3-fluoro-4-methanesulfo- nylaminophenyl)propionamide (26-3)
[0573] The compound 26-2 (30 mg) prepared in Step 2 was dissolved
in toluene (4 ml) and to the solution was added
4-t-butylbenzylamine (150 .mu.l), followed by refluxing for 3
hours. The resulting mixture was concentrated under reduced
pressure and the obtained residue was chromatographed on silica gel
column (ethyl acetate/hexane=1/1) to yield the compound 26-3 (28
mg, 58%).
[0574] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.39(t, 1H, J=8.3
Hz) 7.29(d, 2H), 7.07(d, 2H1), 6.95(m, 2H), 6.33(s, 1H), 5.54(s,
1H), 4.31(d, 2H, J=5.6 Hz), 2.93(s, 3H), 2.92(t, 2H, J=7.4 Hz),
2.41(t, 2H, J=7.6 Hz), 1.24(s, 9H)
EXAMPLE 169
[0575] Synthesis of N-(3-fluoro-4-methanesulfonylaminobenzyl)
4-t-butylbenzamide (27) 282
[0576] Hydrochloride salt 3-4 (100 mg) prepared according to the
same procedure as described in Example 13 was dissolved in
dichloromethane (6 ml) and to the solution were added
4-t-butylbenzoylclhloride (85 mg) and triethylamine (60 .mu.l),
followed by stirring at room temperature for 2 hours. The resulting
mixture was concentrated under reduced pressure and the obtained
residue was colunm-chromatographed (ethyl acetate/hexane=1/1) to
yield the compound 27 (110 mg, 72%).
[0577] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.72(d, 2H),
7.49(t, 1H, J=8.0 Hz) 7.43(d, 2H), 7.13(m, 2H), 6.54(s, 1H),
4.59(d, 2H, J=5.9 Hz), 2.93(s, 3H), 2.99(s, 3H), 1.31(s, 9H)
EXAMPLE 170
[0578] Synthesis of
(3-fluoro-4-methanesulfonylaminobenzyl)dithiocarbamic acid
4-t-butylbenzyl ester (28) 283
[0579] The compound 3-4 (15.4 mg) prepared by Example 13 was
dissolved in dimethylformamide (1 ml) and to the solution were
added tetrabutylammonium iodide (67 mg), cesium (I) carbonate (59
mg) and carbon bisulfide (7 Id), followed by stirring at 0.degree.
C. for 1 hour. To the mixture was added 4-t-butylbenzylbromide (34
0) and stirred at room temperature for 1 hour. After the completion
of the reaction, the resulting mixture was concentrated under
reduced pressure and the obtained residue was chromatographed on
silica gel column eluting with ethyl acetate/hexane ({fraction
(1/3)}) to yield the compound 28 (12 mg, 52%).
[0580] .sup.1H NMR(300 MHz, CD.sub.3OD): .delta. 7.43 (t, 1H, J=8.3
Hz), 7.25-7.34 (m, 4H), 7.10-7.16 (t, 2H, J=8.3 Hz), 4.88 (s, 2H),
4.55 (s, 21), 2.97 (s, 3H), 1.30 (s, 9H)
EXAMPLE 171
[0581] Synthesis of 1-(4-t-butylbenzyl)-3-(3-fluorophenethyl)urea
(29) 284
[0582] 4-t-butylbenzylamine (3.2 g) was dissolved in
dichloromethane (10 ml) and to the solution was added triethylamine
(2.79 ml), followed by cooling to 0.degree. C. and slowly adding
dropwise a solution of triphosgene (1.98 g) in dichloromethane (5
ml). The mixture was stirred at room temperature for 5 hours and
water (10 ml) was added thereto. The resulting mixture was
extracted with dichloromethane, dried over anhydrous sodium
sulfate, and then concentrated under reduced pressure. The obtained
residue was purified by column-chromatography (hexane/etliyl
acetate=20/1) to yield 4-t-butylbenzylisocyanate (880 mg) as a
solid. The obtained compound (400 mg) and 3-fluorophenethylamine
(290 mg) were dissolved in dichloromethane (20 ml) and the solution
was stirred at room temperature for 22 hours. The solvent was
removed therefrom and the residue was purified by
columnn-chromatography (hexane/ethyl acetate=4/1) to yield the
compound 29 (400 mg, 58%) as a solid.
[0583] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.35-6.82(m, 8H),
4.91(s, 1H), 4.39(d, 2H, J=5.4 Hz), 3.60-3.48(m, 2H), 2.79(t, 2H,
J=6.9 Hz), 1.31(s,9H)
EXAMPLE 172
[0584] Synthesis of 1-(4-t-butylbenzyl)-3-(2-fluorobenzoyl)thiourea
(30) 285
[0585] Potassium thiocyanate (KSCN) (240 mg) was dissolved in
acetone (5 ml) and the solution was allowed to warm up to
50.degree. C. To the solution was added 2-fluorobenzoylchloride
(330 mg) and the mixture was stirred at 50.degree. C. for 4 hours.
The produced potassium chloride was filtered off and to the
obtained solution was 4-t-butylbenzylamine (330 mg), followed by
stirrig at room temperature for 24 hours. The resulting mixture was
concentrated and the residue was purified by column-chromatography
(hexane/ethyl acetate=5/1) to yield the compound 30 (156 mg, 23%)
as a liquid.
[0586] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 8.18-8.1 1(m, 1H),
7.50-7.07(m, 81), 7.02(brs, 1H), 4.70-4.65(m, 2H), 1.31(s,9H)
EXAMPLE 173
[0587] Synthesis of
N"-cyano-N-(4-t-butylbenzyl)-N'-(2-pyridinylethyl)guan- idine
(31-1) 286
[0588] N-(4-t-butylbenzyl) N'-cyano-S-methylisothiourea (180 mg)
was dissolved in xylene (10 ml) and to the solution was added
2-(2-aminoethyl)pyridine (86 mg), followed by refluxing for 7
hours. The resulting mixture was concentrated under reduced
pressure and the obtained residue was purified by
column-chromatography (acetone/ethyl acetate=1/1) to yield the
compound 31-1 (70 mg, 30%) as a liquid.
[0589] .sup.1H NMR(300MIz, CDCl.sub.3): .delta. 8.01(brs, 1H),
7.62-7.56(m, 1H), 7.39-7.35(m, 2H), 7.26-7.20(m, 3H), 7.14-7.03(m,
211), 6.42(brs, 11H), 4.34(d,2H, J=5.1 Hz), 3.71-3.65(m, 2H),
3.03-2.98(m, 2H), 1.32(s, 9H)
EXAMPLE 174.about.EXAMPLE 178
[0590] Compounds of Example 174.about.Example 178, which are shown
in the Scheme 31+L, were synthesized according to the similar
procedure as described in Example 173, and properties and spectral
data thereof are shown in below table
19 Examples Compounds R = Spectral data 174 31-2 287 .sup.1H
NMR(300MHz, CDCl.sub.3): .delta. 7.38-7.35(m, 2H), 7.27-7.20(m,
1H), 7.13-7.10(m, 2H), 6.95-6.78(m, 3H), 5.53(brs, 1H), 4.77(brs,
1H), 4.23(d, 2H, J=5.4Hz), 3.49-3.42(m, 2H), 2.79(t, 2H, J=6.9Hz),
1.32(s, 9H) 175 31-3 288 .sup.1H NMR(300MHz, CDCl.sub.3): .delta.
7.40-7.35(m, 2H), 7.14-7.10(m, 2H), 7.08-6.99(m, 1H), 6.93-6.86(m,
1H), 6.82-6.77(m, 1H), 5.75(brs, 1H), 4.84(brs, 1H), 4.25(d, 2H,
J=5.4Hz), 3.46-3.39(m, 2H), 2.76(t, 2H, J=6.9Hz), 1.32(s, 9H) 176
31-4 289 .sup.1H NMR(300MHz, CDCl.sub.3): .delta. 7.39-7.35(m, 2H),
7.32-7.23(m, 2H), 7.19-7.16(m, 2H), 7.12-6.98(m, 2H), 5.65(brs,
1H), 5.35(brs, 1H), 4.42(d, 2H, J=6.0Hz), 4.34(d, 2H, J=5.4Hz),
1.32(s, 9H) 177 31-5 290 .sup.1H NMR(300MHz, CDCl.sub.3): .delta.
7.39-7.35(m, 2H), 7.23-7.20(m, 2H), 7.12-7.05(m, 1H), 6.95-6.88(m,
1H), 6.16(brs, 1H), 5.88(brs, 1H), 4.79(d, 2H, J=5.4Hz), 4.52(d,
2H, J=4.8Hz), 1.31(s, 9H) 178 31-6 291 .sup.1H NMR(300MHz,
CDCl.sub.3): .delta. 7.41-7.37(m, 2H), 7.27-7.15(m, 6H), 6.81(brs,
1H), 5.55(brs, 1H), 5.32(brs, 1H), 4.38-4.34(m, 4H), 3.01(s, 3H),
1.31(s, 9H) 292 293 294 295 296
EXAMPLE 179
[0591] Synthesis of
N"-cyano-N-(4-t-butylbenzyl)-N'-(2,6-diluoro-3-methane-
sulfonylaminobenzyl)guanidine (31-7) 297
[0592]
1-(4-t-butylbenzyl)-3-(2,6-difluoro-3-methanestlfonylaminobenzyl)th-
iourea (44 mg) and lead cyanamide (30 mg) were added to ethyl
acetate (10 ml) and the mixture was refluxed for 18 hours. The
resulting mixture was purified by column-chromatogrphy
(hexane/ethyl acetate=1/1) to yield the compound 31-7 (35 mg,
78%).
[0593] .sup.1H NMR (CDCl.sub.3): .delta. 7.47(dt, J=5.7, 8.7 Hz,
1H), 7.37(d, J=8.4 Hz, 2H), 7.21(d, J=8.4 Hz, 2H), 6.90(t, J=8.7
Hz, 1H), 6.67(bs, 1H), 6.28(bs, 1H), 6.16(bs, 1H), 4.78(d, J=5.4
Hz, 2H), 4.55(d, 4.2 Hz, 2H), 3.00(s, 3H), 1.31(s, 9H)
EXAMPLE 180
[0594] Synthesis of
N"-cyano-N-(4-t-butylbenzyl)-N'-(2-fluoro-5-methanesul-
fonylaminobenzyl)guanidine (31-8) 298
[0595] Compound 31-8 was synthesized according to the similar
procedure as described in Example 179.
[0596] .sup.1H NMR(CDCl.sub.3): .delta. 7.34(d, J=8.1 Hz, 2H),
7.28(dd, J=2.4, 6.0 Hz, 1H), 7.20(d, J=8.1 Hz, 2H), 7.18(m, 1H),
6.98(t, J=9.OHz, 1H), 6.48(bs, 1H), 6.34(bs, 1H), 4.74(d, J=5.7 Hz,
2H), 4.56(d, J=4.2 Hz, 2H), 2.95(s, 3H), 1.29(s, 9H)
EXAMPLE 181
[0597] Synthesis of
N"-cyano-N-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]--N'-[1-(-
4-t-butylbenzyl)]guanidine (31-9) 299
[0598]
1-(4-t-butylbenzyl)-3-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]thiourea
(0.2 g) and lead cyanamide (170 mg) were dissolved in ethyl acetate
(20 ml) and the solution was refluxed for 12 hours. After
confirming the completion of the reaction, the resulting mixture
was filtered to remove the yellow solid, and the obtained residue
was concentrated under reduced pressure and purified by
column-chromatography (ethyl acetate/hexane={fraction (2/3)}) to
yield the compound 31-9 (174 mg, 85%) as a yellow solid.
[0599] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.38(d, 2H),
7.21(d, 2H), 7.15(m, 2H), 6.05(d, 1H, J=2.1 Hz), 4.48(m, 2H),
3.86(m, 2H), 2.99(t, 2H, J=6.9 Hz), 1.31(s, 9H)
EXAMPLE 182
[0600] Synthesis of
1-(4-chlorobenzyl)-3-(6-methoxy-1,2,3,4-tetrahydronaph-
thalen-1-yl)thiourea (32-2) 300
[0601] Step 1: Synthesis of 6-methoxy-1
,2,3,4-tetrahydro-naphthalen-1-yla- ine (32-1)
[0602] 6-methoxy-1-tetralone (881 mg) and hydroxylamine
hydrochloride (1.19 g) were dissolved in methanol (50 ml) and to
the solution was slowly added pyridine (645 mg) at room
temperature, followed by stirring for 18 hours. The resulting
mixture was concentrated under reduced pressure. The concentrate
was dissolved in ethyl acetate (30 ml), washed with water (10
ml.times.2) and aqueous saturated copper sulfate solution (10 ml),
dried over magnesium sulfate, and then concentrated under reduced
pressure. The residue was purified by column-chromatography
(hexane/ethyl acetate=3/1) to yield an intermediate material, oxime
(886 mg, 93%).
[0603] The obtained oxime (586 mg) was dissolved in methanol (50
ml) and the solution was cooled to -30.degree. C., followed by
adding nickel(II) chloride hexahydrate (1.46 g) thereto. After the
solid was completely dissolved, to the solution was slowly added
sodium borohydride (1.16 g) and the mixture was stirred at
-30.degree. C. for 30 minutes. Then, the mixture was stirred at
room temperature for 90 minutes and concentrated under reduced
pressure. The obtained residue was dissolved in 10% hydrochloric
acid (30 ml) and the solution was slowly basified with 1 N aqueous
sodium hydroxide solution. The obtained solution was extracted with
ethyl acetate (50 ml.times.3) and the organic layers were
collected. The total organic layer was washed with brine, dried
over magnesium sulfate, concentrated under reduced pressure, and
then purified by column-chromatography
(dichloromethane/methanol=10/1) to yield the compound 32-1 (385 mg,
71%).
[0604] .sup.1H NMR(CDCl.sub.3): .delta. 7.31(d, J=8.7 Hz, 1H),
6.75(dd, J=8.5, 2.4 Hz, 1H), 6.61(d, J=2.4 Hz, 1H), 3.94(t, J=5.4
Hz, 1H), 3.78(s, 3H), 2.75(m, 2H), 1.96(m, 2H), 1.73(bs, 2H),
1.70(m, 2H)
[0605] The similar compounds 32-3 and 32-5 were synthesized
according to the same procedure as described above.
20 301 Examples- Compounds step No. R.sup.R = Spectral data 183-1
32-3 5-OMe .sup.1H NMR(CDCl.sub.3): .delta. 7.17(t, J=7.8Hz, 1H),
7.02(d, J=7.8Hz, 1H), 6.71(d, J=7.8Hz, 1H), 3.97(t, J=5.7Hz, 1H),
3.81(s, 3H), 2.65(m, 2H), 1.94(m, 2H), 1.76(bs, 2H), 1.73(m, 2H).
184-1 32-5 7-OMe .sup.1H NMR(CDCl.sub.3): .delta. 7.00(d, J=8.7Hz,
1H), 6.97(d, J= 3.0Hz, 1H), 6.73(dd, J=8.7, 3.0Hz, 1H), 3.94(t,
J=5.6Hz, 1H), 3.80(s, 3H), 2.70(m, 2H), 2.00(m, 1H), 1.90(m, 1H),
1.80(bs, 2H), 1.77(m, 2H).
[0606] Step 2: Synthesis of
1-(4-chlorobenzyl)-3-(6-methoxy-1,2,3,4-tetrah- ydronaphthalen-
1-yl)thiourea (32-2)
[0607] The compound 32-1 (100 mg) prepared according to the same
procedure as described in Step 1 was dissolved in ethyl acetate (4
ml) and to the solution were added a solution of
4-chlorobenzylisothiocyanate (123 mg) in ethyl acetate (2 ml),
followed by stirring at room temperarure for 18 hours. The obtained
reaction mixture was concentrated under reduced pressure and
purified by column-chromatography (hexane/ethyl acetate=2/1) to
yield the compound 32-2 (201 mg, 99%).
[0608] .sup.1H NMR(DMSO-d.sub.6): .delta. 7.62(d, J=7.5 Hz, 1H),
7.52(bs, 1H), 7.23(d, J=8.4 Hz, 2H), 7.14(d, J=8.4 Hz, 2H),
6.92(bs, 1H), 6.55(d, J=8.7 Hz, 1H), 6.47(s, 1H), 5.30(bs, 1H),
4.50(bs, 2H), 3.53(s, 3H), 2.52(m, 2H), 1.71(m, 1H), 1.55(m,
3H)
[0609] The similar compounds 32-4 and 32-6.about.32-10 were
synthesized according to the same procedure as described above.
21 302 R.sup.R = Compounds R.sup.S = Examples No. R.sup.T =
Spectral data 183 32-4 R.sup.R = 5-OMe .sup.1H NMR(DMSO-d.sub.6):
.delta. 7.85(d, R.sup.T = Cl J=8.0 Hz, 1H), 7.69(bs, 1H), 7.40(d,
J=8.4 Hz, 2H), 7.32(d, J=8.4 Hz, 2H), 7.12(t, J=8.0 Hz, 1H),
6.81(d, J=8.0 Hz, 1H), 5.54(bs, 1H), 4.68(bs, 2H), 3.76(s, 3H),
2.56(m, 2H), 1.88(m, 2H), 1.73(m, 2H). 184 32-6 R.sup.R = 7-OMe
.sup.1H NMR(CDCl.sub.3): .delta. 7.29(d, R.sup.T = Cl J=8.7 Hz,
2H), 7.22(d, J=8.7 Hz, 2H), 6.99(d, J=9.0 Hz, 1H), 6.74(m, 3H),
6.23(bs, 1H), 5.92(bs, 1H), 5.40(bs, 1H), 4.56(bs, 2H), 3.72(s,
3H), 2.67(m, 2H), 2.05(m, 1H), 1.77(m, 3H). 185 32-7 R.sup.R =
5-OMe .sup.1H NMR(acetone-d.sub.6): .delta. 7.38(d, R.sup.T =
t-butyl J=8.4 Hz, 2H), 7.29(d, J=8.4 Hz, 2H), 7.17(bs, 1H), 7.10(t,
J=8.0 Hz, 1H), 7.04(bs, 1H), 6.91(d, J=8.0 Hz, 1H), 6.78(d, J=8.0
Hz, 1H), 5.71(bs, 1H), 4.77(d, J=5.1 Hz, 2H), 3.80(s, 3H), 2.83(t,
J=6.0 Hz, 2H), 1.89(m, 1H), 1.80(m, 3H), 1.30(s, 9H). 186 32-8
R.sup.R = 6-OMe .sup.1H NMR(acetone-d.sub.6): .delta. 7.38(d,
R.sup.T = t-butyl J=8.4 Hz, 2H), 7.29(d, J=8.4 Hz, 2H), 7.21(d,
J=8.4 Hz, 1H), 7.14(bs, 1H), 7.05(bs, 1H), 6.51(dd, J=8.4, 2.4 Hz,
1H), 6.62(d, J=2.4 Hz, 1H), 5.65(bs, 1H), 4.76(d, J=5.4 Hz, 2H),
3.76(s, 3H), 2.73(m, 2H), 2.02(m, 1H), 1.81(m, 3H), 1.31(s, 9H).
187 32-9 R.sup.R = 7-OMe .sup.1H NMR(acetone-d.sub.6): .delta.
7.37(d, R.sup.T = t-butyl J=8.4 Hz, 2H), 7.30(d, J=8.4 Hz, 2H),
7.20(bs, 1H), 7.11(bs, 1H), 6.98(d, J=8.4 Hz, 1H), 6.92(d, J=2.7
Hz, 1H), 6.73(dd, J=8.4, 2.7 Hz, 1H), 5.71(bs, 1H), 4.77(d, J=4.8
Hz, 2H), 3.71(s, 3H), 2.67(m, 2H), 2.06(m, 1H), 1.81(m, 3H),
1.30(s, 9H). 188 32-10 R.sup.R = 6-OMe .sup.1H NMR(CDCl.sub.3):
.delta. 7.34(d, R.sup.S = 7-OMe J=8.1 Hz, 2H), 7.21(d, R.sup.T =
t-butyl J=8.1 Hz, 2H), 6.76(s, 1H), 6.50(d, 1H), 6.32(bs, 1H),
5.96(bs, 1H), 5.40(bs, 1H), 4.52(bs, 2H), 3.80(s, 3H), 3.75(s, 3H),
2.63(m, 2H), 1.92(m, 2H), 1.70(m, 2H), 1.29(s, 9H). 303 32-4 304
32-6 305 32-7 306 32-8 307 32-9 308 32-10
EXAMPLE 189
[0610] Synthesis of
1-(4-t-butylbenzyl)-3-(5-hydroxy-1,2,3,4-tetrahyronaph-
thalen-1-yl)thiourea (32-11) 309
[0611] The compound 32-3 (570 mg) prepared by Step 1 of Example 183
was dissolved in 48% hydrobromic acid (10 ml) and the mixture was
refluxed for 24 hours. The mixture was cooled to room temperature,
and then concentrated under reduced pressure to remove the
hydrobromic acid (residue: 766 mg, 97%). Part (500 mg) of the
residue was dissolved in dimethylformamide (5 ml) and the solution
was cooled to 0.degree. C. To the obtained mixture was added 5 M
sodium hydroxide (800 .mu.l), followed by stirring for 15 minutes
to obtain a solution. To the solution was slowly added a solution
of 4-t-butylbenzylisothiocyanate (421 mg) in dimethylformamide (5
ml) and the mixture was stirred at room temperature for 48 hours.
Then, to the obtained solution was added water and the resulting
mixture was extracted with ether (50 ml.times.3). The extracted
organic layer was collected, washed with 1 N hydrochloric acid,
water and saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and then concentrated under reduced pressure.
The residue was purified by column-chromatography (hexane/ethyl
acetate=2/1) to yield the compound 32-11 (550 mg, 73%). .sup.1H
NMR(acetone-d.sub.6): .delta. 7.38(d, J=8.4 Hz, 2H), 7.29(d, J=8.4
Hz, 2H), 7.15(bs, 1H), 7.03(bs, 1H), 6.95(t, J=7.8 Hz, 1H), 6.81(d,
J=7.8 Hz, 1H), 6.69(d, J=7.8 Hz, 1H), 5.70(bs, 1H), 4.77(d, J=5.1
Hz, 2H), 2.63(t, J=6.0 Hz, 2H), 2.00(m, 1H), 1.81(m, 3H), 1.30(s,
9H)
[0612] The similar compound 32-12 was synthesized according to the
same procedure as described above.
22 310 Compound R.sup.R = Example No. R.sup.T = Spectral data 190
32-12 R.sup.R = 7-OH .sup.1H NMR(CD.sub.3OD): .delta. R.sup.T = Cl
7.32(s, 4H), 6.89(d, J=8.4 Hz, 1H), 6.71(d, J=2.4 Hz, 1H), 6.59(dd,
J=8.4, 2.4 Hz, 1H), 5.54(bs, 1H), 4.75(bs, 2H), 2.65(m, 2H),
2.03(m, 1H), 1.79(m, 3H). 311 32-12
EXAMPLE 191
[0613] Synthesis of
1-(4-t-butylbenzy1)-3-(3-formylchromone)thiourea (33-2) 312
[0614] 2-amino-3-formylchromone 33-1 (100 mg) was dissolved in
anhydrous tetrahydroflran (15 ml) and the solution was stirred. To
the solution was added sdium hydride (15 mg) at 0.degree. C. and
the mixture was stirred for 30 minutes. To the mixture was added
4-t-butylbenzylisothiocyanate (130 mg), followed by stirng for 6
hours. The resulting mixture was neutralized with an iced water and
concentrated under reduced pressure. The residue was extracted with
ethyl acetate (30 ml.times.3), dried over magnesium sulfate, and
then filtered. The filtrate was purified by column-chromatography
(ethyl acetate/hexane=3/2) to yield the compound 33-2 (25 mg,
10%).
[0615] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.8.75(s, 1H),
8.14(m, 1), 7.77(m, 1H), 7.42(m, 6H, 5.73(s, 2H), 1.33(s, 9H)
EXAMPLE 192
[0616] Synthesis of (4-t-butylbenzyl)thiocarbamic
acid--O--(3,5-dimethylpy- razo1-1-ylmethyl)ester (334) 313
[0617] 3,5-dimethylpyrazo1-1-methanol 33-3 (200 mg) and sodium
hydride (42 mg) were dissolved in anhydrous tetrahydrofiran (20 ml)
and the solution was stirred for 1 hour. To the solution was added
4-t-butylbenzylisothioc- yanate (330 mg) and the mixture was
stirred at room temperature for 12 hours. The resulting mixture was
filtered under reduced pressure and the solvent was removed
therefrom. The residue was purified by column-chromatography (ethyl
acetate/hexane={fraction (1/2)}) to yield the compound 33-4 (253
mg, 48%) as a solid.
[0618] .sup.1H NMR (300 MHz, acetone-d.sub.6) .delta. 7.29(m, 4H),
7.09(m, 1H), 6.30(s, 2H), 4.68(d, 2H, J=2.85 Hz), 2.33(s, 3H),
2.22(s, 3H), 1.30(s, 91J)
EXAMPLE 193
[0619] Synthesis of N-(3-fluoro-4-methanesulfonylaminobenzyl)
3-(4-t-butylphenyl)propionamide (34-5) 314
[0620] Step 1: Synthesis of 4-t-butylcinnamic acid ethyl ester
(34-2)
[0621] 4-t-butylbenzaldehyde (34-1) (69 mg) was dissolved in
acetonitrile (16 ml) and to the solution were added
diusopropylethylamine (84 mg) and triethyl phosphonoacetate (117
mg), followed by stirring at room temperature for 1 hours. The
resulting mixture was diluted with dichloromethane (20 ml), washed
with water and aqueous hydrochloric acid solution, dried over
anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The residue was colurun-chromatographed (ethyl
acetate/hexane=1/5) to yield the compound 34-2 (64 mg, 65%)
[0622] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.65(d, 1H, J=16.1
Hz), 7.467.34 (m, 4H), 6.38(d, 1H,J=16.1 Hz), 4.24(q, 2H, J=7.2
Hz), 1.31(m, 121)
[0623] Step 2: Synthesis of ethyl 3-(4-t-butylphenyl)propionate
(34-3)
[0624] The compound 34-2 (64 mg) according to the same procedure as
described in Step 1 was dissolved in methanol (10 ml) and to the
solution was added a catalytic amount of 10% palladium/carbon,
followed by stirring at room temperature under hydrogen gas
atmosphere for 2 hours. The resulting mixture was diluted with
ether, filtered through celite, and then concentrated under reduced
pressure to yield the compound 34-3 (60 mg, 93%)
[0625] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.28(d, 2H, J=8.0
Hz), 7.11(d, 2H, J-8.OHz), 4.11(q, 2H, J=7.1 Hz), 2.90(t, 2H, J=7.6
Hz), 2.59(t, 2H, J=7.6 Hz), 1.29(s, 9H), 1.21(t, 3H, J=6.8 Hz)
[0626] Step 3: Synthesis of
N-(3-fluoro-4-methanesulfonylaminobenzyl)
3-(4-t-butylphenyl)propionamide (34-5)
[0627] The compound 34-3 (60 mg) prepared according to the same
procedure as described in Step 2 was dissolved in 50% aqueous
tetrahydrofuiran solution (10 ml) and to the solution was added
lithium hydroxide (24 mg). The mixture was stirred at room
temperature for 5 hours to hydrolyze the compound 34-3 and the
solvent was removed therefrom. The residue was dissolved in ethyl
acetate and extracted to the obtain the compound 34-4 (43 mg, 81%).
The compound 34-4 was dissolved in benzene (2 ml) and to the
solution was added dropwise oxalyl chloride (100 .mu.l), followed
by refluxing for 2 hours. The reaction mixture obtained by
concentrating the resultant under reduced pressure and
hydrochloride compound 3-4 (67 mg) prepared in Example 13 were
added to dichloromethane (6 ml), and to the mixture was added
triethylamine (60 .mu.l), followed by stirring at room temperature
for 2 hours. The resulting mixture was concentrated under reduced
pressure and the obtained residue was purified by
column-chromatography (ethyl acetate/hexane=1/1) to yield the
compound 34-5 (34 mg, 38%).
[0628] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta. 7.40(t, 1H, J=8.2
Hz) 7.23(d, 2H, J=8.3 Hz), 7.06(d, 2H, J=8.3 Hz), 6.90(m, 2H),
6.49(s, 1H), 5.68(s, 1H), 4.30(d, 2H, J=5.6 Hz), 2.93(s, 3H),
2.89(t, 2H, J=7.6 Hz), 2.47(t, 2H, J=7.4 Hz ), 1.19(s, 9H)
EXAMPLE 194
[0629] Synthesis of
1-(4-t-butylbenzyl)-3-(4-methylaminosulfonylaminobenzy- l)thiourea
(35-2a) 315
[0630] Step 1: Synthesis of
N-t-butyloxycarbony1-4-methylaminosulfonylamin- obenzylamine
(35-1a)
[0631] Sodium hydride (18 mg) was suspended in dimnethylformamide,
and to the suspension was added a solution of
N-t-butyloxycarbony1-p-aminobenzyl- amine (150 mg) and
methylaminosulfamoylchloride (97 mg) in dimethylfonnamide while the
temperature was controlled to 0.degree. C., followed by stirring at
room temperature for 3 hours. The reaction solution was evaporated
under reduced pressure, and the residue was diluted with ethyl
acetate (70 ml), washed with saturated aqueous sodium bicarbonate
solution, water and saturated saline, and then evaporated under
reduced pressrure. The obtained residue was purified by
column-chromatography (hexane/ethyl acetate=5/1) to yield the
compound 35-1a (170 mg, 79%).
[0632] .sup.1H NMR(300 MHz, DMSO): .delta. 7.27(d, 2H, J=8.5 Hz),
7.10(m, 2H), 4.18(s, 2H), 3.29(s, 3H), 1.43(s, 9H)
[0633] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-(4-methylaminosulfonylam- inobenzyl)thiourea
(35-2a)
[0634] The compound 35-1a (170 mg) prepared in Step 1 was dissolved
in anhydrous dichloromethane (4 ml), and to the solution was added
excess trifluoroacetic acid while the temperature was contolled to
0.degree. C., followed by stirring for 30 minutes. The resulting
mixture was evaporated under reduced pressure to remove excess
trifluoroacetic acid and the residue was dissolved in anhydrous
dichloromethane (4 ml). To the solution were added triethylamine
(98 .mu.l) and 4-t-butylbenzylisothiocy- anate (144 mg) and the
mixture was stirred at room temperature for 3 hours. The reaction
solution was evaporated under reduced pressure, and the remained
was diluted with ethyl acetate (70 ml), washed with water and
saturated saline, and then concentrated under reduced pressure. The
obtained residue was purified by column-chromatography
(hexane/ethyl acetate=10/1) to yield the compound 35-2a (157 mg,
69%).
[0635] .sup.1H NMR(300 MHz, MeOH-d.sub.5): .delta.7.33(d, 2H, J=8.5
Hz), 7.17(m, 2H), 4.65(s, 4H), 2.55(s, 31H), 1.25(s, 9H)
[0636] MS AB) m/e 421[M.sup.+1]
EXAMPLE 195
[0637] Synthesis of
1-(4-t-butylbenzyl)-3-(4-N,N-dimethylaminosulfonylamin-
obenzyl)thiourea (35-2b) 316
[0638] Step 1: Synthesis of
N-t-butyloxycarbony1-4-N,N-dimethylaminosulfon- ylaminobenzylamine
(35-1b)
[0639] Compound 35-1b (393 mg, 53%) was synthesized by adding
dimethylsulfamoylchloride (266 ,uQ) and then by being allowed to
warm up to 60.degree. C. according the procedure as described in
Example 194.
[0640] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.7.18(m, 8H),
4.16(s, 4H), 2.77(s, 3H), 1.45(s, 9H)
[0641] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-(4-N,N-dimethylaminosulf-
onylaminobenzyl)thiourea (35-2b)
[0642] Compound 35-2b (337 mg, 65%) was synthesized according to
the similar procedure as described in Example 194.
[0643] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.7.18(m, 8H),
4.56(s, 4H), 3.92(s, 3H), 1.27(s,
[0644] MS (FAB) m/e 435[M.sup.+1]
EXAMPLE 196
[0645] Synthesis of
1-(4-t-butylbenzyl)-3-(4-aminosulfonylanminobenzyl)thi- ourea
(35-2c) 317
[0646] Step 1: Synthesis of
N-t-butyloxycarbony1-4-N-(t-butyloxycarbonylam-
inosulfonyl)aminobenzylamine (35-1c)
[0647] Compound 35-1c (333 mg, 54%) was synthesized by adding
N-(t-butyloxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-
-ylsulfonyl]azanide (464 mg) and then by being allowed to warm up
to 60.degree. C. according the procedure as described in Example
194.
[0648] .sup.1H NMR(300 MHz, DMSO): .delta.7.12(m, 4H), 4.06(d, 2H,
J=5.9 Hz), 1.37(s, 9H), 1.33(s, 9H)
[0649] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-(4-aminosulfonylaminoben- zyl)thiourea
(35-2c)
[0650] Compound 35-2c (257 mg, 69%) was synthesized according to
the similar procedure as described in Example 194.
[0651] .sup.1H NMR(300 MHz, DMSO): .delta.7.18(m, 8H), 4.58(s,
4H1), 1.25(s, 9H) MS (FAB) m/e 407[M.sup.+1]
EXAMPLE 197: Synthesis of
1-(4-t-butylbenzyl)-3-(4-methanesulfonylamino-3--
nitrobenzyl)thiourea (35-5)
[0652] 318
[0653] Step 1: Synthesis of
4-methanesulfonylamino-3-nitrobenzonitrile (35-4)
[0654] 3-nitro-4-aminobenzonitrile (150 mg) and sodium
bistrimethylsilylamide (2 ml) were dissolved in anhydrous
tetrahydrofiran (6 ml), and to the solution was added
methanesulfonic anhydride (191 mg) at 0.degree. C., followed by
stirring for 3 hours. The reaction solution was evaporated under
reduced pressure and the residue was diluted with ethyl acetate (70
ml), washed with diluted aqueous hydrochloric acid solution,
saturated aqueous sodium bicarbonate solution, water and brine, and
then evapoarated under reduced pressure. The obtained residue was
purified by column-chromatogaphy (hexane/ethyl acetate=5/1) to
yield the compound 35-4 (120 mg, 54%)
[0655] .sup.1H NMR(300 MHz, Pyridine-d.sub.5): .delta.8.60(s, 1H),
8.17(d, 1H, J=8.76 Hz), 7.88(dd, 1H, J=1.95, 8.79 Hz), 3.48(s,
3H)
[0656] Step 2: Synthesis of
1-(4-t-butylbenzyl)-3-(4-methanesulfonylamino--
3-nitrobenzyl)thiourea (35-5)
[0657] The compound 35-4 (90 mg) prepared according to the same
procedure as described in Step 1 was dissolved in ahydrous
tetrahydrofuran and to the solution was added borane (1 M, 1.1 ml),
followed by stirring for 6 hours. The resulting mixture was
evaporated under reduced pressure, and the residue was diluted with
ethyl acetate (50 ml), washed with water and brine, and then
evaporated under reduced pressure to obtain anine. The obtained
amine, which was not purified, was dissolved in dichloromethane (2
ml) and to the solution were added triethylamine (57 i) and
4-t-butylbenzylisothiocyanate (8.4 mg) at 0.degree. C., followed by
stirring at room temperature for 3 hours. The reaction solution was
evaporated under reduced pressure. The residue was diluted with
ethyl acetate (70 ml), and washed with water and brine. The solvent
was evaporated under reduced pressure, and then the obtained
residue was purified by column-chromatography (hexane/ethyl
acetate=30/1) to yield the compound 35-5 (56 mg, 33%).
[0658] .sup.1H NMR(300 MHz, CDCl.sub.3): .delta.8.60(s, 1H),
8.17(d, 1H, J=8.76 Hz), 7.88(dd, 1H, J=1.95, 8.79 Hz), 7.40(m, 4H),
4.80(d, 2H, J=5.13 Hz), 4.55(s, 2H), 3.10(s, 3H), 1.27(s, 9H)
[0659] MS (FAB) m/e 451 [.sup.+1]
EXAMPLE 198
[0660] Synthesis of
1-(4-t-butylbenzyl)-3-(1-(4-methanesulfonylphenyI)ethy- l)thiourea
(36-4) 319
[0661] Step 1: Synthesis of 4-methanesulfonylaminoacetophenone
(36-1)
[0662] 4-aminoacetophenone (300 mg) was dissolved in
dichloromethane, and to the solution were added methanesulfonic
anhydride (2.44 mimol) and pyridine (53.85 .mu.l) at 0.degree. C.,
followed by stirring at room temperature for 3 hours. After
confirng the completion of the reaction using TLC, the reaction was
quenched with saturated sodium bicarbonate solution. The reaction
mixture was diluted with dichloromethane, washed with water and
saturated aqueous sodium chloride solution, dried over anhydrous
sodium sulfate, and then concentrated under reduced pressure to
obtain a solid. The solid was recrystallized with ethyl acetate and
hexane, to yield a pale yellow crystal (293.2 mg, 61.95%).
[0663] mp: 155.1-161.2.degree. C.;
[0664] .sup.1H NMR(400 MHz, CDCl.sub.3): .delta. 7.98(d, 2H, J=8.8
Hz), 7.27(d, 2H, J=8.8 Hz), 3.11(d, 3H, J=1.6 Hz),2.59(d, 3H, J=1.6
Hz)
[0665] IR(KBr pellet, cm.sup.-1): 3290.93, 3003.59, 2928.38,
1667.16, 1600.63, 1469.49, 1330.64, 1279.54, 1146.47
[0666] Step 2: Synthesis of 4-methanesulfonylaminoacetophenonoxime
(36-2)
[0667] 4-methanesulfonylaminoacetophenone (36-1) (360.2 mg) was
dissolved in ethanol and to the solution was added a solution of
hydroxylamine hydrochloride (129.11 mg) and sodium acetate (249.40
mg) in minimal amount of water. To the mixture was added ethanol
until the solution became clear and then the solution was refluxed
for 20 hours, thereby to be changed from transparent yellow to
transparent colorlessness. After confirming the completion of the
reaction using TLC, the ethanol was removed therefrom, and the
residue was extracted with ethyl acetate, washed with water and
saturated aqueous sodium chloride solution, dried over anhydrous
sodium sulfate, and then concentratd under reduced pressure to
obain a solid. The solid was recrystallized with ethyl acetate and
hexane to yield a pale yellow crystal (289.6 mg, 75.11%)
[0668] mp: 181.5- 182.1.degree. C.;
[0669] 1H NMR(400 MHz, CDCl.sub.3): .delta. 7.60(d, 2H, J=7.2 Hz),
7.26(d, 2H, J=7.4 Hz), 2.96(s, 3H), 2.21(s, 3H).
[0670] IR(KBr pellet, cm.sup.-1): 3495.35, 3255.25, 3023.84,
2926.38, 1605.45, 1323.89, 1155.15;
[0671] Step 3: Synthesis of
1-(4-methanesulfonylaminophenyl)ethylamine (36-3)
[0672] 4-methanesulfonylaminoacetophenonoxime (36-2) (279 mg) was
dissolved in methanol and to the solution was added
palladium/carbon (55.8 mg), followed by stirring under hydrogen
atmosphere. After confirming the completion of the reaction using
TLC, palladium/carbon was filtered off and the filtrate was
concentrated under reduced pressure to remove the methanol, thereby
to yield a transparent yellow liquid (251.1 mg, 95.89%).
[0673] 1H NMR(400 MHz, CDCl.sub.3): .delta. 7.28(d, 2H, J=8.8 Hz),
7.15(d, 2H, J=8.8 Hz), 4.09(q, 1H, J=6.6 Hz), 2.95 (s, 3H), 1.35(d,
3H, J=6.4 Hz)
[0674] IR(NaCl neat, cm.sup.-1): 3350.71, 3270.69, 3136.65,
3023.84, 2965.98, 1610.27, 1512.88, 1325.82, 1153.22;
[0675] Step 4: Synthesis of
1-(4-t-butylbenzyl)-3-(1-(4-methanesulfonylphe- nyl)ethyl)thiourea
(36-4)
[0676] The compound 36-3 (56.3 mg) prepared in Step 3 was dissolved
in dichloromethane and to the solution was added
4-t-butylbenzylisothiocyana- te (64.7 mg), followed by stirring at
room temperature for 12 hours. Affter confiming the completion of
the reaction using TLC, dichloromethane was evaporated under
reduced pressure and the residue was purified by
column-chromatography (hexane/ethyl acetate=4/1) to yield a white
solid (41.9 mg, 38.01%).
[0677] mp: 177.8-178.5.degree. C.
[0678] .sup.1H NMR(400 MHz, CDCl.sub.3): .delta. 9.33(s, 1H),
7.28(m, 8H), 5.51(s, 1H), 4.68(s, 2H), 4.08(q, 1H, J=4.8 Hz),
2.93(s, 3H), 1.48(d, 3H, J=4.8 Hz),1.31(s, 9H).
[0679] IR(KBr pellet, cm.sup.-1): 3356.50, 3262.97, 3057.58,
3025.76, 2964.05, 2868.59, 1544.70, 1512.88, 1325.82
EXAMPLE 199
[0680] Synthesis of
1-(1-(4-methanesulfonylphenyl)ethyl)-3-phenethylthiour- ea (36-5)
320
[0681] Solution of compound 36-3 (50 mg) in dichloromethane was
mixed with phenethylisothiocyanate (65.7 mg) and the mixture was
stirred at room temperature for 12 hours, followed by confiing the
completion of the reaction using TLC. Dichloromnethane was
evaporated and the residue was column-chromatographed (hexane/ethyl
acetate=2/1) to yield a white solid (12.8 mg, 14.53%). mp:
190.8-192.1.degree. C.
[0682] .sup.1H NMR(400 MHz, DMSO-d.sub.6): .delta. 9.63(s, 11),
7.78(s, 1H), 7.19(m, 9H), 5.34(s, 1H), 3.56(s, 1H), 2.92(s, 2H),
2.74(t, 2H, J=6.6 Hz), 2.47(s, 3H), 1.33(d, 3H, J=6.6 Hz).IR(NaCl
neat, cm.sup.-1): 3365.17, 3229.22, 3020.94, 1731.76, 1523.49,
1374.03;
EXAMPLE 200
[0683] Synthesis of
1-(4-t-butylbenzyl)-3-(1-(4-methanesulfonylphenyl)ethy-
l)-3-methylthiourea (36-6) 321
[0684] Compound 36-1 (200 mg) was dissolved in methanol and to the
solution was added palladium/carbon (30.0 mg), followed by bringing
the atmosphere of the reactor into an atrnsphere of hydrogen gas.
To the solution was added methylamine solution (2 M) and the
mixture was allowed to be reacted for 5 days. After confirming the
completion of the reaction using TLC, palladiumn/carbon was
filtered off and the filtrate was purified by column-chromatography
eluting with hexanelethyl acetate (3/1) to remove neural material
and subsequently eluting with dichloromethane/methanol (10/1) to
obtain a yellow liquid (70 mg, 32.70%). The obtained compound (70
mg) was dissolved in dichloromethane and to the solution was added
phenethylisothiocyanate (75.5 mg), followed by stirring at room
temperature for 4 hours. After confi g the completion of the
reaction using TLC, the resulting mixture was diluted with
dichloromethane, washed with water and saturated aqueous sodium
chloride solution, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure to obain a solid. The solid was
purified by colunm-chromatography (hexane/ethyl acetate=3/1) to
yield a colorless liquid (42.6 mg, 32%). .sup.1H NMR(400 MHz,
CDCl.sub.3): .delta. 7.27(m, 811), 6.90(q, 1H, J=7.2 Hz), 5.53(s,
1H), 4.84(d, 2H, J=4.4 Hz), 2.98(s, 3H), 2.66(s, 3H), 1.58(s, 1H),
1.52(d, 3H, J=7.2 Hz), 1.29(s, 3).
[0685] IR(NaCl neat, cm.sup.-1): 3386.39, 3267.79, 2963.09,
1512.88, 1326.79;
EXPERIMENTAL EXAMPLE
[0686] Biological Potency Test
[0687] (1)45 Ca influx test
[0688] 1) Separation of spinal dorsal root ganglia (DRG) in newborn
rats and primary culture thereof
[0689] Neonatal(2-day old or younger than 2-day old) SD rats were
put in ice for 5 minutes to anesthetize and disinfected with 70%
ethanol. DRG of all part of spinal cord were dissected (Wood et
al., 1988, J. Neurosci. 8, pp3208-3220) and collected in DME/F12
medium to which 1.2 g/l sodium bicarbonate, 50 mg/l gentamycin were
added. The DRG were incubated sequentially at 37.degree. C. for 30
min in 200 U/mi collagenase and 2.5 mg/ml trypsin, separately. The
ganglia were washed twice with DME/F12 medium supplemented with 10%
horse serum, triturated through a fire-polished Pasteur pipette,
filtered through Nitex 40 membrane to obtain single cell
suspension. This was subjected to centrifugation, then re-suspended
in cell culture medium at certain level of cell density. As the
cell culture medium, DME/F12 medium supplemented with 10% horse
serum, diluted 1:1 with identical medium conditioned by C6 glioma
cells (2 days on a confluent monolayer) was used, and NGF(Nerve
Growth Factor) was added to final concentration of 200 ng/ml. After
the cells were grown 2 days in medium where cytosine arabinoside
(Ara-C, 100 .mu.M was added to kill dividing nonneuronal cells,
medium was changed to one without Ara-C. The resuspended cells were
plated at a density of 1500-1700 neurons/well onto Terasaki plates
previously coated with 10 .mu.g/ml poly-D-ornithine.
[0690] 2) 45 Ca influx experiments
[0691] DRG nerve cells from the primary culture of 2-3 days were
equilibrated by washing 4 times with HEPES (lOmM, pH 7.4)-buffered
Ca.sup.2+, Mg.sup.2+-free HBSS (H-HBSS). The solution in each well
was removed from the individual well. Medium containing the test
compound plus capsaicin (final concentration 0.5 .mu.M) and
.sup.45Ca (final concentration 10 .mu.Ci/ml) in H-HBSS was added to
each well and incubated at room temperature for 10 min. Terasaki
plates were washed six times with H-HBSS and dried in an oven. To
each well, 0.3% SDS (10 .mu.l) was added to elute .sup.45Ca. After
the addition of 2 ml of scintillation cocktail into each well, the
amount of .sup.45Ca influx into neuron was measured by counting
radioactivity. Antagonistic activities of test compounds against
vanilloid receptor were calculated as percent of the inhibition of
maximal response of capsaicin at a concentration of 0.5 .mu.M and
results are given as IC.sub.50(Table 1a, 1b and 1c).
[0692] Agonistic activities of the test compounds for vanrilloid
receptor were determined as a concentration of the test compound
showing 50% of the .sup.45Ca influx, compared to the maximal amount
of .sup.45Ca influx in case of using 3 .mu.M capsaicin and results
are given as EC.sub.50 (Table 1d).
[0693] (2) Channel activity assay
[0694] Antagonistic activities of test compounds were assayed based
on electrical change of cation channel connected to vanilloid
receptor and experiments were conducted according to reference
method (Oh et al., 1996, J. Neuroscience 16, pp1659-1667) (Table
1a, 1b and 1c).
23TABLE 1a Results of Calcium Influx and Patchclamp Tests Calcium
Uptake Patchelamp Test Examples Test(IC.sub.50) (antagonistic
activities) 5 1.1 9 0.23 13 0.037 ++ 15 1.2 17 0.0084 ++ 18 0.72 19
0.0058 ++ 30 1.5 32 0.031 + 33 0.11 36 1.1 44 0.11 + 51 0.7 NR: no
response +: antagonistic potency equal to capsazepine ++:
antagonistic potency 10 times higher than capsazepine
[0695]
24TABLE 1b Results of Calcium Influx and Patchclamp Tests Calcium
Uptake Patchclamp Test Examples Test (IC.sub.50) (antagonistic
activities) 60 1.14 + 61 0.25 + 62 0.06 + 64 0.35 + 65 0.019 + 66
0.25 + 67 0.5 + 68 0.063 + 69 0.77 + 70 0.58 + 73 1.2 83 1.1 90
0.42 96 0.59 +: antagonistic potency equal to capsazepine
[0696]
25TABLE 1c Results of Calcium Influx and Patchclamp Tests Calcium
Uptake Patchclamp Test Examples Test (IC.sub.50) (antagonistic
activities) 134 0.81 152 0.95 + 153 0.38 161 0.46 178 0.11 193 0.21
194 0.31 196 0.15 Capsazepine 0.59 + +: antagonistic potency equal
to capsazepine
[0697]
26TABLE 1d Results of Calcium Influx Tests Calcium Uptake Examples
Test (EC.sub.50) 6 14.6 24 8.2 41 7.0 46 2.6 82 2.8
[0698] (3) Analgesic activity test: Mouse writhing test by inducing
with phenyl-p-quinone
[0699] Male ICR mice (mean body weight 25 g) were maintained in a
controlled lighting environment (12 h on/12 h off) for experiment.
Animals received an intraperitoneal injection of 0.3 ml of the
chemical irritant phenyl-p-quinone (dissolved in saline containing
5% ethanol to be a dose of 4.5mg/kg) and 6 min later, the number of
abdominal constrictions was counted in the subsequent 6 min period.
Animals (10 animals/group) received 0.2 ml of test compounds
solution in vehicle of ethanoVTween 80/saline (10/10/80)
intraperitoneally 30 min before the injection of phenyl-p-quinone.
A reduction in the number of writhes responding to the test drag
compound relative to the number responding in saline control group
was considered to be indicative of an analgesic effect. Analgesic
effect was calculated by % inhibition equation (%
inhibition=(C-T)/C.times.100), wherein C and T represent the number
of writhes in control and compound-treated group, respectively
(Table 2).
[0700] The test results demonstrated that analgesic effect of the
compounds used in this experiment is as potent as indomethacin
which is a very potent antiinflmmato-ry and analgesic agent. In
particular, it is significant to clarify that vanilloid receptor
antagonist can exhibit such potent analgesic effect, and the
results suggests that vanilloid receptor antagonist has potential
as an analgesic agent.
27TABLE 2 Test result of analgesic activity for writhing by
phenyl-p-quinone Analgesic effect Examples Dose(mg/kg) (%
Inhibition) 5 10 53 13 10 82 17 10 98 44 3 92 52 10 94 73 10 88 83
10 85 96 10 58 104 10 95 107 10 44 153 1 57 161 1 73 Indomethacin 3
94
[0701] (4) Antiinflammatory activity test:
TPA(12-O-tetradecanoylphorbol 13-acetate)-induced mouse ear edema
test
[0702] Male JCR mice(body weight 25-30 g), 10 animals/group, were
treated topically on th right ear with 30 .mu.l of TPA (2.5 .mu.g)
solution in acetone and after 15 min, 30 .mu.l of acetone or test
compound solution in acetone was applied topically. After six
hours, a identica treatment was applied again. After twenty four
hours following the tratment of TPA, the animals were sacrificed
and ear tissue was dissected using 6 mm-diameter punch. Ear tissue
dissected were weighed to the nearest 0.1 mg on an electrobalance.
The increased weight of the tissue compared to control group was
considered as an index of inflammation. The percent inhibition is
defined by the following equation:
% inhibition=(C-T)/C.times.100,
[0703] wherein C and T represent an increase of ear weight in
TPA-treated and TPA+drug-treated group, respectively (Table 3).
[0704] The above experiment shows that vanilloid receptor
antagonist exhibits anti-inflammatory effects of the same level
with indomethacin which is very potent anti-inflammatory and
analgesic agent. This phenomenon can be understood by connecting
with the action of vanilloid receptor in neurogenic inflammation,
and suggests potential applicability of vanilloid receptor
antagonist in various inflammatory diseases, in particular,
neurogenic inflammatory diseases.
28TABLE 3 TPA-induced mice ear edema test Anti-inflammtory effect
Examples Dose (mg/ear) (% Inhibition) 13 1 74 17 1 80 33 1 66 44 1
83 73 1 77 107 1 75 Indomethacin 1 74
[0705] (5) Ulcer test: ethanol-induced anti-ulcer test
[0706] Male SD rats (body weight 180-200 g), 5 animals/group, were
fasted for 24 hours, and their stomaches were damaged. The rats
were administered with 10 ml/kg of test drug suspended in 1%
methylcellulose orally and, after 1 hour, 1 rnl of 99% ethanol
orally. After 1 hour without food and water, the rats were
sacrificed by cervical dislocation and stomaches thereof were
removed. The removed stomaches were incised along the greater
curvature and opened. Then, the degree of gastric damage was scored
based on the following ulcer index which is a criterion for
evaluation and the percent inhibition of test drug against ulcer
was calculated compared to control group (1% methylcellulose)
(table 4). % inhibition -[(ulcer index of control group--ulcer
index of drug-treated group)/( ulcer index of control
group)].times.100
[0707] According to the present study using ethano1-induced ulcer
model, the vanilloid receptor antagonist was found out to exhibit
significant anti-ulcerous activities, contrary to ranitidine, which
is a representative antiulcerant but did not show anti-ulcer
activity in the present study. This study is the first to
demonstrate the anti-ulcerous potential of vanilloid receptor
antagonist. Based on the result, possibility that vanilloid
receptor antagonist will be developed as an anti-ulcerant is
suggested.
29 Scoring Ulcer (grade) Index (UI) 0 No lesion 1 One hemorrhagic
ulcer of length less than 5 mm & thin 2 One hemorrhagic ulcer
of length not less than 5 mm & thin 3 More than one ulcer of
grade 2 4 One ulcer of length not less than 5 mm & width not
less than 2 mm 5 Two or three ulcers of grade 4 6 Four or five
ulcers of grade 4 7 More than six ulcers of grade 4 8 Complete
lesion of the mucosa
[0708]
30TABLE 4 Ethanol-induced anti-ulcer test Anti-ulcerous effect
Examples Dose(mg/kg) (% inhibition) 13 30 30 17 30 58 33 30 31 44
30 36 73 30 22 107 30 18 Ranitidine 30 4
[0709] Industrial Applicability
[0710] The compounds according to the present invention are useful
in the prevention or treatment of pain, acute pain, chronic pain,
neuropathic pain, post-operative pain, migraine, arthralgia,
neuropathies, nerve injury, diabetic neuropathy, neurodegeneration,
neurotic skin disorder, stroke, urinary bladder hypersensitiveness,
irritable bowel syndrome, a respiratory disorder such as asthma and
chronic obstructive pulmonary diseases, irritation in slin, eye or
mucous membrane, stomach-duodenal ulcer, inflammatory bowel
disease, inflammatory disease, etc.
* * * * *