U.S. patent application number 09/377569 was filed with the patent office on 2002-04-25 for pyrazoles and pyrazolopyrimidines having crf antagonistic activity.
Invention is credited to FARACI, WILLIAM STEPHAN, WELCH, WILLARD MCKOWEN JR..
Application Number | 20020049227 09/377569 |
Document ID | / |
Family ID | 27035397 |
Filed Date | 2002-04-25 |
United States Patent
Application |
20020049227 |
Kind Code |
A1 |
FARACI, WILLIAM STEPHAN ; et
al. |
April 25, 2002 |
PYRAZOLES AND PYRAZOLOPYRIMIDINES HAVING CRF ANTAGONISTIC
ACTIVITY
Abstract
The pyrazoles and pyrazolopyrimidines of the formula 1 wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4 and A are as defined herein,
have corticotropin releasing factor (CRF) antagonist activity. As
such, they are effective in the treatment of a wide range of
diseases including stress-related illnesses.
Inventors: |
FARACI, WILLIAM STEPHAN;
(EAST LYME, CT) ; WELCH, WILLARD MCKOWEN JR.;
(MYSTIC, CT) |
Correspondence
Address: |
PFIZER INC
150 EAST 42ND STREET
5TH FLOOR - STOP 49
NEW YORK
NY
10017-5612
US
|
Family ID: |
27035397 |
Appl. No.: |
09/377569 |
Filed: |
August 19, 1999 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09377569 |
Aug 19, 1999 |
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08961413 |
Oct 30, 1997 |
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6103900 |
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08961413 |
Oct 30, 1997 |
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08448529 |
Jun 14, 1995 |
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5712303 |
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08961413 |
Oct 30, 1997 |
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07992225 |
Dec 17, 1992 |
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08961413 |
Oct 30, 1997 |
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PCT/US93/10359 |
Nov 3, 1997 |
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Current U.S.
Class: |
514/310 |
Current CPC
Class: |
C07D 231/38 20130101;
C07D 231/44 20130101; C07D 231/18 20130101; C07D 487/04 20130101;
C07D 231/52 20130101; C07D 409/10 20130101; C07D 403/10
20130101 |
Class at
Publication: |
514/310 |
International
Class: |
A61K 031/47 |
Claims
1. A compound of the formula 35wherein A is C.dbd.O or SO.sub.2, or
A and R.sub.1 together with the carbons to which they are attached
form pyrimidinyl or 5-pyridyl which may be substituted by R.sub.5
which is hydrogen, C.sub.1-C.sub.6 alkyl, fluoro, chloro, bromo,
hydroxy, amino, O(C.sub.1-C.sub.6 alkyl), NH(C.sub.1-C.sub.6
alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl), SH,
S(O).sub.n(C.sub.1-C.sub.6 alkyl) wherein n=0, 1 or 2, wherein said
C.sub.1-C.sub.6 alkyl may contain from one to two double or triple
bonds and may be substituted by from 1 to 3 substituents R.sub.6
which is hydroxy, amino, C.sub.1-C.sub.3 alkoxy, dimethylamino,
diethylamino, methylamino, ethylamino, NH(C.dbd.O)CH.sub.3, fluoro,
chloro, bromo or C.sub.1-C.sub.3 thioalkyl. R.sub.1 is hydrogen,
C.sub.1-C.sub.6 alkyl, amino, O(C.sub.1-C.sub.6 alkyl),
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.5
alkyl), wherein said C.sub.1-C.sub.6 alkyl may contain from one to
two double or triple bonds and may be substituted by from 1 to 3
substituents R.sub.6 as defined above; R.sub.2 is hydrogen,
C.sub.1-C.sub.6 alkyl, hydroxy, amino, O(C.sub.1-C.sub.6 alkyl),
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl), SH, S(O).sub.n(C.sub.1-C.sub.6 alkyl) wherein n=0, 1, or 2,
cyano, hydroxy, carboxy, or amido, wherein said alkyls, may be
substituted by one to three of hydroxy, amino, carboxy, amido,
NH(C.dbd.O)(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl), (C.dbd.O)O(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 thioalkyl, fluoro, bromo,
chloro, iodo, cyano or nitro; R.sub.3 is phenyl, naphthyl, thienyl,
benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl,
imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl,
benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl,
benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl,
azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl,
morpholinyl, pyridinyl, tetrazolyl, or 3 to 8-membered cycloalkyl
or 9 to 12 membered bicycloalkyl, optionally containing one to
three of O, S or N--Z wherein Z is hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4alkanoyl, phenyl or phenylmethyl, wherein each one
of the above groups may be substituted independently by from one to
three of fluoro, chloro, bromo, trifluoromethyl, C.sub.1-C.sub.6
alkyl or C.sub.1-C.sub.6 alkoxy, or one of cyano, nitro, amino,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2
alkyl), COO(C.sub.1-C.sub.4 alkyl), CO(C.sub.1-C.sub.4 alkyl),
SO.sub.2NH(C.sub.1-C.sub.4 alkyl), SO.sub.2N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), SO.sub.2NH.sub.2,
NHSO.sub.2(C.sub.1-C.sub- .4 alkyl), S(C.sub.1-C.sub.6 alkyl),
SO.sub.2(C.sub.1-C.sub.6 alkyl), wherein said C.sub.1-C.sub.4 alkyl
and C.sub.1-C.sub.6 alkyl may be substituted by one or two of
fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or
acetyl; and R.sub.4 is phenyl, naphthyl, thienyl, benzothienyl,
pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl,
benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl,
thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl,
pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl,
pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or
9 to 12-membered bicycloalkyl, optionally containing one to three
of O, S or N--Z wherein Z is hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkanoyl, phenyl or phenylmethyl, wherein each of
the above groups may be substituted independently by from one to
three of fluoro, chloro, bromo, trifluoromethyl, C.sub.1-C.sub.6
alkyl or C.sub.1-C.sub.6 alkoxy, or one of cyano, nitro, amino,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2
alkyl), COO(C.sub.1-C.sub.4 alkyl), CO(C.sub.1-C.sub.4 alkyl),
SO.sub.2NH(C.sub.1-C.sub.4 alkyl), SO.sub.2N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), SO.sub.2NH.sub.2,
NH.sub.2SO.sub.2(C.sub.1-C.sub.4 alkyl), S(C.sub.1-C.sub.6 alkyl),
SO.sub.2(C.sub.1-C.sub.6 alkyl), wherein said C.sub.1-C.sub.4 alkyl
and C.sub.1-C.sub.6 alkyl may be substituted by one or two of
fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or
acetyl; provided that R.sub.4 is not unsubstituted phenyl; and
provided that when R.sub.1 is amino, R.sub.2 is methylthio, R.sub.4
is 2,4,6-trichlorophenyl, and A is C.dbd.O, then R.sub.3 is not
2-chlorophenyl.
2. A compound according to claim 1 wherein R.sub.3 is phenyl
substituted independently with one or two of fluoro, chloro, bromo,
methyl, trifluoromethyl, nitro, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkyloxy, SO.sub.2NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6 alkyl), SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, or R.sub.3 is primary, secondary or tertiary alkyl of
from 4-9 carbon atoms wherein said C.sub.4-C.sub.9 alkyl may
contain from one to two double or triple bonds and may be
substituted by from 1 to 3 substituents R.sub.6 which is hydroxy,
amino, C.sub.1-C.sub.3 alkoxy, dimethylamino, diethylamino,
methylamino, ethylamino, NH(C.dbd.O)CH.sub.3, fluoro, chloro,
bromo, or C.sub.1-C.sub.3 thioalkyl.
3. A compound according to claim 1 or 2 wherein R.sub.4 is
2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl,
2,6-dichloro-4-trifluoromet- hylphenyl or
4-bromo-2,6-dimethylphenyl.
4. A compound according to any one of claims 1 to 3 wherein R.sub.1
is amino, methylamino or dimethylamino.
5. A compound according to any one of claims 1 to 4 wherein R.sub.2
is methylthio or ethyl.
6. A compound according to any one of claims 1 to 5 where A is
C.dbd.O.
7. A compound according to any one of claims 1, 2, 3 or 5 wherein A
and R.sub.1 together form a pyrimidine ring, such that the bicyclic
structure formed is pyrazolo[3,4-d]pyrimidine, and R.sub.5 is
substituted at the 6 position.
8. A compound according to claim 1 wherein said compound is
[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyr-
azol-4-yl]-(2,5-dimethylphenyl)methanone,
[5-amino-1-(2,6-dichloro-4-trifl-
uoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-bis-trifluorometh-
ylphenyl)methanone,
[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-me-
thylsulfanyl-1H-pyrazol-4-yl]-(5-isopropyl-2-methylphenyl)methanone,
[5-amino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazol-4-yl]-(5-i-
sopropyl-2-methylphenyl)methanone, or
[5-amino-1-(4-bromo-2,6-dimethylphen-
yl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-dibromophenyl)methanone.
9. A composition for the treatment of (a) illnesses induced or
facilitated by corticotropin releasing factor or (b) stress-induced
illnesses including stress-induced depression and headache,
abdominal bowel syndrome, inflammatory disorders, immune
suppression, HIV infections, Alzheimer's disease, gastrointestinal
diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol
withdrawal symptoms, drug addiction, and fertility problems,
particularly depression, which comprises a compound of the formula
36wherein A is C.dbd.O or SO.sub.2, or A and R.sub.1 together with
the carbons to which they are attached form pyrimidinyl or
5-pyridyl which may be substituted by R.sub.5 which is hydrogen,
C.sub.1-C.sub.6 alkyl, fluoro, chloro, bromo, hydroxy, amino,
O(C.sub.1-C.sub.6 alkyl), NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl), SH,
S(O).sub.n(C.sub.1-C.sub.6 alkyl) wherein n=0, 1 or 2, wherein said
C.sub.1-C.sub.6 alkyl may contain from one to two double or triple
bonds and may be substituted by from 1 to 3 substituents, R.sub.6
which is hydroxy, amino, C.sub.1-C.sub.3 alkoxy, dimethylamino,
diethylamino, methylamino, ethylamino, NH(C.dbd.O)CH.sub.3, fluoro,
chloro, bromo or C.sub.1-C.sub.3 thioalkyl. R.sub.1 is hydrogen,
C.sub.1-C.sub.6 alkyl, amino, O(C.sub.1-C.sub.6 alkyl),
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl), wherein said C.sub.1-C.sub.6 alkyl may contain from one to
two double or triple bonds and may be substituted by from 1 to 3
substituents R.sub.6 as defined above; R.sub.2 is hydrogen,
C.sub.1-C.sub.6 alkyl, hydroxy, amino, O(C.sub.1-C.sub.6 alkyl),
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl), SH, S(O).sub.n(C.sub.1-C.sub.6 alkyl) wherein n=0, 1, or 2,
cyano, hydroxy, carboxy, or amido, wherein said alkyls, may be
substituted by one to three of hydroxy, amino, carboxy, amido,
NH(C.dbd.O)(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl), (C.dbd.O)O(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 thioalkyl, fluoro, bromo,
chloro, iodo, cyano or nitro; R.sub.3 is phenyl, naphthyl, thienyl,
benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl,
imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl,
benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl,
benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl,
azaindolyl, benzoxazolyl, oxazolyl, pyrrlidinyl, thiazolidinyl,
morpholinyl, pyridinyl, tetrazolyl, or 3 to 8-membered cycloalkyl
or 9 to 12 membered bicycloalkyl, optionally containing one to
three of O, S or N--Z wherein Z is hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkanoyl, phenyl or phenylmethyl, wherein each one
of the above groups may be substituted independently by from one to
three of fluoro, chloro, bromo, trifluoromethyl, C.sub.1-C.sub.6
alkyl or C.sub.1-C.sub.6 alkoxy, or one of cyano, nitro, amino,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2
alkyl), COO(C.sub.1-C.sub.4 alkyl), CO(C.sub.1-C.sub.4 alkyl),
SO.sub.2NH(C.sub.1-C.sub.4 alkyl), SO.sub.2N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), SO.sub.2NH.sub.2,
NHSO.sub.2(C.sub.1-C.sub- .4 alkyl), S(C.sub.1-C.sub.6 alkyl),
SO.sub.2(C.sub.1-C.sub.6 alkyl), wherein said C.sub.1-C.sub.4 alkyl
and C.sub.1-C.sub.6 alkyl may be substituted by one or two of
fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or
acetyl; and R.sub.4 is phenyl, naphthyl, thienyl, benzothienyl,
pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl,
benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl,
thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl,
pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl,
pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or
3 to 8-membered cycloalkyl or 9 to 12-membered bicycloalkyl,
optionally containing one to three of O, S or N--Z wherein Z is
hydrogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkanoyl, phenyl or
phenylmethyl, wherein each of the above groups may be substituted
independently by from one to three of fluoro, chloro, bromo,
trifluoromethyl, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy,
or one of cyano, nitro, amino, NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
COO(C.sub.1-C.sub.4 alkyl), CO(C.sub.1-C.sub.4 alkyl),
SO.sub.2NH(C.sub.1-C.sub.4 alkyl), SO.sub.2N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), SO.sub.2NH.sub.2,
NH.sub.2SO.sub.2(C.sub.1- -C.sub.4 alkyl), S(C.sub.1-C.sub.6
alkyl), SO.sub.2(C.sub.1-C.sub.6 alkyl), wherein said
C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.6 alkyl may be substituted
by one or two of fluoro, chloro, hydroxy, amino, methylamino,
dimethylamino or acetyl; provided that R.sub.4 is not unsubstituted
phenyl.
10. A method for the treatment of (a) illnesses induced by
corticotropin releasing factor or (b) stress-induced illnesses
including stress-induced depression and headache, abdominal bowel
syndrome, inflammatory disorders, immune suppression, HIV
infections, Alzheimer's disease, gastrointestinal diseases,
anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal
symptoms, drug addiction, and fertility problems, particularly
depression, which comprises administering to a subject in need of
such treatment a compound of formula I as defined in claim 9.
Description
[0001] This invention relates to pyrazoles and pyrazolopyrimidines,
pharmaceutical compositions containing them, and methods of
administering them to subjects in need of their
corticotropin-releasing factor (CRF) antagonist activity.
[0002] CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642
and 5,063,245 referring to peptides and pyrazolinones,
respectively. The importance of CRF antagonists is set out in the
literature, e.g. as discussed in U.S. Pat. No. 5,063,245, which is
incorporated herein by reference. A recent outline of the different
activities possessed by CRF antagonists is found in M. J. Owens et
al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), also
incorporated herein by reference. Based on the research described
in these two and other references, CRF antagonists are effective in
the treatment of a wide range of diseases including stress-related
illnesses, such as stress-induced depression, anxiety, and
headache; abdominal bowel syndrome; inflammatory diseases; immune
suppression; human immunodeficiency virus (HIV) infections;
Alzheimer's disease; gastrointestinal diseases; anorexia nervosa;
hemorrhagic stress; drug and alcohol withdrawal symptoms; drug
addiction, and fertility problems.
[0003] The compound of formula I below wherein A is C.dbd.O,
R.sub.1 is amino, R.sub.2 is methylthio, R.sub.3 is 2-chlorophenyl,
and R.sub.4 is 2,4,6-trichlorophenyl is a commercial compound of no
known utility.
[0004] The present invention relates to a compound of the formula
2
[0005] and the acid addition salts thereof, wherein
[0006] A is C.dbd.O or SO.sub.2, or A and R.sub.1 together with the
carbons to which they are attached form pyrimidinyl or 5-pyridyl
which may be substituted by R.sub.5 which is hydrogen,
C.sub.1-C.sub.6 alkyl, fluoro, chloro, bromo, hydroxy, amino,
O(C.sub.1-C.sub.6 alkyl), NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl), SH,
S(O).sub.n(C.sub.1-C.sub.6 alkyl) wherein n=0, 1 or 2, wherein said
C.sub.1-C.sub.6 alkyl may be substituted by from 1 to 3
substituents R.sub.6 which is hydroxy, amino, C.sub.1-C.sub.3
alkoxy, dimethylamino, diethylamino, methylamino, ethylamino,
NH(C.dbd.O)CH.sub.3, fluoro, chloro, bromo or C.sub.1-C.sub.3
thioalkyl;
[0007] R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl, amino,
O(C.sub.1-C.sub.6 alkyl), NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl), wherein said
C.sub.1-C.sub.6 alkyl may be substituted by from 1 to 3
substituents R.sub.6 as defined above;
[0008] R.sub.2 is hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy, amino,
O(C.sub.1-C.sub.6 alkyl), NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl), SH,
S(O).sub.n(C.sub.1-C.sub.6 alkyl) wherein n=0, 1, or 2, cyano,
hydroxy, carboxy, or amido, wherein said alkyls may be substituted
by one to three of hydroxy, amino, carboxy, amido,
NH(C.dbd.O)(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl), (C.dbd.O)O(C.sub.1-C.sub.6alkyl),
C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3thioalkyl, fluoro, bromo,
chloro, iodo, cyano or nitro;
[0009] R.sub.3 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl,
quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl,
benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl,
thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl,
pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl,
pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or
9 to 12 membered bicycloalkyl, optionally containing one to three
of O, S or N--Z wherein Z is hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkanoyl, phenyl or phenylmethyl, wherein each one
of the above groups may be substituted independently by from one to
three of fluoro, chloro, bromo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, or trifluoromethyl, or one of cyano, nitro,
amino, NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), COO(C.sub.1-C.sub.4 alkyl),
CO(C.sub.1-C.sub.4 alkyl), SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
SO.sub.2N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
SO.sub.2NH.sub.2, NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
S(C.sub.1-C.sub.6 alkyl), SO.sub.2(C.sub.1-C.sub.6 alkyl), wherein
said C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.6 alkyl may be
substituted by one or two of fluoro, chloro, hydroxy, amino,
methylamino, dimethylamino or acetyl; and
[0010] R.sub.4 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl,
quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl,
benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl,
thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl,
pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl,
pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or
3 to 8-membered cycloalkyl or 9 to 12-membered bicycloalkyl,
optionally containing one to three of O, S or N--Z wherein Z is
hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkanoyl, phenyl
or phenylmethyl, wherein each of the above groups may be
substituted independently by from one to three of fluoro, chloro,
bromo, trifluoromethyl, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6
alkoxy, or one of cyano, nitro, amino, NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
COO(C.sub.1-C.sub.4 alkyl), CO(C.sub.1-C.sub.4 alkyl),
SO.sub.2NH(C.sub.1-C.sub.4 alkyl), SO.sub.2N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), SO.sub.2NH.sub.2,
NH.sub.2SO.sub.2(C.sub.1-C.sub.4 alkyl), S(C.sub.1-C.sub.6 alkyl),
SO.sub.2(C.sub.1-C.sub.6 alkyl), wherein said C.sub.1-C.sub.4 alkyl
and C.sub.1-C.sub.6 alkyl may be substituted by one or two of
fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or
acetyl; provided that (1) R.sub.4 is not unsubstituted phenyl; (2)
when R.sub.1 is amino, R.sub.2 is methylthio, R.sub.4 is
2,4,6-trichlorophenyl, and A is C.dbd.O, then R.sub.3 is not
2-chlorophenyl; and (3) R.sub.1 and R.sub.2 are not both
hydrogen.
[0011] More specific compounds of the formula I include those
wherein R.sub.3 is phenyl substituted independently with one or two
of fluoro, chloro, bromo, methyl, trifluoromethyl, nitro,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyloxy, SO.sub.2NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6 alkyl), SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, or R.sub.3 is primary, secondary or tertiary alkyl of
from 4-9 carbon atoms wherein said C.sub.4-C.sub.9 alkyl may
contain from one to two double or triple bonds and may be
substituted by from 1 to 3 substituents R.sub.6 which is hydroxy,
amino, C.sub.1-C.sub.3 alkoxy, dimethylamino, diethylamino,
methylamino, ethylamino, NH(C.dbd.O)CH.sub.3, fluoro, chloro,
bromo, or C.sub.1-C.sub.3 thioalkyl.
[0012] More specific compounds of the formula I are those wherein A
is C.dbd.O, those wherein R.sub.1 is amino, methylamino or
dimethylamino; those wherein R.sub.2 is ethyl or methylthio and
those wherein R.sub.4is 2,4,6-trichlorophenyl,
2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromet- hylphenyl or
4-bromo-2,6-dimethylphenyl.
[0013] More specific compounds of formula I further include those
wherein R.sub.3 is phenyl which may be substituted at positions 2
or 5 with one or two of methyl, C.sub.2-C.sub.6 straight-chain or
branched alkyl, trifluoromethyl, fluoro, chloro, bromo or nitro,
those wherein A and R.sub.1 together form a pyrimidine ring, such
that the bicyclic structure formed is pyrazolo[3,4-d]pyrimidine,
and R.sub.5 is substituted at the 6 position; and those wherein
R.sub.3 is phenyl substituted independently with one or two of
fluoro, chloro, bromo, methyl, trifluoromethyl, nitro,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyloxy, SO.sub.2NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6 alkyl), or
SO.sub.2N(C.sub.1-C.sub.6alkyl).sub- .2, R.sub.4 is
2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl,
2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6-dimethylphenyl,
and R.sub.2 is methylthio, methyl or ethyl.
[0014] More specific compounds of formula I also include those
wherein R.sub.3 is phenyl substituted independently with one or two
of fluoro, chloro, bromo, methyl, trifluoromethyl, nitro,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyloxy, SO.sub.2NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6 alkyl), SO.sub.2N(C.sub.1-C.sub.6
alkyl).sub.2, or R.sub.3 is primary, secondary or tertiary alkyl of
from 4-9 carbon atoms wherein said C.sub.4-C.sub.9 alkyl may
contain from one to two double or triple bonds and may be
substituted by from 1 to 3 substituents R.sub.6 which is hydroxy,
amino, C.sub.1-C.sub.3 alkoxy, dimethylamino, diethylamino,
methylamino, ethylamino, NH(C.dbd.O)CH.sub.3, fluoro, chloro, bromo
or C.sub.1-C.sub.3 thioalkyl; R.sub.4 is 2,4,6-trichlorophenyl,
2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromethylphenyl or
4-bromo-2,6-dimethylphenyl; R.sub.1 is amino, methylamino or
dimethylamino; and R.sub.2 is methylthio or ethyl.
[0015] The most preferred compounds of the invention are
[0016]
[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl--
1H-pyrazol-4-yl]-(2,5-dimethylphenyl)methanone,
[0017]
[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl--
1H-pyrazol-4-yl]-(2,5-bis-trifluoromethylphenyl)methanone,
[0018]
[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl--
1H-pyrazol-4-yl]-(5-isopropyl-2-methylphenyl)methanone,
[0019]
[5-amino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazol-4-yl-
]-(5-isopropyl-2-methylphenyl)methanone, and
[0020]
[5-amino-1-(4-bromo-2,6-dimethylphenyl)-3-methylsulfanyl-1H-pyrazol-
-4-yl]-(2,5-dibromophenyl)methanone.
[0021] The invention also relates to a composition for the
treatment of illnesses induced or facilitated by corticotropin
releasing factor which comprises a compound of the formula I as
defined above or the known compound of formula I wherein A is
C.dbd.O, R.sub.1 is amino, R.sub.2 is methylthio, R.sub.3 is
2-chlorophenyl, and R.sub.4 is 2,4,6-trichlorophenyl, in an amount
effective in the treatment of said illnesses, and a
pharmaceutically acceptable carrier, and to a composition for the
treatment of inflammatory disorders, stress and anxiety related
disorders including stress-induced depression and headache,
abdominal bowel syndrome, immune supression, HIV infections,
Alzheimer's disease, gastrointestinal diseases, anorexia nervosa,
hemorrhagic stress, drug and alcohol withdrawal symptoms, drug
addiction, and fertility problems, which comprises a compound of
the formula I as well as the known compound, both as defined above
in an amount effective in the treatment of said disorders, and a
pharmaceutically acceptable carrier. More specific and most
preferred compositions for the treatment of such illnesses and
disorders comprise a more specific and most preferred compound of
formula I as defined above.
[0022] The invention further includes a method for the treatment of
illnesses induced or facilitated by corticotropin releasing factor
by administering to a subject in need of such treatment a compound
of formula I or the known compound, both as defined above, and a
method for the treatment of stress and anxiety related disorders,
including stress-induced depression and headache, abdominal bowel
syndrome, inflammatory disorders, immune suppression, HIV
infections, Alzheimer's disease, gastrointestinal diseases,
anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal
symptoms, drug addiction, and fertility problems, particularly
depression, by administering to a subject in need of such treatment
a compound of formula I as well as the known compound, both as
defined above. More specific and most preferred methods for the
treatment of such illnesses and disorders comprise a more specific
and most preferred compound of formula I as described above.
[0023] Whenever reference is made herein to C.sub.1-C.sub.6 alkyl,
a straight or branched chain alkyl of one to six carbon atoms is
meant, such as methyl, ethyl, isopropyl or hexyl.
[0024] Whenever reference is made herein to C.sub.1-C.sub.6 alkyl,
in the definition of R.sub.5 and R.sub.1, this includes unsaturated
C.sub.2-C.sub.6 alkyl, such as C.sub.2-C.sub.6 alkyl having one
double or triple bond, C.sub.3-C.sub.6 alkyl having two double
bonds, and C.sub.4-C.sub.6 alkyl having two triple bonds.
[0025] Whenever reference is made hereafter to a compound of
formula I, this includes the known compound of formula I as
described above.
[0026] Whenever R.sub.3 is a heterocyclic group, the attachment to
A, defined above, is through one of the carbons in the heterocyclic
group. Similarly, when R.sub.4 is a heterocyclic group, the
attachment to the nitrogen in the pyrazole ring is through one of
the carbons in the heterocyclic group.
[0027] Whenever reference is made herein to 3- to 8-membered
cycloalkyl or 9- to 12-membered bicycloalkyl containing one to
three of O, S or N--Z, it is understood that the oxygen and sulfur
ring atoms are not adjacent to each other.
[0028] The compounds of the formula I wherein R.sub.1 is amino or
C.sub.1-C.sub.6 alkyl, and R.sub.2 is methylthio, having the
formula II (not shown), may be prepared from a compound of the
formula 3
[0029] wherein R.sub.10 is cyano or C(O)(C.sub.1-C.sub.6 alkyl) and
A and R.sub.3 are as defined above with reference to formula I, by
reaction with a compound of the formula
R.sub.4--NHNH.sub.2 IV
[0030] wherein R.sub.4 is as defined with reference to formula I.
This reaction is generally carried out in a polar solvent, such as
a C.sub.1-C.sub.6 alcohol. The reaction temperature generally
ranges from about 20.degree. C. to about 160.degree. C., and is
conveniently the reflux temperature of the reaction mixture.
[0031] The compounds of formula III may be prepared by treating a
compound of the formula
R.sub.3--A--CH.sub.2R.sub.10 V
[0032] with a base such as sodium hydride, in the presence of
carbon disulfide followed by reaction of the formed intermediate
with methyl iodide in a reaction solvent such as
dimethylsulfoxide.
[0033] The compounds of formula IV are readily available or may be
obtained by methods known in the art.
[0034] The compounds of formula V may be prepared by known
methods.
[0035] The compounds of the formula I wherein R.sub.2 is alkoxy,
amino, or mono- or disubstituted amino may be prepared by using the
above procedure with R.sub.4NHNH.sub.2 from the corresponding
compounds of the formula 4
[0036] wherein A and R.sub.3 are as defined with reference to
formula I, R.sub.10 is as defined with reference to formula III,
and R, R' and R" are each hydrogen or C.sub.1-C.sub.6 alkyl in
accordance with the definition of R.sub.2 above.
[0037] The compounds of the formula I wherein R.sub.1 is
C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkylthio and R.sub.2 is
C.sub.1-C.sub.6 alkyl may be prepared from a compound of the
formula 5
[0038] wherein R.sub.x is chloro or bromo, R.sub.2 is
C.sub.1-C.sub.6 alkyl, and R.sub.3, R.sub.4 and A are as defined
above with reference to formula I, with a C.sub.1-C.sub.6 alcohol
or C.sub.1-C.sub.6 mercaptan in the presence of a base. The
reaction is generally carried out in a polar solvent such as
ethanol or t-butanol at temperatures from about 20.degree. C. to
about 160.degree. C. and conveniently room temperature.
[0039] The compounds of the formula IX may be prepared by treating
a compound of the formula 6
[0040] with a halogenating agent such as thionlyl chloride or
bromide, or phosphorous oxychloride or pentachloride, or
phosphorous oxybromide or pentabromide. The reaction may be carried
out without a solvent or in an aprotic solvent such as methylene
chloride, or dichloroethane at temperatures of about 0.degree. C.
to about 100.degree. C.
[0041] Compounds of formula X may be prepared by treating compounds
of the formula 7
[0042] with an activated derivative of a carboxylic or sulfonic
acid of the formula R.sub.3AOH, such as an acid chloride of the
formula R.sub.3ACl wherein R.sub.3 and A are as defined with
reference to formula I, in the presence of calcium hydroxide in an
aprotic solvent such as dioxane as described in Jensen, Acta Chem.
Scand., 13, 1668-1670 (1959) at temperatures of from about
20.degree. C. to about 100.degree. C. Compounds of the formula XI
are known in the art.
[0043] The compounds of the formula I wherein R.sub.1 is
C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkylthio and R.sub.2 is
C.sub.1-C.sub.6 alkylthio may be prepared from a compound of the
formula 8
[0044] wherein R.sub.Y is chloro or bromo and R.sub.3, R.sub.4 and
A are as defined above with reference to formula I, with a
C.sub.1-C.sub.6 alcohol or C.sub.1-C.sub.6 mercaptan in the
presence of a base. The reaction is generally carried out in a
polar organic solvent such as ethanol or t-butanol at temperatures
from about 20.degree. C. to about 160.degree. C., conveniently room
temperature.
[0045] The compounds of the formula XII may be prepared from a
compound of the formula 9
[0046] by reaction with a halogenating agent such as thionyl
chloride or bromide, or phosphorous oxychloride or pentachloride,
or phosphorous oxybromide or pentabromide. The reaction may be
carried out with a solvent or in an aprotic solvent such as
methylene chloride or dichloroethane at temperatures of about
0.degree. C. to about 100.degree. C.
[0047] The compounds of the formula XIII may be prepared by
treating a compound of the formula 10
[0048] with activated benzoic or sulfonic acid derivatives,
conveniently an acid chloride, in the presence of calcium hydroxide
in an aprotic solvent such as dioxane as described in the above
reference by Jensen.
[0049] The compounds of the formula XIV may be prepared by treating
a compound of the formula 11
[0050] wherein R is chloro, bromo with a C.sub.1-C.sub.6 mercaptan
in the presence of a base. The reaction is generally carried out in
a polar organic solvent such as t-butanol at temperatures from
about 20.degree. C. to about 160.degree. C., conveniently the
reflux temperatures of the reaction mixture.
[0051] The compounds of the formula XV may be prepared from
compounds of the formula 12
[0052] with a halogenating agent such a thionyl chloride or
bromide, or phosphorous oxychloride or pentachloride, or
phosphorous oxybromide or pentabromide. The reaction may be carried
out without a solvent or in an aprotic solvent such as methylene
chloride or dichloroethane at temperatures of about 0.degree. C. to
about 100.degree. C.
[0053] The compounds of the formula I wherein R.sub.1 is
C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkylthio and R.sub.2 is
C.sub.1-C.sub.6 alkoxy may be prepared from a compound of the
formula 13
[0054] wherein R.sub.XX is chloro or bromo, R.sub.2 is
C.sub.1-C.sub.6 alkoxy and R.sub.3, R.sub.4 and A are as defined
above with reference to formula I, with a C.sub.1-C.sub.6 alcohol
or C.sub.1-C.sub.6 mercaptan in the presence of a base. The
reaction is generally carried out in a polar organic solvent such
as ethanol or t-butanol at temperatures from about 20.degree. C. to
about 160.degree. C., conveniently the reflux temperature of the
reaction mixture.
[0055] The compounds of the formula XVII may be prepared from a
compound of the formula 14
[0056] by reaction with a halogenating agent such as thionyl
chloride or bromide, or phosphorous oxychloride or pentachloride,
or phosphorous oxybromide or pentabromide. The reaction may be
carried out without a solvent or in an aprotic solvent such as
methylene chloride, or dichloroethane at temperatures of about
0.degree. C. to about 100.degree. C.
[0057] The compounds of the formula XVIII may be prepared by
treating a compound of the formula 15
[0058] with an activated derivative of a carboxylic or sulfonic
acid of the formula R.sub.3AOH, conveniently an acid chloride of
the formula R.sub.3ACl wherein R.sub.3 and A are as defined above
with reference to formula I, in the presence of calcium hydroxide
in an aprotic solvent such a dioxane as described by Jensen in the
reference cited above.
[0059] The compounds of the formula XIX may be prepared by treating
a compound of the above formula XV with an alcohol in the presence
of a base. The reaction is generally carried out in a polar organic
solvent such as ethanol at temperatures from about 20.degree. C. to
about 160.degree. C., conveniently the reflux temperatures of the
reaction mixture.
[0060] The compounds of the formula I wherein R.sub.1 is amino and
R.sub.2 is O(C.sub.1-C.sub.6alkyl) may be prepared by reacting a
compound of the formula 16
[0061] wherein R.sub.3, R.sub.4 and A are as defined above with
reference to formula I, with hydrazine in a solvent such as a
C.sub.1-C.sub.6 alcohol, conveniently at the boiling point of the
solvent.
[0062] The compounds of the formula XX may be prepared by treating
a compound of the formula 17
[0063] wherein R.sub.3, R.sub.4 and A are as defined above with
reference to formula I, with an alkylating agent such as
di(C.sub.1-C.sub.6 alkyl) sulfate, and a base such as sodium
hydride, in a solvent such as dimethylsulfoxide.
[0064] The compounds of the formula XXI may be prepared by treating
a compound of the formula 18
[0065] with an activated derivative of a carboxylic or sulfonic
acid of the formula R.sub.3AOH such as an acid chloride of the
formula R.sub.3ACl, wherein R.sub.3 and A are as defined with
reference to formula I, in the presence of a Lewis acid such as
aluminum chloride in an aprotic solvent such as methylene chloride,
dichloroethane, or tetrachloroethane, at temperatures of about
0.degree. C. to about 150.degree. C.
[0066] The compounds of the formula XXII may be prepared by
treatment of a compound of the formula 19
[0067] with phthalic anhydride in acetic acid at the boiling point
of the solvent.
[0068] The compounds of the formula XXIII may be prepared by
contacting cyanoacetyl chloride with R.sub.4NHNH.sub.2 in the
presence of a base followed by heating the resulting hydrazide at
reflux in alcoholic solution in the presence of a base.
[0069] The compounds of formula I wherein A and R.sub.1 are taken
together to form pyrimidinyl have the formula 20
[0070] wherein R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are as
defined above with reference to formula I. These compounds may be
prepared by cyclization of a compound of the above formula I
wherein A is C.dbd.O and R.sub.1 is amino with a compound of the
formula 21
[0071] wherein R.sub.5 is as defined with reference to formula I.
This reaction is generally carried out at 100 to 250.degree. C.,
and conveniently at the reflux temperature of the compound XXV.
[0072] The compounds of formula I wherein A and R.sub.1 are taken
together to form 5-pyridyl have the formula 22
[0073] wherein R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined
with reference to formula I. These compounds may be prepared as
shown in Reaction Scheme 1. 23
[0074] The compounds of formula XXIX are prepared by reacting a
ketone of the formula XXVII with a compound of the formula XXVIII
in a suitable solvent such as tetrahydrofurane in the presence of a
base such as sodium hydride. The reaction is conveniently carried
out at the reflux temperature of the reaction mixture.
[0075] The compound XXIX is reacted with a compound of the formula
R.sub.2C(OCH.sub.3).sub.3 to form the compound XXX. The reaction is
carried out in a suitable solvent such as ethyl acetate,
conveniently at the reflux temperature of the reaction mixture. The
wavy line in formula XXX indicates that either isomer of this
compound is included, in accordance with accepted convention for
indicating stereoisomers.
[0076] The compound XXXI is prepared by reacting compound XXX with
a hydrazine of the formula H.sub.2NNHR.sub.4 wherein R.sub.4 is as
defined with reference to formula I. The reaction is carried out in
a suitable solvent such as ethanol, conveniently at the reflux
temperature of the reaction mixture.
[0077] The compounds of formula XXVI wherein R.sub.5 is linked to
position 6 is formed by first reacting compound XXXI with hydrazine
hydrate in a suitable solvent such as ethanol, conveniently at the
reflux temperature of the reaction mixture. The compound XXXII is
separated from precipitated phthalhydrazide and taken up in an
organic solvent such as toluene. The compound XXVI is formed by
dehydrogenation of compound XXXII with palladium over carbon.
[0078] Reaction Scheme 1 shows the preparation of compounds XXVI
wherein R.sub.5 is in the 6-position. A similar reaction sequence
may be followed to prepare compounds XXVI wherein R.sub.5 is in the
7-position by replacing compound XXVIII by a compound of the
formula 24
[0079] The compounds of formula I wherein A is C.dbd.O and R.sub.1
and R.sub.2 are the same group R.sub.7 may be prepared by reacting
a .beta.-ketone of the formula 25
[0080] with the hydrazine of the formula IV as defined above to
form a pyrazole compound of the formula 26
[0081] The reaction proceeds at reflux in an appropriate solvent
such as ethanol. After bromination of the pyrazole compound, e.g.
with bromine in acetic acid, to form the corresponding 4-bromo
derivative and conventional metallation, e.g. with t-butyl lithium,
at -78.degree. C. in tetrahydrofuran, a suitably activated R.sub.3
carboxylic acid such as the acid chloride R.sub.3C(O)Cl is added to
give the desired compound I.
[0082] The compounds of formula I wherein A is C.dbd.O and R.sub.1
and R.sub.2 are not the same, and wherein R.sub.1 or R.sub.2 is
attached through a C.sub.2H.sub.4 fragment, may be prepared from a
pyranone of the formula 27
[0083] wherein R.sub.3 is as defined above, and R.sub.2 is as
defined above when R.sub.11 is C.sub.3-C.sub.6 alkyl which may be
substituted by 1 to 3 of R.sub.6, or R.sub.2 is R.sub.1 when
R.sub.11 is C.sub.3-C.sub.6 alkyl which may be substituted by one
to three of hydroxy, amino, carboxy, amido,
NH(C.dbd.O)(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl), (C.dbd.O)O(C.sub.1-C.sub.6),
C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 thioalkyl, fluoro, bromo,
chloro, iodo, cyano or nitro. The compound XXXIV is reacted with a
hydrazine of the formula H.sub.2NNHR.sub.4 wherein R.sub.4 is as
defined above to form compounds of the formulae 28
[0084] which on dehydration and hydrogenation result in compounds
of the formulae 29
[0085] The compounds of the formula I wherein A is C.dbd.O and
R.sub.2 is O(C.sub.1-C.sub.6 alkyl) may be prepared by reacting a
hydrazine of the formula R.sub.4NHNH.sub.2 with a compound of the
formula (A) in a suitable solvent 30
[0086] such as THF or methylene chloride and cyclization of the
resulting hydrazide with heat to give the intermediate (B). This
compound may be reacted with an activated carboxyclic acid
derivative such as the acid chloride R.sub.3(C.dbd.O)Cl in the
presence of a Lewis acid such as aluminum trichloride in a solvent
such as ethylene dichloride at temperatures of from about
-10.degree. C. to about 80.degree. C. The formed compound of
formula I wherein R.sub.2 is hydroxy may be reacted with
(C.sub.1-C.sub.6 alkyl)L wherein L is a leaving group such as
chloro, bromo, or tosylate and C.sub.1-C.sub.6 alkyl may be
substituted in accordance with the substituents in the definition
of R.sub.2.
[0087] Those compounds of formula I wherein R.sub.1 is
C.sub.1-C.sub.6 alkylamino or di(C.sub.1-C.sub.6 alkyl)amino may be
prepared from corresponding compounds of formula I wherein R.sub.1
is amino. When R.sub.1 is methylamino or dimethylamino, reaction is
with a methylating agent such as methyl iodide. When R.sub.1 is
C.sub.2-C.sub.6 alkylamino or di(C.sub.2-C.sub.6 alkyl)amino,
reaction is with an alkylating agent such as C.sub.2-C.sub.6
alkyl-L wherein L is a leaving group such as chloro, bromo,
tosylate, or mesylate. Both the methylation and the C.sub.2-C.sub.6
alkylation is in the presence of a base such as sodium hydride and
a solvent such as tetrahydrofuran, dimethyl formamide or dimethyl
sulfoxide.
[0088] The acid addition salts are prepared in a conventional
manner by treating a solution or suspension of the free base of
formula I with one chemical equivalent of a pharmaceutically
acceptable acid. Conventional concentration or crystallization
techniques are employed in isolating the salts. Illustrative of
suitable acids are acetic, lactic, succinic, maleic, tartaric,
citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric,
phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic,
sulfonic acids such as methanesulfonic, benzene sulfonic,
p-toluenesulfonic, and related acids.
[0089] The compound of the invention may be administered alone or
in combination with pharmaceutically acceptable carriers, in either
single or multiple doses. Suitable pharmaceutical carriers include
inert solid diluents or fillers, sterile aqueous solution and
various organic solvents. The pharmaceutical compositions formed by
combining the novel compounds of formula I and the pharmaceutically
acceptable carriers are then readily administered in a variety of
dosage forms such as tablets, powders, lozenges, syrups, injectable
solutions and the like. These pharmaceutical compositions can, if
desired, contain additional ingredients such as flavorings,
binders, excipients and the like. Thus, for purposes of oral
administration, tablets containing various excipients such as
sodium citrate, calcium carbonate and calcium phosphate may be
employed along with various disintegrants such as starch, alginic
acid and certain complex silicates, together with binding agents
such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
Additionally, lubricating agents such as magnesium stearate, sodium
lauryl sulfate and talc are often useful for tabletting purposes.
Solid compositions of a similar type may also be employed as
fillers in soft and hard filled gelatin capsules. Preferred
materials for this include lactose or milk sugar and high molecular
weight polyethylene glycols. When aqueous suspensions or elixirs
are desired for oral administration, the essential active
ingredient therein may be combined with various sweetening or
flavoring agents, coloring matter or dyes and, if desired,
emulsifying or suspending agents, together with diluents such as
water, ethanol, propylene glycol, glycerin and combinations
thereof.
[0090] For parenteral administration, solutions of the novel
compound of formula I in sesame or peanut oil, aqueous propylene
glycol, or in sterile aqueous solution may be employed. Such
aqueous solutions should be suitably buffered if necessary and the
liquid diluent first rendered isotonic with sufficient saline or
glucose. These particular aqueous solutions are especially suitable
for intravenous, intramuscular, subcutaneous and intraperitoneal
administration. The sterile aqueous media employed are all readily
available by standard techniques known to those skilled in the
art.
[0091] Additionally, it is possible to administer the compounds of
the present invention topically when treating inflammatory
conditions of the skin and this may be done by way of creams,
jellies, gels, pastes and ointments, in accordance with standard
pharmaceutical practice.
[0092] The effective dosage for the compound of formula I depends
on the intended route of administration and other factors such as
age and weight of the patient, as generally known to a physician.
The dosage also depends on the illness to be treated, although in
general the daily dosage will range from about 0.1 to 50 mg/kg of
the body weight of the patient. More specifically, the daily dosage
for stress-induced illnesses will generally range from about 0.1 to
50 mg/kg of the body weight of the patient to be treated, for
treatment of inflammatory diseases about 0.1 to about 100 mg/kg
will be needed, for Alzheimer's disease, about 0.1 to about 50
mg/kg, as well as for gastrointestinal diseases, anorexia nervosa,
hemorrhagic stress, and drug and alcohol withdrawal symptoms.
[0093] The methods for testing the compounds for formula I for
their CRF antagonist activity are according to the procedures of
Endocrinology, 116, 1653-1659 (1985) and Peptides, 10, 179-188
(1985) which determine the binding activity of a test compound to a
CRF receptor. The binding activity for the compounds of formula I
generally ranges from about 0.2 nanomolar to about 10
micromolar.
[0094] The following abbreviations are used in the Examples:
Ph=phenyl; iPr=isopropyl; HRMS=high resolution mass spectrum.
EXAMPLE 1
A. 2-Bromo-2',5'-dimethylacetophenone
[0095] A mixture of 10.60 g (0.10 mol) of para-xylene and 16.53 g
(0.105 mol) of .alpha.-bromoacetyl chloride in 300 mL of
1,2-dichloroethane was cooled in an ice bath under an atmosphere of
dry N.sub.2 and treated portionwise with 14.15 g (0.106 mol) of
aluminum chloride. The reaction mixture was stirred for 30 minutes
at 0-5.degree. C. and then for 2.5 hours at room temperature. The
mixture was then poured onto ice and the aqueous layer was
acidified with concentrated HCl. The organic layer was separated
and the aqueous layer was extracted twice with methylene
dichloride. The combined organic extracts were dried with brine
solution and with magnesium sulfate. The solvent was evaporated to
give 23.87 g of an amber oil which was for use in the next reaction
without further purification.
B. 2-Cyano-2',5'-dimethylacetophenone
[0096] The product of the above reaction (approximately 0.10 mol)
was dissolved in 300 mL of ethanol and was treated with a solution
of 16.25 g (0.25 mol) of potassium cyanide in 30 mL of water and
the resulting mixture was refluxed for 90 minutes. After cooling,
the ethanol was stripped from the mixture on the rotary evaporator
and the residues were made slightly acidic with concentrated
hydrogen chloride. The product was extracted into ethyl acetate
using precautions to avoid escape of hydrogen cyanide. The organic
extracts were dried with brine and with magnesium sulfate and
evaporated to a gummy semi-solid. This was triturated repeatedly
with hot hexane which, on cooling, deposited needles to give the
desired product, 8.50 g (49% for the two reactions), m.p.
75-76.degree. C.
C. 3,3-Bis-methylthio-2-(2,5-dimethylbenzoyl)-acrylonitrile
[0097] A solution of 4.96 g (28.6 mmol) of
2-cyano-2',5'-dimethylacetophen- one in 120 mL of dry dimethyl
sulfoxide and 3.43 mL (57.3 mmol) of carbon disulfide in a
flame-dried 3-neck round bottom flask under dry nitrogen was
stirred at 15-18.degree. C. while 1.41 g (58.7 mmol) of oil free
sodium hydride was added in 5 portions. The resulting deep red
solution was stirred for 1 hour at 18.degree. C. and then cooled to
15.degree. C. whereupon 3.92 mL (8.95 g, 63.0 mmol) of methyl
iodide was added dropwise. The temperature rose to about 22.degree.
C. during the addition. After stirring for 2 hours at room
temperature, the reaction mixture was poured into cold water and
the aqueous layer was extracted three times with ethyl acetate. The
combined extracts were washed three times with water and then dried
with brine and magnesium sulfate. Evaporation gave 8.96 g of the
title compound as a heavy orange oil which crystallized in the
refrigerator. The analytical sample crystallized from ethanol, m.p.
74.5-75.5.degree. C.
D.
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2,5-dimethylbenzoyl-
)-3-methylthiopyrazole
[0098] A suspension of 7.94 g (28.6 mmol) of the product of step C
and 7.01 g (28.6 mmol) of
2,6-dichloro-4-trifluoromethylphenylhydrazine in 100 mL of ethanol
was heated at reflux for 2 hours, solution occurring as the
reaction mixture was warmed. Then the ethanol was mostly removed on
the rotary evaporator and the residues were partitioned between
dilute aqueous hydrogen chloride solution and ethyl acetate. The
organic phase was washed once with water and with brine, then dried
with magnesium sulfate and treated with decolorizing carbon. The
filtered solution was evaporated and the residues crystallized from
10:1 hexane/ethyl acetate to give 12.00 g (88%) of the title
product in two crops, m.p. 130-132.degree. C.
EXAMPLE 2
5-Methylamino-4-(2-chlorobenzoyl)-3-methylthio-1-(2,4,6-trichlorophenyl)py-
razole and
5-dimethylamino-4-(2-chlorobenzoyl)-3-methylthio-1-(2,4,6-trich-
lorophenyl)-pyrazole
[0099] A mixture of 0.50 g (1.16 mmol) of
5-amino-4-(2-chlorobenzoyl)-3-me-
thylthio-1-(2,4,6-trichlorophenyl)pyrazole in 5 mL of
tetrahydrofuran was treated with 50 mg (1.16 mmol) of sodium
hydride and stirred at room temperature for 30 minutes. Then 0.75
ml (1.71 g, 12.0 mmol) of methyl iodide was added dropwise and the
reaction mixture was stirred for 60 minutes at room temperature.
The reaction mixture was then quenched with water and the products
were extracted into ethyl acetate. Concentration of the dried
solution and chromatography on silica gel with mixture of hexane
and ethyl acetate gave the less polar dimethylamino title compound
(300 mg, 54%) as a white foam.
[0100] Anal. Calcd. for C.sub.19H.sub.15ON.sub.3SCl.sub.4: C,
48.02; H, 3.18; N, 8.88. Found: C, 47.84; H, 3.09; N, 9.01.
[0101] The more polar monomethyl title compound was isolated from
the column in like manner as a white foam (34 mg, 6%).
[0102] Anal. Calcd. for C.sub.18H.sub.13ON.sub.3SCl.sub.4: C,
46.88; H, 2.84; N, 9.11. Found: C, 46.54; H, 2.89; N, 9.07.
EXAMPLE 3
5-Amino-4-(2-methoxybenzoyl)-3-methylthio-1-(2,4,6-trichlorophenyl)pyrazol-
e
[0103] To a solution of 2-methoxyphenylmagnesium bromide prepared
from 18.7 g (0.10 mol) of 2-bromoanisole and 2.43 g (0.10 mol) of
magnesium turnings in ether under dry nitrogen was added 1.6 g (5.0
mmol) of
5-amino-4-cyano-3-methylthio-1-(2,4,6-trichlorophenyl)pyrazole and
the resulting mixture was stirred and refluxed for 16 hours. Upon
cooling, the reaction was decomposed with 50 mL of saturated
ammonium chloride solution. The organic phase was extracted with
aqueous hydrogen chloride and the acidic extract was treated with
10 mL of concentrated hydrogen chloride and heated at 80-90.degree.
C. for 10 minutes after which the mixture was cooled and made
alkaline. Extraction with methylene dichloride and chromatography
of the extracts with mixtures of hexane and ethyl acetate gave 313
mg (14%) of the title compound, m.p. 200-202.degree. C.
[0104] Anal. Calcd. for C.sub.18H.sub.14O.sub.2N.sub.3SCl.sub.3: C,
48.82; H, 3.18; N, 9.49. Found: C, 48.54; H, 3.32; N, 9.09.
EXAMPLE 4
A. 5-Amino-3-methyl-1-(2,4,6-trichlorophenyl)pyrazole
[0105] To a solution of 0.51 g (22.0 mmol) of sodium in methanol
was added 1.66 g (20.0 mmol) of 5-methylisoxazole. The reaction
mixture as refluxed for 8 hours and then stirred overnight at room
temperature. Then 4.23 g (20.0 mmol) of
2,4,6-trichlorophenylhydrazine was added and the reaction mixture
was again refluxed for 4 hours. A second portion of sodium in
methanol was added and reflux was continued for 24 hours. The
reaction mixture was taken up with ether and dilute hydrogen
chloride. The organic extracts were washed with dilute hydrogen
chloride and brine, and then dried with magnesium sulfate and
evaporated to give crystals, m.p. 132-134.degree. C. Analysis of
this material, particularly two CN bands in the IR spectrum at 2190
cm.sup.-1 and 2250 cm.sup.-1, revealed it to be a mixture of the
cis- and trans-isomers of 1-cyanoacetone-2,4,6-trichl-
orophenylhydrazone. This material was suspended in methanol and
treated with 10.0 mmol of sodium methoxide in 5 mL of methanol.
After 5 minutes at room temperature, water was added to crystallize
the product which was filtered off and washed well with water.
After air drying, the product weighed 2.21 g (40%) and melted at
134.0-135.5.degree. C. Despite the similarity in melting points,
the latter material was distinctly different from the former,
having an R.sub.f of 0.67 vs. 0.78 for the intermediate on silica
gel TLC plates developed with 1:1 hexane ethyl acetate and a
distinctly different 300 MHz proton NMR spectrum.
B.
5-(2-Chlorobenzamido)-4-(2-chlorobenzoyl)-3-methyl-1-(2,4,6-trichloroph-
enyl)pyrazole
[0106] A suspension of 2.34 g (17.50 mmol) of aluminum trichloride
in 20 mL of 1,1,2,2-tetrachloroethane was treated with 2.02 mL
(2.78 g, 15.9 mmol) of 2-chlorobenzoyl chloride and the resulting
solution was stirred for 20 minutes at room temperature. Then 2.00
g (7.23 mmol) of the product of Step A was added and the reaction
mixture was refluxed for 16 hours. The cooled reaction mixture was
poured over ice and the insolubles were filtered off and washed
with ethyl acetate. The organic layer was separated and the aqueous
was washed twice with ethyl acetate. The combined organic layers
were dried over magnesium sulfate and evaporated. The residues were
chromatographed on silica gel, eluting with 4:1 hexane ethyl
acetate to give 2.05 g (51%) of the title product, an amorphous
foam.
[0107] Anal. Calcd. for C.sub.24H.sub.14O.sub.2N.sub.3Cl.sub.5: C,
52.06; H, 2.55; N, 7.593. Found: C, 52.11; H, 2.57; N, 7.27.
C. 5-Amino-4-(2-chlorobenzoyl)-3-methyl-1-(2,4,6-trichlorophenyl)
pyrazole
[0108] A solution of 1.94 g (3.50 mmol of the product of Step B in
20 mL of glacial acetic acid was treated with 20 mL of 48% hydrogen
bromide and stirred at reflux for 8 hours. The cooled reaction
mixture was treated with water to crystallize the product which was
separated by filtration, washed with water and air dried to give
the title product, 1.45 g (100%), m.p. softens about 210.degree. C.
and melts at 222.degree. C.
[0109] Anal. Calcd. for C.sub.17H.sub.11ON.sub.3Cl.sub.4: 412.9656.
Found: 412.9722.
EXAMPLE 5
5-Methylamino-4-(2-chlorobenzoyl)-3-methyl-1-(2,4,6-trichlorophenyl)pyrazo-
le and
5-dimethylamino-4-(2-chlorobenzoyl)-3-methyl-1-(2,4,6-trichlorophen-
yl)pyrazole
[0110] A solution of 0.208 g (0.5 mmol) of the compound of Example
4C in 20 mL of tetrahydrofuran (THF) was stirred in an ice/water
bath while 5.0 mL of 1.0 M sodium hexamethyldisilazide in THF was
added followed by 0.5 mL (1.14 g, 8 mmol) of methyl iodide. The
reaction mixture was then stirred overnight at room temperature.
The reaction mixture was poured into water and the products were
extracted into ethyl acetate, dried and concentrated. The residues
were chromatographed on silica gel using 5:1 hexane/ethyl acetate
as eluent to give the less polar dimethylamino title compound, 52
mg (23%), m.p. 108-109.degree. C. (ether/pentane).
[0111] The more polar product likewise crystallized from
ether/pentane to give 39 mg (18%) of the monomethylamino title
compound, m.p. 174-175.degree. C.
EXAMPLE 6
5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2,5-dimethylbenzoyl)-3-
-(n-propyl)pyrazole
[0112] A solution of 0.52 g (3.0 mmol) of
2,5-dimethylbenzoylacetonitrile, 0.45 g (3.0 mmol) of
trimethylorthobutyrate and 0.632 g (0.58 mL, 6.2 mmol) of acetic
anhydride in 5.0 mL of ethyl acetate was refluxed overnight and
then cooled. The solvents were removed in vacuo and the residues
were dissolved in 10 mL of ethanol. One-half of this solution,
containing 1.5 mmol of
1-cyano-1-(2,5-dimethylbenzoyl)-3-methoxy-1-penten- e was mixed
with 0.7 mL (0.51 g, 5.0 mmol) of triethylamine and 0.37 g (1.50
mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine and refluxed
for 2.5 hours. The reaction mixture was cooled and partitioned
between dilute hydrogen chloride and ethyl acetate. The organic
phase was washed with water and then dried with brine and with
magnesium sulfate. The solvent was evaporated to give an oil which
was chromatographed on silica gel by the flash method eluting with
4:1 hexane/ethyl acetate to give the title compound as an amorphous
foam.
[0113] Anal. Calcd. for C.sub.22H.sub.20ON.sub.3Cl.sub.2F.sub.3,
469.0935. Found: 469.0889.
EXAMPLE 7
A. 5-Amino-3-hydroxy-1-(2,4,6-trichlorophenyl)-pyrazole
[0114] Cyanoacetic acid (8.5 g, 0.10 mol) in 200 mL of dry ether
was treated with 20.8 g (0.10 mol) of phosphorous pentachloride,
warmed briefly to reflux and let cool to room temperature at which
time all of the phosphorous pentachloride, had dissolved. After a
small amount of insoluble material was removed by filtration, the
ether was removed on the rotary evaporator. Then 100 mL of toluene
was added and stripped to remove phosphorous oxytrichloride. The
residual pale yellow oil was immediately dissolved in 50 mL of cold
methylene dichloride and added to a cold suspension of 21.15 g
(0.10 mol) of 2,4,6-trichlorophenylhydrazine in 14.0 mL of
triethylamine and 100 mL of methylene dichloride, keeping the
temperature below 20.degree. C. by use of an ice bath. The reaction
mixture was allowed to warm to room temperature and stirred for one
hour. Then 500 mL of cold water was added. The precipitated solid
was filtered and washed with water and with a little methylene
dichloride to give the intermediate
2-cyano-N-(2,4,6-trichlorophenyl)acethydrazide, 14.92 g (54%), m.p.
166-168.degree. C.
[0115] Anal. Calcd. for C.sub.9H.sub.6ON.sub.3: C, 38.81; H, 2.17;
N, 15.09. Found: C, 38.83; H, 2.06; N, 14.81.
[0116] This material (14.92 g, 53 mmol) was dissolved in a solution
of 2.80 g (0.12 mol) of sodium in 200 mL of methanol and refluxed
for 4 hours. After stirring overnight at room temperature, the
methanol was mostly evaporated and the residues were poured into
water. The aqueous layer was extracted with ether and was then
acidified with concentrated hydrogen chloride. The product was
extracted into ethyl acetate. The extracts were dried with brine
and magnesium sulfate and evaporated to give a foam which
crystallized from ether to give 12.28 g (93%) of the title product,
m.p. 221-223.degree. C.
[0117] Anal. Calcd. for C.sub.9H.sub.6ON.sub.3: C, 38.81; H, 2.17;
N, 15.09. Found: C, 38.81; H, 2.16; N, 14.84.
B. 3-Hydroxy-5-phthalimido-1-(2,4,6-trichlorophenyl)pyrazole
[0118] A mixture of 4.50 g (18.0 mmol) of the compound of Step A
and 2.81 g (19.0 mmol) of phthalic anhydride in 40 mL of glacial
acetic acid was refluxed for 4 hours and stirred overnight at room
temperature. About two volumes of water were added dropwise and the
resulting solid was filtered and washed with water. The damp solid
was taken up in a little ethanol, filtered and washed with a little
ethanol and ether, and air dried to give the title compound, 5.11 g
(69%), m.p. 295-298.degree. C. (dec).
[0119] Anal. Calcd. for C.sub.17H.sub.8O.sub.3N.sub.3Cl.sub.3: C,
49.97; H, 1.97; N, 10.28. Found: C, 49.28; H, 1.95; N, 10.06.
C.
4-(2-Chlorobenzoyl)-3-hydroxy-5-phthalimido-1-(2,4,6-trichlorophenyl)py-
razole
[0120] Aluminum trichloride (2.34 g, 17.6 mmol) was added to a
solution of 2-chlorobenzoyl chloride in 60 mL of
1,1,2,2-tetrachloroethane and the resulting mixture was stirred for
30 minutes at room temperature. Then 2.87 g of the compound of Step
B was added all at once and the reaction mixture was refluxed
overnight. The cooled mixture was poured into water and the aqueous
phase was extracted three times with ethyl acetate. The organic
extracts were dried with brine and magnesium sulfate and evaporated
to give a red oil which was taken up in methanol and crystallized
to give the title compound, 2.97 g (77%), m.p. 245-246.degree.
C.
D.
4-(2-Chlorobenzoyl)-3-ethoxy-5-phthalimido-1-(2,4,6-trichlorophenyl)pyr-
azole
[0121] A solution of 0.55 g (1.0 mmol) of the compound of Step C in
10 mL of dry dimethyl sulfoxide was treated portionwise with 36 mg
(1.5 mmol) of sodium hydride and the resulting mixture was stirred
for 30 minutes at room temperature. Then 0.21 mL (0.25 g, 1.61
mmol) of diethyl sulfate was added and the reaction mixture was
stirred for one hour at room temperature. The reaction mixture was
poured into water and the product was extracted into ethyl acetate.
The extracts were washed with water and dried with brine and
magnesium sulfate, and evaporated to a gum. The product was
crystallized from boiling ethanol to give the product (230 mg, 40%)
as fine crystals, m.p. 215-216.degree. C.
E. 5-Amino-4-(2-chlorobenzoyl)-3-ethoxy-1-(2,4,6-b
Ztrichlorophenyl)pyrazo- le
[0122] A suspension of 184 mg of the compound of Step D in 10 mL of
ethanol was treated with 0.5 mL of 55% hydrazine hydrate and
refluxed for 1 hour. Solids in the cooled reaction mixture were
filtered off and discarded and the filtrate was evaporated to a gum
which was triturated with ether and filtered. The filtrate was
again evaporated to a foam which was shown to be 104 mg of the
analytically pure title compound.
[0123] Anal. Calcd. for C.sub.18H.sub.13O.sub.2N.sub.3Cl.sub.4: C,
48.57; H, 2.94; N, 9.44. Found, C, 48.41; H, 2.52; N, 9.43.
EXAMPLE 8
5-Dimethylamino-4-(2-chlorobenzoyl)-3-methoxy-1-(2,4,6-trichlorophenyl)pyr-
azole
[0124] A solution of 60 mg (0.14 mmol) of
5-amino-4-(2-chlorobenzoyl)-3-me- thoxy-1-(2,4,6-trichlorophenyl)
pyrazole prepared according to Example 7 in 5 mL of dry dimethyl
sulfoxide was treated with 22 mg (0.88 mmol) of oil-free sodium
hydride to give a yellow solution. After 1 hour at room
temperature, 0.2 mL (0.46 g, 3.21 mmol) of methyl iodide was added.
After stirring for 5 hours, the reaction mixture was poured into
water and the product was extracted into ethyl acetate. After
drying with brine and magnesium sulfate, the solvent was removed to
give the title product as a one-spot foam. .sup.1H-NMR
(CDCl.sub.3): 2.77 (6H, s), 3.63 (3H, s), 7.24-7.42 (4H, m), 7.48
(2H, s).
EXAMPLE 9
A. 3,3-Bis-ethoxy-2-(3-trifluoromethylbenzoyl)-acrylonitrile
[0125] Sodium (0.126 g, 5.5 mmol) was dissolved in 15 mL of ethanol
and 20 mL of dioxane was added followed by 1.59 g (5.0 mmol) of
3,3-bis-methylthio-2-(3-trifluoromethylbenzoyl)-acrylonitrile and
the reaction mixture was refluxed for 4 hours and let stir
overnight at room temperature. This compound was relatively
unstable to aqueous conditions and was not isolated as such.
Instead, an aliquot of the mixture was stripped and the product was
identified by 300 MHz proton NMR: NMR (DMSO-d.sub.6): 1.14 (6H,
tJ=7), 3.45 (4H, q, J=7), 7.44-8.16 (4H, m).
B.
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-ethoxy-4-(3-trifluor-
omethylbenzoyl)pyrazole
[0126] An aliquot of the above solution of step A containing
approximately two millimoles of
3,3-bis-ethoxy-2-(3-trifluoromethylbenzoyl)acrylonitril- e was
reacted with 0.49 g (2.0 mmol) of
2,6-dichloro-4-trifluoromethylphen- ylhydrazine in 10 mL of ethanol
under reflux overnight. The cooled mixture was poured into dilute
hydrogen chloride (HCl) and the product was extracted into ethyl
acetate (EtOAc), washed with water and brine, and dried over
magnesium sulfate (MgSO.sub.4). Chromatography on silica gel with
4:1 hexane/EtOAc gave the title product, 320 mg (31%), m.p.
77-78.degree. C. from pentane.
EXAMPLE 10
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2,5-dimethylbenzoyl)-3-
-ethoxypyrazole
[0127] A solution of 0.26 g (1.5 mmol) of
2,5-dimethylbenzoylacetonitrile, 0.34 mL (0.31 g, 1.60 mmol) of
tetraethylorthocarbonate and 0.30 mL (0.33 g, 3.20 mmol) of acetic
anhydride in 10 mL of EtOAc was refluxed overnight. The solvent was
evaporated and 10 mL of absolute ethanol was added and then
stripped. The residues were dissolved in 10 mL of ethanol, 368 mg
(1.5 mmol) of 2,6-dichloro-4-trifluoromethylphenyl-hydrazine and
0.7 mL (0.51 g, 5.0 mmol) of triethylamine were added, and the
mixture was refluxed for 90 minutes. The mixture was poured into
water, extracted with EtOAc and the organic extracts were washed
with dilute HCl and brine, and dried over MgSO.sub.4. Evaporation
gave a gum which was chromatographed on silica gel with 4:1
hexane/EtOAc to give the title product which crystallized from
pentane, 15 mg (2%), m.p. 99-101.degree. C.
EXAMPLE 11
1-(2,6-Dichloro-4-trifluoromethylphenyl)-5-methyl-4-(3-methylbenzoyl)-3-me-
thylthiopyrazole
[0128] A solution of 2.97 g (16.9 mmol) of
4-(3-methylphenyl)butane-2,4-di- one and 4.04 mL (5.14 g, 67.6
mmol) of carbon disulfide in 60 mL of dry dimethyl sulfoxide was
treated portionwise with 0.89 g (37.1 mmol) of oil-free sodium
hydride at 15-18.degree. C. After stirring 30 minutes, 2.31 mL
(5.27 g, 37.1 mmol) of methyl iodide was added dropwise and the
reaction mixture was allowed to stir at room temperature for 1
hour. It was then poured into water and the product was extracted
into ether, backwashed with water and dried over MgSO.sub.4 to give
4.30 g (91%) of an oil which crystallized in the refrigerator
overnight, m.p. 44-46.degree. C. .sup.1H-NMR (CDCl.sub.3): 2.16
(3H, s), 2.38 (6H, s), 2.72 (3H, s), 7.26-7.38 (2H, m), 7.58-7.74
(2H, m). A mixture of 1.95 g (6.96 mmol) of
3,3-bismethylthio-2-(3-methylbenzoyl)-2-acetylethene and 1.71 g of
2,6-dichloro-4-trifluoromethylphenylhydrazine in 20 mL of ethanol
was refluxed for 6 hours and then stirred at room temperature for
48 hours. The reaction mixture was poured into dilute HCl solution
and the product was extracted into EtOAc. The solution was dried
and concentrated and the residues were chromatographed on silica
gel with 10:1 hexane/EtOAc to give the title product which
crystallized from pentane, 1.67 g (52%), m.p. 103-104.degree.
C.
EXAMPLE 12
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(5-[3-hydroxypropyl]-2--
methylbenzoyl)-3-methylthiopyrazole
[0129] A solution of 0.530 g (1.0 mmol) of
5-amino-1-(2,6-dichloro-4-trifl-
uoromethylphenyl)-4-(5-[.beta.-methoxycarbonylethyl]-2-methylbenzoyl)-3-me-
thylthiopyrazole in 10 mL of THF was cooled in an ice bath while
1.33 mL of a 1.5 M solution of DIBAL in THF was added. The reaction
mixture was warmed to room temperature and then quenched with
water. The product was extracted into EtOAc, dried and
concentrated. The residues were chromatographed on silica gel using
mixtures of hexane/EtOAc to elute the title product which was
isolated as an amorphous foam, 174 mg (34%).
[0130] Anal. Calcd. for
C.sub.22H.sub.20O.sub.2N.sub.3SCl.sub.2F.sub.3: C, 50.97; H, 3.88;
N, 8.10. Found, C, 51.10; H, 3.96; N, 7.60.
EXAMPLE 13
[5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfonyl-1H-pyra-
zol-4-yl]-(2,5-dimethylphenyl)methanone
[0131] To a solution of 200 mg (0.42 mmol) of
[5-amino-1-(2,6-dichloro-4-t-
rifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-dimethylpheny-
l)methanone in 10 mL of THF: was added 0.176 g (2.10 mmol) of
anhydrous sodium bicarbonate followed by a solution of 145 mg (0.42
mmol) of 3-chloroperoxybenzoic acid in 8 mL of THF. After two hours
at room temperature, 0.5 g of sodium bicarbonate and an additional
290 mg (0.84 mmol) of 3-chloroperoxybenzoic acid was added. The
reaction mixture was heated briefly to 50.degree. C., let cool and
stirred overnight at room temperature. The reaction mixture was
added to water and the product was extracted into ethyl acetate.
The organic extracts were washed with dilute sodium bicarbonate
solution and then dried and evaporated. The title compound was
crystallized from ether to give 150 mg (70% yield) of colorless
crystals, m.p. 193.5-194.5.degree. C.
EXAMPLE 14
[0132] The following compounds in Tables 1 and 2 were prepared
according to the indicated Example.
1TABLE 1 31 Process Physical Data of R.sub.1 R.sub.2 R.sub.13
R.sub.14 R.sub.15 R.sub.11 R.sub.12 (m.p. in .degree. C.) Example
amino SCH.sub.3 2-Cl 4-Cl 6-Cl 2-Cl H m.p. 178-180 1 amino
SCH.sub.3 2-Cl 4-Cl 6-Cl H H m.p. 178-180 1 amino SCH.sub.3
4-CF.sub.3 H H 2-Cl H m.p. 150-153 1 amino SCH.sub.3 2-Cl 4-Cl 6-Cl
2-F H m.p. 204-206 1 NHCH.sub.3 SCH.sub.3 2-Cl 4-Cl 6-Cl 2-Cl H
m.p. 135-137 2 N(CH.sub.3).sub.2 SCH.sub.3 2-Cl 4-Cl 6-Cl 2-Cl H
m.p. 194-197 2 N(CH.sub.3).sub.2 CH.sub.3 2-Cl 4-Cl 6-Cl 2-Cl H
m.p. 220-222 6 amino SCH.sub.3 2-CF.sub.3 H H 2-Cl H m.p. 186-188 1
amino SCH.sub.3 2-Cl 4-Cl 6-Cl 2- H m.p. 165-167 1 cyclopropyl
amino SCH.sub.3 2-Cl 4-Cl 6-Cl 4-CH.sub.3 H m.p. 230-232 1 amino
SCH.sub.3 2-Cl 4-Cl 6-Cl 2-Cl 4-Cl m.p. Amorphous. 1 Anal. Calc'd
for C17H10N30SCl5: C, 42.39; H, 2.09; N, 8.72. Found: C,41.94; H,
2.06; N, 8.07. N(CH.sub.3).sub.2 CH.sub.3 2-Cl 4-Cl 6-Cl 2-Cl H
m.p. 108-109 6 NH.sub.2 SCH.sub.3 2-F 4-F 6-F 2-Cl H m.p. 156-158 1
N(CH.sub.3).sub.2 SCH.sub.3 2-Cl 4-Cl 6-Cl 2-F H m.p. Amorphous. 2
HRMS for C19H15N3OSCl3F Calc'd: 456.9984 Found: 456.9990 NH.sub.2
SCH.sub.3 2-Cl 6-Cl H 2-F H m.p. 182-184 1 NH.sub.2 SCH.sub.3 2-F
4-F H 2-Cl H m.p. 147-150 1 N(CH.sub.3).sub.2 SCH.sub.3 2-Cl 4-Cl
6-Cl 3-Cl H m.p. 121-125 2 NH.sub.2 NHCH.sub.3 2-Cl 4-Cl 6-Cl 2-Cl
H m.p. 86-90 NH.sub.2 SCH.sub.3 2-Cl 4-Cl 6-Cl 2-OCH.sub.3 H m.p.
200-202 1 NH.sub.2 SCH.sub.3 2-Cl 6-Cl 4-CF.sub.3 2-Cl H m.p.
207-210 1 NH(CH.sub.2).sub.3OC.sub.6H.sub.5 SCH.sub.3 2-Cl 6-Cl
4-Cl 2-Cl H m.p. Amorphous. 5 Anal. Calcd. for C26H21N3O2SCl4: C,
53.71; H, 3.64; N, 7.22. Found: C, 53.57; H, 3.41; N, 7.46.
NH.sub.2 SCH.sub.3 2-Cl 6-Cl 4-Cl 3-CH.sub.3 H m.p. 178-180 1
NH.sub.2 SCH.sub.3 2-Cl 6-Cl 4-CF.sub.3 3-Cl H m.p. 149-151 1
NH.sub.2 SCH.sub.3 2-Cl 6-Cl 4-CF.sub.3 3-CH.sub.3 H m.p. 150-153 1
N(CH.sub.3).sub.2 SCH.sub.3 2-Cl 6-Cl 4-CF.sub.3 3-Cl H m.p.
120-122 2 NH.sub.2 SCH.sub.3 2-Cl 6-Cl 4-Cl 3-CF.sub.3 H m.p.
158-160 1 NHCH.sub.2COOH SCH.sub.3 2-Cl 6-Cl 4-Cl 2-Cl H m.p.
>250 1 HRMS for C.sub.19H.sub.13N.sub.3O.sub.3SCl.sub.4: Calcd:
525.9930 Found: 525.9348 NH.sub.2 SCH.sub.3 2-Cl 6-CF.sub.3 4-Cl
3-CF.sub.3 H m.p. Amorphous. 1 Anal. Calcd. for C19H11N3OSCl2F6: C,
44.30; H, 2.15; N, 8.15. Found: C, 44.51; H, 2.29; N, 7.98 NH.sub.2
SCH.sub.3 2-CH.sub.3 4-Cl H 2-Cl H m.p. 125-129 1 NH.sub.2
SCH.sub.3 2-CH.sub.3 4-Cl H 3-Cl H m.p. 112-115 1 NH.sub.2
SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 2-CH.sub.3 5-CH.sub.3 m.p. 130-132 1
NH.sub.2 SCH.sub.3 2-CH.sub.3 6-CH.sub.3 H 3-Cl H m.p. 148-151 1
N(CH.sub.3).sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 3-CF.sub.3 H m.p.
Amorphous. 2 Anal. Calcd. for C21H15N3OSCl2F6: C, 46.50; H, 2.78;
N, 7.74. Found: C, 46.75; H, 2.93; N, 7.58 NH.sub.2 SCH.sub.3 2-Cl
4-CF.sub.3 H 3-Cl H m.p. 124-127 1 NH.sub.2 SCH.sub.3 2-CH.sub.3
6-CH.sub.3 H 3-Cl H m.p. 139-142 1 NH.sub.2 SCH.sub.3 2-Cl 4-Cl
6-Cl 2-CH.sub.3 5-CH.sub.3 m.p. 182-184 1 CH.sub.3 SCH.sub.3 2-Cl
4-Cl 6-Cl 3-CH.sub.3 H m.p. 116-117 NH.sub.2 SCH.sub.3 2-CH.sub.3
4-Cl 6-CH.sub.3 3-CF.sub.3 H m.p. Amorphous. 1 Anal. Calcd. for
C20H17N3OSClF3: C, 54.48; H, 3.88; N, 9.53. Found: C, 54.60; H,
3.91; N, 9.08 NH.sub.2 SCH.sub.3 2-CH.sub.3 4-Cl 6-CH.sub.3 3-Cl H
m.p. Amorphous. 1 Anal. Calcd. for C19H17N3OSCl2: C, 56.16; H,
4.21; N, 10.34. Found: C, 55.93; H, 4.21; N, 10.01 NH.sub.2
SCH.sub.3 2-CH.sub.3 4-CH.sub.3 6-CH.sub.3 3-Cl H m.p. 163-165 1
NH.sub.2 SCH.sub.3 2-CH.sub.3 4-CH.sub.3 6-CH.sub.3 3-CH.sub.3 H
m.p. 124-127 1 NH.sub.2 SCH.sub.3 2-CH.sub.3 4-CH.sub.3 6-CH.sub.3
3-CF.sub.3 H m.p. 143-146 1 NH.sub.2 SCH.sub.3 2-CH.sub.3 4-Br
6-CH.sub.3 3-CF.sub.3 H m.p. Amorphous. 1 Anal. Calcd. for
C20H17N3OSBrF3: C, 49.59; H, 3.53; N, 8.67. Found: C, 49.45; H,
3.49; N, 8.37 NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 2-CH.sub.3
3-CH.sub.3 m.p. 196-198 1 NH.sub.2 SCH.sub.3 2-CH.sub.3 4-Br
6-CH.sub.3 3-Cl H m.p. Amorphous. 1 Anal. Calcd. for
C19H17N3OSBrCl: C, 50.63; H, 3.80; N, 9.32. Found: C, 50.40; H,
3.77; N, 8.94 NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 2-CH.sub.3
5-(CH.sub.2).sub.3-- m.p. Amorphous. 1 CO.sub.2CH.sub.3 Anal.
Calcd. for C24H22N3O3SCl2F 3: C, 51.43; H, 3.96; N, 7.50. Found: C,
51.59; H, 4.10; N, 7.17 NH.sub.2 SCH.sub.3 2-CH.sub.3 6-CH.sub.3
4-Br 2-CH.sub.3 5-CH.sub.3 m.p. Amorphous. 1 Anal. Calcd. for
C.sub.21H.sub.22N.sub.3OS: C, 56.76; H, 4.99; N, 9.45. Found: C,
56.37; H, 5.01; N, 9.04 NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl
2-OCH.sub.3 H m.p. 172-174 1 NH.sub.2 OCH.sub.3 2-Cl 4-Cl 6-Cl 2-Cl
H m.p. Amorphous. 7 .sup.1H-NMR(CDCl.sub.3): 3.68 (3H, s), 5.86(2H,
broad s), 7.26- 7.44(4H, m) 7.51(2H, s). NH.sub.2 OCH.sub.2CH.sub.3
2-Cl 4-Cl 6-Cl 2-Cl H m.p. Amorphous. 7 Anal. Calcd. for
C18H13N302Cl4: C, 48.57; H, 2.94; N, 9.44. Found: C, 48.41; H,
2.52; N, N(CH.sub.3).sub.2 OCH.sub.3 2-Cl 4-Cl 6-Cl 2-Cl H m.p.
Amorphous. 8 HRMS for C19H15N3O2Cl4: Calcd: 456.9913 Found:
456.9960 NH.sub.2 OCH.sub.2CH.sub.3 2-Cl 4-CF.sub.3 6-Cl 3-CF.sub.3
5-CF.sub.3 m.p. Amorphous. 1 Anal. Calcd. for C20H10N3OSCl2F9: C,
41.25; H, 1.73; N, 7.21. Found: C, 41.49; H, 2.01; N, 7.01 NH.sub.2
OCH.sub.3 2-Cl 4-Cl 6-Cl 2-Cl H m.p. Amorphous. 7
.sup.1H-NMR(CDCl.sub.3): 3.68 (3H, s), 5.86(2H, broad s), 7.26-
7.44(4H, m) 7.51(2H, s). NH.sub.2 OCH.sub.2CH.sub.3 2-Cl 4-Cl 6-Cl
2-Cl H m.p. Amorphous. 7 Anal. Calcd. for C18H13N3O2Cl4: C, 48.57;
H, 2.94; N, 9.44. Found: C, 48.41; H, 2.52; N, 9.43
N(CH.sub.3).sub.2 OCH.sub.3 2-Cl 4-Cl 6-Cl 2-Cl H m.p. Amorphous. 8
HRMS for C19H15N3O2Cl4: Calcd: 456.9913 Found: 456.9960 NH.sub.2
OCH.sub.2CH.sub.3 2-Cl 4-CF.sub.3 6-Cl 3-CF.sub.3 5-CF.sub.3 m.p.
Amorphous. 1 Anal. Calcd. for C20H10N3OSCl2F9: C, 41.25; H, 1.73;
N, 7.21. Found: C, 41.49; H, 2.01; N, 7.01 NH.sub.2
OCH.sub.2CH.sub.3 2-Cl 4-CF.sub.3 6-Cl 2-CH.sub.3 5-CH.sub.3 m.p.
Amorphous. 1 High Resolution Mass Spectrum Calcd. for
C22H20N3OCl2F3: 472.0806. Found, 472.0817 NH.sub.2
CH.sub.2CH.sub.2-- 2-Cl 4-CF.sub.3 6-Cl 2-CH.sub.3 5-CH.sub.3 m.p.
Amorphous. 6 CH.sub.3 High Resolution Mass Spectrum Calcd. for
C.sub.21H.sub.20N.sub.3OC- .sub.12F.sub.3: 469.0935. Found:
469.0889 NH.sub.2 CH.sub.2CH.sub.2-- 2-Cl 4-Cl 6-Cl 2-CH.sub.3
5-CH.sub.3 m.p. Amorphous. 6 CH.sub.3 High Resolution Mass Spectrum
Calcd. for C22H20N3OCl2F3: 436.0761. Found: 436.0764 NH.sub.2
SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 3-OCH.sub.3 H m.p. Amorphous. 3
.sup.1H-NMR(CDCl.sub.3) .delta. 2.38(3H, s), 3.90(3H, s), 5.79(2H,
broad s), 7.07(1H, d, J = 7), 7.16(1H, s), 7.23(1H, d, J = 7),
7.39(1H, t, J = 7), 7.79(2H, s) NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3
6-Cl 2-CH.sub.3 5- m.p. Amorphous. 12 (CH.sub.2).sub.4OH High
Resolution Mass Spectrum Calcd. for C23H22N3O2SCl2F 3: 532.0840.
Found: 532.0871 NH.sub.2 CH.sub.2CH.sub.3 2-Cl 4-CF.sub.3 6-Cl
2-CH.sub.3 5-CH.sub.3 m.p. Amorphous. 6 Anal. Calcd. for
C21H18N3OCl2F3: C, 55.29; H, 3.97; N, 8.21. Found: C, 55.62; H,
4.35; N, 8.15 NH.sub.2 CH.sub.2CH.sub.3 2-Cl 4-Cl 6-Cl 2-CH.sub.3
5-CH.sub.3 m.p. Amorphous. 6 Anal. Calcd. for C20H18N3OCl3: C,
56.81; H, 4.29; N, 9.94. Found: C, 56.88; H, 4.09; N, 9.62 NH.sub.2
SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 2-CF.sub.3 5-CF.sub.3 m.p.
Amorphous. 1 Anal. Calcd. for C20H20N3OSCl2F9: C, 41.25; H, 1.71;
N, 7.21. Found: C, 41.20; H, 1.87; N, 6.89 NH.sub.2 SCH.sub.3 2-Cl
4-CF.sub.3 6-Cl 2-CH.sub.3 5-CH.sub.2CO.sub.2-- m.p. Amorphous. 1
C.sub.2H.sub.5 Anal. Calcd. for C23H20N3O3SCl2F 3: C, 50.55; H,
3.68; N, 7.69. Found: C, 50.50; H, 3.50; N, 7.29 NH.sub.2 SCH.sub.3
2-Cl 4-CF.sub.3 6-Cl 2-CH.sub.3 5- m.p. Amorphous. 12
(CH.sub.2).sub.2OH HRMS for C21H18N3O2SCl2F 3 Calcd: 503.0646
Found: 503.0147 NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 2-OCH.sub.3
5-OCH.sub.3 m.p. Amorphous. 1 .sup.1H-NMR(CDCl.sub.3) .delta.
2.30(3H, s), 3.60(6H,s), 5.85(2H, broad s), 6.80- 6.96(3H, m),
7.74(2H, s). NH.sub.2 OCH.sub.2CH.sub.3 2-Cl 4-CF.sub.3 6-Cl
3-CF.sub.3 H m.p. 112-114 9 NH.sub.2 OCH.sub.2CH.sub.3 2-Cl
4-CF.sub.3 6-Cl 3-CF.sub.3 H m.p. 77-78 9 NH.sub.2
OCH.sub.2CH.sub.3 2-Cl 4-CF.sub.3 6-Cl 3-CH.sub.3 H m.p. 103-104 9
NH.sub.2 OCH.sub.2CH.sub.3 2-CH.sub.3 4-Br 6-CH.sub.3 3-CF.sub.3 H
m.p. 158-160 9 NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 2-CH.sub.3
5-isopropyl m.p. Amorphous. 1 Anal. Calcd. for C22H20N3OSCl2F3: C,
52.59; H, 3.98; N, 8.36. Found: C, 52.39; H, 4.01; N, 8.08 NH.sub.2
SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 2-CH.sub.3 5- m.p. Amorphous. 12
(CH.sub.2).sub.3OH Anal. Calcd. for C22H20N3O2SCl2F 3: C, 50.97; H,
3.88; N, 8.10. Found: C, 51.10; H, 3.96; N, 7.60 NH.sub.2 SCH.sub.3
2-Cl 4-CF.sub.3 6-Cl 2-COOC.sub.2H.sub.5 H m.p. 211-216 1 NH.sub.2
SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl R.sub.11 and R.sub.12 H m.p. 115-118
1 with the phenyl to which they are attached form 1- naphthyl
NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 3-Br H m.p. Amorphous. 1
Calcd. for C18H11N3OSBrCl2F 3C 41.16, H 2.11, N 8.00. Found C
41.37, H 1.92, N 7.85. NH.sub.2 SCH.sub.3 2-Cl 4-SO.sub.2-- 6-Cl
3-CF.sub.3 H m.p. 272-274 1 NH.sub.2 NH.sub.2 SCH.sub.3 2-Cl
4-CF.sub.3 6-Cl 3-SO.sub.2NH.sub.2 H m.p. 99-100 1 NH.sub.2
SCH.sub.3 2-CH.sub.3 4-Br 6-CH.sub.3 3-SO.sub.2NH.sub.2 H m.p.
242-244 1 NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 3- H m.p.
Amorphous. 1 SO.sub.2N(CH.sub.3).sub.2 Anal. Calcd. for
C20H17N4O3S2Cl2 F3/1/4C4H100: C, 44.10; H, 3.44; N, 9.80. Found: C,
43.88; H, 3.29; N, 9.68 NH.sub.2 SCH.sub.3 2-CH.sub.3 4-Br
6-CH.sub.3 3- H m.p. Amorphous. 1 SO.sub.2N(CH.sub.3).sub.2 Anal.
Calcd. for C21H23N4O3S2Br: C,48.18; H, 4.43; N, 10.70. Found: C,
48.42; H, 4.24; N, 10.52 NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 3-
H m.p. 192-194 1 SO.sub.2N(CH.sub.3).sub.2 NH.sub.2 SCH.sub.3 2-Cl
4-Cl 6-Cl 2-(2-thienyl) H m.p. 171.5-172.5 1 NH.sub.2 SCH.sub.3
2-Cl 6-Cl 4-CF.sub.3 H H m.p. 192-194 1 NH.sub.2 CH.sub.3 2-Cl 6-Cl
4-CF.sub.3 2-CH.sub.3 5-CH.sub.3 m.p. 175-176 6 NH.sub.2 CH.sub.3
2-CH.sub.3 6-CH.sub.3 4-Br 2-CH.sub.3 5-CH.sub.3 m.p. 158-160 6
NH.sub.2 SCH.sub.3 2-Cl 6-Cl 4-CF.sub.3 3-N(CH.sub.3).sub.2 H HRMS
for 1 C.sub.20H.sub.17ON.sub.4SCl.sub.2F.sub.3 Calcd: 488.0452
Found: 488.0408 NH(C.sub.3H.sub.7) SCH.sub.3 2-Cl 6-Cl 4-Cl 2-Cl H
Calcd. C, 49.10; H, 5 3.50; N, 8.54; Found: C, 50.37; H, 3.28; N,
8.47. NH.sub.2 SO.sub.2CH.sub.3 2-Cl 6-Cl 4-CF.sub.3 2-CH.sub.3
5-CH.sub.3 m.p. 193.5-194.5 13 NH.sub.2 SCH.sub.3 2-Cl 6-Cl
4-CF.sub.3 3-phenyl H m.p. 124-127 1 NH.sub.2 SCH.sub.3 2-Cl 6-Cl
4-CF.sub.3 2-pyrrolyl H HRMS Calcd. 1 510.0295 Found 510.0455
N(CH.sub.3)(C.sub.2H.sub.5) SCH.sub.3 2-Cl 6-Cl 4-Cl 2-Cl H FAB
Mass Spectrum: 5 490 NH.sub.2 SCH.sub.3 2-Cl 6-Cl 4-Cl 2-CH.sub.3
5-iPr HRMS Calcd. 1 467.0393 Found 467.0395 NH.sub.2 SCH.sub.3 2-Cl
6-Cl 4-CF.sub.3 2-CH.sub.3 5-n-butyl HRMS Calcd. 1 515.0809 Found
515.0892 N(C.sub.2H.sub.5).sub.2 SCH.sub.3 2-Cl 6-Cl 4-CF.sub.3
2-CH.sub.3 5-iPr HRMS Calcd. 5 557.1277 Found 557.1287 NH.sub.2
CH.sub.3 2-Cl 6-Cl 4-Cl 2-CH.sub.3 5-iPr HRMS Calcd. 1 435.0669
Found 435.0682 N(C.sub.2H.sub.5)(C.sub.3H.sub.7) SCH.sub.3 2-Cl
6-Cl 4-CF.sub.3 2-CH.sub.3 5-iPr MS parent 571, 529, 5 494, 360,
160 (100%) N(C.sub.2H.sub.5) (sec- SCH.sub.3 2-Cl 6-Cl 4-CF.sub.3
2-CH.sub.3 5-iPr HRMS Calcd. 5 butyl) 585.1589 Found 585.1500
N(CH.sub.3)(C.sub.2H.sub.5) SCH.sub.3 2-Cl 6-Cl 4-CF.sub.3
2-CH.sub.3 5-iPr HRMS Calcd. 5 543.1121 Found 543.11 66
N(C.sub.2H.sub.5)(C.sub.3H.- sub.7) SCH.sub.3 2-Cl 6-Cl 4-CF.sub.3
2-CH.sub.3 5-iPr HRMS Calcd. 5 569.1277 Found 569.1433 NH.sub.2
SCH.sub.3 2-Cl 6-Cl 4-CF.sub.3 2-n-propyl 5-CH.sub.3 HRMS Calcd. 1
501.0653 Found 501.0551 NH.sub.2 SCH.sub.3 2-Cl 6-Cl 4-CF.sub.3
2-CH.sub.3 5-n-propyl HRMS Calcd. 1 501.0653 Found 501.0698
N(CH.sub.3)(C.sub.2H.sub.5) SCH.sub.3 2-Cl 6-Cl 4-CF.sub.3
2-CH.sub.3 5-iPr HRMS Calcd. 5 555.1121 Found 555.0756 NH.sub.2
SCH.sub.3 2-Cl 4-Cl 6-Cl 2-CH.sub.3 6-CH.sub.3 HRMS Calcd. 1
439.0080 Found 439.0097 NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl
2-Cl 6-Cl m.p. 212-213 1 NH.sub.2 SCH.sub.3 2-CH.sub.3 4-Br
6-CH.sub.3 2-Cl 6-Cl m.p. 252-254 1 NH.sub.2 SCH.sub.3 2-Cl 4-Cl
6-Cl 2-Cl 6-Cl m.p. 237-239 1 NH.sub.2 SCH.sub.3 2-Cl 4-Cl 6-Cl
2-OCH.sub.3 H m.p. 168-171 1 NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3
6-Cl 2-OiPr 5-Cl MS 537 (parent ion) 1 480, 341 (100%), 308, 255,
155 NH.sub.2 SCH.sub.3 2-CH.sub.3 4-Br 6-CH.sub.3 2-OCH.sub.3 5-Br
m.p. 191-193 1 NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 2-OCH.sub.3
5-Br m.p. 192-194 1 NH.sub.2 SCH.sub.3 2-Cl 4-Cl 6-Cl 2-OCH.sub.3
5-Br m.p. 218-220 1 NH.sub.2 SCH.sub.3 2-Cl 4-Cl 6-Cl 2-Br 5-Br
m.p. 229-231 1 NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 2-Br 5-Br
m.p. 172-174 1 NH.sub.2 SCH.sub.3 2-CH.sub.3 4-Br 6-CH.sub.3 2-Br
5-Br m.p. 179-181 1 NH.sub.2 SCH.sub.3 2-CH.sub.3 4-CH.sub.3
6-CH.sub.3 2-Br 5-Br m.p. 195-197 1 NH.sub.2 SCH.sub.3 2-CH.sub.3
4-Br 6-CH.sub.3 2-CH.sub.3 5-NO.sub.2 m.p. 118-119 1 NH.sub.2
SCH.sub.3 2-Cl 4-Cl 6-Cl 2-C.sub.2H.sub.5 H m.p. 146-150 1 NH.sub.2
SCH.sub.3 2-Cl 4-Cl 6-Cl 2-CF.sub.3 H m.p. 175-177 1 NH.sub.2
SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 2-Cl 5-NO.sub.2 m.p. 98.0-98.5 1
NH.sub.2 SCH.sub.3 2-CH.sub.3 4-Br 6-CH.sub.3 2-Cl 5-NO.sub.2 m.p.
116-118 1 NH.sub.2 SCH.sub.3 2-Cl 4-CF.sub.3 6-Cl 2-CH.sub.3
5-NO.sub.2 m.p. 99-100 1 NH.sub.2 SCH.sub.3 2-CH.sub.3 4-CH.sub.3
6-CH.sub.3 2-CH.sub.3 5-NO.sub.2 m.p. 193-195 1 NH.sub.2 SCH.sub.3
2-Cl 4-Cl 6-Cl 2-OC.sub.3H.sub.7 H .sup.1H-NMR (CDCl.sub.3) .delta.
1 0.87 (3H, t, J = 7), 1.68(2H, m), 2.32(3H, s), 3.96(2H, q, J =
7), 5.80 (1H, broad s), 6.93 (1H, d, J = 7), 7.03 1H, t, J = 7),
7.27 (1H, d, J = 7), 7.42 (1H, t, J = 7), 7.52 (2H, s)
[0133]
2TABLE 2 32 Process Phys. Data of Ex- R.sub.3 R.sub.4 (m.p. in
.degree. C.) ample C.sub.2H.sub.5CHC.sub.4H.sub.9
2,6-Cl.sub.2-4-CF.sub.3Ph HRMS Calcd. 1 467.0809. Found 467.0913.
C.sub.3H.sub.7CH.dbd.CH--C.sub.2H.sub.5 2,6-Cl.sub.2-4-CF.sub.3Ph
FAB Mass 1 Spectrum: 466 2- 2,4,6-Cl.sub.3Ph HRMS Calcd. 1
methylcyclopentyl 417.0236. Found 417.0328.
2-OC.sub.2H.sub.5-1-naphthyl 2,6-Cl.sub.2-4-CF.sub.3Ph m.p. 149-151
1 2-OC.sub.2H.sub.5-1-naph- thyl 2,4,6-Cl.sub.3Ph m.p. 125-128 1
3-CF.sub.3-Ph 1,3-(CH.sub.3).sub.2-4-NO.sub.2-- Calcd. for 1
pyrazol-5-yl C.sub.17H.sub.15O.sub.3N.sub.6SF.sub.3: C, 46.36; H,
3.43; N, 19.08. Found: C, 46.51; H, 3.37; N, 18.10.
EXAMPLE 15
A. 3-Trifluoromethylphenylthioacetonitrile
[0134] To sodium (0.62 g, 27.0 mmol) dissolved in 40 mL of ethanol
was added 4.79 g (26.9 mmol) of 3-trifluoromethylthiophenol and
2.04 g (27.0 mmol) of chloroacetonitrile. The reaction mixture was
heated at reflux for 1 hour and then stirred overnight at room
temperature. To the cooled reaction mixture was added one volume of
ether and the precipitated solids were removed by filtration. The
filtrate was evaporated on the rotary evaporator to give the
product as an oil in essentially quantitative yield. This material
was used in the following reaction without further
purification.
B. 3-Trifluoromethylphenylcyanomethylsulfoxide
[0135] A solution of 3.00 g (13.8 mmol) of
3-trifluoromethylphenylthioacet- onitrile in 130 mL of methylene
chloride was cooled to 5.degree. C. under dry N.sub.2 and treated
with 4.89 g (28.35 mmol) of m-chloroperbenzoic acid. The reaction
mixture was stirred for 48 hours at room temperature and then
cooled in ice, after which the insolubles were removed by
filtration. The filtrate was washed with 10% sodium sulfate
solution until all traces of peroxides had been removed and then
dried over magnesium sulfate and evaporated to a pale yellow oil
which was used in the subsequent reaction without further
purification.
C.
3,3-Bis-methylthio-2-(3-trifluoromethylphenylsulfonyl)acrylonitrile
[0136] A solution of 13.82 mmol (crude product) of
3-trifluoromethylphenyl- cyanomethylsulfoxide in 30 mL of dry
dimethylsulfoxide and 1.25 mL (1.58 g, 20.7 mmol) of CS.sub.2 was
cooled to about 15.degree. C. in an ice bath under dry nitrogen.
Then 0.99 g (41.5 mmol) of oil-free sodium hydride was added
portionwise below 20.degree. C. and the deep red solution was let
stir at room temperature for 75 minutes. The reaction mixture was
cooled to 15.degree. C., quenched with 2.58 mL (5.89 g, 41.5 mmol)
of methyl iodide and let stir overnight at room temperature. The
reaction mixture was poured into ice/water and let granulate for
3.5 hours. The product was filtered and air dried to give 3.51 g
(72%) of the product. The analytical sample was crystallized from
EtOH/H.sub.2O, m.p. 109-110.degree. C.
D.
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(3-trifluoromethylbe-
nzenesulfonyl)-3-methylthiopyrazole
[0137] A suspension of 0.50 g (1.42 mmol) of
3,3-bis-methylthio-2-(3-trifl-
uoromethylphenylsulfonyl)acrylonitrile and 0.35 g (1.42 mmol) of
2,6-dichloro-4-trifluoromethylphenylhydrazine in 10 mL of ethanol
was heated at reflux for 2.5 hours, solution occurring as the
reaction mixture was warmed. The mixture was stirred overnight at
room temperature and was then poured into cold water. The product
was extracted into ethyl acetate and the extracts were dried with
magnesium sulfate and evaporated. The residues were crystallized
from ether, and the product was filtered off and air dried to give
314 mg (40%) of the desired product, m.p. 201-203.degree. C.
[0138] Anal. Calcd. for
C.sub.18H.sub.11O.sub.2N.sub.3S.sub.2Cl.sub.2F.sub- .6: C, 39.28;
H, 2.02; N, 7.64. Found: C, 39.35; H, 2.19; N, 7.48.
E.
5-Dimethylamino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(benzenesulf-
onyl)-3-methylthiopyrazole
[0139] A solution of 0.241 g (0.5 mmol) of
5-amino-1-(2,6-dichloro-4-trifl-
uoromethylphenyl)-4-(benzenesulfonyl)-3-methylthiopyrazole in 5 mL
of dry dimethylsulfoxide was treated with 36 mg (1.5 mmol) of
oil-free sodium hydride under dry nitrogen in a flame-dried flask
at room temperature. After 30 minutes, a clear, pale yellow
solution had formed. This solution was treated with 0.5 mL (8.0
mmol) of methyl iodide and stirred for 1 hour. Then the reaction
mixture was poured into water and extracted twice with ethyl
acetate. The combined extracts were dried with brine and with
magnesium sulfate and evaporated. The residues crystallized from
ether to give the desired product in 81% yield, m.p.
163-164.degree. C.
EXAMPLE 16
[0140] The following compounds were prepared in accordance with
Example 15.
3 33 M.P. (.degree. C.) or R.sub.11 R.sub.13,R.sub.14,R.sub.15
R.sub.1 Analysis H 2,4,6-trichloro NH.sub.2 161-162 H
2,4,6-trichloro N(CH.sub.3).sub.2 200-202 2-(i-propyl)
2,4,6-trichloro NH.sub.2 180-182 2-OCH.sub.3 2,4,6-trichloro
NH.sub.2 212-215 2-Cl 2,4,6-trichloro NH.sub.2 Anal. Calcd. for
C.sub.16H.sub.11O.sub.2N.sub.3S.sub.2Cl.sub.4: C, 39.60; H, 2.39;
N, 8.33. Found: C,39.76; H, 229; N, 8.69 H 2,6-Cl.sub.2-4-CF.sub.3
NH.sub.2 209.5-210.5 H 2,6-Cl.sub.2-4-CF.sub.3 N(CH.sub.3).sub.2
163-164 3-CF.sub.3 2,6-Cl.sub.2-4-CF.sub.3 NH.sub.2 201-203
3-CF.sub.3 2,6-Cl.sub.2-4-CF.sub.3 N(CH.sub.3).sub.2 137-138
EXAMPLE 17
4-(2-Chlorophenyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylthiopy-
razolo[3,4-d]pyrimidine
[0141] A suspension of 669 mg (1.39 mmol) of
5-amino-1-(2,6-dichloro-4-tri-
fluoromethylphenyl)-4-(2-chlorobenzoyl)-3-methylthiopyrazole in 5
mL of formamide was heated at 150.degree. C. overnight. A pale
yellow solid precipitated upon cooling of the reaction mixture. A
total of 50 mL of water was added to the stirred suspension to
complete the precipitation of the product which was filtered off
and washed with water. An inseparable trace of starting material
was observed in the product by thin layer chromatography (TLC) and
so the above procedure was repeated on the mixture giving a brown
solid containing no trace of starting material. Trituration of this
solid with methylene chloride gave a pale yellow solution which was
concentrated to give the desired product as a white crystalline
solid, m.p. 156-158.degree. C.
EXAMPLE 18
[0142] The following compounds were prepared in accordance with
Example 17.
4 34 R.sub.3 R.sub.9 R.sub.13 m.p.(.degree. C.) or HRMS 2-Cl-Ph H
Cl 193-195 3-Cl-Ph H Cl 171-173 2-Cl-Ph H CF.sub.3 156-158 2-Cl-Ph
OH Cl 313-316 2-Cl-Ph Cl Cl 193-195 2-Cl-Ph 4- Cl 222-225
ethoxycarbonyl- piperazinyl 1-naphthyl H CF.sub.3 171-173 2-Cl-Ph
CH.sub.3 Cl 210-212 2-CH.sub.3-5-iPrPh CH.sub.3 Cl 141-142
2,6-(CH.sub.3).sub.2-Ph CH.sub.3 Cl HRMS Calcd. 462.0239. Found,
462.0369. 2-(OC.sub.2H.sub.5)-Ph CH.sub.3 Cl 189.192
2-(OC.sub.2H.sub.5)-1- CH.sub.3 Cl HRMS: Calcd.: naphthyl 528.0345
Found: 528.0226 2-OCH.sub.3-Ph CH.sub.3 Cl 214-216
2-C.sub.2H.sub.5-Ph CH.sub.3 Cl HRMS: Calcd. 462.0239 Found:
462.0219 Ph CH.sub.3 CF.sub.3 114-116 2,5-(CH.sub.3).sub.2-Ph
CH.sub.3 CF.sub.3 HRMS: Calcd. 497.0579 Found: 497.0602
2-CF.sub.3-Ph CH.sub.3 Cl HRMS: Calcd. 501.9800 Found: 501.9778
* * * * *