U.S. patent application number 10/912267 was filed with the patent office on 2005-02-10 for corticotropin releasing factor antagonists.
This patent application is currently assigned to PFIZER INC.. Invention is credited to Chen, Yuhpyng L..
Application Number | 20050032846 10/912267 |
Document ID | / |
Family ID | 34119962 |
Filed Date | 2005-02-10 |
United States Patent
Application |
20050032846 |
Kind Code |
A1 |
Chen, Yuhpyng L. |
February 10, 2005 |
Corticotropin releasing factor antagonists
Abstract
A pharmaceutical composition for treatment of a disorder or
condition the treatment of which can be effected or facilitated by
antagonizing Corticotropin Releasing Factor (CRF). The
pharmaceutical composition includes a pharmaceutically acceptable
carrier and an effective amount to treat the disorder or condition
of the following compound: 1 or a pharmaceutically acceptable salt
thereof, wherein A, B, Z, R.sub.3, R.sub.4, and R.sub.5 are as
defined herein.
Inventors: |
Chen, Yuhpyng L.;
(Waterford, CT) |
Correspondence
Address: |
LADAS & PARRY
26 WEST 61ST STREET
NEW YORK
NY
10023
US
|
Assignee: |
PFIZER INC.
PFIZER PRODUCTS INC.
|
Family ID: |
34119962 |
Appl. No.: |
10/912267 |
Filed: |
August 5, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10912267 |
Aug 5, 2004 |
|
|
|
09580791 |
May 30, 2000 |
|
|
|
09580791 |
May 30, 2000 |
|
|
|
08741066 |
Oct 30, 1996 |
|
|
|
6403599 |
|
|
|
|
09580791 |
|
|
|
|
09254387 |
Mar 4, 1999 |
|
|
|
6316631 |
|
|
|
|
09254387 |
Mar 4, 1999 |
|
|
|
PCT/IB95/00437 |
Jun 6, 1995 |
|
|
|
60006333 |
Nov 8, 1995 |
|
|
|
Current U.S.
Class: |
514/350 ;
514/352; 546/298 |
Current CPC
Class: |
A61K 31/52 20130101;
A61K 31/505 20130101; A61K 31/519 20130101; A61K 31/435 20130101;
A61K 31/506 20130101; A61K 31/437 20130101 |
Class at
Publication: |
514/350 ;
546/298; 514/352 |
International
Class: |
C07D 213/62; C07D
213/78; A61K 031/44 |
Claims
1-28. (cancelled)
29. A pharmaceutical composition for the treatment of (a) a
disorder or condition the treatment of which can be effected or
facilitated by antagonizing CRF or (b) a disorder or condition
selected from inflammatory disorders, pain, asthma, psoriasis and
allergies; generalized anxiety disorder; panic; phobias;
obsessive-compulsive disorder; post-traumatic stress disorder;
sleep disorders induced by stress; pain perception; mood disorders,
mood disorders associated with premenstrual syndrome, and
postpartum depression; dysthemia; bipolar disorders; cyclothymia;
chronic fatigue syndrome; stress-induced headache; cancer;
irritable bowel syndrome, Crohn's disease; spastic colon; post
operative ileus; ulcer; diarrhea; stress-induced fever; human
immunodeficiency virus infections; neurodegenerative diseases;
gastrointestinal diseases; eating disorder; hemorrhagic stress;
chemical dependencies or addictions; drug or alcohol withdrawal
symptoms; stress-induced psychotic episodes; euthyroid sick
syndrome; syndrome of inappropriate antidiuretic hormone; obesity;
infertility; head trauma; spinal cord trauma; ischemic neuronal
damage; excitotoxic neuronal damage; stroke; immune dysfunctions;
muscular spasms; urinary incontinence; senile dementia of the
Alzheimer's type; multi infarct dementia; amyotrophic lateral
sclerosis; hypertension; tachycardia; congestive heart failure;
osteoporosis; premature birth; hypoglycemia, and Syndrome X in a
mammal or bird, comprising a pharmaceutically acceptable carrier
and an amount of the following compound that is effective in the
treatment of such disorder or condition: 19or a pharmaceutically
acceptable salt thereof, wherein A is --CR.sub.7; B is
--NR.sub.1R.sub.2, --CR.sub.1R.sub.2R.sub.11,
--C(.dbd.CR.sub.2R.sub.12)R- .sub.1, --NHCHR.sub.1R.sub.2,
--OCHR.sub.1R.sub.2, --SCHR.sub.1R.sub.2, --CHR.sub.2OR.sub.1,
--CHR.sub.1OR.sub.2, --CHR.sub.2SR.sub.1, --CHR.sub.2NR.sub.1R2,
--CHR.sub.1NHR.sub.2, --CHR.sub.1,N(CH.sub.3)R.sub- .2, or
--NR.sub.12NR.sub.1R.sub.2; Z is NH, O, S, --N (C.sub.1-C.sub.2
alkyl)-, --N(C(O)CF.sub.3), - or --C(R.sub.13R.sub.14)--, wherein
R.sub.13 and R.sub.14 are each, independently, hydrogen,
trifluoromethyl or methyl, or one of R.sub.13 and R.sub.14 is cyano
and the other is hydrogen or methyl, or --C(R.sub.13R.sub.14) is a
cyclopropyl group, or Z is nitrogen or CH and forms a five or six
membered heterocyclic ring fused with R.sub.5, which ring
optionally comprises two or three further hetero members selected
independently from oxygen, nitrogen, NR.sub.12, and S(O).sub.m, and
optionally comprises from one to three double bonds, and is
optionally substituted with halo, C.sub.1-C.sub.4 alkyl,
--O(C.sub.1-C.sub.4 alkyl), NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, CF.sub.3, or OCF.sub.3, with the proviso that
said ring does not contain any --S--S--, --S--O--, --N--S--, or
--O--O-- bonds, and does not comprise more than two oxygen or
S(O).sub.m heterologous members; R.sub.1 is C(O)H,
C(O)(C.sub.1-C.sub.6 hydrocarbyl), C(O)(C.sub.1-C.sub.6
hydrocarbylene)(C.sub.3-C.sub.8 cyclohydrocarbyl),
C(O)(C.sub.3-C.sub.8 cyclohydrocarbylene )(C.sub.3-C.sub.8
cyclohydrocarbyl), C(O)(C.sub.1-C.sub.6
hydrocarbylene)(C.sub.4-C.sub.8 heterocyclohydrocarbyl ),
--C(O)(C.sub.3-C.sub.8 cyclohydrocarbylene)(C.s- ub.4-C.sub.8
heterocyclohydrocarbyl), C.sub.3-C.sub.8 cyclohydrocarbyl,
C.sub.4-C.sub.8 heterocyclohydrocarbyl, --(C.sub.1-C.sub.6
hydrocarbylene (C.sub.3-C.sub.8 cyclohydrocarbyl ),C.sub.3-C.sub.8
cyclohydrocarbylene)(C.sub.3-C.sub.8 cyclohydrocarbyl),
--(C.sub.1-C.sub.6hydrocarbylene)(C.sub.4-C.sub.8
heterocyclohydrocarbyl)- , --(C.sub.3-C.sub.8
cyclohydrocarbylene)(C.sub.4-C.sub.8 heterocyclohydrocarbyl), or
--O-aryl, or --O--(C.sub.1-C.sub.6 hydrocarbylene)-aryl; wherein
said aryl, C.sub.4-C.sub.8 heterocyclohydrocarbyl, C.sub.1-C.sub.6
hydrocarbyl, C.sub.3-C.sub.8 cyclohydrocarbyl, C.sub.3-C.sub.8
cyclohydrocarbylene, and C.sub.1-C.sub.6 hydrocarbylene groups may
each independently be optionally substituted with from one to six
fluoro and may each independently be optionally substituted with
one or two substituents R.sub.8 independently selected from the
group consisting of C.sub.1-C.sub.4 hydrocarbyl, --C.sub.3-C.sub.8
1 cyclohydrocarbyl, hydroxy, chloro, bromo, iodo, CF.sub.3,
--O--(C.sub.1-C.sub.6 hydrocarbyl), --O--(C.sub.3-C.sub.5
cyclohydrocarbyl), --O--CO--(C.sub.1-C.sub.4 hydrocarbyl),
--O--CO--NH(C.sub.1-C.sub.4 hydrocarbyl),
--O--CO--N(R.sub.24)(R.sub.25), --N(R.sub.24)(R.sub.25),
--S(C.sub.1-C.sub.4 hydrocarbyl), --S(C.sub.3-C.sub.5
cyclohydrocarbyl) [-]-N(C.sub.1-C.sub.4
hydrocarbyl)CO(C.sub.1-C.sub.4 hydrocarbyl), --NHCO(C.sub.1-C.sub.4
hydrocarbyl), --COO(C.sub.1-C.sub.4 hydrocarbyl),
--CONH(C.sub.1-C.sub.4 hydrocarbyl), --CONC.sub.1-C.sub.4
hydrocarbyl)(C.sub.1-C.sub.2 hydrocarbyl), CN, NO.sub.2,
--OSO.sub.2(C.sub.1-C.sub.4 hydrocarbyl), S.sup.+(C.sub.1-C.sub.6
hydrocarbyl)(C.sub.1-C.sub.2 hydrocarbyl) I.sup.-, --SO(C.sub.1-C
.sub.4 hydrocarbyl) and --SO.sub.2(C.sub.1-C.sub.4 hydrocarbyl);
and wherein the C.sub.1-C.sub.6 hydrocarbyl, C.sub.1-C.sub.6
hydrocarbylene, C.sub.5-C.sub.8 cyclohydrocarbyl, C.sub.5-C.sub.8
cyclohydrocarbylene, and C.sub.5-C.sub.8 heterocyclohydrocarbyl
moieties of R.sub.1 may optionally independently contain from one
to three double or triple bonds; and wherein the C.sub.1-C.sub.4
hydrocarbyl moieties and C.sub.1-C.sub.6 hydrocarbyl moieties of
R.sub.8 can optionally independently be substituted with hydroxy,
amino, C.sub.1-C.sub.4 alkyl, aryl, --CH.sub.2-aryl,
C.sub.3-C.sub.5 cycloalkyl, or --O--(C.sub.1-C.sub.4 alkyl), and
can optionally independently be substituted with firom one to six
fluoro, and can optionally contain one or two double or triple
bonds; and wherein each heterocyclohydrocarbyl group of R.sub.1
contains from one to three heteromoieties selected from oxygen,
S(O).sub.m, nitrogen, and NR.sub.12; R.sub.2 is hydrogen,
C.sub.1-C.sub.12 hydrocarbyl, C.sub.3-C.sub.8 cyclohydrocarbyl,
C.sub.4-C.sub.8 heterocyclohydrocarbyl, --(C.sub.1-C.sub.6
hydrocarbylene)(C.sub.3-C.sub.8 cyclohydrocarbyl),
--(C.sub.3-C.sub.8 cyclohydrocarbylene)(C.sub.3-C.sub.8
cyclohydrocarbyl), --(C.sub.1-C.sub.6
hydrocarbylene)(C.sub.4-C.sub.8 heterocyclohydrocarbyl),
--(C.sub.3-C.sub.6 cyclohydrocarbylene)(C.sub.4-- C.sub.8
heterocyclohydrocarbyl), aryl, --(C.sub.1-C.sub.6
hydrocarbylene)aryl, or --(C.sub.3-C.sub.8
cyclohydrocarbylene)(aryl); wherein each of the foregoing R.sub.2
groups may optionally be substituted with from one to three
substituents independently selected from chloro, fluoro, and
C.sub.1-C.sub.6 alkyl, wherein one of said one to three
substituents can further be selected from bromo, iodo,
C.sub.1-C.sub.6 alkoxy, --OH, --O--CO--(C.sub.1-C.sub.6 alkyl),
--O--CO--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl), --S
(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--S(O).sub.2(C.sub.1-C.sub.6 alkyl), S.sup.+(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.2 alkyl)I', CN, and NO.sub.2; and wherein the
C.sub.1-C.sub.12 hydrocarbyl, --(C.sub.1-C.sub.6 hydrocarbylene),
and cyclohydrocarbyl gropups of 5-8 carbon atoms,
cyclohydrocarbylene groups of 5 to 8 carbon atoms and
heterocyclohydrocarbyl groiups of 5 to 8 atoms of R.sub.2 may
optionally independently contain from one to three double or triple
bonds; and wherein each heterocyclohydrocarbyl group of R.sub.2
contains from one to three heteromoieties selected from oxygen,
S(O).sub.m, nitrogen, and NR.sub.12; or when R.sub.1 and R.sub.2
are as in --NHCHR.sub.1R.sub.2, --OCHR.sub.1R.sub.2,
--SCHR.sub.1R.sub.2, --CHR.sub.1R.sub.2 or --NR.sub.1R.sub.2,
R.sub.1 and R.sub.2 of B may form a saturated 5- to 8-membered ring
which may optionally contain one or two double bonds and in which
one or two of the ring carbons may optionally be replaced by an
oxygen, S(O).sub.m, nitrogen or NR.sub.12; and which carbocyclic
ring can optionally be substituted with from 1 to 3 substituents
selected from the group consisting of hydroxy, C.sub.1-C.sub.4
alkyl, fluoro, chloro, bromo, iodo, CF.sub.3, --O--(C.sub.1-C.sub.4
alkyl), --O--CO--(C.sub.1-C.sub.4 alkyl),
--O--CO--NH(C.sub.1-C.sub.4 alkyl), --O--CO--N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.2 alkyl)(C.sub.1-C.sub.4 alkyl),
--S(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.4
alkyl)CO(C.sub.1-C.sub.4 alkyl), --NHCO(C.sub.1-C.sub.4
alkyl),--COO(C.sub.1-C.sub.4 alkyl), --CONH(C.sub.1-C.sub.4 alkyl),
--CON(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl), CN, NO.sub.2,
--OSO.sub.2(C.sub.1-C.sub.4 alkyl), --SO(C.sub.1-C.sub.4 alkyl),
and --SO(C.sub.1-C.sub.4 alkyl), wherein one of said one to three
substituents can further be selected from phenyl; R.sub.3 is
methyl, ethyl, fluoro, chloro, bromo, iodo, cyano, methoxy,
OCF.sub.3, NH.sub.2, NH(C.sub.1-C.sub.2 alkyl), N(CH.sub.3).sub.2,
--NHCOCF.sub.3, --NHCH.sub.2CF.sub.3, S(O).sub.m(C.sub.1-C.sub.4
alkyl), CONH.sub.2, --CONHCH.sub.3, CON(CH.sub.3).sub.2,
--CF.sub.3, or CH.sub.2OCH.sub.3; R.sub.4 is hydrogen,
C.sub.1-C.sub.4 hydrocarbyl, C.sub.3-C.sub.5 cycloalkyl,
--(C.sub.1-C.sub.4 hydrocarbylene)(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.3-C.sub.5 cycloalkylene)(C.sub.3-C.sub.6 cycloalkyl),
cyano, fluoro, chloro, bromo, iodo, --OR.sub.24 C.sub.1-C.sub.6
alkoxy, --O-- cycloalkyl), --O--(C.sub.1-C.sub.4
hydrocarbylene)(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.3-C.sub.5
cycloalkylene)(C.sub.3-C.sub.5 cycloalkyl),
--CH.sub.2SC(S)O(C.sub.1-C.sub.4 alkyl), CH.sub.2OCF.sub.3,
CF.sub.3, amino, nitro, --NR.sub.24R.sub.25, --(C.sub.1-C.sub.4
hydrocarbylene)-OR.sub.24, --(C.sub.1-C.sub.4 hydrocarbylene)Cl,
--(C.sub.1-C.sub.4 hydrocarbylene)NR.sub.24R.sub.25,
--NHCOR.sub.24, --NHCONR.sub.24R.sub.25, --CH.dbd.NOR.sub.24,
--NHNR.sub.24R.sub.25, --S(O).sub.mR.sub.24, --C(O)R.sub.24,
--OC(O)R.sub.24, --C(O)CN, --C(O)NR.sub.24R.sub.25,
--C(O)NHNR.sub.24R.sub.25, and --COOR.sub.24, wherein the
hydrocarbyl and hydrocarbylene groups of R.sub.4 may optionally
independently contain one or two double or triple bonds and may
optionally independently be substituted with one or two
substituents R.sub.10 independently selected from hydroxy, amino,
--NHCOCH.sub.3, --NHCOCH.sub.2Cl, --NH(C.sub.1-C.sub.2 alkyl),
--N(C.sub.1-C.sub.2 alkyl)(C.sub.1-C.sub.2alkyl),
--COO(C.sub.1-C.sub.4 alkyl), --COOH, --CO(C.sub.1-C.sub.4 alkyl),
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 thioalkyl, cyano and nitro,
and with one to four substituents independently selected from
fluoro and chloro; R.sub.5 is aryl or heteroaryl and is substituted
with from one to four substituents R.sub.27 independently selected
from halo, C.sub.1-C.sub.10 hydrocarbyl, --(C.sub.1-C.sub.4
hydrocarbylene)(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.1-C.sub.4
hydrocarbylene)(C.sub.4-C.sub.8 heterocycloalkyl),
--(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.4-C.sub.8
heterocycloalkyl), --(C.sub.3-C.sub.8
cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.3-C.sub.8
cycloalkylene)(C.sub.4-C.sub.8 heterocycloalkyl), C.sub.1-C.sub.4
haloallyl, C.sub.1-C.sub.4 haloalkoxy, nitro, cyano,
--NR.sub.24R.sub.25, --NR.sub.24COR.sub.25,
--NR.sub.24CO.sub.2R.sub.26, --COR.sub.24, --OR.sub.25,
--CONR.sub.24R.sub.25, --CON(OR.sub.22)R.sub.2- 3,
--CO.sub.2R.sub.26, --C.dbd.N(OR.sub.22)R.sub.23, and --S(O)
.sub.mR.sub.23; wherein said C.sub.1-C.sub.10 alkyl,
C.sub.3-C.sub.8 cycloalkyl, (C.sub.1-C.sub.4 hydrocarbylene),
(C.sub.3-C.sub.8 cycloalkyl), (C.sub.3-C.sub.8 cycloalkylene), and
(C.sub.4-C.sub.8 heterocycloalkyl) groups can be optionally
substituted with from one to three substituents independently
selected form C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.8 cycloalkyl,
(C.sub.1-C.sub.4 hydrocarbylene)(C.sub.3-C.su- b.8 cycloalkyl),
--(C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl),
C.sub.1-C.sub.4 haloalkyl, hydroxy, C.sub.1-C.sub.6 alkoxy, nitro,
halo, cyano, --NR.sub.24R.sub.25, --NR.sub.24COR.sub.25,
NR.sub.24CO.sub.2R.sub.26, --COR.sub.24, --OR.sub.25,
--CONR.sub.24R.sub.25, CO.sub.2R.sub.26, --CO(NOR.sub.22)R.sub.25,
and --S(O).sub.mR.sub.23; and wherein two adjacent substituents of
the R.sub.5 group can optionally form a 5-7 membered ring,
saturated or unsaturated, fused to R.sub.5, which ring optionally
can contain one, two, or three heterologous members independently
selected from O, S(O).sub.m, and N, but not any --S--S--, --O--O--,
--S--O--, or --N--S-- bonds, and which ring is optionally
substituted with C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.8 cycloalkyl,
--(C.sub.1-C.sub.4 alkylene)(C.sub.3-C.sub.8 cycloalkyl),
--(C.sub.3-C.sub.8 cyloalkylene)(C.sub.3-C.sub.8 cycloalkyl),
C.sub.1-C.sub.4 haloalkyl, nitro, halo, cyano --NR.sub.24R.sub.25,
NR.sub.24COR.sub.25, NR.sub.24CO.sub.2R.sub.26, --COR.sub.24,
--OR.sub.25, --CONR.sub.24R.sub.25, CO.sub.2R.sub.26,
--CO(NOR.sub.26)R.sub.25, or --S(O).sub.mR.sub.23; wherein one of
said one to four optional substituents R.sub.27, can further be
selected from --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH(C.sub.1-C.sub.4 alkylene )(C.sub.3-C.sub.8
cycloalkyl), SO.sub.2NH(C.sub.3-C.sub.8 cycloalkyl),
--SO.sub.2NH(C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8
cycloalkyl), --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),
--NHSO.sub.2(C.sub.3-C.sub.8 cycloalkyl),
--NHSO.sub.2(C.sub.1-C.sub.4 alkylene)(C.sub.3-C.sub.8 cycloalkyl),
and --NHSO.sub.2(C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8
cycloalkyl); and wherein the hydrocarbyl, and hydrocarbylene groups
of R.sub.5 may independently optionally contain one double or
triple bond; R.sub.6 is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, --(C.sub.1-C.sub.6
alkylene)(C.sub.3-C.sub.8 cycloalkyl), or --(C.sub.3-C.sub.8
cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl), wherein said alkyl and
cycloalkyl may optionally be substituted with one hydroxy, methoxy,
ethoxy or fluoro group; or R.sub.6 and R.sub.4 can together form an
oxo (.dbd.O) group, or can be connected to form a 3-8 membered
carbocyclic ring, optionally containing one to three double bonds,
and optionally containing one, two, or three heterologous ring
members selected from O, SO.sub.m, N, and NR.sub.12, but not
containing any --O--O--, --S--O--, --S--S--, or --N--S-- bonds, and
further optionally substituted with C.sub.1- C.sub.4 hydrocarbyl or
C.sub.3-C.sub.6 cycloalkyl, wherein said C.sub.1-C.sub.4
hydrocarbyl substituent may optionally contain one double or triple
bond; R.sub.7 is hydrogen, methyl, fluoro, chloro, bromo, iodo,
cyano, hydroxy, --O(C.sub.1-C.sub.2) alkyl), --O(cyclopropyl),
--COO(C.sub.1-C.sub.2 alkyl), --COO(C.sub.3-C.sub.8 cycloalkyl),
--OCF.sub.3, --CF.sub.3, --CH.sub.2OH or CH.sub.2OCH.sub.3;
R.sub.11 is hydrogen, hydroxy, fluoro, ethoxy, or methoxy; R.sub.12
is hydrogen or C.sub.1-C.sub.4 alkyl; R.sub.22 is independently at
each occurrence selected from hydrogen, C.sub.1-C.sub.14 alkyl,
C.sub.1-C.sub.14 haloalkyl, C.sub.3-C.sub.6 alkenyl,
C.sub.3-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
(C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl), and
(C.sub.1-C.sub.4) alkylene)(C.sub.3-C.sub.8 cycloalkyl); R.sub.23
is independently at each occurrence selected from C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.2-C.sub.8 alkoxyalkyl,
C.sub.3-C.sub.8 cycloalkyl, --(C.sub.1-C.sub.4
alkylene)(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.3-C.sub.8
cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl), aryl,
--(C.sub.1-C.sub.4 alkylene)aryl, piperidine, pyrrolidine,
piperazine, N-methylpiperazine, morpholine, and thiomorpholine;
R.sub.24 and R.sub.2, are independently at each occurrence selected
from hydrogen, --C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
--(C.sub.1-C.sub.4 alkylene)OH, --(C.sub.1-C.sub.4
alkylene)--O--(C.sub.1-C.sub.4 alkyl), --(C.sub.1-C.sub.4
alkylene)--O--(C.sub.3-C.sub.5 cycloalkyl), C.sub.3-C.sub.8
cycloalkyl, --(C.sub.1-C.sub.4 alkylene)(C.sub.3-C.sub.8
cycloalkyl), --(C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8
cycloalkyl), --C.sub.4-C.sub.8 heterocyclohydrocarbyl,
--(C.sub.1-C.sub.4 alkylene)(C.sub.4-C.sub.8
heterocyclohydrocarbyll), --(C.sub.3-C.sub.8
cycloalkylene)(C.sub.4-C.sub.8 heterocyclohydrocarbyl), aryl, and
--(C.sub.1-C.sub.4 alkylene)(aryl), wherein the --C.sub.4-C.sub.8
heterocyclohydrocarbyl groups can each independently optionally be
substituted with aryl, CH.sub.2-aryl, or C.sub.1-C.sub.4 alkyl, and
can optionally contain one or two double or triple bonds; or, when
R.sub.24 and R.sub.25 are as NR.sub.24R.sub.25,
--C(O)NR.sub.24R.sub.25,
--(C.sub.1-C.sub.4alkylene)NR.sub.24R.sub.25, or
--NHCONR.sub.24R.sub.25, then NR.sub.24R.sub.25 may further
optionally form a 4 to 8 membered heterocyclic ring optionally
containing one or two further hetero members independently selected
from S(O).sub.m, oxygen, nitrogen, and NR.sub.12, and optionally
containing from one to three double bonds; R.sub.26 is
independently at each occurrence selected from C.sub.1-C.sub.4
alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.8 cycloalkyl,
--(C.sub.1-C.sub.4 alkylene)(C.sub.3-C.sub.8 cycloalkyl),
--(C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl),
aryl, and --(C.sub.1-C.sub.4 alkylene)(aryl); and wherein each m is
independently zero, one, or two, with the proviso that
heterocyclohydrocarbylene groups of the compound of formula I, do
not comprise any --S--S--, --S--O--, --N--S--, or --O--O-- bonds,
and do not comprise more than two oxygen or S(O).sub.m heterologous
members.
30. A pharmaceutical composition according to claim 29 for the
treatment of a disorder selected from inflammatory disorders; pain,
asthma, psoriasis and allergies; generalized anxiety disorder;
panic; phobias; obsessive compulsive disorder; post-traumatic
stress disorder; sleep disorders induced by stress; pain
perception; mood disorders; dysthemia; bipolar disorders;
cyclothymia; fatigue syndrome; stress induced headache; cancer;
irritable bowel syndrome, Crohn's disease; spastic colon; human
immunodeficiency virus (HIV) infections; neurodegenerative
diseases; gastrointestinal diseases; eating disorders; chemical
dependencies and addictions; obesity; infertility; head traumas;
spinal cord trauma; ischemic neuronal damage; excitotoxic neuronal
damage; epilepsy; stroke; immune dysfunctions; muscular spasms;
urinary incontinence; senile dementia of the Alzheimer's type;
multi infarct dementia; amyotrophic lateral sclerosis; and
hypoglycemia in a mammal.
31. A pharmaceutical composition as claimed in claim 29 for
treatment of a mood disorder selected from the group consisting of
rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis
and allergies.
32. A pharmaceutical composition as claimed in claim 29 for
treatment of an inflammatory disorder selected from the group
consisting of rheumatoid arthritis and osteoarthritis.
33. A pharmaceutical composition as claimed in claim 30 for
treatment of depression, selected from the group consisting of
major depression, single episode depression, recurrent depression,
and child abuse induced depression.
34. A pharmaceutical composition as claimed in claim 30 for
treatment of neurodegenerative diseases selected from the group
consisting of Alzheimer's disease, Parkinson's disease and
Huntington's disease.
35. A pharmaceutical composition as claimed in claim 30 for
treatment of chemical dependencies or addictions, selected from the
group consisting of dependencies or addictions to alcohol, cocaine,
heroin, benzodiazapines, or other drugs.
36. A pharmaceutical composition as claimed in claim 30 for
treatment of cerebral ischemia.
37. A pharmaceutical composition as claimed in claim 30 for
treatment of stress induced immune dysfunctions selected from the
group consisting of porcine stress syndrome, bovine shipping fever,
equine paroxysmal fibrillation, confinement dysfunction in chicken,
sheering stress in sheep, and human animal interaction stress in
dogs.
38. A pharmaceutical composition as claimed in claim 30 for
treatment of fibromyalgia.
39. A pharmaceutical composition as claimed in claim 30 for
treatment of anorexia or bulimia nervosa.
40. A pharmaceutical composition as claimed in claim 30 for
treatment of cerebral ischemia selected from cerebral hippocampal
ischemia.
41. A pharmaceutical composition as claimed in claim 30 for
treatment of including social phobia, agoraphobia or specific
phobias.
42. The pharmaceutical composition according to claim 29 wherein
the pain perception is fibromyalgia.
43. The pharmaceutical composition according to claim 29 wherein
the ischemic neuronal damage is cerebral ischemia.
44. The pharmaceutical composition according to claim 30 wherein
mood disorder is depression or postpartum depression.
45. The pharmaceutical composition according to claim 30 wherein
the ischemic neuronal damage is cerebral ischemia.
46. The pharmaceutical composition according to claim 30 wherein
the mammal is a human.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to pyridines, pyrimidines, purinones,
pyrrolopyrimidinones and pyrrolopyridinones, processes for
preparing them, pharmaceutical compositions containing them, and
methods of using them to treat certain central nervous system (CNS)
and other disorders.
[0002] CRF antagonists are mentioned in U.S. Pat. No. 4,605,642,
issued Aug. 12, 1986, and U.S. Pat. No. 5,063,245, issued Nov. 5,
1991, referring to peptides and pyrazolinones, respectively. CRF
antagonists are also described in U.S. Pat. No. 5,962,479, issued
Oct. 5, 1999. 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 stress-related illnesses, such as
depression, anxiety, headache, irritable bowel syndrome,
inflammatory diseases, immune suppression, Alzheimer's disease,
gastrointestinal diseases, anorexia nervosa, hemorrhagic stress,
drug and alcohol withdrawal symptoms, drug addiction, infertility,
head trauma, stroke, and stress-induced infections in humans and
animals. The use of CRF antagonists for treatment of Syndrome X has
also been described in U.S. Provisional Patent Application No.
60/162,340, filed Oct. 29, 1999, which is also incorporated in its
entirety herein by reference. Methods for using CRF antagonists to
treat congestive heart failure are described in U.S. Ser. No.
09/248,073, filed Feb. 10, 1999, which is also incorporated herein
in its entirety by reference.
SUMMARY OF THE INVENTION
[0003] The present invention provides compounds of the formula
2
[0004] and pharmaceutically acceptable salts thereof, wherein
[0005] the dashed lines represent optional double bonds, with the
proviso that when the dashed line in C=G represent a double bond,
then the dashed line in N(R.sub.6)=C does not represent a double
bond; and with the proviso that when the dashed line in
N(R.sub.6)=C represents a double bond, R.sub.6 is absent in formula
III and the dashed line in C.dbd.G does not represent a double
bond;
[0006] A is --CR.sub.7or N;
[0007] B is --NR.sub.1R.sub.2, --CR.sub.1R.sub.2R.sub.11,
--C(.dbd.CR.sub.2R.sub.12)R.sub.11, --NHCHR.sub.1R.sub.2,
--OCHR.sub.1R.sub.2, --SCHR.sub.1R.sub.2, --CHR.sub.2OR.sub.1,
--CHR.sub.1OR.sub.2, --CHR.sub.2SR.sub.1, --C(S)R.sub.2,
--C(O)R.sub.2, --CHR.sub.2NR.sub.1R.sub.2, --CHR.sub.1NHR.sub.2,
--CHR.sub.1N(CH.sub.3)R- .sub.2, or --NR.sub.12NR.sub.1R.sub.2;
[0008] when the dashed line in C.dbd.G represents a double bond,
then G is hydrogen, oxygen, sulfur, NH, or N(C.sub.1-C.sub.4
alkyl);
[0009] when the dashed line in C.dbd.G does not represent a double
bond, then C.dbd.G is --C(H)(NH.sub.2), CH.sub.2, --C(H)(methoxy),
--C(H)(ethoxy), --C(H)(O(C.sub.3-C.sub.4 alkyl)), --C(H)(halo),
--C(H)(trifluoromethoxy), --C(H)(methyl), --C(H)(ethyl),
--C(H)(C.sub.3-C.sub.4 alkyl), --C(H)(S(C.sub.1-C.sub.4 alkyl)),
--C(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), cyclopropyl,
--C(H)(cyclopropyl), thiomethoxy, --C(H)(NH.sub.2),
--C(H)(NHCH.sub.3), --C(H)(N(CH.sub.3).sub.2), or
--C(H)(trifluoromethyl);
[0010] wherein said cyclopropyl, methoxy, ethoxy, C.sub.3-C.sub.4
alkyl, and C.sub.1-C.sub.4 alkyl groups of C.dbd.G may optionally
be substituted by one OH, methoxy, or trifluoromethoxy, or may
optionally be substituted by from one to six fluoro atoms;
[0011] Y is CH or N;
[0012] Z is NH, O, S, --N(C.sub.1-C.sub.2 alkyl), --NC(O)CF.sub.3,
or --C(R.sub.13R.sub.14), wherein R.sub.13 and R.sub.14 are each,
independently, hydrogen, trifluoromethyl or methyl, or one of
R.sub.13 and R.sub.14 is cyano and the other is hydrogen or methyl,
or --C(R.sub.13R.sub.14) is a cyclopropyl group, or Z is nitrogen
or CH and forms a five or six membered heterocyclic ring fused with
R.sub.5, which ring optionally comprises two or three further
hetero members selected independently from oxygen, nitrogen,
NR.sub.12, and S(O).sub.m, and optionally comprises from one to
three double bonds, and is optionally substituted with halo,
C.sub.1-C.sub.4 alkyl, --O(C.sub.1-C.sub.4 alkyl), NH.sub.2,
NHCH.sub.3, N(CH.sub.3).sub.2, CF.sub.3, or OCF.sub.3, with the
proviso that said ring does not contain any --S--S--, --S--O--,
--N--S--, or --O-- bonds, and does not comprise more than two
oxygen or S(O).sub.m heterologous members;
[0013] R.sub.1 is C(O)H, C(O)(C.sub.1-C.sub.6 alkyl),
C(O)(C.sub.1-C.sub.6 alkylene)(C.sub.3-C.sub.8 cycloalkyl),
C(O)(C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl),
C(O)(C.sub.1-C.sub.6 alkylene)(C.sub.4-C.sub.8 heterocycloalkyl),
--C(O)(C.sub.3-C.sub.8 cycloalkylene)(C.sub.4-C.sub.8
heterocycloalkyl), C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.4-C.sub.8 heterocycloalkyl, --(C.sub.1-C.sub.6
alkylene)(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.3-C.sub.8
cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl), -(C.sub.1-C.sub.6
alkylene)(C.sub.4-C.sub.8 heterocycloalkyl), --(C.sub.3-C.sub.8
cycloalkylene)(C.sub.4-C.sub.8 heterocycloalkyl), or O-aryl, or
--O--(C.sub.1-C.sub.6 alkylene)aryl; wherein said aryl,
C.sub.4-C.sub.8 heterocycloalkyl, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkylene, and
C.sub.1-C.sub.6 alkylene groups may each independently be
optionally substituted with from one to six fluoro and may each
independently be optionally substituted with one or two
substituents R.sub.8 independently selected from the group
consisting of C.sub.1-C.sub.4 alkyl, --C.sub.3-C.sub.8 cycloalkyl,
hydroxy, fluoro, chloro, bromo, iodo, CF.sub.3,
--O--(C.sub.1-C.sub.6 alkyl), --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--CO--(C.sub.1-C.sub.4 alkyl), --O--CO--NH(C.sub.1-C.sub.4
alkyl), --O--CO--N(R.sub.24)(R.sub.25- ), --N(R.sub.24)(R.sub.25),
--S(C.sub.1-C.sub.4 alkyl), --S(C.sub.3-C.sub.5 cycloalkyl),
--N(C.sub.1-C.sub.4alkyl)CO(C.sub.1-C.su- b.4 alkyl),
--NHCO(C.sub.1-C.sub.4 alkyl), --COO(C.sub.1-C.sub.4 alkyl),
--CONH(C.sub.1-C.sub.4 alkyl), --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), CN, NO.sub.2,
--OSO.sub.2(C.sub.1-C.sub.4 alkyl), S.sup.+(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.2 alkyl)I.sup.-, --SO(C.sub.1-C.sub.4 alkyl)
and --SO.sub.2(C.sub.1-C.sub.4 alkyl); and wherein the
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylene, C.sub.5-C.sub.8
cycloalkyl, C.sub.5-C.sub.8 cycloalkylene, and C.sub.5-C.sub.8
heterocycloalkyl moieties of R.sub.1 may optionally independently
contain from one to three double or triple bonds; and wherein the
C.sub.1-C.sub.4 alkyl moieties and the C.sub.1-C.sub.6 alkyl
moieties of R.sub.8 can optionally independently be substituted
with hydroxy, C.sub.1-C.sub.4 alkyl, amino, aryl, --CH.sub.2-aryl,
--C.sub.3-C.sub.5 cycloalkyl, or --O--(C.sub.1-C.sub.4 alkyl), and
can optionally independently be substituted with from one to five
fluoro, and can optionally contain one or two double or triple
bonds; and wherein each heterocycloalkyl group of R.sub.1 contains
from one to three heteromoieties selected from oxygen, S(O).sub.m,
nitrogen, and NR.sub.12;
[0014] R.sub.2 is hydrogen, C.sub.1-C.sub.12 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.4-C.sub.8 heterocycloalkyl, --(C.sub.1-C.sub.6
alkylene)(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.3-C.sub.8
cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.1-C.sub.6
alkylene)(C.sub.4-C.sub.8 heterocycloalkyl), --(C.sub.3-C.sub.8
cycloalkylene)(C.sub.4-C.sub.8 heterocycloalkyl), aryl,
C.sub.1-C.sub.6 alkylene)aryl, or --(C.sub.3-C.sub.8
cycloalkylene)(aryl); wherein each of the foregoing R.sub.2 groups
may optionally be substituted with from one three substituents
independently selected from chloro, fluoro, and C.sub.1-C.sub.6
alkyl, wherein one of said one to three substituents can further be
selected from bromo, iodo, C.sub.1-C.sub.6 alkoxy, --OH,
--O--CO--(C.sub.1-C.sub.6 alkyl), --O--CO--N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), --S(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --S(O).sub.2(C.sub.1-C.sub.6 alkyl),
S.sup.+(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.2 alkyl)I.sup.-, CN,
and NO.sub.2; and wherein the C.sub.1-C.sub.12 alkyl,
--(C.sub.1-C.sub.6 alkylene), --(C.sub.5-C.sub.8 cycloalkyl),
--(C.sub.5-C.sub.8 cycloalkylene), and --(C.sub.5-C.sub.8
heterocycloalkyl) moieties of R.sub.2 may optionally independently
contain from one to three double or triple bonds; and wherein each
heterocycloalkyl group of R.sub.2 contains from one to three
heteromoieties selected from oxygen, S(O).sub.m, nitrogen, and
NR.sub.12;
[0015] or where R.sub.1 and R.sub.2 are as in --NHCHR.sub.1R.sub.2,
--OCHR.sub.1R.sub.2, --SCHR.sub.1R.sub.2, --CHR.sub.1R.sub.2 or
--NR.sub.1R.sub.2, R.sub.1 and R.sub.2 of B may form a saturated 5
to 8-membered ring which may optionally contain one or two double
bonds and in which one or two of the ring carbons may optionally be
replaced by an oxygen, S(O).sub.m, nitrogen or NR.sub.12; and which
carbocyclic ring can optionally be substituted with from 1 to 3
substituents selected from the group consisting of hydroxy,
C.sub.1-C.sub.4 alkyl, fluoro, chloro, bromo, iodo, CF.sub.3,
--O--(C.sub.1-C.sub.4 alkyl), --O--CO--(C.sub.1-C.sub.4 alkyl),
--O--CO--NH(C.sub.1-C.sub.4 alkyl), --O--CO--N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.2 alkyl)(C.sub.1-C.sub.4 alkyl),
--S(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.4
alkyl)CO(C.sub.1-C.sub.4 alkyl), --NHCO(C.sub.1-C.sub.4
alkyl),--COO(C.sub.1-C.sub.4 alkyl), --CONH(C.sub.1-C.sub.4 alkyl),
--CON(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl), CN, NO.sub.2,
--OSO.sub.2(C.sub.1-C.sub.4 alkyl), --SO(C.sub.1-C.sub.4 alkyl),
and --SO.sub.2(C.sub.1-C.sub.4 alkyl), wherein one of said one to
three substituents can further be selected from phenyl;
[0016] R.sub.3 is methyl, ethyl, fluoro, chloro, bromo, iodo,
cyano, methoxy, OCF.sub.3, NH.sub.2, NH(C.sub.1-C.sub.2 alkyl),
N(CH.sub.3).sub.2, --NHCOCF.sub.3, --NHCH.sub.2CF.sub.3,
S(O).sub.m(C.sub.1-C.sub.4 alkyl), CONH.sub.2, --CONHCH.sub.3,
CON(CH.sub.3).sub.2, --CF.sub.3, or CH.sub.2OCH.sub.3;
[0017] R.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
cycloalkyl, --(C.sub.1-C.sub.4 alkylene)(C.sub.3-C.sub.5
cycloalkyl), --(C.sub.3-C.sub.5 cycloalkylene)(C.sub.3-C.sub.5
cycloalkyl), cyano, fluoro, chloro, bromo, iodo, --OR.sub.24,
C.sub.1-C.sub.6 alkoxy, --O--(C.sub.3-C.sub.5 cycloalkyl),
-O-(C.sub.1-C.sub.4 alkylene) (C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.3-C.sub.5 cycloalkylene)(C.sub.3-C.sub.5 cycloalkyl),
--CH.sub.2SC(S)O(C.sub.1-C.su- b.4 alkyl), --CH.sub.2OCF.sub.3,
CF.sub.3, amino, nitro, --NR.sub.24R.sub.25, --(C.sub.1-C.sub.4
alkylene)--OR.sub.24, --(C.sub.1-C.sub.4 alkylene)Cl,
--(C.sub.1-C.sub.4 alkylene)NR.sub.24R.sub.25, --NHCOR.sub.24,
--NHCONR.sub.24R.sub.25, --C.dbd.NOR.sub.24, --NHNR.sub.24R.sub.25,
--S(O).sub.mR.sub.24, --C(O)R.sub.24, --OC(O)R.sub.24, --C(O)CN,
--C(O)NR.sub.24R.sub.25, --C(O)NHNR.sub.24R.sub.25, and
--COOR.sub.24, wherein the alkyl and alkylene groups of R.sub.4 may
optionally independently contain one or two double or triple bonds
and may optionally independently be substituted with one or two
substituents R.sub.10 independently selected from hydroxy, amino,
--NHCOCH.sub.3, --NHCOCH.sub.2Cl, --NH(C.sub.1-C.sub.2 alkyl),
--N(C.sub.1-C.sub.2 alkyl)(C.sub.1-C.sub.2 alkyl),
--COO(C.sub.1-C.sub.4 alkyl), --COOH, --CO(C.sub.1-C.sub.4 alkyl),
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 thioalkyl, cyano and nitro,
and with one to four substituents independently selected from
fluoro and chloro;
[0018] R.sub.5 is aryl or heteroaryl and is substituted with from
one to four substituents R.sub.27 independently selected from halo,
C.sub.1-C.sub.10 alkyl, --(C.sub.1-C.sub.4
alkylene)(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.1-C.sub.4
alkylene)(C.sub.4-C.sub.8 heterocycloalkyl), --(C.sub.3-C.sub.8
cycloalkyl), --(C.sub.4-C.sub.8 heterocycloalkyl),
--(C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl),
--(C.sub.3-C.sub.8 cycloalkylene)(C.sub.4-C.sub.8
heterocycloalkyl), C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
haloalkoxy, nitro, cyano, --NR.sub.24R.sub.25,
--NR.sub.24COR.sub.25, --NR.sub.24CO.sub.2R.sub.26, --COR.sub.24,
--OR.sub.25, --CONR.sub.24R.sub.25, --CO(NOR.sub.22)R.sub.23,
--CO.sub.2R.sub.26, --C.dbd.N(OR.sub.22)R.sub.23, and
--S(O).sub.mR.sub.23; wherein said C.sub.1-C.sub.10 alkyl,
C.sub.3-C.sub.8 cycloalkyl, (C.sub.1-C.sub.4 alkylene),
(C.sub.3-C.sub.8 cycloalkyl), (C.sub.3-C.sub.8 cycloalkylene), and
(C.sub.4-C.sub.8 heterocycloalkyl) groups can be optionally
substituted with from one to three substituents independently
selected form C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.8 cycloalkyl,
(C.sub.1-C.sub.4 alkylene)(C.sub.3-C.sub.8 cycloalkyl),
--(C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl),
C.sub.1-C.sub.4 haloalkyl, hydroxy, C.sub.1-C.sub.6 alkoxy, nitro
halo, cyano, --NR.sub.24R.sub.25, --NR.sub.24COR.sub.25,
NR.sub.24CO.sub.2R.sub.26, --COR.sub.24, --OR.sub.25,
--CONR.sub.24R.sub.25, CO.sub.2R.sub.26, --CO(NOR.sub.22)R.sub.25,
and --S(O).sub.mR.sub.23; and wherein two adjacent substituents of
the R.sub.5 group can optionally form a 57 membered ring, saturated
or unsaturated, fused to R.sup.5, which ring optionally can contain
one, two, or three heterologous members independently selected from
O, S(O).sub.m, and N, but not any --S--S--, --O--O--, --S--O--, or
--N--S-- bonds, and which ring is optionally substituted with
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.4
alkylene)(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.3-C.sub.8
cyloalkylene)(C.sub.3-C.sub.8 cycloalkyl), C.sub.1-C.sub.4
haloalkyl, nitro, halo, cyano --NR.sub.24R.sub.25,
NR.sub.24COR.sub.25, NR.sub.24CO.sub.2R.sub.26, --COR.sub.24,
--OR.sub.25, --CONR.sub.24R.sub.25, CO.sub.2R.sub.26,
--CO(NOR.sub.26)R.sub.25, or --S(O).sub.mR.sub.23; wherein one of
said one to four optional substituents R.sub.27 can further be
selected from --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH(C.sub.1-C.sub.4 alkylene)(C.sub.3-C.sub.8 cycloalkyl),
--SO.sub.2NH(C.sub.3-C.sub.8 cycloalkyl),
--SO.sub.2NH(C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8
cycloalkyl), --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),
--NHSO.sub.2(C.sub.3-C.sub.8 cycloalkyl),
--NHSO.sub.2(C.sub.1-C.sub.4 alkylene)(C.sub.3-C.sub.8 cycloalkyl),
and --NHSO.sub.2(C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8
cycloalkyl); and wherein the alkyl, and alkylene groups of R.sub.5
may independently optionally contain one double or triple bond;
[0019] R.sub.6 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, --(C.sub.1-C.sub.6 alkylene)(C.sub.3-C.sub.8
cycloalkyl), or C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8
cycloalkyl), wherein said alkyl and cycloalkyl may optionally be
substituted with one hydroxy, methoxy, ethoxy or fluoro group;
[0020] or, wherein the compound is a compound of formula II,
R.sub.6 and R.sub.4 can together form an oxo (.dbd.O) group or can
be connected to form a 38 membered carbocyclic ring, optionally
containing one to three double bonds, and optionally containing
one, two, or three heterologous ring members selected from O,
SO.sub.m, N, and NR.sub.12, but not containing any --O--O--,
--S--O--, --S--S--, or --N--S-- bonds, and further optionally
substituted with C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.8
cycloalkyl, wherein said C.sub.1-C.sub.4 alkyl substituent may
optionally contain one double or triple bond;
[0021] R.sub.7 is hydrogen, methyl, fluoro, chloro, bromo, iodo,
cyano, hydroxy, --O(C.sub.1-C.sub.2 alkyl), --O(cyclopropyl),
--COO(C.sub.1-C.sub.2 alkyl), --COO(C.sub.3-C.sub.8 cycloalkyl),
--OCF.sub.3, CF.sub.3, --CH.sub.2OH, or CH.sub.2OCH.sub.3;
[0022] R.sub.11 is hydrogen, hydroxy, fluoro, ethoxy, or
methoxy;
[0023] R.sub.12 is hydrogen or C.sub.1-C.sub.4 alkyl;
[0024] R.sub.16 and R.sub.17 are each, independently, hydrogen,
hydroxy, methyl, ethyl, methoxy, or ethoxy, except that R.sub.16
and R.sub.17 are not both methoxy or ethoxy;
[0025] or R.sub.16 and R.sub.17 together form an oxo (.dbd.O)
group;
[0026] or R.sub.16 and R.sub.17 are connected to form a 3-8
membered carbocyclic ring, optionally containing one to three
double bonds, and optionally containing from one to three
heterologous ring members selected from O, SO.sub.m, N, and
NR.sub.12, but not containing any --O--O--, --S--O--, --S--S--, or
--N--S-- bonds, and further optionally substituted with
C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.6 cycloalkyl, wherein said
C.sub.1-C.sub.4 alkyl substituent may optionally contain one double
or triple bond;
[0027] R.sub.22 is independently at each occurrence selected from
hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6 alkynyl, C.sub.3-C.sub.8
cycloalkyl, (C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8
cycloalkyl), and (C.sub.1-C.sub.4 alkylene)(C.sub.3-C.sub.8
cycloalkyl);
[0028] R.sub.23 is independently at each occurrence selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.2-C.sub.8
alkoxyalkyl, C.sub.3-C.sub.8 cycloalkyl, --(C.sub.1-C.sub.4
alkylene)(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.3-C.sub.8
cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl), aryl,
--(C.sub.1-C.sub.4 alkylene)aryl, piperidine, pyrrolidine,
piperazine, N-methylpiperazine, morpholine, and thiomorpholine;
[0029] R.sub.24 and R.sub.25 are independently at each occurrence
selected from hydrogen, --C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, especially CF.sub.3, --CHF.sub.2, CF.sub.2CF.sub.3, or
CH.sub.2CF.sub.3, --(C.sub.1-C.sub.4 alkylene)OH,
--(C.sub.1-C.sub.4 alkylene)--O--(C.sub.1-C.sub.4 alkyl),
--(C.sub.1-C.sub.4 alkylene)--O--(C.sub.3-C.sub.5 cycloalkyl),
C.sub.3-C.sub.8 cycloalkyl, --(C.sub.1-C.sub.4
alkylene)(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.3-C.sub.8
cycloalkylene)(C.sub.3-C.sub.8 cycloalkyl), --(C.sub.4-C.sub.8
heterocycloalkyl), --(C.sub.1-C.sub.4 alkylene)(C.sub.4-C.sub.8
heterocycloalkyl), --(C.sub.3-C.sub.8
cycloalkylene)(C.sub.4-C.sub.8 heterocycloalkyl), aryl, and
--(C.sub.1-C.sub.4 alkylene)(aryl), wherein the --C.sub.4-C.sub.8
heterocycloalkyl groups can each independently optionally be
substituted with aryl, CH.sub.2-aryl, or C.sub.1-C.sub.4 alkyl, and
can optionally contain one or two double or triple bonds; or, when
R.sub.24 and R.sub.25 are as NR.sub.24R.sub.25,
--C(O)NR.sub.24R.sub.25, --(C.sub.1-C.sub.4
alkylene)NR.sub.24R.sub.25, or --NHCONR.sub.24R.sub.25, then
NR.sub.24R.sub.25 may further optionally form a 4 to 8 membered
heterocyclic ring optionally containing, one or two further hetero
members independently selected from S(O)m, oxygen, nitrogen, and
NR,.sub.2, and optionally containing from one to three double
bonds;
[0030] R.sub.26 is independently at each occurrence selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.8
cycloalkyl, --(C.sub.1-C.sub.4 alkylene)(C.sub.3-C.sub.8
cycloalkyl), --(C.sub.3-C.sub.8 cycloalkylene)(C.sub.3-C.sub.8
cycloalkyl), aryl, and - (C.sub.1-C.sub.4 alkylene)(aryl); and
[0031] wherein each m is independently zero, one, or two,
[0032] with the proviso that heterocycloalkyl groups of the
compound of formula I, II, or III do not comprise any --S--S--,
--S--O--, --N--S--, or --O--O-- bonds, and do not comprise more
than two oxygen or S(O).sub.m heterologous members.
[0033] In one embodiment of the invention, the compound of the
invention is of formula 3
[0034] wherein
[0035] the dashed lines represent optional double bonds;
[0036] A is --CR.sub.7 or N;
[0037] B is --NR.sub.1R.sub.2, --CR.sub.1R.sub.2R.sub.11,
--C(.dbd.CR.sub.2R.sub.12)R.sub.1, --NHCHR.sub.1R.sub.2,
--OCHR.sub.1R.sub.2, --SCHR.sub.1R.sub.2, --CHR.sub.2OR.sub.12,
--CHR.sub.2SR.sub.12, --C(S)R.sub.2 or --C(O)R.sub.2;
[0038] G is oxygen, sulfur, NH, NH.sub.3, hydrogen, methoxy,
ethoxy, trifluoromethoxy, methyl, ethyl, thiomethoxy, NH.sub.2,
NHCH.sub.3, N(CH.sub.3).sub.2 or trifluoromethyl;
[0039] Y is --CH or N;
[0040] Z is NH, O, S, --N(C.sub.1-C.sub.2 alkyl) or
--C(R.sub.13R.sub.14), wherein R.sub.13 and R.sub.14 are each,
independently, hydrogen, trifluoromethyl or methyl, or one of
R.sub.13 and R.sub.14 is cyano and the other is hydrogen or
methyl;
[0041] R.sub.1 is C.sub.1-C.sub.6 alkyl which may optionally be
substituted with one or two substituents R.sub.8 independently
selected from the group consisting of hydroxy, fluoro, chloro,
bromo, iodo, CF.sub.3, C.sub.1-C.sub.4 alkoxy,
--O--CO--(C.sub.1-C.sub.4 alkyl), --O--CO--NH(C.sub.1-C.sub.4
alkyl), --O--CO--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--NH(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.2
alkyl)(C.sub.1-C.sub.4 alkyl), --S(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4alkyl)CO(C.sub.1-C.sub.4 alkyl),
--NHCO(C.sub.1-C.sub.4 alkyl), --COO(C.sub.1-C.sub.4 alkyl),
--CONH(C.sub.1-C.sub.4 alkyl), --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), CN, NO.sub.2, --SO(C.sub.1-C.sub.4
alkyl) and --SO.sub.2(C.sub.1-C.sub.4 alkyl), and wherein said
C.sub.1-C.sub.6 alkyl and the (C.sub.1-C.sub.4)alkyl moieties in
the foregoing R.sub.1 groups may optionally contain one
carbon-carbon double or triple bond;
[0042] R.sub.2 is C.sub.1-C.sub.12 alkyl, aryl or
--(C.sub.1-C.sub.4 alkylene)aryl wherein said aryl is phenyl,
naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl,
pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,
isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl,
indolyl, or benzoxazolyl; 3- to 8-membered cycloalkyl or
--(C.sub.1-C.sub.6 alkylene)cycloalkyl, wherein one or two of the
ring carbons of said cycloalkyl having at least 4 ring members and
the cycloalkyl moiety of said --(C.sub.1-C.sub.6
alkylene)cycloalkyl having at least 4 ring members may optionally
be replaced by an oxygen or sulfur atom or by N-R.sub.9 wherein
R.sub.9 is hydrogen or C.sub.1-C.sub.4 alkyl; and wherein each of
the foregoing R.sub.2 groups may optionally be substituted with
from one to three substituents independenty selected from chloro,
fluoro and C.sub.1-C.sub.4 alkyl, or with one substituent selected
from bromo, iodo, C.sub.1-C.sub.6 alkoxy, --O--CO--(C.sub.1-C.sub.6
alkyl), --O--CO--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--S(C.sub.1-C.sub.6 alkyl), CN, NO.sub.2, --SO(C.sub.1-C.sub.4
alkyl), and --SO.sub.2(C.sub.1-C.sub.4 alkyl), and wherein said
C.sub.1-C.sub.12 alkyl and the C.sub.1-C.sub.4 alkylene moiety of
said --(C.sub.1-C.sub.4 alkylene)aryl may optionally contain one
carbon-carbon double or triple bond;
[0043] or --NR.sub.1R.sub.2 or --CR.sub.1R.sub.2R.sub.11 may form a
saturated 5- to 8-membered carbocyclic ring which may optionally
contain one or two carbon-carbon double bonds and in which one or
two of the ring carbons may optionally be replaced by an oxygen or
sulfur atom;
[0044] R.sub.3 is methyl, ethyl, fluoro, chloro, bromo, iodo,
cyano, methoxy, OCF.sub.3, methylthio, methylsulfonyl, CH.sub.2OH,
or CH.sub.2OCH.sub.3;
[0045] R.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, fluo, bromo,
iodo, C.sub.1-C.sub.4 alkoxy, trifluoromethoxy,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2OF.sub.3, CF.sub.3, amino,
nitro, --NH(C.sub.1-C.sub.4 alkyl), --N(CH.sub.3).sub.2,
--NHCOCH.sub.3, --NHCONHCH.sub.3, --SO.sub.n(C.sub.1-C.sub.4 alkyl)
wherein n is 0, 1 or 2, cyano, hydroxy, --CO(C.sub.1-C.sub.4
alkyl), --CHO, cyano or --COO(C.sub.1-C.sub.4 alkyl) wherein said
C.sub.1-C.sub.4 alkyl may optionally contain one double or triple
bond and may optionally be substituted with one substituent
selected from hydroxy, amino, --NHCOCH.sub.3, --NH(C.sub.1-C.sub.2
alkyl), --N(C.sub.1-C.sub.2 alkyl).sub.2, --COO(C.sub.1-C.sub.4
alkyl), --CO(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 thioalkyl, fluoro, chloro, cyano and nitro;
[0046] R.sub.5 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl,
quinolyl, pyrazinyl, pyrimidyl, furanyl, benzofuranyl,
benzothiazolyl, or indolyl, wherein each of the above groups
R.sub.5 is substituted with from one to three substituents
independently selected from fluoro, chloro, C.sub.1-C.sub.6 alkyl,
and C.sub.1-C.sub.6 alkoxy, or with one substituent selected from
hydroxy, iodo, bromo, formyl, cyano, nitro, trifluoromethyl,
amino,--(C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6)alkyl,
--NHCH.sub.3, --N(CH.sub.3), --COOH, --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) and --SO.sub.2(C.sub.1-C.sub.6 alkyl),
and wherein the C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.6 alkyl
moieties of the foregoing R.sub.5 groups may optionally be
substituted with one or two fluoro groups or with one substituent
selected from hydroxy, amino, methylamino, dimethylamino and
acetyl;
[0047] R.sub.6 is hydrogen or C.sub.1-C.sub.6 alkyl, wherein said
C.sub.1-C.sub.6 alkyl may optionally be substituted with one
hydroxy, methoxy, ethoxy or fluoro group;
[0048] R.sub.7 is hydrogen, methyl, fluoro, chloro, bromo, iodo,
cyano, hydroxy, --O(C.sub.1-C.sub.4 alkyl), --C(O)(C.sub.1-C.sub.4
alkyl), --C(O)O(C.sub.1-C.sub.4 alkyl), --OCF.sub.3, CF.sub.3,
--CH.sub.2OH, --CH.sub.2OCH.sub.3 or
--CH.sub.2OCH.sub.2CH.sub.3;
[0049] R.sub.11 is hydrogen, hydroxy, fluoro, or methoxy;
[0050] R.sub.12 is hydrogen or C.sub.1-C.sub.4 alkyl; and
[0051] R.sub.16 and R.sub.17 are each, independently, hydrogen,
hydroxy, methyl, ethyl, methoxy, or ethoxy, except that R.sub.16
and R.sub.17 are not both methoxy or ethoxy;
[0052] or R.sub.16 and R.sub.17 together form an oxo (.dbd.O)
group;
[0053] with the proviso that when G is oxygen, sulfur, NH or
NCH.sub.3, it is double bonded to the five membered ring of
structure III, and with the further proviso that R.sub.6 is absent
when the nitrogen to which it is attached is double bonded to an
adjacent ring carbon atom;
[0054] or a pharmaceutically acceptable salt of such compound.
[0055] More specific embodiments of this invention include
compounds of the formula I, II or III wherein: (a) B is
--NR.sub.1R.sub.2, --NHCHR.sub.1R.sub.2, --SCHR.sub.1R.sub.2 or
OCHR.sub.1R.sub.2; R.sub.1 is C.sub.1-C.sub.6 alkyl, which may
optionally be substituted with one hydroxy, fluoro, CF.sub.3, or
C.sub.1-C.sub.2 alkoxy group and may optionally contain one double
or triple bond; and R.sub.2 is benzyl or C.sub.1-C.sub.6 alkyl
which may optionally contain one carbon-carbon double or triple
bond, wherein said C.sub.1-C.sub.6 alkyl or the phenyl moiety of
said benzyl may optionally be substituted with fluoro, CF.sub.3,
C.sub.1-C.sub.2 alkyl, or C.sub.1-C.sub.2 alkoxy; or (b) B is
--CR.sub.1R.sub.2R.sub.11 wherein R.sub.1 is C.sub.1-C.sub.6 alkyl
which may optionally be substituted with one Cl-C.sub.2 alkoxy,
CF.sub.3, fluoro or hydroxy group; R.sub.2 is benzyl or
C.sub.1-C.sub.6 alkyl wherein said C.sub.1-C.sub.6 alkyl or the
phenyl moiety of said benzyl may optionally be substituted with one
C.sub.1-C.sub.2 alkyl, CF.sub.3, C.sub.1-C.sub.2 alkoxy, fluoro,
chloro or bromo group; and R.sub.11 is hydrogen or fluoro.
[0056] Other more specific embodiments of this invention include
compounds of the formula I, II or III wherein R.sub.1 is
C.sub.1-C.sub.6 alkyl which may optionally be substituted by
fluoro, CF.sub.3, hydroxy, C.sub.1-C.sub.2 alkyl or C.sub.1-C.sub.2
alkoxy and may optionally contain one carbon-carbon double or
triple bond, and R.sub.2 is C.sub.1-C.sub.4 alkyl which may
optionally be substituted with fluoro, chloro, CF.sub.3,
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy.
[0057] Other more specific embodiments of this invention include
compounds of the formula I, II or III wherein R.sub.3 is methyl,
chloro, or methoxy, R.sub.4 is methyl, --CH.sub.2OH, cyano,
trifluoromethoxy, methoxy, trifluoromethyl, chloro, --COOCH.sub.3,
--CH.sub.2OCH.sub.3, --CH.sub.2Cl, --CH.sub.2F, amino or nitro;
R.sub.6 is hydrogen, methyl or ethyl and R.sub.5 is phenyl or
pyridyl wherein said phenyl or pyridyl is substituted by two or
three substituents independently selected from fluoro, chloro,
bromo, iodo, C.sub.1-C.sub.4 alkoxy, trifluoromethyl,
C.sub.1-C.sub.6 alkyl which may optionally be substituted with one
hydroxy, C.sub.1-C.sub.2 alkoxy or fluoro group and may optionally
contain one carbon-carbon double or triple bond, --(C.sub.1-C.sub.4
alkylene)O(C.sub.1-C.sub.2 alkyl), C.sub.1-C.sub.3 hydroxyalkyl,
hydroxy, formyl, --COO(C.sub.1-C.sub.2 alkyl), --(C.sub.1-C.sub.2
alkylene)amino, and --(C(O)(C.sub.1-C.sub.4 alkyl).
[0058] Examples of preferred compounds of this invention are:
[0059] 4-(1
-ethyl-propoxy)-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimi-
dine;
[0060]
2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-p-
yridine;
[0061]
2-(4-ethyl-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-p-
yridine;
[0062]
3-ethyl-4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-py-
ridine;
[0063]
2-(2,6-dimethyl-4-propyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl--
pyridine;
[0064]
4-(1-ethyl-propoxy)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-
-pyridine;
[0065]
2-(4-ethoxy-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl--
pyridine;
[0066]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl--
pyridine;
[0067]
4-(1-methoxymethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy-
)-pyridine;
[0068]
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-diethyl-ami-
ne;
[0069]
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propy-
l-amine;
[0070]
[2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl](1-ethyl-p-
ropyl)-amine;
[0071]
butyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-
-amine;
[0072]
4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-
-pyridine;
[0073]
butyl-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-
-ethyl-amine;
[0074]
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicoti-
nic acid methyl ester;
[0075]
[3,6-dimethyl-[2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4-yl]-eth-
yl-propyl-amine;
[0076]
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridi-
n-3-yl]-methanol;
[0077]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-
-propyl-amine;
[0078]
1-(ethyl-propyl)-[6-ethyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyrid-
in-4-yl]-amine;
[0079]
N4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-py-
ridine-2,4-diamine;
[0080]
N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-
,4-diamine;
[0081]
3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-(2,2,2-
-trifluoro-ethyl)-amine;
[0082]
N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2-
,3,4-triamine;
[0083]
[3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)pyridin-4yl]-(1-
-ethyl-propyl)-amine;
[0084]
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-pr-
opyl)-amine;
[0085]
(1-ethyl-propyl)-[2-methyl-5-nitro-6-(2,4,6-trimethyl-pyridin-3-ylo-
xy)-pyrimidin-4-yl]-amine;
[0086]
(1-ethyl-propyl)-[3-methoxymethyl-6-methyl-2-(2,4,6-trimethyl-pheno-
xy)-pyridin-4-yl]-amine;
[0087]
(N-(1-ethyl-propyl)-2-methyl-5-nitro-N'-(2,4,6-trimethyl-pyridin-3--
yl)-pyrimidine-4,6-diamine;
[0088]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-dieth-
yl-amine;
[0089]
4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridin-
e;
[0090]
butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrol-
o[2,3-d]pyrimidin-4-yl]-ethyl-amine;
[0091]
4-(butyl-ethylamino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dih-
ydro-pyrrolo[2,3-d]pyrimidin-6-one;
[0092]
4-(1-ethylpropoxy)-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidi-
ne;
[0093]
N-butyl-N-ethyl-2,5-dimethyl-N'-(2,4,6-trimethylphenyl)-pyrimidine--
4,6-diamine;
[0094]
(1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,-
5-b]pyridin-7-yl]-amine;
[0095]
[2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-
-yl]-(1-ethyl-propyl)-amine;
[0096]
N4-(1-ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyrid-
ine-3,4-diamine;
[0097]
N4-(1-ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-p-
yridine-3,4-diamine;
[0098]
6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-
-4,5-diamine;
[0099]
[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethylphe-
nyl)-amine; and
[0100]
6-(ethyl-propyl-amino)-2,7-dimethyl-9-(2,4,6-trimethylphenyl)-7,9-d-
ihydro-purin-8-one.
[0101] Other preferred compounds of this invention are:
[0102]
4-(1-ethyl-propoxy)-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimid-
ine;
[0103]
2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-p-
yridine;
[0104]
2-(4-ethyl-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-p-
yridine;
[0105]
3-ethyl-4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-py-
ridine;
[0106]
2-(2,6-dimethyl-4-propyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl--
pyridine;
[0107]
4-(1-ethyl-propoxy)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-
-pyridine;
[0108]
2-(4-ethoxy-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl--
pyridine;
[0109]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl--
pyridine;
[0110]
4-(1-methoxymethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy-
)-pyridine;
[0111]
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-diethyl-ami-
ne;
[0112]
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propy-
l-amine;
[0113]
[2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl](1-ethyl-p-
ropyl)-amine;
[0114]
butyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-
-amine;
[0115]
4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-
-pyridine;
[0116]
butyl-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-
-ethyl-amine;
[0117]
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicoti-
nic acid methyl ester;
[0118]
[3,6-dimethyl-[2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4-yl]-eth-
yl-propyl-amine;
[0119]
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridi-
n-3-yl]-methanol;
[0120]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-
-propyl-amine;
[0121]
1-(ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyri-
din-4-yl]-amine;
[0122]
N4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-py-
ridine-2,4-diamine;
[0123]
N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-
,4-diamine;
[0124]
3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-(2,2,2-
-trifluoro-ethyl)-amine;
[0125]
N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2-
,3,4-triamine;
[0126]
[3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)pyridin-4-yl]-(-
1-ethyl-propyl)-amine;
[0127]
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-pr-
opyl)-amine;
[0128]
(1-ethyl-propyl)-[2-methyl-5nitro-6-(2,4,6-trimethyl-pyridin-3-ylox-
y)-pyrimidin-4-yl]-amine;
[0129]
(1-ethyl-propyl)-[3-methoxymethyl-6-methyl-2-(2,4,6-trimethyl-pheno-
xy)-pyridin-4-yl]-amine;
[0130]
(N-(1-ethyl-propyl)-2-methyl-5-nitro-N'-(2,4,6-trimethyl-pyridin-3--
yl)-pyrimidine-4,6-diamine;
[0131]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-dieth-
yl-amine;
[0132]
4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridin-
e;
[0133]
butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrol-
o[2,3-d]pyrimidin-4-yl]-ethyl-amine;
[0134]
4-(butyl-ethylamino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dih-
ydro-pyrrolo[2,3-d]pyrimidin-6-one;
[0135]
4-(1-ethylpropoxy)-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidi-
ne;
[0136]
N-butyl-N-ethyl-2,5-dimethyl-N'-(2,4,6-trimethylphenyl)-pyrimidine--
4,6-diamine;
[0137]
(1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,-
5-b]pyridin-7-yl]-amine;
[0138]
[2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-
-yl]-(1-ethyl-propyl)-amine;
[0139]
N4-(1-ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyrid-
ine-3,4-diamine;
[0140]
N4-(1-ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-p-
yridine-3,4-diamine;
[0141]
6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-
-4,5-diamine;
[0142]
[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethylphe-
nyl)-amine; and
[0143]
6-(ethyl-propyl-amino)-2,7-dimethyl-9-(2,4,6-trimethylphenyl)-7,9-d-
ihydro-purin-8-one .
[0144] Examples of preferred compounds of this invention are:
[0145]
2-[2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-(S)-
-ylamino]-butan-1-ol;
[0146]
(1-methoxymethyl-propyl)-[6-methyl-3-nitro-2-(4-trifluoromethoxy-ph-
enoxy)-pyridin-4-yl]-amine;
[0147]
2-(2-amino-4,6-dichloro-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1--
methoxymethyl-propyl)-amine;
[0148]
3-methoxy-2-[4-(1-methoxymethyl-propylamino)-6-methyl-3-nitro-pyrid-
in-2-yloxy]-benzaldehyde;
[0149]
[2-(2,6-dibromo-4-trifluoromethoxy-phenoxy)-6-methyl-3-nitro-pyridi-
n-4-yl]-(1-methoxymethyl-propyl)-amine;
[0150]
[2-(2-bromo-4-chloro-6-methoxy-phenoxy)-6-methyl-3-nitro-pyridin-4--
yl]-(1-methoxymethyl-propyl)-amine;
[0151]
[2-(2,4-dichloro-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxy-
methyl-propyl)-amine;
[0152]
[2-(2-bromo-6-chloro-4-methoxy-phenoxy)-6-methyl-3-nitro-pyridin-4--
yl]-(1-methoxymethyl-propyl)-amine;
[0153]
(1-methoxymethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethoxy-phen-
oxy)-pyridin-4-yl]-amine;
[0154]
2-chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phe-
noxy)-pyridin-3-yl]-acetamide;
[0155]
3-chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phe-
noxy)-pyridin-3-yl]-propionamide;
[0156]
2-chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phe-
noxy)-pyridin-3-yl]-propionamide;
[0157]
N3-allyl-N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-p-
yridine-3,4-diamine;
[0158]
N3-(3-chloro-propyl)-N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-pyridine-3,4-diamine;
[0159]
N4-(1-ethyl-propyl)-6-methyl-N3-propa-1,2-dienyl-2-(2,4,6-trimethyl-
-phenoxy)-pyridine-3,4-diamine;
[0160]
2-[3-amino-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-
-ylamino]-butan-1-ol;
[0161]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl--
nicotinic acid methyl ester;
[0162]
2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-n-
icotinic acid methyl ester;
[0163]
4-(1-ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-n-
icotinic acid methyl ester;
[0164]
4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phe-
noxy)-nicotinic acid methyl ester;
[0165]
4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-2-(2,4,6-trimethyl-pheno-
xy)-nicotinic acid methyl ester;
[0166]
2-(4-bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino-
)-6-methyl-nicotinic acid methyl ester;
[0167]
2-(4-bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-methoxymethyl-propylamino-
)-6-methyl-nicotinic acid methyl ester;
[0168]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-
-methyl-nicotinic acid methyl ester;
[0169]
2-(4-chloro-2-methoxy-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)--
6-methyl-nicotinic acid methyl ester;
[0170]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-
-6-methyl-nicotinic acid methyl ester;
[0171]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methoxy-propylamino)-
-6-methyl-nicotinic acid methyl ester;
[0172]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-m-
ethyl-nicotinic acid methyl ester;
[0173]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-m-
ethyl-nicotinic acid methyl ester;
[0174]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(4-ethyl-2-oxo-oxazolidin-3-
-yl)-6-methyl-nicotinic acid methyl ester;
[0175]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-[(2-hydroxy-ethylamino)--
methyl]-propylamino)-6-methyl-nicotinic acid methyl ester;
[0176]
4-[ethyl-(2-hydroxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-pheno-
xy)-nicotinic acid methyl ester;
[0177]
4-[ethyl-(2-methanesulfonyloxy-ethyl)-amino]-6-methyl-2-(2,4,6-trim-
ethyl-phenoxy)-nicotinic acid methyl ester;
[0178]
4-[(2-hydroxy-ethyl)-thiophen-2-ylmethyl-amino]-6-methyl-2-(2,4,6-t-
rimethyl-phenoxy)-nicotinic acid methyl ester;
[0179]
4-(2,2-dimethyl-4-phenyl-[1,3]dioxan-5-ylamino)-6-methyl-2-(2,4,6-t-
rimethyl-phenoxy)-nicotinic acid methyl ester;
[0180]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamin-
o)-6-methyl-nicotinic acid ethyl ester;
[0181]
4-[ethyl-(2-methoxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-pheno-
xy)-nicotinic acid methyl ester;
[0182]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S,R)-&(S,S)-(1-ethyl-2-hydroxy-
-propylamino)-6-methyl-nicotinic acid methyl ester;
[0183]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(R)-(1-hydroxymethyl-propylamin-
o)-6-methyl-nicotinic acid methyl ester;
[0184]
4-(2-hydroxy-1-hydroxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-nicotinic acid methyl ester;
[0185]
4-(2-methoxy-1-methoxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-nicotinic acid methyl ester;
[0186]
4-(1-hydroxymethyl-2-methoxy-ethylamino)-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-nicotinic acid methyl ester;
[0187]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-butylamino)--
6-methyl-nicotinic acid methyl ester;
[0188]
[2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-
-pyridin-3-yl]-methanol;
[0189]
[2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl--
pyridin-3-yl]-methanol;
[0190]
2-[3-hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(-
S)-ylamino]-butan-1-ol;
[0191]
3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyrid-
in-4-ylamino]-pentan-2-ol;
[0192]
2-[2-(2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylam-
ino]-butan-1-ol;
[0193]
3-[3-hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-y-
lamino]-pentan-2-ol;
[0194]
2-[2-(4-chloro-2-methoxy-phenoxy)-3-hydroxymethyl-6-methyl-pyridin--
4-ylamino]-butan-1-ol;
[0195]
2-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyrid-
in-4-ylamino]-butan-1-ol;
[0196]
2ethyl-[3-hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridi-
n-4-yl]-amino)-ethanol;
[0197]
4-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyrid-
in-4-ylamino]-hexan-3-ol;
[0198]
2-[2-(4-chloro-2-methoxy-phenoxy)-3-hydroxymethyl-6-methyl-pyridin--
4-(S)-ylamino]-butan-1-ol;
[0199]
4-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyrid-
in-4-ylamino]-hexan-3-ol;
[0200]
[2-(2,4-dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-
-pyridin-3-yl]-methanol;
[0201]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamin-
o)-6-methyl-nicotinic acid;
[0202]
4-(1-ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-n-
icotinic acid;
[0203]
2-(4-bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-methoxymethyl-propylamino-
)-6-methyl-nicotinic acid;
[0204]
4-(2-methoxy-1-methoxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-nicotinic acid;
[0205]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3-isobutoxymethyl-6-methyl-pyrid-
in-4-yl]-(1-ethyl-propyl)-amine;
[0206]
[3-ethoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]--
(1-ethyl-propyl)-amine;
[0207]
2-[3-butoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl-
amino]-butan-1-ol;
[0208]
1-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyr-
idin-3-yl]-ethanol;
[0209] acetic acid
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phe-
noxy)-pyridin-3-ylmethyl ester;
[0210]
2-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-(1-hydroxy-1-methyl-ethyl)-6-
-methyl-pyridin-4-(S)-ylamino]-butan-1-ol;
[0211]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-et-
hyl-propyl)-amine;
[0212]
[2-(2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propy-
l)-amine;
[0213]
[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-eth-
yl-propyl)-amine;
[0214]
4-[4-(1-ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy[-3,5-dimeth-
yl-benzaldehyde;
[0215]
{4-[4-(1-ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimet-
hyl-phenyl)-methanol;
[0216]
(1-ethyl-propyl)-[2-(4-methoxymethyl-2,6-dimethyl-phenoxy)-3,6-dime-
thyl-pyridin-4-yl]-amine;
[0217]
[2-(4-ethyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-eth-
yl-propyl)-amine;
[0218]
2-{4-[4-(1-ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dim-
ethyl-phenyl)-propan-2-ol;
[0219]
1-{4-[4-(1-ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dim-
ethyl-phenyl)-ethanol;
[0220]
(1-ethyl-propyl)-[2-(4-isopropenyl-2,6-dimethyl-phenoxy)-3,6-dimeth-
yl-pyridin-4-yl]-amine;
[0221]
(1-ethyl-propyl)-[2-(4-isopropyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-
-pyridin-4-yl]-amine;
[0222]
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-
allyl)-amine;
[0223]
(1-ethyl-propyl)-[2-(4-fluoro-2,6-dimethyl-phenoxy)-3,6-dimethyl-py-
ridin-4-yl]-amine;
[0224]
2-[2-(2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-butan-1-
-ol;
[0225]
2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-ylamino]--
butan-1-ol;
[0226]
3-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-pent-
an-2-ol;
[0227]
3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino-
]-pentan-2-ol;
[0228]
benzyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethy-
l-amine;
[0229]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-me-
thoxymethyl-propyl)-amine;
[0230]
2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-3-ph-
enyl-propan-1-ol;
[0231]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-me-
thoxymethyl-propyl)-amine;
[0232]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-et-
hoxymethyl-propyl)-amine;
[0233]
[3,6-dimethyl-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-(1-methoxy-
methyl-propyl)-amine;
[0234]
[2-(4-bromo-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]--
(1-ethy-propyl)-amine;
[0235]
(1-ethyl-propyl)-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-py-
ridin-4-yl]-amine;
[0236]
[2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-3-propyl-pyridin-4-yl]--
(1-ethyl-propyl)-amine;
[0237]
[2-(4-bromo-2,6-dimethyl-phenoxy)-6-methyl-3-propyl-pyridin-4-yl]-(-
1-ethyl-propyl)-amine;
[0238]
(1-ethyl-propyl)-[6-methyl-3-propyl-2-(2,4,6-trimethyl-phenoxy)-pyr-
idin-4-yl]-amine;
[0239]
[2-(2,4-dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-
-(1-ethyl-propyl)-amine;
[0240]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-
-(1-ethyl-propyl)-amine;
[0241]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-
-(1-methoxymethyl-propyl)-amine;
[0242]
[2-(2,4-dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-
-(1-methoxymethyl-propyl)-amine;
[0243]
[2-(4-chloro-2-methoxy-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-
-methoxymethyl-propyl)-amine;
[0244]
[2-(3-chloro-2,6-dimethoxy-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl-
]-(1-methoxymethyl-propyl)-amine;
[0245]
(1-methoxymethyl-propyl)-[3-methoxy-6-methyl-2-(2,4,6-trimethoxy-ph-
enoxy)-pyridin-4-yl]-amine;
[0246]
[3-methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-yl-
]-(1-ethoxymethyl-propyl)-amine;
[0247]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3-ethoxy-6-methyl-pyridin-4-yl]--
(1-methoxymethyl-propyl)-amine;
[0248]
2-(2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-(S)-yla-
mino]-butan-1-ol;
[0249]
2-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-yla-
mino]-butan-1ol;
[0250]
2-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-y-
lamino]-butan-1-ol;
[0251]
4-[4-(1-hydroxymethyl-propylamino)-3-methoxy-6-methyl-pyridin-2-ylo-
xy]-3,5-dimethyl-benzonitrile;
[0252]
3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino-
]-pentan-2-ol;
[0253]
2-[2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-butan-1--
ol;
[0254]
(1-ethyl-prop-2-ynyl)-[2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridin-
-4-yl]-amine];
[0255]
2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-p-
yridin-3-ol;
[0256]
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridi-
n-3-ol;
[0257]
4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phe-
noxy)-pyridin-3-ol;
[0258]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-
-methyl-pyridin-3-ol;
[0259]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl--
pyridin-3-ol;
[0260] chloro-acetic acid
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimet-
hyl-phenoxy)-pyridin-3-yl ester;
[0261]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-[(1-ethyl-propyl)-methyl-amino]-
-6-methyl-pyridin-3-ol;
[0262]
[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyrid-
in-3-yl]-acetonitrile;
[0263]
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridi-
ne-3-carbaldehyde;
[0264]
(1-ethyl-propyl)-[3-[(1-ethyl-propylimino)-methyl]-6-methyl-2-(2,4,-
6-trimethyl-phenoxy)-pyridin-4-yl]-amine;
[0265]
2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyr-
idin-3-ylmethyl]-malonic acid dimethyl ester;
[0266]
2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyr-
idin-3-ylmethyl]-malonic acid diisopropyl ester;
[0267]
4-(1-ethyl-propoxy)-6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-py-
ridine;
[0268]
4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3--
ylamine;
[0269]
[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-
3-yl]-dimethyl-amine;
[0270]
N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethy-phenoxy)-pyridin--
3-yl]-succinamic acid;
[0271]
4-(1-ethyl-propoxy)-3,6-dimethyl-2-[3-(2,4,6-trimethyl-pyridinoxy)]-
-pyridine;
[0272]
6-ethyl-4-(1-ethyl-propoxy)-3-methyl-2-(2,4,6-trimethyl-phenoxy)-py-
ridine;
[0273]
4-(1-ethyl-propoxy)-2-(4-fluoro-2,6-dimethyl-phenoxy)-3,6-dimethyl--
pyridine;
[0274]
[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethyl-ph-
enyl)-amine;
[0275]
[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyrid-
in-3-yl]-methanol;
[0276]
[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyrid-
in-3-yl]-oxo-acetonitrile;
[0277]
[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyrid-
in-3-yl]-imidazol-1-yl-methanone;
[0278]
2-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyr-
idin-3-yl]-propan-2-ol;
[0279]
2-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyr-
idin-3-ylmethyl]-malonic acid dimethyl ester;
[0280]
3-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyr-
idin-3-yl]-propionic acid;
[0281]
[3-aminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-tr-
imethyl-phenyl)-amine;
[0282]
2-chloro-N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenyla-
mino)-pyridin-3-ylmethyl]-acetamide;
[0283]
[3-dimethylaminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(-
2,4,6-trimethyl-phenyl)-amine hydrochloride salt;
[0284] dithiocarbonic acid O-ethyl ester
S-[4-(1-ethyl-propoxy)-6-methyl-2-
-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl] ester;
[0285]
4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicoti-
namide;
[0286]
4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicoti-
nonitrile;
[0287]
4-(1-ethyl-propoxy)-6,N,N-trimethyl-2-(2,4,6-trimethyl-phenylamino)-
-nicotinamide;
[0288]
[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyrid-
in-3-yl]-acetonitrile;
[0289]
[2-(4-bromo-2,6-dimethyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl--
pyridin-3-yl]-methanol;
[0290]
[2-(4-chloro-2,6-dimethyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-
-pyridin-3-yl]-methanol;
[0291]
[2-(2,4-dichloro-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin--
3-yl]-methanol;
[0292]
[2-(2,4-dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-
-pyridin-3-yl]-methanol;
[0293]
[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyrid-
in-3-yl]-imidazol-1-yl-methanone;
[0294]
1-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyr-
idin-3-yl]-ethanone;
[0295]
(1-ethyl-propyl)-[6-methyl-3-propyl-2-(2,4,6-trimethyl-phenoxy)-pyr-
idin-4-yl]-amine;
[0296]
2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyr-
idin-3-ylmethyl]-2-methyl-malonic acid dimethyl ester;
[0297]
[4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl-
)-amine;
[0298]
2-ethyl-1-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-
-yl]-butan-1-ol;
[0299]
1-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-2-m-
ethyl-butan-1-ol;
[0300]
1-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1--
ol;
[0301]
4-(1-methoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyrid-
ine;
[0302]
4-(1-ethoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridi-
ne;
[0303]
4-(1-allyloxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyri-
dine;
[0304]
4-(1-butoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridi-
ne;
[0305]
1-[2-(2,4-dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-y-
l]-2-ethyl-butan-1-ol;
[0306]
1-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-2,2,2-tri-
fluoro-ethanol;
[0307]
1-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-2,2-
,2-trifluoro-ethanol;
[0308]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-pyrid-
in-2-yl-methanol;
[0309]
1-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-y-
l]-2-ethyl-butan-1-ol;
[0310]
1-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1--
one;
[0311]
1-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-2,2-
,2-trifluoro-ethanone;
[0312]
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-pyrid-
in-2-yl-methanone;
[0313]
1-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-y-
l]-2-ethyl-butan-1-one;
[0314]
4-(1-ethoxy-2,2,2-trifluoro-ethyl)-3,6-dimethyl-2-(2,4,6-trimethyl--
phenoxy)-pyridine;
[0315]
2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butan-2-o-
l;
[0316]
3-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-pentan-3--
ol;
[0317]
1-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-hydroxy-6-methyl-pyridin-4-y-
l]-2-ethyl-butan-1-one;
[0318]
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicoti-
namide;
[0319]
4-(1-ethyl-propylamino)-6,N-dimethyl-2-(2,4,6-trimethyl-phenoxy)-ni-
cotinamide;
[0320]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamin-
o)-6-methyl-nicotinamide;
[0321]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamin-
o)-6-methyl-nicotinic acid hydrazide;
[0322]
2-(4-chloro-2,6-dimethyl-phenoxy)-N-ethyl-4-(S)-(1-hydroxymethyl-pr-
opylamino)-6-methyl-nicotinamide;
[0323]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamin-
o)-6,N-dimethyl-nicotinamide;
[0324]
2-(4-chloro-2,6-dimethyl-phenoxy)-N-cyclopentyl-4-(S)-(1-hydroxymet-
hyl-propylamino)-6-methyl-nicotinamide;
[0325]
2-(4-chloro-2,6-dimethyl-phenoxy)-N-cyctopropylmethyl-4-(S)-(1-hydr-
oxymethyl-propylamino)-6-methyl-nicotinamide;
[0326]
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-ni-
cotinamide;
[0327]
4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimi-
dine-5-carboxylic acid amide;
[0328]
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicoti-
nonitrile;
[0329]
[4-(1-ethyl-propoxy)-6-methyl-3-nitro-pyridin-2-yl]-(2,4,6-trimethy-
l-phenyl)-amine;
[0330]
4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2-
,3-diamine;
[0331]
2-chloro-N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenyla-
mino)-pyridin-3-yl]-acetamide;
[0332]
N-butyl-N-ethyl-6-methyl-3-nitro-N-(2,4,6-trimethyl-phenyl)-pyridin-
e-2,4-diamine;
[0333]
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-ni-
cotinic acid;
[0334]
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-ni-
cotinic acid methyl ester;
[0335]
N4-(1-ethyl-propyl)-3,6-dimethyl-N2-(2,4,6-trimethyl-phenyl)-pyridi-
ne-2,4-diamine;
[0336]
2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-
-pyridin-3-ylmethyl]-malonic acid dimethyl ester;
[0337]
[2-(4-bromo-2,6-dimethyl-phenylamino)-4-(1-ethyl-propylamino)-6-met-
hyl-pyridin-3-yl]-methanol;
[0338]
N2-(2,4-dichloro-phenyl)-N4-(1-ethyl-propyl)-3,6-dimethyl-pyridine--
2,4-diamine;
[0339]
[2-(2,4-dichloro-phenylamino)-4-(1-ethyl-propylamino)-6-methyl-pyri-
din-3-yl]-methanol;
[0340]
2-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenylamino)-pyridin-4-ylami-
no]-butan-1-ol;
[0341]
2-[4-(1-ethyl-propylamino)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyr-
imidin-5-yl]-propionic acid ethyl ester;
[0342]
[3-aminomethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(-
1-ethyl-propyl)-amine;
[0343]
[2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl--
pyridin-3-yl]-acetonitrile;
[0344]
[2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-
-pyridin-3-yl]-acetonitrile hydrogen chloride;
[0345]
[6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phen-
yl)-amine;
[0346]
2-[2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino-
]-butan-1-ol;
[0347]
[3-aminomethyl-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-
-(S)-yl]-(1-chloromethyl-propyl)-amine;
[0348]
2-[2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-3-methylaminomethyl-p-
yridin-4-(S)-ylamino]-butan-1-ol;
[0349]
2-[3-aminomethyl-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-
-4-(S)-ylamino]-butan-1-ol;
[0350]
[3-bromo-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethy-
l-propyl)-amine;
[0351]
2-[3,5-dibromo-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-
-ylamino]-butan-1-ol;
[0352]
2-[3-bromo-6-(4-chloro-2,6-dimethyl-phenoxy)-2-methyl-pyridin-4-(S)-
-ylamino]-butan-1-ol;
[0353]
2-[3-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S-
)-ylamino]-butan-1-ol;
[0354]
2-[3,5-dichloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin--
4-ylamino]-butan-1-ol;
[0355]
2-[3-chloro-6-(4-chloro-2,6-dimethyl-phenoxy)-2-methyl-pyridin-4-(S-
)-ylamino]-butan-1-ol;
[0356]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(4-ethyl-2-oxo-oxazolidin-3-
-yl)-6-methyl-nicotinonitrile;
[0357]
2-(2,4-dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl--
nicotinic acid;
[0358]
4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimi-
dine-5-carbonitrile;
[0359]
N-(1-ethyl-propyl)-2,5-dimethyl-N'-(2,4,6-trimethyl-phenyl)-pyrimid-
ine-4,6-diamine;
[0360]
5-chloro-N4-(1-ethyl-propyl)-2-methyl-N6-(2,4,6-trimethyl-phenyl)-p-
yrimidine-4,6-diamine;
[0361]
5-bromo-N-(1-ethyl-propyl)-2-methyl-N'-(2,4,6-trimethyl-phenyl)-pyr-
imidine-4,6-diamine;
[0362]
4-(1-ethyl-propylamino)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-py-
rimidine-5-carboxylic acid;
[0363]
[4-(cyclopropylmethyl-propyl-amino)-2-methyl-6-(2,4,6-trichloro-phe-
nylamino)-pyrimidin-5-yl]-methanol;
[0364]
6-(1-ethyl-propoxy)-2,N5,N5-trimethyl-N4-(2,4,6-trimethyl-phenyl)-p-
yrimidine-4,5-diamine;
[0365]
[5-bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl-(2,4,6-trimeth-
yl-phenyl)-amine;
[0366]
4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimi-
dine-5-carboxylic acid;
[0367]
[4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrim-
idin-5-yl]-methanol;
[0368]
[6-(1-ethyl-propoxy)-5-methoxymethyl-2-methyl-pyrimidin-4-yl]-(2,4,-
6-trimethyl-phenyl)-amine;
[0369]
[5-aminomethyl-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6--
trimethyl-phenyl)-amine;
[0370]
4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimi-
dine-5-carbonitrile;
[0371]
7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[-
4,5-b]pyridin-2-ylamine;
[0372]
7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[-
4,5-b]pyridine;
[0373]
7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-
-imidazo[4,5-b]pyridin-2-one;
[0374]
7-(1-ethyl-propoxy)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1,3-dih-
ydro-imidazo[4,5-b]pyridin-2-one;
[0375]
(1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,-
5-b]pyridin-7-yl]-amine;
[0376]
[2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-
-yl]-(1-ethyl-propyl)-amine;
[0377] N7-(1-ethyl-propyl)-5-methyl-3-(2,4,6-trimethyl-phenyl
)-3H-imidazo[4,5-b]pyridine-2,7-diamine;
[0378]
6-(1-ethyl-propylamino)-2,7-dimethyl-9-(2,4,6-trimethyl-phenyl)-7,9-
-dihydro-purin-8-one;
[0379]
6-(1-ethyl-propoxy)-2,7-dimethyl-9-(2,4,6-trimethyl-phenyl)-7,9-dih-
ydro-purin-8-one;
[0380]
[2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]--
(1-methoxymethyl-propyl)-amine;
[0381]
(1-ethyl-propyl)-[2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-p-
yridin-4-yl]-amine;
[0382]
2-[2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamin-
o]-butan-1-ol;
[0383]
sec-butyl-[3-methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-py-
ridin-4-yl]-amine;
[0384]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(4-ethyl-oxazolidin-3-yl)-3,6-d-
imethyl-pyridine;
[0385]
4-(4-ethyl-oxazolidin-3-yl)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6--
dimethyl-pyridine;
[0386]
2-(4-methoxy-2,6-dimethyl-phenoxy)-N%4&-(1-methoxymethyl-propyl)-6--
methyl-pyridine-3,4-diamine;
[0387]
3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyrid-
in-4-ylamino]-pentan-2-ol;
[0388]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-m-
ethyl-nicotinic acid methyl ester;
[0389]
3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxymethyl-6-methyl-pyrid-
in-4-ylamino]-pentan-2-ol;
[0390]
3-[2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamin-
o]-pentan-2-ol;
[0391]
4-sec-butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicoti-
nic acid methyl ester;
[0392]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-2-methyl-pro-
pylamino)-6-methyl-nicotinic acid methyl ester;
[0393]
4-(1-hydroxymethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)--
6-methyl-nicotinic acid methyl ester;
[0394]
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-3-methylsulfan-
yl-propylamino)-6-methyl-nicotinic acid methyl ester;
[0395]
2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-yl-
amino)-nicotinic acid methyl ester;
[0396]
{3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxycarbonyl-6-methyl-py-
ridin-4-ylamino]-4-hydroxy-butyl}-dimethyl-sulfonium iodide;
[0397]
4-(1-hydroxymethyl-3-methylsulfanyl-propylamino)-2-(4-methoxy-2,6-d-
imethyl-phenoxy)-6-methyl-nicotinic acid methyl ester;
[0398]
4-(1-hydroxymethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)--
6,N-dimethyl-nicotinamide;
[0399]
4-sec-butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-ni-
cotinamide;
[0400]
2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-y-
lamino)-nicotinic acid methyl ester;
[0401]
4-sec-butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicoti-
namide; and
[0402] and pharmaceutically acceptable salts thereof.
[0403] The invention also relates to a pharmaceutical composition
for the treatment of (a) a disorder or condition the treatment of
which can be effected or facilitated by antagonizing CRF, including
but not limited to disorders induced or facilitated by CRF, or (b)
a disorder or condition selected from inflammatory disorders such
as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis
and allergies; generalized anxiety disorder; panic; phobias,
including social phobia, agoraphobia, and specific phobias;
obsessive-compulsive disorder; post-traumatic stress disorder;
sleep disorders induced by stress; pain perception such as
fibromyalgia; mood disorders such as depression, including major
depression, single episode depression, recurrent depression, child
abuse induced depression, mood disorders associated with
premenstrual syndrome, and postpartum depression; dysthemia;
bipolar disorders; cyclothymia; chronic fatigue syndrome;
stress-induced headache; cancer, irritable bowel syndrome, Crohn's
disease; spastic colon; post operative ileus; ulcer; diarrhea;
stress-induced fever; human immunodeficiency virus infections;
neurodegenerative diseases such as Alzheimer's disease, Parkinson's
disease and Huntington's disease; gastrointestinal diseases; eating
disorders such as anorexia and bulimia nervosa; hemorrhagic stress;
chemical dependencies or addictions, including dependencies or
addictions to alcohol, cocaine, heroin, benzodiazapines, or other
drugs; drug or alcohol withdrawal symptoms; stress-induced
psychotic episodes; euthyroid sick syndrome; syndrome of
inappropriate antidiuretic hormone; obesity; infertility; head
trauma; spinal cord trauma; ischemic neuronal damage, including
cerebral ischemia, for example cerebral hippocampal ischemia;
excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions
including stress induced immune dysfunctions, including porcine
stress syndrome, bovine shipping fever, equine paroxysmal
fibrillation, confinement dysfunction in chicken, sheering stress
in sheep, and human-animal interaction stress in dogs; muscular
spasms; urinary incontinence; senile dementia of the Alzheimer's
type; multiinfarct dementia; amyotrophic lateral sclerosis;
hypertension; tachycardia; congestive heart failure; osteoporosis;
premature birth; hypoglycemia, and Syndrome X in a mammal,
including a human, or bird comprising an amount of a compound of
the formula I, II or III, or a pharmaceutically acceptable salt
thereof, that is effective in the treatment of such disorder or
condition, and a pharmaceutically acceptable carrier.
[0404] The invention further includes a method for the treatment of
(a) a disorder or condition the treatment of which can be effected
or facilitated by antagonizing CRF, including but not limited to
disorders induced or facilitated by CRF, or (b) a disorder or
condition selected from inflammatory disorders such as rheumatoid
arthritis and osteoarthritis, pain, asthma, psoriasis and
allergies; generalized anxiety disorder; panic; phobias, including
social phobia, agoraphobia, and specific phobias;
obsessive-compulsive disorder; post-traumatic stress disorder;
sleep disorders induced by stress; pain perception such as
fibromyalgia; mood disorders such as depression, including major
depression, single episode depression, recurrent depression, child
abuse induced depression, mood disorders associated with
premenstrual syndrome, and postpartum depression; dysthemia;
bipolar disorders; cyclothymia; chronic fatigue syndrome;
stress-induced headache; cancer; irritable bowel syndrome, Crohn's
disease; spastic colon; post operative ileus; ulcer; diarrhea;
stress-induced fever; human immunodeficiency virus infections;
neurodegenerative diseases such as Alzheimer's disease, Parkinson's
disease and Huntington's disease; gastrointestinal diseases; eating
disorders such as anorexia and bulimia nervosa; hemorrhagic stress;
chemical dependencies or addictions, including dependencies or
addictions to alcohol, cocaine, heroin, benzodiazapines, or other
drugs; drug or alcohol withdrawal symptoms; stress-induced
psychotic episodes; euthyroid sick syndrome; syndrome of
inappropriate antidiuretic hormone; obesity; infertility; head
trauma; spinal cord trauma; ischemic neuronal damage, including
cerebral ischemia, for example cerebral hippocampal ischemia;
excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions
including stress induced immune dysfunctions, including porcine
stress syndrome, bovine shipping fever, equine paroxysmal
fibrillation, confinement dysfunction in chicken, sheering stress
in sheep, and human-animal interaction stress in dogs; muscular
spasms; urinary incontinence; senile dementia of the Alzheimer's
type; multiinfarct dementia; amyotrophic lateral sclerosis;
hypertension; tachycardia; congestive heart failure; osteoporosis;
premature birth; hypoglycemia, and Syndrome X in a mammal,
including a human, or bird comprising administering to a subject in
need of said treatment an amount of a compound of the formula I, II
or III or a pharmaceutically acceptable salt thereof, that is
effective in treating such disorder or condition.
[0405] Specific embodiments of the invention provide a
pharmaceutical composition and a method for treatment of (a) a
disorder the treatment of which can be effected or facilitated by
antagonizing CRF, including but not limited to disorders induced or
facilitated by CR, or (b) a disorder selected from inflammatory
disorders such as rheumatoid arthritis and osteoarthritis, pain,
asthma, psoriasis and allergies; generalized anxiety disorder;
panic; phobias; obsessive-compulsive disorder; post-traumatic
stress disorder, sleep disorders induced by stress; pain perception
such as fibromyalgia; mood disorders such as depression, including
major depression, single episode depression, recurrent depression,
child abuse induced depression, and postpartum depression;
dysthemia; bipolar disorders; cyclothymia; fatigue syndrome;
stress-induced headache; cancer; irritable bowel syndrome, Crohn's
disease; spastic colon; human immunodeficiency virus (HIV)
infections; neurodegenerative diseases such as Alzheimer's disease,
Parkinson's disease and Huntington's disease; gastrointestinal
diseases; eating disorders such as anorexia and bulimia nervosa;
hemorrhagic stress; chemical dependencies and addictions (eg,
dependencies on alcohol, cocaine, heroin, benzodiazepines, or other
drugs); drug and alcohol withdrawal symptoms; stress-induced
psychotic episodes; euthyroid sick syndrome; syndrome of
inappropriate antidiuretic hormone (ADH); obesity; infertility;
head traumas; spinal cord trauma; ischemic neuronal damage (eg.,
cerebral ischemia such as cerebral hippocampal ischemia);
excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions
including stress induced immune dysfunctions (e.g, porcine stress
syndrome, bovine shipping fever, equine paroxysmal fibrillation,
and dysfunctions induced by confinement in chickens, sheering
stress in sheep or human-animal interaction related stress in
dogs); muscular spasms; urinary incontinence; senile dementia of
the Alzheimer's type; multiinfarct dementia; amyotrophic lateral
sclerosis; and hypoglycemia in a mammal, including a human.
[0406] The present invention also provides a pharmaceutical
composition for and a method of treating a condition comprising
administering a compound of I, II, or III, in an amount effective
to treat said condition, wherein said condition is selected from
the group consisting of: a) abnormal circadian rhythm; b)
depression, further wherein a second compound for treating
depression is administered, said second compound for treating
depression having an onset of action that is delayed with respect
to that of said CRF antagonist; and c) emesis. The aforementioned
method can practiced according to the information provided in U.S.
Provisional Patent Application No. 60/151,183, filed Aug. 27, 1999,
which describes treatment of the aforementioned conditions using
CRF antagonists in general and which is incorporated herein by
reference in its entirety.
[0407] The compounds of formula I, II, and III, described herein
can also be used to treat forms of heart failure described in U.S.
Ser. No. 09/248,073, supra, and can be made into pharmaceutical
compositions therefore.
[0408] Examples of more specific forms or manifestations of
abnormal circadian rhythm that can be treated according to the
present invention include, but are not limited to, time zone change
syndrome resulting, seasonal disorder, shift-work sleep disorder,
irregular sleep-wake pattern, delayed sleep phase syndrome
resulting from said abnormal circadian rhythm, advanced sleep phase
syndrome, or non-24 hour sleep wake disorder resulting from said
abnormal circadian rhythm. Moreover, the compound of formula I, II,
or III can be combined in the method or pharmaceutical composition
for treatment of abnormal circadian rhythm with a second compound
that is useful for treating a sleep disorder, for example
tachykinin antagonists, agonists for GABA brain receptors,
metalonergic compounds, GABA brain receptor agonists, 5HT.sub.2
receptor antagonists, and D4 receptor binding compounds. However,
other compounds or substances useful for treating a sleep disorder
can be combined with a compound of formula I, II, or III. Such
methods and compositions are described in greater detail in U.S.
Provisional Patent Application No. 60/151,183, supra.
[0409] In another embodiment, said condition is depression, and the
second compound having delayed action for treating depression is
selected from the group consisting of selective serotonin reuptake
inhibitors, tricyclic antidepressants, norepinephrine uptake
inhibitors, lithium, bupropion, sertraline, fluoxetine, trazodone,
and a tricyclic antidepressant selected from the group consisting
of imipramine, amitriptyline, trimipramine, doxepin, desipramine,
nortriptyline, protriptyline, amoxapine, clomipramine, maprotiline,
and carbamazepine, and pharmaceutically acceptable salts and esters
of the above-recited compounds.
[0410] In another embodiment, the condition being treated is
emesis, and the method further comprises administering a second
compound for treating emesis. The second compound for treating
emesis can be selected from, but is not limited to, tachykinin
antagonists, 5HT3 antagonists, GABA agonists, and substance P
inhibitors. More specific categories of emesis encompassed in the
present invention include emesis induced by a condition or agent
selected from the group consisting of pregnancy, vestibular
disorder, post-operative sickness, gastrointestinal obstruction,
reduced gastrointestinal motility, visceral pain, migraine, change
in intercranial pressure, chemotherapy, radiation, toxins, and
opioid analgesics.
[0411] The invention further includes intermediate compounds of
formula 4
[0412] wherein R.sub.4 and R.sub.7 are defined as they are for
formula I above; D is chloro, hydroxy or cyano; R.sub.19 is methyl
or ethyl; R.sub.5 is phenyl or pyridyl and R.sub.5 is substituted
by two or three substituents independently selected from
C.sub.1-C.sub.4 alkyl, chloro and bromo, except that no more than
one such substituent can be bromo; A is N, CH or CCH.sub.3; and Z
is O, NH, N(CH.sub.3), S or CH.sub.2, with the proviso that when A
is CH or CCH.sub.3, then Z must be O or S.
[0413] More specific embodiments of this invention relate to
compounds of the formula X or XI wherein R.sub.7 is hydrogen or
methyl.
[0414] This invention further include intermediate compounds of
formula 5
[0415] wherein R.sub.19 is methyl or ethyl; A is N, CH or
CCH.sub.3; and wherein when A is N, then B" and R.sub.4 are
defined, respectively, as B and R.sub.4 are defined for formula I,
and when A is CH or CH.sub.3, then B" is --NR.sub.1R.sub.2,
--NHR.sub.1R.sub.2, --OCHR.sub.1R.sub.2 or cyano and R.sub.4 is an
electron deficient group such as NO.sub.2, --COO(C.sub.1-C.sub.4
alkyl), --C(.dbd.O)CH.sub.3, --COOH or CN.
[0416] A more specific embodiment of this invention relates to
compounds of the formula XII wherein B" is --NR.sub.1R.sub.2 or
--NHCHR.sub.1R.sub.2 and A is CH or CH.sub.3.
[0417] This invention also relates to a process for preparing a
compound of the formula I, 6
[0418] or a pharmaceutically acceptable salt thereof, wherein
[0419] A is --CR.sub.7 or N;
[0420] B is --NR.sub.1R.sub.2, --NHCHR.sub.1R.sub.2,
--OCHR.sub.1R.sub.2 or --SCHR.sub.1R.sub.2;
[0421] Z is NH, O, S, --N(C.sub.1-C.sub.2 alkyl) or
--C(R.sub.13R.sub.14), wherein R.sub.13 and R.sub.14 are each,
independently, hydrogen, trifluoromethyl or methyl, or one of
R.sub.13 and R.sub.14 is cyano and the other is hydrogen or
methyl;
[0422] R.sub.1 is C.sub.1-C.sub.6 alkyl which may optionally be
substituted with one or two substituents R.sub.8 independently
selected from the group consisting of hydroxy, fluoro, chloro,
bromo, iodo, CF.sub.3 and C.sub.1-C.sub.4 alkoxy, and wherein said
C.sub.1-C.sub.6 alkyl and the (C.sub.1-C.sub.4)alkyl moiety of said
C.sub.1-C.sub.4 alkoxy may optionally contain one carbon-carbon
double or triple bond;
[0423] R.sub.2 is C.sub.1-C.sub.12 alkyl, aryl or
--(C.sub.1-C.sub.4 alkylene)aryl wherein said aryl is phenyl,
naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl,
pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,
isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl,
indolyl, or benzoxazolyl; 3- to 8-membered cycloalkyl or
--(C.sub.1-C.sub.6 alkylene)cycloalkyl, wherein one or two of the
ring carbons of said cycloalkyl having at least 4 ring members and
the cycloalkyl moiety of said --(C.sub.1-C.sub.6
alkylene)cycloalkyl having at least 4 ring members may optionally
be replaced by an oxygen or sulfur atom or by N-R.sub.9 wherein
R.sub.9 is hydrogen or C.sub.1-C.sub.4 alkyl; and wherein each of
the foregoing R.sub.2 groups may optionally be substituted with
from one to three substituents independently selected from chloro,
fluoro and C.sub.1-C.sub.4 alkyl, or with one substituent selected
from bromo, iodo, C.sub.1-C.sub.6 alkoxy, --O--CO--(C.sub.1-C.sub.6
alkyl), --O--CO--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--S(C.sub.1-C.sub.6 alkyl), CN, NO.sub.2, --SO(C.sub.1-C.sub.4
alkyl), and --SO.sub.2(C.sub.1-C.sub.4 alkyl), and wherein said
C.sub.1-C.sub.12 alkyl and the C.sub.1-C.sub.4 alkylene moiety of
said --(C.sub.1-C.sub.4 alkylene)aryl may optionally contain one
carbon-carbon double or triple bond;
[0424] or --NR.sub.1R.sub.2 may form a saturated 5 to 8-membered
carbocyclic ring which may optionally contain one or two
carbon-carbon double bonds and in which one or two of the ring
carbons may optionally be replaced by an oxygen or sulfur atom;
[0425] R.sub.3 is methyl or ethyl;
[0426] R.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, fluoro, chloro,
bromo, iodo, C.sub.1-C.sub.4 alkoxy, trifluoromethoxy,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2OF.sub.3, CF.sub.3, amino,
nitro, --NH(C.sub.1-C.sub.4 alkyl), --N(CH.sub.3).sub.2,
--NHCOCH.sub.3, --NHCONHCH.sub.3, --SO.sub.n(C.sub.1-C.sub.4 alkyl)
wherein n is 0, 1 or 2, cyano, hydroxy, --CO(C.sub.1-C.sub.4
alkyl), --CHO, cyano or --COO(C.sub.1-C.sub.4 alkyl) wherein said
C.sub.1-C.sub.4 alkyl may optionally contain one double or triple
bond and may optionally be substituted with one substituent
selected from hydroxy, amino, --NHCOCH.sub.3, --NH(C.sub.1-C.sub.2
alkyl), --N(C.sub.1-C.sub.2 alkyl).sub.2, --COO(C.sub.1-C.sub.4
alkyl), --CO(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 thioalkyl, fluoro, chloro, cyano and nitro;
[0427] R.sub.5 is phenyl or pyridyl, and R.sub.5 is substituted
with from one to three substituents independently selected from
fluoro, chloro, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy,
or with one substituent selected from hydroxy, iodo, bromo, formyl,
cyano, nitro, trifluoromethyl, amino, --(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6)alkyl, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--COOH, --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) and
--SO.sub.2(C.sub.1-C.sub.6 alkyl), and wherein the C.sub.1-C.sub.4
alkyl and C.sub.1-C.sub.6 alkyl moieties of the foregoing R.sub.5
groups may optionally be substituted with one or two fluoro groups
or with one substituent selected from hydroxy, amino, methylamino,
dimethylamino and acetyl; and
[0428] R.sub.7 is hydrogen or methyl;
[0429] or a pharmaceutically acceptable salt of such compound;
[0430] comprising reacting a compound of the formula 7
[0431] wherein R.sub.19 is methyl or ethyl, D is chloro and A, Z,
R.sub.4 and R.sub.5 are defined as above, with a compound of the
formula BH, wherein B is defined as above, in the presence of a
base; and then optionally converting the compound of formula I
formed in such reaction into a pharmaceutically acceptable
salt.
[0432] This invention also relates to a process for preparing a
compound of the formula 8
[0433] or a pharmaceutically acceptable salt thereof, wherein
[0434] A is --CR.sub.7 or N;
[0435] B is --NR.sub.1R.sub.2, --CR.sub.1R.sub.2R.sub.11,
--C(.dbd.CR.sub.2R.sub.12)R.sub.1, --NHCHR.sub.1R.sub.2,
--OCHR.sub.1R.sub.2, --SCHR.sub.1R.sub.2, --CHR.sub.2OR.sub.12,
--CHR.sub.2SR.sub.12, --C(S)R.sub.2 or --C(O)R.sub.2;
[0436] Z is NH, O, S, --N(C.sub.1-C.sub.2 alkyl) or
--C(R.sub.13R.sub.14), wherein R.sub.13 and R.sub.14 are each,
independently, hydrogen, trifluoromethyl or methyl, or one of
R.sub.13 and R.sub.14 is cyano and the other is hydrogen or
methyl;
[0437] R.sub.1 is C.sub.1-C.sub.6 alkyl which may optionally be
substituted with one or two substituents R.sub.8 independently
selected from the group consisting of hydroxy, fluoro, chloro,
bromo, iodo, CF.sub.3 and C.sub.1-C.sub.4 alkoxy, and wherein said
C.sub.1-C.sub.6 alkyl and the (C.sub.1-C.sub.4)alkyl moiety of said
C.sub.1-C.sub.4 alkoxy may optionally contain one carbon-carbon
double or triple bond;
[0438] R.sub.2 is C.sub.1-C.sub.12 alkyl, aryl or
--(C.sub.1-C.sub.4 alkylene)aryl wherein said aryl is phenyl,
naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl,
pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,
isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl,
indolyl, or benzoxazolyl; 3- to 8-membered cycloalkyl or
--(C.sub.1-C.sub.6 alkylene)cycloalkyl, wherein one or two of the
ring carbons of said cycloalkyl having at least 4 ring members and
the cycloalkyl moiety of said --(C.sub.1-C.sub.6
alkylene)cycloalkyl having at least 4 ring members may optionally
be replaced by an oxygen or sulfur atom or by N-R.sub.9 wherein
R.sub.9 is hydrogen or C.sub.1-C.sub.4 alkyl; and wherein each of
the foregoing R.sub.2 groups may optionally be substituted with
from one to three substituents independently selected from chloro,
fluoro and C.sub.1-C.sub.4 alkyl, or with one substituent selected
from bromo, iodo, C.sub.1-C.sub.6 alkoxy, --O--CO--(C.sub.1-C.sub.6
alkyl), --O--CO--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--S(C.sub.1-C.sub.6 alkyl), CN, NO.sub.2, --SO(C.sub.1-C.sub.4
alkyl), and --SO.sub.2(C.sub.1-C.sub.4 alkyl), and wherein said
C.sub.1-C.sub.12 alkyl and the C.sub.1-C.sub.4 alkylene moiety of
said C.sub.1-C.sub.4 alkylene)aryl may optionally contain one
carbon-carbon double or triple bond;
[0439] or --NR.sub.1R.sub.2 may form a saturated 5- to 8-membered
carbocyclic ring which may optionally contain one or two
carbon-carbon double bonds and in which one or two of the ring
carbons may optionally be replaced by an oxygen or sulfur atom;
[0440] R.sub.3 is methyl, ethyl, fluoro, chloro, bromo, iodo,
cyano, methoxy, OCF.sub.3, methylthio, methylsulfonyl, CH.sub.2OH,
or CH.sub.2OCH.sub.3;
[0441] R.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, fluoro, chloro,
bromo, iodo, C.sub.1-C.sub.4 alkoxy, trifluoromethoxy,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2OF.sub.3, CF.sub.3, amino,
nitro, --NH(C.sub.1-C.sub.4 alkyl), --N(CH.sub.3).sub.2,
--NHCOCH.sub.3, --NHCONHCH.sub.3, --SO.sub.n(C.sub.1-C.sub.4 alkyl)
wherein n is 0, 1 or 2, cyano, hydroxy, --CO(C.sub.1-C.sub.4
alkyl), --CHO, cyano or --COO(C.sub.1-C.sub.4 alkyl) wherein said
C.sub.1-C.sub.4 alkyl may optionally contain one double or triple
bond and may optionally be substituted with one substituent
selected from hydroxy, amino, --NHCOCH.sub.3, --NH(C.sub.1-C.sub.2
alkyl), --N(C.sub.1-C.sub.2 alkyl).sub.2, --COO(C.sub.1-C.sub.4
alkyl), --CO(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 thioalkyl, fluoro, chloro, cyano and nitro;
[0442] R.sub.5 is phenyl or pyridyl and R.sub.5 is substituted with
from one to three substituents independently selected from fluoro,
chloro, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy, or with
one substituent selected from hydroxy, iodo, bromo, formyl, cyano,
nitro, trifluoromethyl, amino, --(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6)alkyl, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--COOH, --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) and
--SO.sub.2(C.sub.1-C.sub.6 alkyl), and wherein the C.sub.1-C.sub.4
alkyl and C.sub.1-C.sub.6 alkyl moieties of the foregoing R.sub.5
groups may optionally be substituted or two fluoro groups or with
one substituent selected from hydroxy, amino, methylamino,
dimethylamino and acetyl; and
[0443] R.sub.7 is hydrogen or methyl;
[0444] with the proviso that when A is CH or CCH.sub.3, then
R.sub.4 is an electron deficient group such as NO.sub.2,
--COO(C.sub.1-C.sub.4)alkyl, --C(.dbd.O)CH.sub.3, --COOH or CN;
[0445] or a pharmaceutically acceptable salt of such compound;
[0446] comprising reacting a compound of the formula 9
[0447] wherein R.sub.19 is methyl or ethyl and A is N, CH or
CCH.sub.3; and wherein when A is N, then B" and R.sub.4 are
defined, respectively, as B and R.sub.4 are defined in claim 1, and
when A is CH or CH.sub.3, then B" is --NR.sub.1R.sub.2,
--NHR.sub.1R.sub.2, --OCHR.sub.1R.sub.2 or cyano and R.sub.4 is an
electron deficient group such as NO.sub.2, --COO(C.sub.1-C.sub.4
alkyl), --C(.dbd.O)CH.sub.3, --COOH or CN;
[0448] with a compound of the formula R.sub.5ZH, wherein R.sub.5
and Z are defined as above, and then optionally converting the
compound of formula I formed by such reaction into a
pharmaceutically acceptable salt.
[0449] This invention also relates to a process for preparing a
compound of the formula 10
[0450] a wherein R.sub.19 is methyl or ethyl;
[0451] D is chloro;
[0452] A is --CR.sub.7 or N;
[0453] Z is NH, O, S, --N(C.sub.1-C.sub.2 alkyl) or
--C(R.sub.13R.sub.14), wherein R.sub.13 and R.sub.14 are each,
independently, hydrogen, trifluoromethyl or methyl, or one of
R.sub.13 and R.sub.14 is cyano and the other is hydrogen or
methyl;
[0454] R.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, fluoro, chloro,
bromo, iodo, C.sub.1-C.sub.4 alkoxy, trifluoromethoxy,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2OF.sub.3, CF.sub.3, amino,
nitro, --NH(C.sub.1-C.sub.4 alkyl), --N(CH.sub.3).sub.2,
--NHCOCH.sub.3, --NHCONHCH.sub.3, --SO.sub.n(C.sub.1-C.sub.4 alkyl)
wherein n is 0, 1 or 2, cyano, hydroxy, --CO(C.sub.1-C.sub.4
alkyl), --CHO, cyano or --COO(C.sub.1-C.sub.4 alkyl) wherein said
C.sub.1-C.sub.4 alkyl may optionally contain one double or triple
bond and may optionally be substituted with one substituent
selected from hydroxy, amino, --NHCOCH.sub.3, --NH(C.sub.1-C.sub.2
alkyl), --N(C.sub.1-C.sub.2 alkyl).sub.2, --COO(C.sub.1-C.sub.4
alkyl), --CO(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 thioalkyl, fluoro, chloro, cyano and nitro; and
[0455] R.sub.5 is phenyl or pyridyl, and R.sub.5 is substituted
with from one to three substituents independently selected from
fluoro, chloro, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy,
or with one substituent selected from hydroxy, iodo, bromo, formyl,
cyano, nitro, trifluoromethyl, amino, C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6)alkyl, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--COOH, --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) and
--SO.sub.2(C.sub.1-C.sub.6 alkyl), and wherein the C.sub.1-C.sub.4
alkyl and C.sub.1-C.sub.6 alkyl moieties of the foregoing R.sub.5
groups may optionally be substituted with one or two fluoro groups
or with one substituent selected from hydroxy, amino, methylamino,
dimethylamino and acetyl;
[0456] comprising reacting a compound of the formula 11
[0457] wherein R.sub.19, R.sub.4 and R.sub.5 are defined as above
and R.sub.7 is hydrogen, methyl, fluoro, chloro, bromo, iodo,
cyano, hydroxy, --O(C.sub.1-C.sub.4 alkyl), --C(O)(C.sub.1-C.sub.4
alkyl), --C(O)O(C.sub.1-C.sub.4 alkyl), --OCF.sub.3, CF.sub.3,
--CH.sub.2OH, --CH.sub.2OCH.sub.3 or --CH.sub.2OCH.sub.2CH.sub.3,
with phorphorus trichloride.
[0458] This invention also relates to a process for preparing a
compound of the formula 12
[0459] wherein R.sub.19 is methyl or ethyl;
[0460] A is --CR.sub.7 or N;
[0461] Z is O, S, or --C(R.sub.13R.sub.14), wherein R.sub.13 and
R.sub.14 are each, independently, hydrogen, trifluoromethyl or
methyl, or one of R.sub.13 and R.sub.14 is cyano and the other is
hydrogen or methyl;
[0462] R.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, fluoro, chloro,
bromo, iodo, C.sub.1-C.sub.4 alkoxy, trifluoromethoxy,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2OF.sub.3, CF.sub.3, amino,
nitro, --NH(C.sub.1-C.sub.4 alkyl), --N(CH.sub.3).sub.2,
--NHCOCH.sub.3, --NHCONHCH.sub.3, --SO.sub.n(C.sub.1-C.sub.4 alkyl)
wherein n is 0, 1 or 2, cyano, hydroxy, --CO(C.sub.1-C.sub.4
alkyl), --CHO, cyano or --COO(C.sub.1-C.sub.4 alkyl) wherein said
C.sub.1-C.sub.4 alkyl may optionally contain one double or triple
bond and may optionally be substituted with one substituent
selected from hydroxy, amino, --NHCOCH.sub.3, --NH(C.sub.1-C.sub.2
alkyl), --N(C.sub.1-C.sub.2 alkyl).sub.2, --COO(C.sub.1-C.sub.4
alkyl), --CO(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 thioalkyl, fluoro, chloro, cyano and nitro; and
[0463] R.sub.5 is phenyl or pyridyl, and R.sub.5 is substituted
with from one to three substituents independently selected from
fluoro, chloro, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy,
or with one substituent selected from hydroxy, iodo, bromo, formyl,
cyano, nitro, trifluoromethyl, amino, --(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6)alkyl, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--COOH, --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) and
--SO.sub.2(C.sub.1-C.sub.6 alkyl), and wherein the C.sub.1-C.sub.4
alkyl and C.sub.1-C.sub.6 alkyl moieties of the foregoing R.sub.5
groups may optionally be substituted with one or two fluoro groups
or with one substituent selected from hydroxy, amino, methylamino,
dimethylamino and acetyl;
[0464] comprising reacting a compound of the formula 13
[0465] wherein R.sub.4, R.sub.7 and R.sub.19 are defined as above,
with a compound of the formula R.sub.5OH or R.sub.5SH, wherein
R.sub.5 is defined as above, in the presence of a base.
DETAILED DESCRIPTION OF THE INVENTION
[0466] Methods of preparing the compounds and compositions of this
invention are described below. In the discussion and reaction
schemes that follow, R.sub.1 through R.sub.9, R.sub.11, R.sub.12,
R.sub.16, R.sub.17, R.sub.19, A, B, G, the dashed lines and
structural formulae I, II, III, X, XI, XII and IV, unless otherwise
indicated, are defined as above.
[0467] Whenever reference is made herein to alkyl, both straight
and branched chain alkyl groups are encompassed. For example,
"C.sub.1-C.sub.6 alkyl" encompasses both straight and branched
chain alkyl groups of one to six carbon atoms, including (but not
limited to) methyl, ethyl, isopropyl, t-butyl and hexyl.
[0468] Whenever R.sub.2 or R.sub.5 is a heterocyclic group,
attachment of the group is through a carbon atom.
[0469] Whenever reference is made herein to C.sub.1-C.sub.4 alkyl
or C.sub.1-C.sub.6 alkyl which "may contain one double or triple
bond" in the above definitions, it is understood that at least two
carbons are present in the alkyl for one double or triple bond.
[0470] Whenever reference is made herein to halo or halogen;
fluoro, chloro, bromo or iodo is meant unless indicated
otherwise.
[0471] The terms "treatment", "treating", and the like, are meant
to include both slowing or reversing the progression of a disorder,
as well as curing the disorder. These terms also include
alleviating or reducing the symptoms of a disorder or condition,
even if the disorder or condition is not actually eliminated and
even if progression of the disorder or condition is not itself
slowed or reversed. The term "treatment" and like terms also
include prophylactic treatment of disorders and conditions.
[0472] The term "haloalkyl" refers to an alkyl group substituted by
one or more halogen atoms, i.e. one or more fluoro, bromo, iodo, or
chloro atoms. Moreover, it is understood that when an alkyl group
can be, according to this specification and claims, substituted
with, e.g., one to nine, e.g., nine atoms, that the optional one to
nine fluorine atoms are only an option when a sufficient number of
carbon atoms is present in the alkyl group.
[0473] The term "aryl" in the definitions above means, unless
otherwise indicated, an organic radical derived from an aromatic
hydrocarbon by removal of one hydrogen atom, which aromatic
hydrocarbon. Examples of aryl groups are phenyl and naphthyl.
[0474] The term "heterocycloalkyl", unless otherwise specified
means a 4 to 8 membered mono-carbocyclic ring or bicyclic ring,
wherein at least one carbon atom is replaced with a hetero member
selected from oxygen, nitrogen, N-(alkyl), or S(O).sub.m, wherein m
is zero, 1, 2, or 3. Generally, heterocycloalkyl groups comprise up
to four hetero members, preferably 1, 2, or 3 hetero members.
Heterocycloalkyl groups of the compounds of the invention can
contain optionally from one to three double bonds. The term
"heterocycloalkyl" also includes heteroaryl groups. Examples of
heteroaryl groups include thienyl, benzothienyl, pyridyl,
thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl,
benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl,
benzisoxazolyl, benzimidazolyl, indolyl, and benzoxazolyl. Other
examples of aryl groups are pyrazolyl, triazolyl, tetrazolyl,
isoxazolyl, oxazolyl, pyrrolyl, isoquinolinyl, cinnolinyl,
indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,
isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.
Preferred heteroaryl groups are thiazolyl, thienyl, benzothienyl,
pyridyl, quinolyl, quinazolinyl, quinoxalinyl, pyrazinyl,
pyrimidinyl, indazolyl, imidazolyl, furanyl, benzimidazolyl,
benzofuranyl, benzothiazolyl, benzisoxazolyl, isothiazolyl,
pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl,
benzoxazolyl, and benzothiadiazolyl. Other preferred
heterocycloalkyl groups are tetrahydrofurano, tetrahydropyrano,
morpholino, pyrrolidino, piperidino, piperazino,
[2,2,1]-azabicyclic rings, [2,2,2]-azabicyclic rings,
[3,3,1]azabicyclic rings, quinuclidino, azetidino, azetidinono,
oxindolo, dihydroimidazolo, and pyrrolidinono. Heterocyclolalkyl
groups in the compounds of the invention may be C-attached or
N-attached where such is possible.
[0475] Compounds of the formula I wherein B is --NR.sub.1R.sub.2,
--NHCHR.sub.1R.sub.2, --OCHR.sub.1R.sub.2 or --SCHR.sub.1R.sub.2,
and R.sub.3 is methyl, ethyl or chloro (hereinafter R.sub.19) may
be prepared by reaction of a compound of the formula IV wherein D
is Cl, and A, R.sub.4, R.sub.5, and Z are as defined above with
reference to formula I, with a compound of the formula BH wherein B
is as defined immediately above. The reaction is carried out in a
solvent in the presence of a base at a temperature of between about
0.degree. to about 230.degree. C. Suitable solvents are organic
solvents such as tetrahydrofuran (THF), acetonitrile,
dimethylsulfoxide (DMSO), acetone, C.sub.2-C.sub.15 alkyl alcohol,
chloroform (CHCl.sub.3), benzene, xylene, toluene, sulfolane,
pyridine, quinoline, 2,4,6-trimethylpyridine, acetamide,
di-(C.sub.1-C.sub.2) alkylacetamide or
1-methyl-2-pyrrolidinone.
[0476] A preferred method of preparing compounds of the formula I
wherein A is --CR.sub.7 and B is --NR.sub.1R.sub.2 or
--NHCHR.sub.1R.sub.2 is the two step procedure described below.
First, a compound of the formula IV is reacted with an excess of
R.sub.1NH.sub.2 or NH.sub.3 or an equivalent NH.sub.3 precursor
(e.g., NaN.sub.3, nBu.sub.4N.sup.+N.sub.3-- or NH.sub.2OH) at
temperature from about 75.degree. C. to about 250.degree. C. and at
a pressure from about 0 to about 300 psi, in an appropriate
solvent, as described above, to form a compound of the formula I
wherein B is --NHR.sub.1, --NH.sub.2, --NH.sub.2OH or --N.sub.3.
Compounds of the formula I wherein B is --N.sub.3 or --NH.sub.2OH
can be converted into the corresponding compounds of formula I
wherein B is --NH.sub.2 by methods well known in the art such as
hydrogenation or reduction. Alkylation of a compound of the formula
I wherein B is --NHR, or --NH.sub.2 with an appropriate alkyl
halide in the presence of an appropriate base such as lithium or
sodium bistrimethylsilylamide, lithium or sodium diisopropylamide,
n-butyllithium or potassium t-butoxide, in an appropriate solvent
such as THF, dioxane or methylene chloride, will yield the
corresponding compound of formula I wherein B is --NR.sub.1R.sub.2.
Alternatively, reductive amination of a compound of the formula I
wherein B is --NHR.sub.1 or --NH.sub.2, for example, acylation,
followed by reduction with a borohydride (eg., sodium borohydride)
will form the corresponding compound of formula I wherein B is
--NR.sub.1R.sub.2 or NHCHR.sub.1R.sub.2.
[0477] When B is --NR.sub.1R.sub.2 or --NHCHR.sub.1R.sub.2, an
excess of BH may be used both as a reagent and as a base. Bases
other than BH such as potassium carbonate,
tri-(C.sub.1-C.sub.6)alkylamine or sodium hydride may also be used.
The reaction is carried out at a temperature of about 75.degree. to
230.degree. C. When the reaction is carried out in the presence of
a base, such as sodium hydride, potassium C.sub.1-C.sub.4 alkoxide,
or an organolithium compound such as n-butyllithium, a molar
equivalent of the amine is used.
[0478] When B is --OCHR.sub.1R.sub.2 or --SCHR.sub.1R.sub.2, a base
which is capable of deprotonating BH may be used, such as an alkali
metal hydride such as sodium or potassium hydride, or an
organometallic base such as sodium diisopropylamide, sodium
bis(trimethylsilyl)amide, lithium diisopropylamide, lithium
bis(trimethylsilyl)amide, sodium or potassium C.sub.1-C.sub.4
alkoxide, or n-butyllithium. The solvent used can be, for example,
tetrahydrofuran, acetonitrile, dimethylsulfoxide, acetone,
methylene chloride, toluene, a C.sub.2-C.sub.5 alcohol, chloroform,
benzene, xylene, or 1-methyl-2-pyrrolidinone, and the reaction
temperature can range from about 0.degree. C. to about 180.degree.
C., and is preferably from about 50.degree. C. to about 80.degree.
C.
[0479] Compounds of the formulae I, II and III wherein B is as
defined with reference to formulae I, II and III and R.sub.3 is
defined with reference to the same except that R.sub.3 is not
methyl or ethyl (hereinafter R.sub.20, which is defined as R.sub.3
with the exception that it can not be methyl or ethyl) may be
prepared by reacting a compound of the formulae I, II or III
wherein R.sub.3 is chloro with a nucleophile of the formula
R.sub.20H with or without an organic or inorganic base. Suitable
bases include sodium and sodium hydride, when R.sub.20H is an
alkanol or an alkane thiol; and weaker bases such as potassium
carbonate or triethylamine when R.sub.20H is an amine. The
compounds of formula I wherein R.sub.20 is fluoro may be prepared
from the corresponding compounds wherein R.sub.20 is chloro on
reaction with tetrabutylammonium fluoride. Suitable solvents are
dimethylsulfoxide, tetrahydrofuran, or methylene chloride,
preferably tetrahydrofuran.
[0480] Compounds of the formula I wherein B is
--CR.sub.1R.sub.2R.sub.11, --C(C.dbd.CR.sub.2R.sub.12)R.sub.1,
--CHR.sub.2OR.sub.12, --CHR.sub.2SR.sub.12, or --C(O)R.sub.2, and
R.sub.3 is R.sub.19, as defined above, may be prepared as depicted
in Scheme 1. 14
[0481] Compounds of the formula IV wherein D is cyano and A,
R.sub.4, R.sub.5, and R.sub.19 are as defined above having formula
IVA (not shown), prepared by reacting the corresponding compound
wherein D is chloro with potassium cyanide or copper cyanide in
dimethylsulfoxide, 1-methyl-2-pyrrolidinone, N,N-dimethylformamide
(DMF) or acetamide, are reacted with a Grignard reagent containing
group R.sub.2, as defined above, to form the compounds of formula
IA. Further reaction of the compound of formula IA with a Grignard
reagent containing R.sub.1 as defined above provides the compound
of formula IB. Corresponding compounds of formula IC wherein B" is
--CR.sub.1R.sub.2R.sub.11, or --C(C.dbd.CR.sub.2R.sub.12)R.sub.1
may be prepared by conventional methods. Thus, reaction of IB with
an acid, such as concentrated sulfuric acid in acetic acid, or
Burgess inner salt, such as (carboxysulfamoyl)triethylammonium
hydroxide methyl ester, gives a compound of formula IC wherein B'
is --C(.dbd.CR.sub.2R.sub.12)R.sub.1. Hydrogenation of a compound
wherein B' is --C(.dbd.CR.sub.2R.sub.12)R.sub- .1 using a
palladium/carbon (Pd/C) or platinum dioxide catalyst gives a
compound IC wherein B' is CHR.sub.1R.sub.2. Reaction of compound IB
with diethylaminosulfur trifluoride or
triphenylphosphine/carbontetrachloride affords a compound IC
wherein B' is --CR.sub.1R.sub.2F or --CR.sub.1R.sub.2Cl,
respectively. Reduction of a compound of formula IA with sodium
borohydride gives a compound I wherein B is --CHR.sub.2OH.
Alkylation of this --CHR.sub.2OH group with alkyl halide such as
alkyl iodide in the presence of a base such as sodium hydride at
room temperature affords a compound of formula I wherein B is
--CHR.sub.2OR.sub.12.
[0482] Compounds of the formula II wherein R.sub.3 is R.sub.19 as
defined above may be prepared from compounds of the formula IV
wherein R.sub.19, R.sub.4, R.sub.5 and A are as defined before, D
is chloro, and YR.sub.21 is NH or --CHR.sub.21 wherein R.sub.21 is
cyano or --COO(C.sub.1-C.sub.4 alkyl), hereafter formula IVB, as
shown in Scheme 2. 15
[0483] Compounds of the formula VII wherein R.sub.4 and R.sub.6 are
each hydrogen and Y is N may be prepared by heating compounds of
formula IVB with an acid catalyst in a suitable solvent such as
toluene, benzene, t-butanol, acetonitrile and acetone, preferably
toluene. The acid catalyst may be sulfuric acid, hydrochloric acid,
p-toluene sulfonic acid, or methylsulfonic acid, preferably
p-toluene sulfonic acid.
[0484] When Y in formula IVB is CH or N, a base may be used to
deprotonate the proton of the compound of formula IVB. Suitable
solvents are tetrahydrofuran, toluene, and methylene chloride,
suitable reaction temperatures are between about -78.degree. C. and
100.degree. C., preferably -78.degree. to 50.degree. C., and
suitable bases are sodium hydride, potassium hydride, potassium
t-butoxide, lithium bis(trimethylsilyl) amide, and lithium or
sodium diisopropylamide.
[0485] Compounds of the formula VII wherein R.sub.4 and R.sub.6 are
each hydrogen may be deprotonated with a base such as sodium
hydride, or an organometallic compound such as lithium
bis(trimethylsilyl)amide followed by quenching with an electrophile
compound containing the group R.sub.4, such as R.sub.4L wherein L
is a leaving group such as iodo, bromo, mesylate, tosylate or with
p-tolyl-N-fluoro-N-C.sub.1-C.sub.6 alkyl sulfonamide, iodine,
p-nitrobenzene, dimethylformamide, di(C.sub.1-C.sub.4 alkyl)ketone,
formaldehyde, (C.sub.1-C.sub.4 alkyl) aldehyde or bromine, to
provide a compound of formula VII wherein R.sub.4 is fluoro,
chloro, bromo, iodo, hydroxy, C.sub.1-C.sub.4 alkyl,
S(C.sub.1-C.sub.4 alkyl), CHO, CH(OH)(C.sub.1-C.sub.4 alkyl),
C(OH)(di-C.sub.1-C.sub.4 alkyl) or CH.sub.2OH. Further conventional
alkylation of the hydroxy group or oxidation of the thioalkyl group
leads to compounds of formula VII wherein R.sub.4 is
C.sub.1-C.sub.4 alkoxy and SO.sub.n(C.sub.1-C.sub.4 alkyl) wherein
n is 1 or 2, respectively. Oxidation of compounds of formula VII
wherein R.sub.4 is hydroxy and R.sub.6 is hydrogen affords
corresponding compounds wherein CR.sub.4R.sub.6 is C.dbd.O, which
on reductive amination with an appropriate amine convert into
corresponding compounds wherein R.sub.4 is amino. The compounds of
formula VII wherein R.sub.4 is nitro or amino may be formed by
reacting compounds of formula VII wherein R.sub.4 and R.sub.6 are
both hydrogen with alkyl nitrite to form compounds wherein
CR.sub.4R.sub.6 is C.dbd.NOH and oxidizing or reducing to give the
compounds of formula VII wherein R.sub.4 is nitro or amine,
respectively.
[0486] Compounds of the formula VII, when one of R.sub.4 and
R.sub.6 is hydrogen, may be converted into corresponding compounds
wherein R.sub.16 and R.sub.17 are both hydrogen by reduction with a
reducing agent such as lithium aluminum hydride in tetrahydrofuran.
The same reduction leads to compounds wherein R.sub.16 is hydrogen
and R.sub.17 is hydroxy, when both of R.sub.4 and R.sub.6 are not
hydrogen. Alkylation of R.sub.17 is hydroxy with C.sub.1-C.sub.4
alkyl iodide in the presence of sodium hydride gives the
corresponding compound wherein R.sub.17 is O(C.sub.1-C.sub.4
alkyl). Reaction of compounds of formula VII with an organometallic
compound such as di(C.sub.1-C.sub.6 alkyl)zinc, C.sub.1-C.sub.6
alkyl lithium, or C.sub.1-C.sub.6 alkyl magnesiumbromide affords
compounds of formula VIII wherein one of R.sub.16 or R.sub.17 is
C.sub.1-C.sub.6 alkyl and the other is hydroxy.
[0487] The conversion of compounds of formula VIII to corresponding
compounds of formula IIA is by the methods described above for
preparation of compounds of formula I.
[0488] The compounds of formula III wherein G is oxygen or sulfur
and R.sub.6 is hydrogen may be prepared by reacting compounds of
formula I wherein R.sub.4 is amino and Z is NH with phosgene,
diphosgene, triphosgene or thiophosgene. The reaction is in the
presence of a base such as tri(C.sub.1-C.sub.4 alkyl)amine in a
suitable solvent, preferable tetrahydrofurane at about -78.degree.
to about 50.degree. C., preferably at 0.degree. C. to room
temperature. Standard alkylation of these compounds wherein R.sub.6
is hydrogen with a suitable base such as sodium hydride in a
suitable solvent such as dry tetrahydrofuran provides compounds of
the formula III wherein R.sub.6 is C.sub.1-C.sub.4 alkyl.
[0489] Compounds of the formula III wherein G is alkyl may be
prepared by reacting a compound of the formula I wherein R.sub.4 is
amino and Z is NH with a compound of the formula
GC(OC.sub.1-C.sub.2 alkyl).sub.3 in the presence of an acid such as
p-toluenesulfonic acid (p-TsOH), methanesulfonic acid (MsOH),
hydrogen chloride gas (HCl.sub.g) or concentrated sulfuric acid
(H.sub.2SO.sub.4) in an appropriate sovlent such as toluene,
xylene, benzene, dioxane or THF at a tempeature from about room
temperature to about 140.degree. C., preferably from about
50.degree. C. to about the reflux temperature. Alternatively, a
compound of the formula I wherein R.sub.4 is amino and Z is NH can
be reacted with [G(C.dbd.O)].sub.2O, G(C.dbd.O)Cl or G(C.dbd.O)F in
the presence of a base such as pyridine, a derivative of pyridine
or a tri-(C.sub.1-C.sub.4)alkylamine, in an appropriate solvent
such as CH.sub.2Cl.sub.2, CHCl.sub.3, THF, dioxane, toluene or
benzene, at a temperature from about 0.degree. C. to about the
reflux temperature of the reaction mixture, preferably from about
0.degree. C. to about room temperature, followed by ring
cyclization under acidic conditions (e g, with pTSOH, MSOH,
HCl.sub.g, hydrogen bromide gas (HBr.sub.g) or concentrated
H.sub.2SO.sub.4). The ring cydization can be carried out in an
appropriate solvent such as a C.sub.1-C.sub.5 alcohol, toluene,
xylene, benzene, dioxane or THF. Suitable temperatures for this
reaction can range from about room temperature to about 140.degree.
C. Preferably, the reaction temperature is between about 50.degree.
C. and about the reflux temperature.
[0490] Compounds of the formula III wherein G is
--O--(C.sub.1-C.sub.2 alkyl) or --OCF.sub.3 may be prepared by
reacting a compound of the formula III wherein G is oxygen and
R.sub.6 is hydrogen with a compound of the formula
GOSO.sub.2CF.sub.3 in the presence of a base such as
tri(C.sub.1-C.sub.4 alkyl)amine, or with lithium
bistrimethylsilylamide in HMPA or DMF, and then quenching the
reaction with a compound of the formula GOSO.sub.2OG or G-X wherein
X is bromo, chloro or SO.sub.3CF.sub.3.
[0491] The compounds of formula IV wherein D is chloro and ZR.sub.5
is NHR.sub.5 may be prepared from compounds of formula V: 16
[0492] wherein A and R.sub.4 are as defined with reference to
formula I and R.sub.19 is as defined above, by reaction with
R.sub.5NH.sub.2. The reaction is in tetrahydrofuran or
dimethylsulfoxide at about 0.degree. C. to about 150.degree. C.,
preferably 50.degree. to 130.degree. C. The compounds of formula IV
wherein D is chloro and Z is O, S, CHR.sub.21 wherein R.sub.21 is
an electron deficient group such as cyano, C(.dbd.O)R, COOR,
wherein R is C.sub.1-C.sub.4 alkyl, benzoyl or allyl, or SO.sub.n--
phenyl wherein n=0, 1 or 2 may be prepared by reacting compounds of
formula V with R.sub.5OH, R.sub.5SH, R.sub.5NH.sub.2 or
R.sub.5CHR.sub.21. The reaction proceeds in the presence of a base
which is capable of deprotonating R.sub.5ZH, such as sodium
hydride, potassium hydride, potassium carbonate, lithium or sodium
bis(trimethylsilyl)amide, lithium or sodium dialkylamide, sodium or
potassium (C.sub.1-C.sub.4 alkoxide) or n-butyllithium, with or
without other organometal halides such as copper (I) bromide,
iodide or chloride, copper (II) oxide, copper (I) oxide, copper
metal and trialkyltinchloride. Examples of solvents that may be
used are tetrahydrofuran, dimethylsulfoxide, acetonitrile,
methylene chloride, 1-methyl-2-pyrrolidinone, pyridine, quinoline,
N,N-dialkylacetamides, 2,4,6-trimethylpyridine,
N,N-dialkylformamides, eg., N,N-dimethylformamide (DMF), hexamethyl
phosphoramide and toluene. The reaction temperature may range from
about 0.degree. C. to about 180.degree. C., and is preferably from
about 0.degree. to about 150.degree. C.
[0493] Compounds of the formula IV wherein A is CR.sub.7, D is
chloro and Z is O, S, CHR.sub.2, may be prepared by reduction of
compounds of formula X, depicted below, wherein R.sub.7 and Z are
as defined immediately above, with a reducing agent such as
phosphorous trichloride in an appropriate solvent such as methylene
chloride or chloroform at temperature from about 0.degree. C. to
about 100.degree. C., preferably from about room temperature to
about the reflux temperature of the solvent. 17
[0494] Compounds of the formula X may be prepared from compounds of
the formula XI, depicted above, wherein R.sub.4 is as defined as it
is for formula I and R.sub.19 is as defined above (i.e., methyl or
ethyl), by reaction with a compound of the formula R.sub.5OH,
R.sub.5SH or R.sub.5CHR.sub.21. This reaction proceeds in the
presence of a base which is capable of deprotonating R.sub.5ZH,
such as sodium hydride, potassium hydride, lithium, sodium or
potassium bis(trimethylsilyl)amide, lithium, sodium or potassium
dialkylamide, sodium or potassium C.sub.1-C.sub.4alkoxide, or
n-butyllithium. Suitable solvents include tetrahydrofuran, dioxane,
dimethylsulfoxide, 1-methyl-2-pyrrolidinone, pyridine,
N,N-di-C.sub.1-C.sub.4 alkyl)acetamides, acetamide,
N,N-di-(C.sub.1-C.sub.4 alkyl)formamides, acetonitrile, methylene
chloride, touluene and xylene. Suitable reaction temperatures may
range from about - 78.degree. C. to about 150.degree. C., and are
preferably between about 40.degree. C. to about 150.degree. C.
[0495] Compounds of the formula XI may be prepared by reacting the
corresponding compounds of formula V wherein A is --CR.sub.7 and
R.sub.4 and R.sub.19 are defined as above, with an oxidizing agent
such as m-chloroperbenzoic acid, peracetic acid or
pertrifluoroacetic acid, in a solvent such as methylene chloride,
chloroform, acetic acid, DMF, methanol or a mixture of one or more
of the foregoing solvents, at temperature from about 0.degree. C.
to about 100.degree. C., preferably from about room temperature to
about 60.degree. C.
[0496] When R.sub.4 is an electron withdrawing group such as a
NO.sub.2, --COO(C.sub.1-C.sub.4 alkyl), --COOH, CN or
--CO(C.sub.1-C.sub.4)alkyl, the reaction order for the coupling
reactions that introduce the B and ZR.sub.5 groups in the synthesis
of compounds of formula I may be reversed. The B group may be
introduced before the ZR.sub.5 coupling step using the methods
analogous to those described above. For example, compounds of the
formula I wherein R.sub.4 is an election deficient group may be
prepared by reacting a compound of the formula XII with a compound
of the formula HZR.sub.5. Compounds of the formula XII may be
prepared by reacting a compound of the formula V wherein A is
CR.sub.7 and R.sub.19 and R.sub.4 are defined as above with a
compound of the formula B"H in the presence of a base.
[0497] Compounds of the formula IV wherein D is chloro and Z is
--N(C.sub.1-C.sub.4 alkyl) may be prepared by reacting the
corresponding compounds wherein Z is NH with a base, at a
temperature from about -78.degree. C. to about 100.degree. C.,
preferably from about 0.degree. C. to about room temperature,
followed by quenching with C.sub.1-C.sub.4 alkyl iodide or bromide.
Suitable bases include, for example, sodium hydride, lithium or
sodium bis(trimethylsilyl)amide, lithium or sodium dialkylamide,
and n-butyllithium. Suitable solvents include, for example,
tetrahydrofuran, dimethylsulfoxide, toluene, benzene or methylene
chloride.
[0498] Compounds of the formula IV wherein D is chloro, hydroxy or
OP wherein P is a standard protecting group for hydroxy and Z is
--CR.sub.13R.sub.14 may be prepared by alkylation, using an
R.sub.13 containing alkylating agent such as R.sub.13I, compounds
of the formula IV wherein Z is --CHR.sub.21 in the presence of a
base that is capable of deprotonating the proton in the Z group, as
mentioned above, followed by quenching with an R.sub.14 containing
alkylating agent such as R.sub.14I. Heating compounds of the
formula IV wherein D is chloro or hydrogen and Z is --CH(CN) in
about 85% phosphoric acid at about the reflux temperature yields
the corresponding compounds of formula IV wherein D is hydroxy and
Z is CH.sub.2. Deprotonation of the compounds of formula IV wherein
Z is CH.sub.2 with a base, such as described above for
deprotonation of R.sub.5ZH, followed by quenching with a suitable
electrophile such as a (C.sub.1-C.sub.6 alkyl)iodide, iodine,
bromine, acetylchloride, formaldehyde, acetone,
p-tolyl-N-fluoro-N-(C.sub.1-C.sub.6 alkyl)sulfonamide,
nitrobenzene, C.sub.1-C.sub.6 alkylnitrite, ethylene oxide or
dihaloethane yields the corresponding compounds of formula IV
wherein Z is --CHR.sub.13, --CH(OH), cyclopropyl or --C(NOH).
Further alkylation of compounds wherein Z is --CHR.sub.13, e.g., as
described immediately above, with an alkylating agent of the
formula R.sub.14I, produces the corresponding compounds wherein Z
is --C(R.sub.13R.sub.14).
[0499] Conversion of --C(R.sub.5)NOH or --CH(OH)R.sub.5 to
C(O)R.sub.5 may be accomplished by known methods. Hydrogenation or
reduction of compounds wherein Z is --C.dbd.NOH provides compounds
wherein Z is --CHNH.sub.2. Some of the intermediates may require a
protecting or deprotecting procedure to control the reaction
selectivity using standard organic chemistry.
[0500] Compounds of the formula V wherein A is N (hereinafter
referred to as compounds of the formula VB) or A is CR.sub.7 (i.e.,
compounds of the formula VA), and R.sub.4 and R.sub.19 are defined
as they are for formula I, may be prepared by reacting the
corresponding compounds of formulae VIB and VIA, respectively, with
1 equivalent or an excess of POCl.sub.3 at a temperature from about
room temperature to about 180.degree. C., preferably at the reflux
temperature, with or without a solvent. Compounds of formula VIA
may be prepared by the methods analogous to those described in the
literature and well known to those skilled in the art. (See Helv.
Chimica Acta., 25, p. 1306-1313 (1942)).
[0501] Compounds of formula VIB may be prepared by reacting 1
equivalent of the HCl salt of R.sub.19C(.dbd.NH)(NH.sub.2), 1
equivalent of R.sub.4CH(COO--(C.sub.1-C.sub.2 alkyl)).sub.2, and 2
equivalents of a base such as a sodium alkoxide, e.g., sodium
methoxide in a mixture of an alcohol (e.g., methanol), and acetone
at a temperature from about 50.degree. C. to about 200.degree. C.,
preferably at the reflux temperature. 18
[0502] When compounds of this invention contain one or more chiral
centers, it is understood that the invention includes the racemic
mixtures as well as all individual enantiomers and diastereomers of
such compounds, and mixtures thereof.
[0503] The acid addition salts of compounds of the formulae I, II
and III ("the active compounds of this invention) can be prepared
in a conventional manner by treating a solution or suspension of
the corresponding free base with one chemical equivalent of a
pharmaceutically acceptable acid. Conventional concentration or
crystallization techniques can be employed to isolate 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.
[0504] The active compounds of this 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
solutions and various organic solvents. The pharmaceutical
compositions formed by combining the novel compounds of formulae I,
II and III and their pharmaceutically acceptable carriers can then
be 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, methylcellulose, 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.
[0505] For parenteral administration, solutions containing an
active compound of this invention or a pharmaceutically acceptable
salt thereof 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.
[0506] The effective dosages for compounds of the formulae I, II or
III and their salts will depend on the intended route of
administration and factors such as the age and weight of the
patient, as generally known to a physician. The dosages will also
depend on the particular illness to be treated. For instance, the
daily dosage for stress-induced illnesses, inflammatory disorders,
Alzheimer's disease, gastrointestinal diseases, anorexia nervosa,
hemorrhagic stress and drug and alcohol withdrawal symptoms will
generally range from about 0.1 to about 50 mg/kg body weight of the
patient to be treated. The effective dose can be determined by
those of ordinary skill in the art by reference to texts pertaining
to treatment of the particular disorder or condition to be
treated.
[0507] Methods that may be used to determine the CRF antagonist
acivity of the active compounds of this invention and their
pharmaceutically acceptable salts are described in Endocrinology,
116, 1653-1659 (1985) and Peptides, 10, 179-188 (1985). The binding
activities for compounds of formulae I, II and III, expressed as
IC.sub.50 values, generally range from about 0.5 nanomolar to about
10 micromolar.
[0508] The present invention is illustrated by the following
examples. It will be understood, however, that the invention is not
limited to the specific details of these examples. Melting points
are uncorrected. Proton nuclear magnetic resonance spectra (.sup.1H
NMR) and C.sup.13 nuclear magnetic resonance spectra (C.sup.13 NMR)
were measured for solutions in deuterochloroform (CDCl.sub.3) and
peak positions are expressed in parts per million (ppm) downfield
from tetramethylsilane (TMS). The peak shapes are denoted as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; b, broad.
[0509] The following abbreviations are used in the Examples:
Ph=phenyl; iPr=isopropyl; HRMS=high resolution mass spectrum.
EXAMPLE 1
A. Butyl-(6-chloro-2,5-dimethyl-pyrimidin-4-yl)-ethylamine
[0510] A mixture of 2,5-dimethyl-4,6-dichloro-pyrimidine (0.999 g,
5.64 mmol) in 5 ml of acetonitrile was treated with triethylamine
(0.571 g, 5.65 mmol) and N-butyl-ethyl-amine (0.570 g, 5.65 mmol)
and heated at reflux overnight. The mixture was cooled, diluted
with water and dilute hydrogen chloride, and extracted with ethyl
acetate. The organic layer was neutralized with saturated potassium
carbonate, washed with brine, dried and concentrated to give 0.877
g (64%) of title compound as a yellow oil. .sup.1H NMR (CDCl.sub.3)
.delta. 0.90 (t, 3 H), 1.15 (t, 3 H), 1.22-1.36(m, 2 H), 1.5-1.6(m,
2 H), 2.20 (s, 3 H), 2.45 (s, 3 H), 3.25-3.48 (m, 4 H) ppm.
B.
N-Butyl-N-ethyl-2,5-dimethyl-N'-(2,4,6-trimethylphenyl)-pyrimidine-4,6--
diamine
[0511] A mixture of
butyl-(6-chloro-2,5-dimethyl-pyrimidin-4-yl)-ethylamin- e (398 mg,
1.65 mmol), 2,4,6-trimethylaniline (4.04 g, 30 mmol) and
diisopropyl-ethyl-amine (200 mg, 1.55 mmol) was heated at 210 to
230.degree. C. overnight. The mixture was quenched with water and
dilute hydrogen chloride, and extracted with ethyl acetate. The
organic layer was neutralized with saturated potassium carbonate,
washed with brine, dried and concentrated to give a dark oil. The
oil was distilled to give 579 mg of dark oil which was then
purified through silica gel column chromatography using 1:1 hexane
to chloroform as eluent to give 327 mg of title compound as a
yellow solid. .sup.1H NMR (CDCl.sub.3) .delta. 0.92 (t, 3 H), 1.14
(t, 3 H), 1.2-1.4 (m, 2 h), 1.45-1.60 (m, 2 H), 1.85 (s, 3 H), 2.16
(s, 6 H), 2.30 (s, 3 H), 2.33 (s, 3 H), 3.2-3.4 (m, 4 H), 5.8 (brs,
1 H), 6.90 (s, 2 H) ppm.
EXAMPLE 2
A. Butyl-(6-chloro-2-methyl-pyrimidin-4-yl)-ethylamine
[0512] A mixture of 2-methyl-4,6-dichloro-pyrimidine (1.63 g, 10
mmol) in 5 ml of acetonitrile was treated with N-butyl-ethyl-amine
(2.000 g, 20 mmol) and heated at reflux for 0.5 hours. The mixture
was cooled, diluted with water and extracted withethyl acetate. The
organic layer was washed with brine, dried and concentrated to give
2.271 g (100%) of title compound as a light-brown oil. .sup.1H NMR
(CDCl.sub.3) .delta. 0.93 (t, 3 H), 1.13 (t, 3 H), 1.22-1.36 (m, 2
H), 1.45-1.6 (m, 2 H), 2.43 (s, 3 H), 3.25-3.60 (m, 4 H), 6.15 (s,1
H) ppm.
B.
N-Butyl-N-ethyl-2-methyl-N'-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diam-
ine
[0513] A mixture of
butyl-6-chloro-2-methyl-pyrimidin-4-yl)-ethylamine (1.006 g, 4.42
mmol), and 2,4,6-trimethylaniline (3 ml) was heated at reflux
overnight. The mixture was quenched with water and extracted with
ethyl acetate. The organic layer was dried and concentrated to give
2.862 g of a brown oil. The oil was purified through silica gel
column chromatography to give 981 mg (68%) of title compound as a
yellow oil. .sup.1H NMR (CDCl.sub.3) .delta. 0.80 (t, 3 H), 1.1-1.3
(m, 2 H), 1.3-1.5 (m, 2 H), 2.17 (s, 6 H), 2.27 (s, 3 H), 2.41 (s,
3 H), 3.2 (m, 2 H), 3.36 (m, 2 H), 4.66 (s, 1 H), 6.90 (s, 2 H)
ppm.
EXAMPLE 3
A. Butyl-(6-chloro-2-methyl-5-ethyl-pyrimidin-4-yl)-ethylamine
[0514] A mixture of 2-methyl-5-ethyl-4,6-dichloro-pyrimidine (1.009
g, 5.28 mmol) in 5 ml of acetonitrile was treated with
triethylamine (0.571 g, 5.65 mmol) and N-butyl-ethyl-amine (0.540
g, 5.31 mmol) and heated at reflux overnight. The mixture was
diluted with water and dilute hydrogen chloride, and extracted with
ethyl acetate. The organic layer was neutralized with saturated
potassium carbonate and washed with brine, dried and concentrated
to give 1.193 g of yellow oil which was purified through silica gel
column chromatography to give 1.157 g (86%) of title compound as a
yellow oil. .sup.1H NMR (CDCl.sub.3) .delta. 0.90 (t, 3 H), 1.13
(t, 3 H), 1.18 (t, 3 H), 1.1-1.33 (m, 2 H), 1.4-1.6 (m, 2 h), 2.41
(s, 3 H), 2.62 (q, 2 H), 3.25-3.48 (m, 4 H) ppm.
B.
N-Butyl-N-ethyl-2-methyl-5-ethyl-N'-(2,4,6-trimethylphenyl)-pyrimidine--
4,6-diamine
[0515] A mixture of
butyl-(6-chloro-2-methyl-5-ethyl-pyrimidin-4-yl)-ethyl- amine (200
mg, 0.78 mmol) and 2,4,6-trimethylaniline (0.963 g, 7.1 mmol) was
heated at reflux for 4 hours. The mixture was quenched with water
and extracted with ethyl acetate. The organic layer was washed with
saturated potassium carbonate and brine, dried and concentrated to
give a dark oil. The oil was distilled to give 579 mg of the dark
oil which was then purified through silica gel column
chromatography using chloroform as eluent to give the title
compound as a brown oil. .sup.1H NMR (CDCl.sub.3) .delta. 0.93 (t,
3 H), 1.14 (t, 3 H), 1.1-1.4 (m, 4 H), 1.45-1.60 (m, 2 H), 2.17 (s,
6 H), 2.30 (s, 3 H), 2.33 (s, 3 H), 3.2-3.4 (m, 4 H), 6.90 (s, 2 H)
ppm.
EXAMPLE 4
2-Methyl-5-nitro-N,N'-bis-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine
[0516] A mixture of 2-methyl-5-nitro-4,6-dichloropyrimidine (0.513
g, 2.47 mmol) in 6 ml of acetonitrile was treated with
2,4,6-trimethylaniline (0.333 g, 2.46 mmol) and triethylamine (1
ml) and stirred at room temperature for 4 hours. The mixture was
quenched with water and extracted with ethyl acetate. The organic
layer was washed with brine, dried and concentrated to give 0.622 g
of bright yellow solid. The solid was purified through silica gel
column chromatography to give
(6-chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(2,4,6-trimethylphenyl)
amine and the title compound. .sup.1H NMR (CDCl.sub.3) for
6-(chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(2,4,6-trimethylphenyl)
amine .delta. 2.16 (s, 6 H), 2.33 (s, 3 H), 2.43 (s, 3 H), 6.95 (s,
2 H), 8.79 (s, 1 H) ppm. .sup.1H NMR (CDCl.sub.3) for
2-methyl-5-nitro-N,N'-bis-2,4,-
6-trimethylphenyl)-pyrimidine-4,6-diamine: .delta. 2.11 (s, 3 H),
2.22 (s, 12 H), 2.33 (s, 3 H), 6.96 (s, 4 H), 10.44 (s, 2 H)
ppm.
EXAMPLE 5
N-Butyl-N-ethyl-2-methyl-5-nitro-N'-(2,4,6-trimethylphenyl)-pyrimidine-4,6-
-diamine
[0517] A mixture of
6-(chloro-2-methyl-5-nitropyrimidin-4-yl-(2,4,6-trimet-
hyl-phenyl)amine (838 mg, 2.10 mmol) and N-ethyl-n-butyl-amine (555
mg, 5.48 mmol) in 15 ml acetonitrile was heated at reflux for 2
hours. The mixture was quenched with water and extracted with ethyl
acetate. The organic layer was washed with brine, dried and
concentrated to give 0.837 g of yellow oil. The solid was purified
through silica gel column chromatography using 1:1 hexane to
chloroform as eluent to give 753 mg of the title compound as a
yellow oil. .sup.1H NMR (CDCl.sub.3) .delta. 0.95 (t, 3 H), 1.26
(t, 3 H), 1.2-1.4 (m, 2 H), 1.55-1.75 (m, 2 H), 2.17 (s, 6 H), 2.23
(s, 3 H), 2.31 (s, 3 H), 3.4-3.6 (m, 4 H), 6.93 (s, 2 H), 9.43 (s,
1 H) ppm.
EXAMPLE 6
[0518] The following compounds were prepared by a method analogous
to that of Examples 3 or 5 starting with an appropriate amine and
appropriate
(6-chloro-2-methyl-5-substituted-pyrimidin-4-yl)-(2,4,6-trimethylphenyl)
amine.
[0519]
N-Propyl-N-ethyl-2-methyl-5-nitro-N'-(2,4,6-trimethylphenyl)-pydmid-
ine-4,6-diamine: .sup.1H NMR (CDCl.sub.3) .delta. 0.93 (t, 3 H),
1.26 (t, 3 H). 1.6-1.8 (m, 2 H), 2.17 (s, 6 H), 2.23 (s, 3 H). 2.31
(s, 3 H), 3.4-3.55 (m, 4 H), 6.93 (s, 2 H), 9.41 (s, 1 H) ppm.
[0520]
N-Butyl-5-ethyl-2-methyl-N'-(2,4,6-trimethylphenyl)-pyrimidine-4,6--
diamine: .sup.1H NMR (CDCl.sub.3) .delta. 0.98 (t, 3 H), 1.12 (t, 3
H), 1.3-1.5 (m, 2 H), 1.5-1.7 (m, 2 H), 2.17 (s, 3 H), 2.30 (s, 3
H), 3.4-3.5 (m, 2 H), 4.30 (brs, 1 H), 5.65 (brs, 1 H), 6.91 (s, 2
H) ppm.
[0521]
5,N-Diethyl-2-methyl-N'-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diam-
ine: .sup.1H NMR (CDCl.sub.3) .delta. 1.09 (t, 3 H), 1.25 (t, 3 H),
2.17 (s, 3 H), 2.30 (s, 3 H), 2.31 (s, 3 H), 3.4-3.6 (m, 2 H), 4.35
(brs, 1 H), 6.90 (s, 2 H) ppm.
EXAMPLE 7
N-Butyl-N-ethyl-2-methyl-N'-(2,4,6-trimethylphenyl)-pyrimidine-4,5,6-triam-
ine
[0522] A mixture of
N-butyl-N-ethyl-2-methyl-5-nitro-N'-(2,4,6-trimethylph-
enyl)-pyrimidine-4,6-diamine (242 mg, 0.65 mmol) and platinum oxide
(35 mg) in 50 ml ethanol was hydrogenated at 40 psi for 24 hours.
The mixture was filtered through celite and concentrated to dryness
to give 217 mg of yellow oil. The oil was purified through silica
gel column chromatography to give 135 mg (61%) of title compound.
.sup.1H NMR (CDCl.sub.3) .delta. 0.91 (t, 3 H), 1.09 (t, 3 H),
1.2-1.4 (m, 2 H), 1.4-1.6 (m, 2 H), 2.18 (s, 6 H), 2.30 (s, 3 H),
2.34 (s, 3 H), 3.0 (brs, 2 H), 3.1-3.3 (m, 4 H), 5.89 (s, 1 H),
6.92 (s, 2 H) ppm.
EXAMPLE 8
[0523] The following compounds were prepared by the method of
Example 7 by hydrogenation of the corresponding 5-nitro
derivatives.
[0524]
N-Propyl-N-ethyl-2-methyl-N'-(2,4,6-trimethylphenyl)-pyrimidine-4,5-
,6-triamine:
[0525] .sup.1H NMR (CDCl.sub.3) .delta. 0.89 (t, 3 H), 1.09 (t, 3
H), 1.45-1.60 (m, 2 H), 2.18 (s, 6 H), 2.30 (s, 3 H), 2.34 (s, 3
H), 3.80 (brs, 2 H), 3.1-3.30 (m, 4 H), 5.95 (brs, 1 H), 6.92 (s, 2
H) ppm.
[0526]
2-Methyl-N,N'-bis-(2,4,6-trimethylphenyl)-pyrimidine-4,5,6-triamine-
:
[0527] .sup.1H NMR (CDCl.sub.3) .delta. 2.04 (brs, 2 H), 2.21 (s,
12 H), 2.22 (s, 3 H), 2.30 (s, 6 H), 6.30 (s, 2 H), 6.92 (s, 4 H)
ppm.
EXAMPLE 9
6-(Ethyl-propyl-amino-2-methyl-9-(2,4,6-trimethylphenyl)-7,9-dihydropurin--
8-one
[0528] A mixture of
N-propyl-N-ethyl-2-methyl-N'-(2,4,6-trimethyl-phenyl)--
pyrimidine-4,5,6-triamine (120 mg, 0.35 mmol) and triethylamine (87
mg, 0.86 mmol) in 5 ml of dry tetrahydrofuran was treated with
triphosgene (41 mg, 0.14 mmol) at 0.degree. C. Precipitate formed
immediately and the reaction mixture was warmed to room
temperature. After stirring for 30 minutes the mixture was
filtered. The filtrate was concentrated to dryness to give 125 mg
(100%) of title compound of a greenish color. .sup.1H NMR
(CDCl.sub.3) .delta. 0.90 (t, 3 H), 1.21 (t, 3 H), 1.65 (m, 2 H),
2.10 (s, 6 H), 2.34 (s, 3 H), 2.39 (s, 3 H), 3.48 (dd, 2 H), 3.58
(q, 2 H), 6.99 (s, 2 H), 9.63 (s, 1 H) ppm.
EXAMPLE 10
6-(Ethyl-propyl-amino)-2,7-dimethyl-9-(2,4,6-trimethylphenyl)-7,9-dihydrop-
urin-8-one
[0529] A mixture of the title compound of Example 9 (54 mg, 0.15
mmol) in 3 ml of dry tetrahydrofuran was treated with sodium
hydride (9 mg, 0.23 mmol, 60% in oil) at room temperature. The
mixture was then treated with 0.02 ml of methyl iodide and stirred
at room temperature overnight. The mixture was quenched with water
and extracted with ethyl acetate. The organic layer was dried and
concentrated to give 60 mg of brown oil. The oil was purified
through silica gel column chromatography using chloroform as eluent
to give 56 mg of the title compound as a yellow oil which
crystallized on standing. .sup.1H NMR (CDCl.sub.3) .delta. 0.92 (t,
3 H), 1.17 (t, 3 H), 1.63 (m, 2 H), 2.06 (s, 6 H), 2.33 (s, 3 H),
2.46 (s, 3 H), 3.32 (dd, 2 H), 3.40 (q, 2 H), 3.63 (s, 3 H), 7.00
(s, 2 H) ppm.
EXAMPLE 11
[0530] The following compounds were prepared by the method of
Example 10 by reacting the title compound of Example 9 with an
appropriate alkyl iodide.
[0531]
7-Ethyl-6-(ethyl-propyl-amino)-2-methyl-9-(2,4,6-trimethylphenyl)-7-
,9-dihydropurin)-8-one:
[0532] .sup.1H NMR (CDCl.sub.3) .delta. 0.92 (t, 3 H), 1.14 (t, 3
H), 1.23 (m, 3 H), 1.58 (m, 2 H), 2.04 (s, 6 H), 2.31 (s, 3 H),
2.45 (s, 3 H), 3.32 (dd, 2 H), 3.36 (q, 2 H), 4.08 (q, 2 H), 7.00
(s, 2 H) ppm.
[0533]
6-(Ethyl-propyl-amino)-2-methyl-7-propyl-9-(2,4,6-trimethylphenyl)--
7,9-dihydropurin-8-one:
[0534] .sup.1H NMR (CDCl.sub.3) .delta. 0.87 (t, 3 H), 0.90 (t, 3
H), 1.15 (t, 3 H), 1.5-12.8 (m, 4 H), 2.05 (s, 6 H), 2.33 (s, 3 H),
2.47 (s, 3 H), 3.32 (dd, 2 H), 3.38 (q, 2 H), 4.01 (q, 2 H), 7.00
(s, 2 H) ppm.
EXAMPLE 12
[4-Chloro-2-methyl-6-(2,4,6-bimethylphenylamino)-pyrimidin-5-yl]-acetic
acid ethyl ester
[0535] A mixture of (2-methyl-4,6-dichloro-pyrimidine-5-yl)-acetic
acid ethyl ester (1.470 g, 5.9 mmol) and 2,4,6-trimethylaniline
(2.56 ml, 17.7 mmol), in 15 ml of dimethylsulfoxide was heated at
120.degree. C. ovemight and 138.degree. C. for 5 hours. The mixture
was quenched with water and extracted with ethyl acetate. The
organic layer was washed with brine, dried and concentrated to give
a brown oil. The oil was purified through silica gel column
chromatography to give 1.070 g (52%) of the title compound as a tan
solid. .sup.1H NMR (CDCl.sub.3) .delta. 1.30 (t, 3 H), 2.14 (s, 6
H), 2.32 (s, 3 H), 2.37 (s, 3 H), 3.79 (s, 2 H), 4.23 (q, 2 H),
7.00 (s, 2 H), 7.02 (s, 1 H) ppm.
EXAMPLE 13
[0536] A.
4-Chloro-2-methyl-7-(2,4,6-trimethylphenylamino)-5,7-dihydro-pyr-
rolo[2,3-d]pyrimidin-6-one
[0537] A mixture of the title compound of Example 12 (960 mg, 2.76
mmol) and p-toluene sulfonic acid (105 mg, 0.55 mmol) in 10 ml of
toluene was heated at reflux under Dean-Stark trap for 8 hours. The
mixture was quenched with water and extracted with ethyl acetate.
The organic layer was washed with brine, dried and concentrated to
give 800 mg of a brown mass which was purified through silica gel
column chromatography to give 348 mg (42%) of the title compound as
a yellow powder. .sup.1H NMR (CDCl.sub.3) .delta. 2.06 (s, 6 H),
2.34 (s, 3 H), 2.56 (s, 3 H), 3.75 (s, 2 H), 7.02 (s, 2 H) ppm.
[0538] B.
4-(1-Hydroxymethyl-propylamino)-2-methyl-7-(2,4,6-trimethylpheny-
l)-5,7-dihydro-pyrrolo[2,3d]pyrimidine-6-one
[0539] A mixture of the compound prepared under A (168 mg, 0.557
mmol) and (S)-2-amino-butanol (0.27 ml, 2.78 mmol) in 5 ml of
dimethyl sulfoxide was heated at 145.degree. C. for 5 hours. The
mixture was quenched with water and extracted with ethyl acetate.
The organic layer was washed with brine, dried and concentrated to
give an oil. The oil was purified through silica gel column
chromatography, followed by recrystallization with diethyl ether to
give 166 mg of the title compound as a grey solid.
[0540] .sup.1H NMR (CDCl.sub.3) .delta. 1.25 (t, 6 H), 1.5-1.8 (m,
2 H), 2.07 (s, 6 H), 2.31 (s, 3 H), 2.37 (s, 3 H), 3.50 (s, 2 H),
3.4-3.9 (m, 2 H), 4.0 (m, 1 H), 4.* (d, 1 H), 7.00 (s, 2 H)
ppm.
EXAMPLE 14
4-Diethylamino-2-methyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3--
d]pyrimidin-6-one
[0541] The title compound was prepared by the method of Example 13B
with diethylamine instead of (S)-2-amino-butanol. .sup.1H NMR
(CDCl.sub.3) .delta. 1.02 (t, 3 H), 2.08 (s, 6 H), 2.31 (s, 3 H),
2.37 (s, 3 H), 3.55 (q, 4 H), 3.85 (s, 2 H), 6.95 (s, 2 H) ppm.
EXAMPLE 15
[0542] A.
4-Chloro-2,5,5-trimethyl-7-(2,4,6-trimethylphenylamino)-5,7-dihy-
dro-pyrrolo[2,3-d]pyrmidin-6-one and
4-Chloro-2,5-dimethyl-7-(2,4,6-trimet-
hylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
[0543] A mixture of
4-chloro-2-methyl-7-(2,4,6-trimethylphenylamino)-5,7-d-
ihydro-pyrrolo[2,3-d]pyrimidin-6-one (93 mg, 0.31 mmol) and sodium
hydride (14 mg, 0.34 mmol, 60% in oil) in tetrahydrofuran (THF) was
stirred for 5 minutes, then treated with an excess of methyl iodide
and stirred for 1 hour. The mixture was quenched with water and
extracted with ethyl acetate. The organic layer was washed with
brine, dried and concentrated to give an oil. The oil was purified
through silica gel column chromatography to give 32 mg of
4chloro-2,5,5-trimethyl-7-(2,4,6-trimethy-
lphenyl-amino)-5,7-dihydro-pyrrolo [2,3-d]pyrimidin-4-one and 64 mg
of 4-chloro-2,5-dimethyl-7-(2,
4,6-trimethylyphenylamino)-5,7-dihydro-pyrrol-
o[2,3-d]pyrimidin-6-one.
[0544] .sup.1H NMR (CDCl.sub.3)
(4-chloro-2,5,5-trimethyl-7-(2,4,6-trimeth-
ylphenylamino)-5,7-dihydropyrrolo [2,3-d]pyrimidin-6-one) .delta.
1.61 (s, 6 H), 2.03 (s, 6 H), 2.32 (s, 3 H), 2.53 (s, 3 H), 7.00
(s, 2 H) ppm.
[0545] .sup.1H NMR (CDCl.sub.3)
(4-chloro-2,5-dimethyl-7-(2,4,6-trimethylp-
henylamino)-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one) .delta. 1.65
(d, 2 H), 2.03 (s, 3 H), 2.06 (s, 3 H), 2.34 (s, 3 H), 2.56 (s, 3
H), 3.72 (q, 1 H), 7.00 (s, 2 H) ppm.
[0546] B.
4-(1-hydroxymethylpropylamino)-2,5,5-trimethyl-7-(2,4,6-trimethy-
lphenyl)-5,7-dihydropyrrolo [2,3d]pyrimidin-6-one
[0547] The title compound was prepared by the method of Example 13B
from
4chloro-2,5,5-trimethyl-7-(2,4,6-trimethylphenylamino)-5,7-dihydro-pyrrol-
o [2,3-d]pyrimidin-6-one) and (S)-2-amino-butanol in
dimethylsulfoxide at 140.degree. C. .sup.1H NMR (CDCl.sub.3)
.delta. 1.02 (t, 3H), 1.53 (s, 6 H), 1.5-1.8 (m, 2 H), 2.04 (s, 6
H), 2.32 (s, 3 H), 2.38 (s, 3 H), 3.6-3.9 (m, 2 H), 4.0 (m, 1 H),
4.5 (d, 1 H), 5.25 (brs, 1 H), 7.00 (s, 2 H) ppm.
EXAMPLE 16
[0548]
5-Hydroxy-4-(1-hydroxymethylpropylamino)-2,5-dimethyl-7-(2,4,6-trim-
ethyl-phenyl)-5,7-dihydropyrrolo [2,3d]pyrimidin-6-one
[0549] The title compound was prepared by the method of Example 13B
from 4-chloro-2,5-dimethyl-7-(2,
4,6-trimethylphenylamino)-5,7-dihydro-pyrrodo-
[2,3-d]pyrimidin-6-one) and (S)-2-amino-butanol in
dimethylsulfoxide (DMSO) at 140.degree. C. Two diastereomers were
obtained. The spectra for both diastereomers are shown below:
[0550] One isomer: .sup.1H NMR (CDCl.sub.3) .delta. 1.03 (t, 3 H),
1.55-1.75 (m, 2 H), 1.77 (s, 3 H), 2.05 (s, 3 H), 2.07 (s, 3 H),
2.32 (s, 3 H), 2.37 (s, 3 H), 3.55-3.85 (m, 2 H), 4.0 (m, 1 H), 5.1
(d, 1 H), 5.3 (brs, 1 H), 7.00 (s, 2 H) ppm.
[0551] The other isomer: .sup.1H NMR (CDCl.sub.3) .delta. 1.03 (t,
3 H), 1.55-1.75 (m, 2 H), 1.73 (s, 3 H), 2.02 (s, 3 H), 2.05 (s, 3
H), 2.32 (s, 3 H), 2.36 (s, 3 H), 3.58 (dd, 1 H), 3.77 (dd, 1 H),
4.1 (m, 1 H), 5.03 (d, 1 H), 7.00 (s, 2 H) ppm.
EXAMPLE 17
5-Methoxy-4-(butyl-ethyl-amino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-
-dihydro-pyrrolo [2,3-d]pyrimidin-6-one
[0552]
5-Hydroxy-4-(butyl-ethyl-amino)-2,5-dimethyl-7-(2,4,6-trimethylphen-
yl)-5,7-dihydro-pyrrolo [2,3-d]pyrimidin-6-one was prepared by the
method analogous to that of Example 16 starting with
4-chloro-2,5-dimethyl-7-(2,-
4,6-trimethylphenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one)
and N-butyl-ethyl-amine in DMSO at 140.degree. C. Methylation of
5-hydroxy-4-(butyl-ethyl-amino)-2,5-dimethyl-7-(2,
4,6-trimethylphenyl)-
[0553] 5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with sodium
hydride and methyl iodide using the method of Example 10 provides
the title compound. .sup.1H NMR (CDCl.sub.3) .delta. 6.97 (d, 2 H),
3.5-4.0 (m, 4 H), 3.23 (s, 3 H), 2.34 (s, 3 H), 2.32 (s, 3 H), 2.12
(s, 3 H), 2.03 (s, 3 H), 1.69 (s, 3 H), 1.6-1.8 (m, 2 H), 1.3-1.5
(m, 2 H), 1.24 (t, 3 H), 0.99 (t, 3 H) ppm.
EXAMPLE 18
4-(Butyl-ethyl-amino)-2-methyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrro-
lo[2,3-d]pyrimidin-6-one
[0554] The title compound was prepared by the method analogous to
that of Example 13 (B) starting with
4-chloro-2-methyl-7-(2,4,6-trimethylphenylam-
ino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one) and
N-butyl-ethyl-amine in DMSO at 135.degree. C. for 2.5 hours to give
an oil. .sup.1H NMR (CDCl.sub.3) 7.00 (s, 2 H), 3.85 (s, 2 H), 3.62
(q, 2 H), 3.53 (t, 2 H), 2.35 (s, 3 H), 2.32 (s, 3 H), 2.10 (s, 3
H), 1.55-1.70 (m, 2 H), 1.35-1.50 (m, 2 H), 1.25 (t, 3 H), 1.00 (t,
3 H) ppm.
EXAMPLE 19
4-(Butyl-ethyl-amino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-p-
yrrolo[2,3-d]pyrimidin-6-one
[0555] A solution of
4-(butyl-ethyl-amino)-2-methyl-7-(2,4,6-trimethylphen-
yl)-5,7-dihydro-pyrrolo [2,3-d]pyrimidin-6-one (285 mg, 0.78 mmol)
in 5 ml of dry THF was treated with lithium
bis(trimethylsilyl)amide (1.05 mmol) at -78.degree. C. and stirred
for 5 minutes. The mixture was quenched with methyl iodide (0.054
ml, 0.858 mmol) at -78.degree. C. After stirring for 10 minutes,
the mixture was warmed to 0.degree. C. and stirred at that
temperature for 20 minutes. The mixture was quenched with saturated
ammonium chloride and extracted with ethyl acetate. The organic
layer was washed with brine, dried and concentrated to give a
purple form. The form was purified through silica gel column
chromatography to give 4-(butyl-ethyl-amino)-2,5-dimethyl-7-(2,
4,6-trimethylphenyl)-5,7-di- hydro-pyrrolo[2,3-d]pyrimidin-6-one
(120 mg) as a purple glass, 4-(butyl-ethyl-amino)-2,
5,5-trmethyl-7-(2,4,6-trimethylphenyl)-5,7-dihyd-
ro-pyrrolo[2,3-d]pyrimidin-6-one (35 mg) as a purple glass, and 98
mg of a mixture of the two components as a purple glass.
[0556] .sup.1H NMR (CDCl.sub.3)
(4-(butyl-ethyl-amino)-2,5-dimethy-7-(2,4,-
6-trimethylphenyl)-5,7-dihydro-pyrrolo [2,3-d]pyrimidin-6-one)
.delta. 6.96 (s, 2 H), 3.7-3.9 (m, 2 H), 3.51 (q, 1 H), 3.15-3.4
(m, 2 H), 2.34 (s, 3 H), 2.30 (s, 3 H), 2.08 (s, 3 H), 2.05 (s, 3
H), 1.53 (d, 3 H), 1.5-1.65 (m, 2 H), 1.3-1.4 (m, 2 H), 1.17 (t, 3
H), 0.95 (t, 3 H) ppm.
[0557] .sup.1H NMR (CDCl.sub.3)
(4-butyl-ethyl-amino)-2,5,5-trimethy-7-(2,-
4,6-trimethylphenyl)-5,7-dihydro-pyrrolo [2,3-d]pyrimidin-6-one)
.delta. 6.98 (s, 2 H), 3.45 (q, 2 H), 3.34 (t, 2 H), 2.34 (s, 3 H),
2.33 (s, 3 H), 2.06 (s, 6 H), 1.55-1.7 (m, 2 H), 1.3-1.45 (m, 2 H),
1.23 (t, 3 H), 0.99 (t, 3 H) ppm.
EXAMPLE 20
Butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3d]-
pyrimidin-4-yl]-ethylamine
[0558] A solution of
(4-butyl-ethyl-amino)-2,5-dimethyl-7-(2,4,6-trimethyl-
phenyl)-5,7-dihydro-pyrrolo [2,3-d]pyrimidin-6-one) (111 mg, 0.292
mmol) in dry THF was treated with lithium aluminum hydride at room
temperature. The resulting mixture was heated at reflux for 5
hours. After standard work-up, 97 mg of crude material as an oil
was obtained. The oil was purified through a chromatotron using 10%
ethyl acetate in hexane as eluent to give
butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro--
5H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethylamine as a clear pale yellow
oil. .sup.1H NMR (CDCl.sub.3) .delta. 6.91 (d, 2 H), 3.7-3.9 (m, 2
H), 3.2-3.4 (m, 4 H), 2.5 (q, 1 H), 2.28 (s, 6 H), 2.22 (s, 3 H),
2.05 (s, 3 H), 1.5-1.7 (m, 2 H), 1.3-1.5 (m, 5 H), 1.17 (t, 3 H),
0.97 (t, 3 H) ppm. High MS (C23H34N4) calc. 366.2776, found
366.27622.
EXAMPLE 21
4-(Butyl-ethyl-amino)-2,5,5-trimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydr-
o-5H-pyrrolo[2,3-d]pyrimidin-6-ol
[0559] The title compound was prepared by the method of Example 20
starting from (4-(butyl-ethyl-amino)-2,
5,5-trimethyl-7-(2,4,6-trimethylp-
henyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one) to give a pale
yellow solid, mp 142-145.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta. 6.95 (d, 2 H), 4.90 (s, 1 H), 3.1-3.4 (m, 4 H), 2.4 (brs, 1
H), 2.3 (s, 3 H), 2.31 (s, 3 H), 2.21 (s, 3 H), 2.17 (s, 3 H), 1.50
(s, 3 H), 1.45 (s, 3 H), 1.25-1.60 (m, 4 H), 1.11 (t, 3 H), 0.93
(t, 3 H) ppm.
EXAMPLE 22
Butyl-ethyl-[6-methoxy-2,5,5-trimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihyd-
ro-5H-pyrrolo [2,3-d]pyrimidin-4-yl]-amine
[0560] To a solution of
4-(butyl-ethyl-amino)-2,5,5-trimethyl-7-(2,4,6-tri-
methylphenyl)-6,7-dihydro-5H-pyrrolo [2,3-d]pyrimidin-6-ol (20 mg,
0.05 mmol) in 1 ml of dry THF was treated with sodium hydride (60%
in oil, 4 mg, 0.1 mmol) and then methyl iodide (0.3 ml) was added
at room temperature. After stirring at room temperature for 2.5
hours, the mixture was quenched with saturated ammonium chloride
and extracted with ethyl acetate. The organic layer was washed with
brine, dried and concentrated to give 26 mg of crude material.
After silica gel column purification with 10% ethyl acetate in he
mg of a colorless oil of the title compound was obtained. .sup.1H
NMR (CDCl.sub.3) .delta. 6.92 (s, 1 H), 6.89 (s, 1 H), 4.48 (s, 1
H), 3.1-3.3 (m, 4 H), 3.11 (s, 3 H), 2.32 (s, 3 H), 2.28 (s, 3 H),
2.20 (s, 3 H), 2.19 (s, 3 H), 1.45 (s, 3 H), 1.44 (s, 3 H),
1.4-1.52 (m, 2 H), 1.2-1.4 (m, 2 H), 1.10 (t, 3 H), 0.90 (t, 3 H)
ppm.
EXAMPLE 23
4-(Butyl-ethyl-amino)-2-methyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]-
pyrimidine-5,6-dione
[0561] To a solution of
4-(butyl-ethyl-amino)-2-methyl-7-(2,4,6-trimethyph-
enyl)-5,7-dihydro-pyrrolo [2,3-d]pyrimidin-6-one (76 mg, 0.207
mmol), POCl.sub.3 (0.039 ml, 0.415 mmol), triethylamine (0.059 ml),
and dimethylamine (1 ml) in 2 ml acetonitrile was heated at reflux
for 1 hour. The mixture was quenched with water and extracted with
ethyl acetate. The organic layer was dried and concentrated to give
a brown form (105 mg). After silica gel column chromatography, the
title compound was isolated as a yellow glass (10 mg). .sup.1H NMR
(CDCl.sub.3) .delta. 7.00 (s, 2 H), 3.95-4.15 (m, 2 H), 3.65-3.85
(m, 2 H), 2.38 (s, 3 H), 2.32 (s, 3 H), 2.10 (s, 6 H), 1.55-1.75
(m, 2 H), 1.35-1.55 (m, 2 H), 1.25 (t, 3 H), 1.00 (t, 3 H) ppm.
EXAMPLE 24
N-Butyl-N-ethyl-2,5,N'-trimethyl-N'-(2,4,6-trimethylphenyl)-pyrimidine-4,6-
-diamine
[0562] A mixture of
(6-chloro-2,5-dimethyl-pyrimidin-4-yl)-methyl-(2,4,6-t-
rimethylphenyl)-amine (200 mg) and N-butyl-ethylamine (0.3 ml) in 1
ml of DMSO was heated in oil bath of 160.degree. C. for 15 hours.
The mixture was quenched with water and extracted with ethyl
acetate. The organic layer was separated, dried and concentrated to
give the crude material. After silica gel column purification using
chloroform as eluent, the title compound was obtained as an oil.
.sup.1H NMR (CDCl.sub.3) .delta. 6.83 (s, 2 H), 3.22 (s, 3 H), 3.12
(m, 4 H), 2.44 (s, 3 H), 2.26 (s, 3 H), 2.01 (s, 6 H), 1.35-1.42
(m, 2 H), 1.1-1.25(m, 2 H), 1.00 (t, 3 H), 0.90 (t, 3 H) ppm.
EXAMPLE 25
[2,5-Dimethyl(tetrahydrofuran-3-yloxy)-pyrimidin-4-yl]-(2,4,6-trimethylphe-
nyl)-amine
[0563] A mixture of 3-hydroxy-tetrahydrofuran (0.5 ml) and sodium
hydride (60% in oil, 53 mg, 1.33 mmol) in dry THF was stirred at
room temperature for 5 minutes,
(6-chloro-2,5-dimethyl-pyrimidin-4-yl)-(2,
4,6-trimethylphenyl)-amine (107 mg, 0.388 mmol) was added. The
mixture was heated at reflux for 15 hours. The mixture was quenched
with water and extracted with ethyl acetate. The organic layer was
separated, dried and concentrated to give a yellow oil. The oil was
purified through silica gel column chromatography using 20% ethyl
acetate in hexane as eluent to give 48 mg of the title compound as
off-white crystals, mp 126-128.degree. C. .sup.1H NMR (CDCl.sub.3)
.delta. 6.89 (s, 2 H), 5.60 (brs, 2 H), 3.8-4.0 (m, 4 H), 2.27 (s,
6 H), 2.13 (s, 6 H), 2.1-2.25 (m, 2 H), 1.93 (s, 3 H) ppm.
EXAMPLE 26
[0564]
2-(S)-[2,5-Dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidin-4-ylamino]-
-butan-ol
[0565] A mixture of
4-chloro-2,5-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyri- midine (30
mg) and 2-(S)-amino-1-butanol (0.5 ml) in 0.5 ml of DMSO was heated
at 130.degree. C. for 4 hours. The mixture was quenched with water
and extracted with ethyl acetate. The organic layer was separated,
dried and concentrated to give a crude material. The crude residue
was purified through silica gel column chromatography to give 24 mg
of the title compound as white crystals. High MS for
(C.sub.19H.sub.27N.sub.3O.sub.2) calc. 329.2103, found 329.21249;
IR(KBr) 3400, 2940, 1580 cm-1; .sup.1H NMR (CDCl.sub.3) .delta.
6.841 (s, 2 H), 5.72 (brs, 1 H), 4.45 (d, 1 H), 3.82-3.96 (m, 1 H),
3.72-3.9 (m, 1 H), 3.5-3.6 (m, 1 H), 2.27 (s, 3 H), 2.21 (s, 3 H),
2.08 (s, 3 H), 2.02 (s, 6 H), 1.4-1.7 (m, 2 H), 1.03 (t, 3 H)
ppm.
EXAMPLE 27
4-(1-Ethyl-propoxy)-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidine
[0566] A mixture of 3-pentanol (0.3 ml) and sodium hydride (60% in
oil, 32 mg, 0.81 mmol) in DMSO was stirred at room temperature for
5 minutes.
4-Chloro-2,5-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyrimidine (150
mg, 0.54 mmol) was added and the resulting mixture was heated at
150.degree. C. for 5 hours. The mixture was quenched with water and
extracted with ethyl acetate. The organic layer was separated,
dried and concentrated to give a beige solid. The solid was
purified through silica gel column chromatography using 20%
chloroform in hexane as eluent to give the title compound as white
crystals, mp 93.5-95.5.degree. C. .sup.1H NMR (CDCl.sub.3) .delta.
6.85 (s, 2H), 5.11 (t, 1 H), 2.27 (s, 3 H), 2.26 (s, 3 H), 2.11 (s,
3 H), 2.03 (s, 6 H), 1.68 (p, 4 H), 0.92 (t, 6 H) ppm.
EXAMPLE 28
[[6-(Butyl-N-ethylamino)-2-methylpyrimidin-4-yl]-(2,4,6-trimethylphenyl)-a-
mino]-acetic acid ethyl ester
[0567] A mixture of
[(6-chloro-2-methylpyrimidin-4-yl-(2,4,6-trimethylphen-
y)-amino]-acetic acid ethyl ester (85 mg, 0.244 mmol) and
N-butyl-ethylamine (0.17 ml, 1.1 mmol) in 4 ml DMSO was heated at
135.degree. C. for 15 hours. An additional 1 ml of
N-butyl-ethylamine was added and the reaction was heated at that
temperature for an additional 15 hours (tlc showed no starting
material). The mixture was quenched with water and extracted with
ethyl acetate. The organic layer was separated, dried and
concentrated to give 123 mg of a light amber oil. The oil was
purified through silica gel chromatotron using 5% ethyl acetate in
hexane as eluent to give 92 mg (91%) of the title compound as a
white glass. .sup.1H NMR (CDCl.sub.3) .delta. 6.94 (s, 2 H), 4.69
(s, 1 H), 4.23 (s, 2 H), 4.22 (q, 2 H), 3.35 (q, 2 H), 3.15 (t, 2
H), 2.36 (s, 3 H), 2.31 (s, 3 H), 2.21 (s, 6 H), 1.3-1.5 (m, 2 H),
1.34 (t, 3 H), 1.1-1.3 (m, 2 H), 1.01 (t, 3 H), 0.80 (t, 3 H)
ppm.
EXAMPLE 29
4-(1-Ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine
[0568] To a solution of 3-pentanol (0.2 ml, 0.5205 mol) in DMSO (1
ml) was added 60% sodium hydride in oil (30 mg) in a portionwise.
After stirring at room temperature for 5 min, a solution of
4-chloro-2,5-dimethyl-6-(2,4- ,6-trimethylphenoxy)-pyridine (98 mg)
in 0.5 ml of dry THF was added and the resulting mixture was heated
at 130.degree. C. for 5 hours. The mixture was quenched with water
and extracted with ethyl acetate. The organic layer was separated,
dried and concentrated to give a yellow solid. The solid was
purified through silica gel column chromatography using 20%
chloroform in hexane to chloroform as eluent to give 7 mg of the
title compound as white crystals, mp 72.5-74.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 6.84 (s, 2 H), 6.26 (s, 1 H), 4.16 (m, 1 H),
2.27 (s, 3 H), 2.17 (s, 6 H), 2.04 (s, 6 H), 1.69 (m, 4 H), 0.95
(t, 6 H) ppm.
[0569] The mesylate salt of
4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trim-
ethyl-phenoxy)-pyridine was prepared by addition of 1 equivalent of
methanesulfonic acid in ethyl acetate. The white crystals formed
from ethyl acetate. Mp 117-119.degree. C.
EXAMPLE 30
[6-(Butyl-ethyl-amino)-2,5-dimethylpyrimidin-4-yl]-(2,4,6-trimethylphenyl)-
- acetonitrile
[0570] A solution of mesitylacetonitrile (66 mg, 0.41 mmol) in 1 ml
of DMSO was treated with NaH (60% in oil, 20 mg, 0.50 mmol) and
stirred at room temperature for 20 minutes,
butyl-(6-chloro-2,5-dimethylpyrimidin-4-- yl)-ethylamine (100 mg,
0.414 mmol) was added and the resulting mixture was heated at
130.degree. C. for 15 hours. The mixture was quenched with water
and extracted with ethyl acetate. The organic layer was separated,
dried and concentrated to give 160 mg of brown oil. The oil was
purified through silica gel column chromatography using 5% ethyl
acetate in hexane as eluent to give the title compound as a brown
oil. .sup.1H NMR (CDCl.sub.3) .delta. 6.83 (s, 2 H), 5.49 (s,
.sup.1H), 3.2-3.4 (m, 2 H), 3.0-3.2 (m, 2 H), 2.51 (s, 3 H), 2.24
(s, 3 H), 2.21 (s, 6 H), 1.66 (s, 3 H), 1.35-1.50 (m, 2 H), 1.1-1.3
(m, 2 H), 1.05 (t, 3 H), 0.84 (t, 3 H) ppm.
EXAMPLE 31
2-[6-(1-Ethyl-propoxy)-2,5-dimethylpyrimidin-4-yl]-2-(2,4,6-trimethylpheny-
l)-propionitrile
[0571] To a solution of 3-pentanol (140 mg, 1.59 mmol) in 2 ml of
dry THF was added sodium hydride (60% in oil, 38 mg) and the
mixture was stirred at room temperature for 5 minutes.
2-(6-Chloro-2,5-dimethylpyrimidin-4-yl- )-2-(2,
4,6-trimethylphenyl)-propionitrile (100 mg, 0.319 mmol) was added
to the reaction mixture, and the resulting mixture was heated at
reflux for 4 hours. The mixture was quenched with water and
extracted with ethyl acetate. The organic layer was separated,
dried and concentrated to give a brown oil (170 mg). The residue
was purified through chromatotron using 20% ethyl acetate in hexane
as eluent to give a mixture of two isomers as a yellow glass form
and both having a M+ of 365 from GC/Ms. .sup.1H NMR (CDCl.sub.3)
.delta. 6.8 and 6.76 (s, 2 H), 4.08 and 3.96 (m, .sup.1H), 3.25 and
3.22 (s, 3 H), 2.36 and 2.30 (s, 3 H), 2.21, 2.20 and 2.06 (s,
total of 9 H), 1.5-1.7 (m, 4 H), 1.04 (s, 3 H), 0.96 and 0.90 (t, 3
H) ppm.
EXAMPLE 32
4-(1-Ethyl-propoxy)-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine
[0572] The title compound was prepared by the method analogous to
that in Example 32 starting with
4-Chloro-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)- -pyrimidine and
3-pentanol. White crystals, mp. 82-84.degree. C.
[0573] The title compounds of Example 33-39 were prepared by a
method analogous to that of Example 27, starting with the
appropriate 4-chloro-2-methyl-5-substituted
6-substituted-phenoxy)-pyrimidine and 3-pentanol.
EXAMPLE 33
4-(2,4-Dimethyl-phenoxy)-6-(1-ethyl-propoxy)-2,5-dimethyl-pyrimidine
[0574] .sup.1H NMR (CDCl.sub.3) .delta. 6.8-7.0 (m, 3 H), 5.13 (m,
1 H), 2.30 (s, 6 H), 2.10 (s, 3 H), 2.09 (s, 3 H), 1.68 (m, 4 H),
0.92 (t, 6 H) ppm.
EXAMPLE 34
4-(2,6-Dimethyl-phenoxy)-6-(1-ethyl-propoxy)-2,5-dimethyl-pyrimidine
[0575] .sup.1H NMR (CDCl.sub.3) .delta. 7.04 (m, 3 H), 5.12 (m, 1
H), 2.25 (s, 3 H), 2.13 (s, 3 H), 2.07 (s, 6 H), 1.66 (m, 4 H),
0.92 (t, 6 H) ppm.
EXAMPLE 35
4-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine-5-carb-
onitrile
[0576] mp 128-130.degree. C., .sup.1H NMR (CDCl.sub.3) .delta. 6.8
(s, 2 H), 5.18 (m, 1 H), 2.30 (s, 3 H), 2.21 (s,3 H), 2.00 (s,6 H),
1.4-1.58 (m, 4 H), 0.90 (t, 6 H) ppm.
EXAMPLE 36
5-tert-Butyl-4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyri-
midine
[0577] .sup.1H NMR (CDCl.sub.3) .delta. 6.85 (s, 2 H), 5.25 (m, 1
H), 2.29 (s, 3 H), 2.20 (s, 3 H), 2.03 (s, 6 H), 1.65-1.80 (m, 4
H), 1.52 (s, 9 H), 0.90 (t, 6 H) ppm.
EXAMPLE 37
4-(1-Ethyl-propoxy)-5-isopropyl-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrim-
idine
[0578] .sup.1H NMR (CDCl.sub.3) .delta. 6.85 (s, 2 H), 5.17 (m, 1
H), 3.50 (m, 1 H), 2.27 (s, 3 H), 2.23 (s, 3 H), 2.03 (s, 6 H),
1.69 (m, 4 H), 1.33 (s, 3 H), 1.31 (s, 3 H), 0.92 (t, 6 H) ppm.
EXAMPLE 38
5-Bromo-4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-
e
[0579] .sup.1H NMR (CDCl.sub.3) .delta. 6.86 (s, 2 H), 5.16 (m, 1
H), 2.29 (s, 3 H), 2.28 (s, 3 H), 2.06 (s, 6 H), 1.65-1.80 (m, 4
H), 1.52 (s, 9 H), 0.95 (t, 6 H) ppm.
EXAMPLE 39
5-Chloro-4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidi-
ne
[0580] .sup.1H NMR (CDCl.sub.3) .delta. 6.86 (s, 2 H), 5.16 (m, 1
H), 2.28 (s, 3 H), 2.27 (s, 3 H), 2.06 (s, 6 H), 1.65-1.80 (m, 4
H), 1.52 (s, 9 H), 0.94 (t, 6 H) ppm.
[0581] The title compounds of Examples 40-41 were prepared by a
method analogous to that described in Example 24, starting from
4chloro-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidine and the
appropriate amine.
EXAMPLE 40
[2,5-Dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl](1-ethyl-propyl)--
amine
[0582] .sup.1H NMR (CDCl.sub.3) .delta. 6.84 (s, 2 H), 4.10 (m, 2
H, NH and CH), 2.27 (s, 3 H), 2.21 (s, 3 H), 2.04 (s, 9 H), 1.3-1.6
(m, 4 H), 0.91 (t, 6 H) ppm.
EXAMPLE 41
Butyl-[2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl]-ethyl-amin-
e
[0583] .sup.1H NMR (CDCl.sub.3) .delta. 6.87 (s, 2 H), 3.76 (m, 2
H), 3.68 (t, 2 H), 2.73 (s, 3 H), 2.28 (s, 6 H), 1.99 (s, 6 H),
1.5-1.7 (m, 4 H), 1.27 (t, 3 H), 0.94 (t, 3 H) ppm.
[0584] The title compounds of Examples 42-54 were prepared by a
method analogous to that described in Example 29, starting with the
appropriate 4-chloro-2-methyl-6-(substituted phenoxy or
thiophenoxy)-pyridine and the appropriate alcohol.
EXAMPLE 42
2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine
[0585] .sup.1H NMR (CDCl.sub.3) .delta. 7.18 (s, 2 H), 6.30 (s, 1
H), 4.22 (m, 1 H), 2.20 (s, 6 H), 2.05 (s, 6 H), 1.73 (m, 4 H),
1.00 (t, 6 H) ppm.
EXAMPLE 43
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-
e
[0586] .sup.1H NMR (CDCl.sub.3) .delta. 7.05 (s, 2 H), 6.31 (s, 1
H), 4.20 (m, 1 H), 2.20 (s, 6 H), 2.08 (s, 6 H), 1.73 (m, 4 H),
0.99 (t, 6 H) ppm.
EXAMPLE 44
3-Ethyl-4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine
[0587] .sup.1H NMR (CDCl.sub.3) .delta. 6.85 (s, 2 H), 6.26 (s, 1
H), 4.18 (m, 1 H), 2.73(q,2 H), 2.28 (s, 3 H), 2.17 (s, 3 H), 2.05
(s, 6 H), (m, 4 H), 1.18 (t, 3 H), 0.96 (t, 6 H) ppm.
EXAMPLE 45
4-(1-ethyl-propenyloxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine
(A mixture of cis and trans isomers)
[0588] .sup.1H NMR (CDCl.sub.3) .delta. 6.85 (s, 2 H), 6.30 (s, 0.3
H), 6.21 (s, 0.7 H), 5.10 (m, 0.7 H), 4.95 (m, 0.3 H), 2.27 (s, 3
H), 2.24 (s, 2.1 H), 2.19 (s, 0.9 H), 2.14 (s, 3 H), 2.05 (s, 6 H),
1.65 (d, 0.9 H), 1.50 (d, 2.1 H), 1.08 (t, 1.8 H), 1.05 (t, 4.2 H)
ppm.
EXAMPLE 46
Methanesulfonic acid salt of
4-(1-ethyl-propoxy)-2,3,5-trimethyl-6-(2,4,6--
trimethyl-phenoxy)-pyridine
[0589] Mp 58-60.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 6.90
(s, 2 H), 4.20 (m, 1 H), 2.70 (s, 3 H), 2.61 (s, 3 H), 2.28 (s, 3
H), 2.16 (s, 3 H), 2.08 (s, 6 H), 1.5-1.8 (m, 4 H), 0.96 (t, 6 H)
ppm.
EXAMPLE 47
4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic
acid methyl ester
[0590] .sup.1H NMR (CDCl.sub.3) .delta. 6.84 (s, 2 H), 6.39 (s, 1
H), 5.04 (m, 1 H), 3.85 (s, 3 H), 2.27 (s, 3 H), 2.23 (s, 3 H),
2.05 (s, 6 H), 1.5-1.7 (m, 4 H), 0.95 (s, 6 H) ppm.
EXAMPLE 48
4-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridine
[0591] .sup.1H NMR (CDCl.sub.3) .delta. 6.90 (s, 2 H), 6.34 (d, J-2
Hz,1 H), 5.70 (d, J=2 Hz,1 H), 4.05 (m, 1 H), 2.40 (s, 3 H), 2.30
(s, 3 H), 2.11 (s, 6 H), 1.62 (m, 4 H), 0.89 (t, 6 H) ppm.
EXAMPLE 49
3,6-Dimethyl-4-(tetrahydro-furan-3-yloxy)-2-(2,4,6-trimethyl-phenoxy)-pyri-
dine
[0592] .sup.1H NMR (CDCl.sub.3) .delta. 6.88 (s, 2 H), 6.25 (s, 1
H), 4.99 (m, 1 H), 3.9-4.1 (m, 4 H), 2.31 (s, 3 H), 2.23 (s, 3 H),
2.20 (s, 3 H), 2.1-2.3 (m, 2 H), 2.07 (s, 6 H) ppm.
EXAMPLE 50
4-(1-Methoxymethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyrid-
ine
[0593] .sup.1H NMR (CDCl.sub.3) .delta. 6.88 (s, 2 H), 6.38 (s, 1
H), 4.42 (m, 1 H), 3.5-3.7 (m, 2 H), 3.42 (s, 3 H), 2.31 (s, 3 H),
2.21 (s, 6 H), 2.07 (s, 6 H), 1.7-1.85 (m, 2 H), 1.02 (t, 3 H)
ppm.
EXAMPLE 51
3-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yloxy]-pentan-2-ol
[0594] .sup.1H NMR (CDCl.sub.3) .delta. 6.88 (s, 2 H), 6.34 (s, 1
H), 4.25-4.45 (m, 1 H0, 3.6-3.8 (m, .sup.1H), 2.30 (s, 3 H)2.21 (s,
3 H), 2.20 (s, 3 H), 2.06 (s, 6 H), 1.2-1.4 (m, 5 H0, 1.07 (t, 3 H)
ppm.
EXAMPLE 52
4-sec-Butoxy-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine
[0595] .sup.1H NMR (CDCl.sub.3) .delta. 6.88 (s, 2 H), 6.31 (s, 1
H), 4.35 (m, 1 H), 2.30 (s, 3 H), 2.21 (s, 3 H), 2.19 (s, 3 H),
2.07 (s, 6 H0, 1.7-1.9 (m, 2 H), 1.34 (d, 3 H), 1.01 (t, 3 H)
ppm.
EXAMPLE 53
2-(2,4-Dimethyl-phenylsulfanyl)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine
[0596] Golden oil. .sup.1H NMR (CDCl.sub.3) .delta. 7.19 (d, j=8
Hz,1 H0, 7.06 (s, 1 H), 6.94 (d, J=8 Hz,1 H), 6.42 (s, 1 H), 4.19
(m, 1 H), 2.34 (s, 3 H), 2.33 (s, 3 H), 2.32 (s, 3 H), 2.18 (s, 3
H), 1.69 (m, 4 H), 0.95 (t, 6 H) ppm.
EXAMPLE 54
[0597]
4-(1-Ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-
-pyridine .sup.1H NMR (CDCl.sub.3) .delta. 6.97 (s, 2 H), 6.30 (s,
1 H), 4.15 (m, 1 H), 2.35 (s, 6 H), 2.30 (s, 3 H), 2.23 (s, 3 H),
2.20 (s, 3 H), 1.68 (m, 4 H), 0.95 (t, 6 H) ppm.
EXAMPLE 55
2-(4-Ethyl-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine
[0598] To a solution of 2.5 N n-BuLi in hexane (0.47 ml, 1.18 mmol)
in 5ml of dry THF was added a solution of
2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1--
ethyl-prpoxy)-3,6-dimethyl-pyridine (465 mg, 1.18 mmol) in 5 ml of
dry THF at -78.degree. C. After stirring at that temperature for 5
min, an excess of ethyl iodide (0.4 ml) was added and the resulting
mixture was stirred at -78.degree. C. for 30 min, then at 0.degree.
C. for 15 min. The mixture was quenched with saturated ammonium
chloride and extracted with ethyl acetate. The organic layer was
dried and concentrated to give a light brown oil The oil was
puriified through silica gel column chromatography using chloroform
as eluent to give 260 mg of the title compound as white solid.
.sup.1H NMR (CDCl.sub.3) .delta. 6.90 (s, 2 H), 6.38 (s, 1 H), 4.20
(m, 1 H), 2.61(q,2 H), 2.24 (s, 3 H), 2.21 (s, 3 H), 2.10 (s, 6 H),
1.70 (m, 4 H), 1.30 (t, 3 H), 0.98 (t, 6 H) ppm.
[0599] The title compounds of Examples 56-62 were prepared by a
method analogous to that described in Example 55, starting from
n-BuLi and
2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-prpoxy)-3,6-dimethyl-pyridine-
, followed by quenching with an appropriate electrophile.
EXAMPLE 56
4-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzalde-
hyde
[0600] .sup.1H NMR (CDCl.sub.3) .delta. 9.94 (s, 1 H), 7.61 (s, 2
H), 6.32 (s, 1 H), 4.20 (m, 1 H), 2.21 (s, 3 H), 2.16 (s, 9 H)1.70
(m, 4 H), 0.98 (t, 6 H) ppm.
EXAMPLE 57
2-(2,6-Dimethyl-4-propyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-
e
[0601] .sup.1H NMR (CDCl.sub.3) .delta. 6.88 (s, 2 H), 6.30 (s, 1
H), 4.20 (m, 1 H), 2.54(dd,2 H), 2.22 (s, 3 H), 2.20 (s, 3 H), 2.09
(s, 6 H), 1.6-1.8 (m, 6 H), 0.9-1.1 (m, 9 H) ppm.
EXAMPLE 58
2-(2,6-Dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine
[0602] .sup.1H NMR (CDCl.sub.3) .delta. 7.06 (m, 3 H), 6.30 (s, 1
H), 4.20 (m, 1 H), 2.21 (s, 6 H), 2.11 (s, 6 H), 1.73 (m, 4 H),
0.99 (t, 6 H) ppm.
EXAMPLE 59
2-{4-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-pheny-
l)-propan-2-ol
[0603] .sup.1H NMR (CDCl.sub.3) .delta. 7.15 (s, 2 H), 6.25 (s, 1
H), 4.20 (m, 1 H), 2.20 (s, 3 H), 2.19 (s, 3 H), 2.10 (s, 6 H),
1.85 (brs, .sup.1H),1.70 (m, 4 H), 1.60 (s, 6 H), 0.95 (t, 6 H)
ppm.
EXAMPLE 60
4-(1-Ethyl-propoxy)-2-(4-iodo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine
[0604] .sup.1H NMR (CDCl.sub.3) .delta. 7.39 (s, 2 H), 6.30 (s, 1
H), 4.19 (m, 1 H), 2.20 (s, 3 H), 2.18 (s, 3 H), 2.05 (s, 6 H),
1.72 (m, 4 H), 0.98 (t, 6 H) ppm.
EXAMPLE 61
4-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenol
[0605] .sup.1H NMR (CDCl.sub.3) .delta. 7.85 (brs, 1 H), 6.36 (s, 1
H), 6.24 (s, 2 H), 4.24 (m, 1 H), 2.39 (s, 3 H), 2.20 (s, 3 H),
2.02 (s, 6 H), 1.74 (m, 4 H), 1.00 (t, 6 H) ppm.
EXAMPLE 62
1-{4-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-pheny-
l)-pyrrolidin-2-one
[0606] .sup.1H NMR (CDCl.sub.3) .delta. 7.30 (s, 2 H), 6.30 (s, 1
H), 4.20 (m, 1 H), 3.88 (t, 2 H), 2.61 (t, 2 H) ppm.
EXAMPLE 63
{4-[4-(1Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}
-methanol
[0607] A mixture of
4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3-
,5-dimethyl-benzaldehyde (114 mg, 0.41 mmol) and sodium borohydride
(63 mg, 1.6 mmol) in 3 ml of methanol was stirred at room
temperature for 2 hours. The reaction mixture was quenched with
water and extracted with ethyl acetate. The organic layer was dried
and concentrated to give yellow oil. The oil was purified through
silica gel using chloroform as eluent to give 70 mg of the title
compound as a colorless oil. .sup.1H NMR (CDCl.sub.3) .delta. 7.04
(s, 2 H), 6.32 (s, 1 H), 4.55 (s, 2 H), 4.21 (m, 1 H), 2.30 (brs, 1
H), 2.22 (s, 3 H), 2.21 (s, 3 H), 2.12 (s, 6 H), 1.73 (m, 4 H),
0.91 (t, 6 H) ppm.
EXAMPLE 64
4-(1-Ethyl-propoxy)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridi-
ne
[0608] To a solutionof
4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy-
]-3,5-dimethyl-phenol (40 mg, 0.12 mmol) in 3 ml of dry THF was
added 10 mg of 60% sodium hydride in oil at room temperature. After
stirring for 5 min, 0.3 ml of methyl iodide was added and the
resulting mixture was stirred at room temperature overnight. The
mixture was quenched with water and extracted with ethyl acetate.
The organic layer was dried and concentrated to give a yellow
solid. The solid was purified through silica gel column
chromatography using hexane to 1:1 chloroform:hexane as eluent to
yield 20 mg of the Utle compound as yellow solid. .sup.1H NMR
(CDCl.sub.3) .delta. 6.66 (s, 2 H), 6.28 (s, 1 H), 4.20 (m, 1 H),
3.79 (s, 3 H), 2.20 (s, 3 H), 2.19 (s, 3 H0, 2.08 (s, 6 H), 1.71
(m, 4 H), 0.97 (t, 6 H) ppm.
EXAMPLE 65
4-(1-Ethyl-propoxy)-2-(4-isopropoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyr-
idine
[0609] To a solution of
4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-ylox-
y]-3,5-dimethyl-phenol (58 mg, 0.176 mmol) in 3 ml of dry THF was
added triphenylphosphine (70 mg, 0.264 mmol) and isopropanol (60
mg, 0.22 mmol). The resulting mixture was stirred at room
temperature for 5 min, diethyl azodicarboxylate (46 mg, 0.264 mmol)
was added. The mixture was stirred at room temperature overnight.
An additional 20 mg of diethyl azodicarboxylate was added and the
mixture was stirred for an additional 4 hours. The mixture was
quenched with water and extracted with methylene chloride. The
organic layer was dried and concentrated to give an oil. The oil
residue was purified through silica gel column chromatography using
1:1 hexane:chloroform to 1:2 hexane: chloroform as eluent to give
38 mg (58%) of the title compound as a colorless oil. .sup.1H NMR
(CDCl.sub.3) .delta. 6.60 (s, 2 H), 6.28 (s, 1 H), 4.50 (m, 1 H),
4.18 (m, 1 H), 2.20 (s, 3 H), 2.19 (s, 3 H), 2.079s,6 H), 1.71 (m,
4 H), 1.34 (d, 6 H), 0.98 (t, 6 H) ppm.
[0610] The title compounds of Examples 66-67 were prepared by a
method analogous to that described in Example 64, starting with an
appropriate pyridine-3,5-dimethylphenol or
pyridine-3,5-dimethyl-phenyl methanol with a base, followed by
quenching with an appropriate alkyl halide.
EXAMPLE 66
2-(4-Ethoxy-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-
e
[0611] .sup.1H NMR (CDCl.sub.3) .delta. 6.60 (s, 2 H), 6.28 (s, 1
H), 4.19 (m, 1 H), 3.99(q,2 H), 2.19 (s, 3 H), 2.18 (s, 3 H), 2.07
(s, 6 H), 1.74 (m, 4 H), 1.40 (t, 3 H), 0.97 (t, 6 H) ppm.
EXAMPLE 67
4-(1-Ethyl-propoxy)-2-(4-methoxymethyl-2,6-dimethyl-phenoxy)-3,6-dimethyl--
pyridine
[0612] Mp 58-60.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 7.05
(s, 2 H), 6.30 (s, 1 H), 4.41 (s, 2 H), 4.19 (m, 1 H), 3.42 (s, 3
H), 2.21 (s, 3 H), 2.18 (s, 3 H), 2.11 (s, 6 H), 1.72 (m, 4 H),
0.98 (s, 6 H) ppm.
EXAMPLE 68
[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine
[0613] A mixture of
4-chloro-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyrid- ine (1.330
g, 4.822 mmol) and 20 ml of ethyl amine in 13 ml of
1-methyl-2-pyrrolidinone was heated at 150.degree. C. at 250 psi
overnight in a pressure reactor. The reaction was heated an
additional 24 hours at 175.degree. C. and 300 psi. The reaction
mixture cooled to room temperature and diluted with water and
extracted with ethyl acetate. The organic layer was dried and
concentrated to give a brown oil. The oil residue was purified
through silica gel column chromatography using chloroform to 2%
methanol in chloroform as eluent to give 0.820 g (60%) of the title
compound as a white solid, mp 115-116.degree. C.
[0614] .sup.1H NMR (CDCl.sub.3).delta. 6.87 (s, 2 H), 6.11 (s, 1
H), 3.85 (t, 1 H), 3.24 (m, 2 H), 2.30 (s, 3 H), 2.17 (s, 3 H),
2.13 (s, 3 H), 2.08 (s, 6 H), 1.32 (t, 3 H) ppm.
[0615] The title compounds of Examples 69-71 were prepared by the
method analogous to that described in Example 68 starting with an
appropriate 4-chloro-2-substituted phenoxy-pyridine and an
appropriate amine.
EXAMPLE 69
[3,6-Dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4-yl]-(1-ethyl-pr-
opyl)-amine
[0616] Mp 108-110.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 6.95
(s, 2 H), 6.09 (s, 1 H), 3.63 (d, 1 H), 3.28 (m, 1 H), 2.36 (s, 6
H), 2.30 (s, 3 H), 2.17 (s, 3 H), 2.11 (s, 3 H), 1.4-1.75 (m, 4 H0,
0.93 (t, 6 H) ppm. The hydrogen chloride salt, mp 148-150.degree.
C.; .sup.1H NMR (CDCl.sub.3) .delta. 6.95 (s, 2 H), 6.30 (s, 1 H),
5.75 (d, .sup.1H), 3.38 (m, 1 H), 2.69 (s, 3 H), 2.33 (s, 6 H),
2.28 (s, 3 H0, 2.02 (s, 3 H), 1.72 (m, 4 H), 0.93 (t, 6 H) ppm.
EXAMPLE 70
2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-amine;
white solid
[0617] .sup.1H NMR (CDCl.sub.3) .delta. 7.04 (s, 2 H), 6.13 (s, 1
H), 3.88 (t, 1 H), 3.24 (m, 2 H), 2.17 (s, 3 H), 2.17 (s, 3 H),
2.08 (s, 6 H), 1.32 (t, 3 H) ppm.
EXAMPLE 71
[3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)pyridin-4-yl]-ethyl-amine
[0618] Tan crystals, mp 114-116.degree. C. .sup.1H NMR (CDCl.sub.3)
.delta. 6.94 (s, 2 H), 6.12 (s, 1 H), 3.76 (t, 1 H), 3.21 (m, 2 H),
2.35 (s, 6 H), 2.30 (s, 3 H), 2.19 (s, 3 H), 2.10 (s, 3 H), 1.29
(t, 3 H) ppm.
EXAMPLE 72
[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propyl-amine
[0619] To a solution of
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin--
4-yl]-ethyl-amine (7.00 g, 24.6 mmol) in 100 ml of dry THF was
added 1.0 M lithium bis(trimethylsilyl)amide in hexane (32 ml, 32
mmol) at -78.degree. C. After stirring at that temperature for 10
min, the reaction mixture was treated with iodopropane (13 ml, 125
mmol) at -70.degree. C. After stirring at that temperature for 20
min, the dry ice bath was removed and the reaction mixture was
stirred at room temperature for 3 hours. The reaction mixture was
quenched with water and extracted with ethyl acetate. The organic
layer was dried and concentrated to give an oil. The oil residue
was purified through silica gel column chromatography using 1:1
chloroform:hexane to chloroform as eluent to give 5.04 g (62.5%) of
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin--
4-yl]-ethyl-propyl-amine as yellow solid; .sup.1H NMR (CDCl.sub.3)
.delta. 6.88 (s, 2 H), 6.41 (s, 1 H), 3.11(q,2 H), 3.03(dd,2 H),
2.30 (s, 3 H), 2.25 (s, 3 H), 2.19 (s, 3 H), 2.07 (s, 6 H), 1.55
(m, 2 H), 1.08 (t, 3 H), 0.90 (t, 3 H) ppm. The corresponding HCl
salt, white crystals; mp167-169.degree. C.; .sup.1H NMR (MeOH-d4)
.delta. 7.00 (s, 2 H), 6.75 (s, 1 H), 3.54(q,2 H), 3.43 (t, 2 H),
2.35 (s, 3 H), 2.31 (s, 3 H), 2.27 (s, 3 H), 2.08 (s, 6 H), 1.69
(m, 2 H), 1.25 (t, 3 H0, 0.94 (t, 3 H) ppm;
[0620] The title compounds of Examples 73-79 were prepared by the
method analogous to that described in Example 72 starting with an
appropriate 2-(substituted phenoxy or thiophenoxy)
pyridin-4-yl-ethyl amine and a base (lithium
bis(trimethylsilyl)amide or lithium diisopropylamide), followed by
quenching with an appropriate alkyl halide.
EXAMPLE 73
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-diethyl-amine
[0621] .sup.1H NMR (CDCl.sub.3) .delta. 6.87 (s, 2 H), 6.40 (s, 1
H), 3.10(q,4 H), 2.30 (s, 3 H), 2.24 (s, 3 H), 2.19 (s, 3 H), 2.06
(s, 6 H), 1.08 (t, 6 H) ppm. The HCl salt, white crystals, mp
180-181.degree. C.; .sup.1H NMR (CD.sub.3OD) .delta. 7.01 (s, 2 H),
6.78 (s, 1 H), 3.58(q,4 H), 2.38 (s, 3 H), 2.32 (s, 6 H), 2.10 (s,
6 H), 1.28 (t, 6 H) ppm.
EXAMPLE 74
[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-methyl-amine
[0622] .sup.1H NMR (CDCl.sub.3) .delta. 6.86 (s, 2 H), 6.38 (s, 1
H), 3.05(q,2 H), 2.75 (s, 3 H), 2.29 (s, 3 H), 2.25 (s, 3 H), 2.18
(s, 3 H), 2.06 (s, 6 H), 1.18 (t, 3 H) ppm. The HCl salt, mp
173-174.degree. C.
EXAMPLE 75
Butyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine
[0623] .sup.1H NMR (CDCl.sub.3) .delta. 6.88 (s, 2 H), 6.41 (s, 1
H), 3.0-3.3 (m, 4 H), 2.31 (s, 3 H), 2.25 (s, 3 H), 2.19 (s, 3 H),
2.08 (s, 6 H), 1.3-1.6 (m, 4 H), 1.09 (t, 3 H), 0.93 (t, 3 H)
ppm.
EXAMPLE 76
Butyl-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl--
amine
[0624] .sup.1H NMR (CDCl.sub.3) .delta. 7.03 (s, 2 H), 6.39 (s, 1
H), 3.09(q,2 H), 3.01(dd,2 H), 2.21 (s, 3 H), 2.16 (s, 3 H), 2.05
(s, 6 H), 1.4-1.6 (m, 2 H), 1.25-1.40(m, 2 H), 1.06 (t, 3 H), 0.87
(t, 3 H) ppm. The HCl salt, mp 177-178.degree. C.; .sup.1H
NMR(DMSO-d6) .delta. 7.20 (s, 2 H), 6.74 (s, 1 H), 3.1-3.4 (m, 4
H), 2.24 (s, 3 H), 2.17 (s, 3 H), 2.00 (s, 6 H), 1.4-1.6 (m, 2 H),
1.25-1.40 (m, 2 H), 1.05 (t, 3 H), 0.86 (t, 3 H) ppm.
EXAMPLE 77
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-propyl-
-amine
[0625] .sup.1H NMR (CDCl.sub.3) .delta. 7.04 (s, 2 H), 6.41 (s, 1
H), 3.11(q,2 H), 3.00 (m, 2 H), 2.24 (s, 3 H), 2.17 (s, 3 H), 2.07
(s, 6 H), 1.54 (m, 2 H), 1.08 (t, 3 H), 0.90 (t, 3 H) ppm. The HCl
salt, white crystals, mp 74-76.degree. C. .sup.1H NMR(CD3OD)
.delta. 7.23 (s, 2 H), 6.81 (s, 1 H), 3.58(q,2 H), 3.46 (m, 2 H),
2.38 (s, 3 H), 2.31 (s, 3 H), 2.13 (s, 6 H), 1.6-1.8 (m, 2 H), 1.26
(t, 3 H), 0.96 (t, 3 H) ppm.
EXAMPLE 78
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-diethyl-amin-
e
[0626] .sup.1H NMR (CDCl.sub.3) .delta. 7.05 (s, 2 H), 6.41 (s, 1
H), 3.11(q,4 H), 2.24 (s, 3 H), 2.18 (s, 3 H), 2.07 (s, 6 H), 1.09
(t, 6 H) ppm. The HCl salt, white crystals, mp 184-185.degree. C.
.sup.1H NMR(CD3OD) .delta. 7.23 (s, 2 H), 6.81 (s, 1 H), 3.56(q,4
H), 2.37 (s, 3 H), 2.33 (s, 3 H), 2.12 (s, 6 H), 1.26 (t, 6 H)
ppm.
EXAMPLE 79
[3,6-Dimethyl-[2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4-yl]-ethyl-prop-
yl-amine
[0627] .sup.1H NMR (CDCl.sub.3) .delta. 6.95 (s, 2 H), 6.45 (s, 1
H), 3.02 (q,2 H), 2.97 (dd,2 H), 2.35 (s, 6 H), 2.31 (s, 3 H), 2.21
(s, 3 H), 2.20 (s, 3 H), 1.49 (m, 2 H), 1.02 (t, 3 H), 0.86 (t, 3
H) ppm. The HCl salt, white crystals, mp 110-112.degree. C.;
.sup.1H NMR (CDCl.sub.3) .delta. 6.92 (s, 2 H), 6.51 (s, 1 H), 3.27
(q,2 H), 3.19 (dd,2 H), 284 (s, 3 H), 2.32 (s, 6 H), 2.28 (s, 3 H),
1.82 (s, 3 H), 1.52 (m, 2H), 1.15 (t, 3H), 0.84 (t, 3H) ppm.
EXAMPLE 80
N-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N-ethyl-2,2,2-tr-
ifluoro-acetamide
[0628] To a solution of
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin--
4-yl]-ethyl-amine (200 mg, 0.7 mmol) in dry methylene chloride was
added triethylamine (0.1 ml, 0.73 mmol) and trifluoroacetic
anhydride (0.11 ml, 0.74 mmol) and stirred at room temperature for
2 hours. The reaction mixture was quenched with water and extracted
with ethyl acetate. The organic layer was dried and concentrated to
give the crude material . The crude material was purified through
silica gel column chromatography using 25% hexane in chloroform as
eluent to give 225 mg (83%) of the title compound as white
crystals, mp 110-111.degree. C., .sup.1H NMR (CDCl.sub.3) .delta.
6.91 (s, 2 H), 6.57 (s, 1 H), 4.16 (m, 1 H), 3.39 (m, 1 H), 2.32
(s, 3H), 2.27 (s, 3 H), 2.24 (s, 3 H), 2.07 (s, 3 H), 2.05 (s, 3
H), 1.26 (t, 3 H) ppm.
EXAMPLE 81
3,6-Dimethyl-2)-2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-(2,2,2-triflu-
oro-ethyl)-amine
[0629] To a solution of
N-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridi-
n-4-yl]-N-ethyl-2,2,2-trifluoro-acetamide (292 mg, 0.77 mmol) in 15
ml of dry THF was added 2M BH.sub.3.DMS in THF (0.96 ml, 1.92 mmol)
at room temperature. The resulting mixture was heated at reflux
overnight. The mixture was quenched with water and extracted with
ethyl acetate. The organic layer was dried and concentrated to give
300 mg of white solid. The solid was recrystallized from hexane and
2 drops of methanol to give white crystals (298 mg, 96%). .sup.1H
NMR (CDCl.sub.3) .delta. 6.85 (s, 2 H), 6.47 (s, 1 H), 3.70 (q,2
H), 3.25 (q,2 H), 2.32 (s, 3 H), 2.27 (s, 3 H), 2.20 (s, 3 H), 2.05
(s, 3 H), 1.13 (t, 3 H) ppm. The HCl salt, white crystals, mp
73-74.degree. C. .sup.1H NMR(CD.sub.3OD) .delta. 6.97 (s, 1 H),
6.96 (s, 2 H), 4.09 (q,2 H), 3.46 (q,2 H), 2.34 (s, 3 H), 2.30 (s,
3 H), 2.28 (s, 3 H), 2.05 (s, 6 H), 1.17 (t, 3 H) ppm.
EXAMPLE 82
4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic
acid methyl ester
[0630] A mixture of
4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotini- c acid
methyl ester (500 mg, 1.56 mmol) and 1-ethyl-propyl-amine (0.8 ml)
in 1 ml of DMSO was heated at reflux for 15 hours. The mixture was
quenched with sat. ammonium chloride and extracted with ethyl
acetate. The organic layer was dried and concentrated to give 445.6
mg of yellow solid. The solid was purified through silica gel
column chromatography using 1:1 ratio of chloroform:hexane as
eluent to give (289 mg, 50%)of the title compound as white
crystals, mp 98-102.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta.
8.04 (d, 1 H), 6.85 (s, 2 H), 6.06 (s, 1 H), 3.85 (s, 3 H), 3.32
(m, 1 H), 2.28 (s, 3 H), 2.10 (s, 3 H), 2.07 (s, 3 H), 1.62 (m, 4
H), 0.95 (t, 6 H) ppm.
EXAMPLE 83
4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-
-methanol
[0631] A mixture of
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-ph-
enoxy)nicotinic acid methyl ester (220 mg, 0.594 mmol) and 1 M
lithium aluminum hydride in THF (4 ml, 4 mmol) in dry THF (3 ml)
was heated at reflux for 10 min, then stirred at rt ovemight. The
mixture was quenched with 0.3 ml of water, 0.3 ml of 2N NaOH, then
0.8 ml of water and stirred at room temperature for 10 min. White
solid formed and was filtered through celite. The filtrate was
concentrate to dryness to give 207 mg (100%) of the title compound
as white solid. .sup.1H NMR (CDCl.sub.3) .delta. 6.83 (s, 2 H),
6.06 (s, 1 H), 4.96 (d, 1 H,NH), 4.88 (d, 2 H), 3.28 (m, 1 H), 2.26
(s, 3 H), 2.11 (s, 3 H), 2.04 (s, 6 H), 1.4-1.6 (m, 4 H), 1.4 (t, 1
H,OH), 0.93 (t, 6 H) ppm.
EXAMPLE 84
4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic
acid
[0632] A mixture of
4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-ph-
enoxy)-nicotinic acid methyl ester (16 mg, 0.043 mmol) and lithium
hydroxide (30 mg) in dioxane (1 ml) and water (1 ml) was stirred at
rt over night. The mixture was quenched with water and adjusted to
pH 7.0 and extracted with chloroform. The organic layer was dried
and concentrated to give the crude material. The crude material was
purified through silica gel column chromatography using 10% ethyl
acetate in chloroform as eluent to give 7 mg of the ttle compound
as white solid. .sup.1H NMR (CDCl.sub.3) .delta. 9.12 (d, 1 H),
6.87 (s, 2 H), 6.16 (s, 1 H), 3.35 (m, 1 H), 2.29 (s, 3 H), 2.10
(s, 3 H), 2.07 (s, 6 H), 1.4-1.6 (m, 4 H), 0.94 (t, 6 H) ppm.
EXAMPLE 85
[3-Chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethy-
l-propyl)-amine hydrogen chloride
[0633] To a solution of
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-pyridin-3-yl]-methanol (40 mg, 0.117 mmol) in 0.3 ml of
dry methylene chloride was added thionyl chloride (o.15 ml) and
stirred at rt for 1 hr. The mixture was concentrated to dryness and
pumped in vacuo to give white glass form. The glass form was
trituated with ether to give the title compound (47 mg, 100%) as a
white solid. .sup.1H NMR (CDCl.sub.3) .delta. 6.92 (s, 2 H), 6.24
(s, 1 H), 5.50 (d, 1 H), 4.72 (s, 2 H), 3.50 (m, 1 H), 2.73 (s, 3
H), 2.27 (s, 3 H), 2.15 (s, 6 H), 1.5-1.8 (m, 4 H), 0.97 (t, 6 H)
ppm.
EXAMPLE 86
[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-a-
mine
[0634] To a solution of
[3-Chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenox-
y)-pyridin-4-yl]-(1-ethyl-propyl)-amine (35 mg, 0.088 mmol) in dry
THF (0.5 ml) was added1M lithium aluminum hydride in THF (0.3 ml,
0.3 mmol) and the resulting mixture was stirred at rt for 1.5
hours. The mixture was quenched with 0.1 ml of water, 0.1 ml of 2N
NaOH and 0.3 ml of water and stirred for 5 min. The mixture was
filtered and washed with THF. The filtrate was concentrated to
dryness. The residue was dissolved in chloroform and dried over
anhydrous sodium sulfate, filtered, and concentrated to dryness to
give 28 mg (100%) of oil. The oil was purified through silica gel
column chromatography using chloroform as eluent to give 26 mg of
the title compound as an oil. .sup.1H NMR (CDCl.sub.3) .delta. 6.85
(s, 2 H), 6.08 (s, 1 H), 3.72 (d, NH,1 H), 3.35 (m, 1 H), 2.30 (s,
3 H), 2.16 (s, 3 H), 2.13 (s, 3 H), 2.05 (s, 6 H), 1.45-1.75 (m, 4
H), 0.98 (t, 6 H) ppm. The corresponding HCl salt was prepared and
trituated with ether to give 20 mg of white solid. .sup.1H NMR
(CDCl.sub.3) .delta. 6.88 (s, 2 H), 6.19 (s, 1 H), 4.98 (brs, 1 H),
3.50 (m, 1 H), 2.71 (s, 3 H), 2.26 (s, 3 H), 2.12 (s, 6 H), 2.00
(s, 3 H), 1.5-1.8 (m, 4 H), 0.95 (t, 6 H) ppm.
EXAMPLE 87
(1-Ethyl-propyl)-[3-methoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyr-
idin-4-yl]-amine
[0635] To a solution of
4-(1-ethyl-propylamino-6-methyl-2-(2,4,6-trimethyl-
-phenoxy)-pyridin-3-yl]-methanol (46 mg, 0.134 mmol) in dry THF
(0.5 ml) was added 60% sodium hydride in oil (6 mg, 0.134 mmol) and
stirred for 2 min. Methyl iodide (0.1 ml) was added and the mixture
was stirred at room temperature overnight. The reaction mixture was
quenched with water and extracted with ethyl acetate. The organic
layer was dried and concentrated to give the title compound as an
oil (40 mg, 84%). .sup.1H NMR (CDCl.sub.3) .delta. 6.84 (s, 2 H),
6.06 (s, 1 H), 5.13 (d, 1 H), 4.78 (s, 2 H), 3.33 (s, 3 H), 3.29
(m, 1 H), 2.27 (s, 3 H), 2.12 (s, 3 H), 2.04 (s, 6 H), 1.3-1.6 (m,
4 H), 0.93 (t, 6 H) ppm.
EXAMPLE 88
(1-Ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-y-
l]-amine
[0636] To a mixture of
(2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-p- ropyl)-amine
(80 mg, 0.31 mmol) and 2,4,6-trimethylphenol (43 mg, 0.31 mmol) in
2 ml of dry THF was added potassium tert-butoxide (35 mg, 0.31
mmol) and the resulting mixture was stirred at rt ovemight. The
mixture was quenched with water and extracted with ethyl acetate.
The organic layer was dried and concentrated to give a yellow
solid. The solid was purified through silica gel column
chromatography using 6:4 ratio of chloroform:hexane as eluent to
give 91 mg (83%) of the title compound as yellow solid, mp
160-162.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 7.62 (d, 1 H),
6.87 (s, 2 H), 6.18 (s, 1 H), 3.40 (m,1 H), 2.30 (s, 3 H), 2.15 (s,
3 H), 2.10 (s, 6 H), 1.5-1.8 (m, 4 H), 0.99 (t, 6 H) ppm.
EXAMPLE 89
N4-(1-Ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-pyridine--
2,4-diamine
[0637] A mixture of
(2-chloro-6-methyl-3-nitro-pyridin-4-yl-(1-ethyl-propy- lyamine
(250 mg, 0.97 mmol) and 2,4,6-trimethylaniline (262 mg, 1.94 mmol)
in 4 ml of dry DMSO was heated at 130.degree. C. overnight. The
mixture was quenched with water and extracted with ethyl acetate.
The organic layer was dried and concentrated to give a yellow oil.
The oil was purified through silica gel column chromatography to
give 150 mg (43%) of the title compound as yellow solid, mp
104-107.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 10.36 (s, 1 H),
9.24 (d, 1 H), 6.93 (s, 2 H), 5.86 (s, 1 H), 3.45 (m, 1 H), 2.32
(s, 3 H), 2.18 (s, 6 H), 2.13 (s, 3 H), 1.55-1.80 (m, 4 H), 0.99
(t, 6 H) ppm.
EXAMPLE 90
N4-(1-Ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diam-
ine
[0638] A mixture of
(1-ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl--
phenoxy)-pyridin-4-yl]-amine (40 mg, 0.112 mmol) and 4 mg of 10%
Pd/C in 10 ml of ethanol was hydrogenated at 50 psi overnight. The
mixture was filtered through Celite.TM. and the filtrate was
concentrated to dryness to give a light brown crystals which were
purified through silica gel column chromatography using 1:1
chloroform:hexane as eluent to give the title compound as golden
crystals (36 mg, 97%), mp 105-107.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 6.88 (s, 2 H), 6.11 (s, 1 H), 4.00 (brs, 1 H),
3.28 (m, 1 H), 3.10 (brs, 2 H), 2.31 (s, 3 H), 2.16 (s, 3 H), 2.10
(s, 6 H), 1.45-1.75 (m, 4 H), 0.98 (t, 6 H) ppm. The corresponding
HCl salt was prepared as white solid, mp 174-178.degree. C.,
.sup.1H NMR(D.sub.2O) .delta. 7.09 (s, 2 H), 6.63 (s, 1 H), 3.65
(m, 1 H), 2.31 (s, 3 H), 2.25 (s, 3 H), 2.11 (s, 6 H), 1.45-1.80
(m, 4 H), 0.91 (t, 6 H) ppm.
EXAMPLE 91
[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-ethyl-
-propyl)-amine
[0639] To a mixture of
(2-chloromethyl-3-nitro-pyridin-4-yl)-(1-ethyl-prop- yl)-amine (850
mg, 3.30 mmol) and 4-chloro-2,6-dimethylphenol (516 mg, 3.30 mmol)
in 25 ml of dry THF was added potassium tert-butoxide (370 mg, 3.30
mmol) and the resulting mixture was stirred at room temperature
overnight. The mixture was quenched with water and extracted with
ethyl acetate. The organic layer was dried and concentrated to give
a yellow solid (1.31 g). The solid was purified through silica gel
column chromatography using 6:4 ratio of chloroform:hexane as
eluent to give 1.10 g (88%) of the title compound as yellow solid,
mp 152-154.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 7.65 (d, 1
H), 7.05 (s, 2 H), 6.21 (s, 1 H), 3.41 (m, 1 H), 2.15 (s, 3 H),
2.11 (s, 6 H), 1.5-1.8 (m, 4 H), 0.99 (t, 6 H) ppm.
EXAMPLE 92
2-(2,6-Dimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyl-pyridine-3,4-diamine
[0640] A mixture of
(1-ethyl-propyl[6-methyl-3-nitro-2-(4-chloro-2,6-dimet-
hyl-phenoxy)-pyridin-4-yl]-amine (800 mg, 2.12 mmol) and 160 mg of
10% Pd/C in 150 ml of ethanol was hydrogenated at 50 psi overnight.
The mixture was filtered through Celite.TM. and the filtrate was
concentrated to dryness to give a purple glass form (810 mg) which
was purified through silica gel column chromatography using 1:1
chloroform:hexane as eluent to give the title compound as tan
crystals (360 mg), mp 98-100.degree. C. .sup.1H NMR (CDCl.sub.3)
.delta. 7.05 (m, 3 H), 6.11 (s, 1 H), 4.00 (brs, 1 H), 3.28 (m, 1
H), 3.09 (brs, 2 H), 2.14 (s, 9 H), 1.45-1.75 (m, 4 H), 0.98 (t, 6
H) ppm. The corresponding HCl salt was prepared as white solid, mp
158-162.degree. C., .sup.1H NMR(D.sub.2O) .delta. 7.27 (s, 3 H),
6.67 (s, 1 H), 3.65 (m, 1 H), 2.27 (s, 3 H), 2.16 (s, 6 H),
1.45-1.80 (m, 4 H), 0.93 (t, 6 H) ppm.
EXAMPLE 93
N4-(1-Ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-tr-
iamine
[0641] A mixture of
N4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimeth-
yl-phenyl)-pyridine-2,4-diamine (40 mg, 0.112 mmol) and 8 mg of 10%
palladium/carbon (Pd/C) in 20 ml of ethanol was hydrogenated at 50
psi overnight. The mixture was filtered through celite and the
filtrate was concentrated to dryness to give adark residue (40 mg).
.sup.1H NMR (CDCl.sub.3) .delta. 6.88 (s, 2 H), 5.97 (s, 1 H), 4.32
(d, 1 H), 3.28 (m, 1 H),2.27 (s, 3 H), 2.26 (s, 3 H), 2.18 (s, 6
H), 1.45-1.75 (m, 4 H), 0.93 (t, 6 H) ppm. The corresponding di-HCl
salt was prepared as a tan solid, mp 213-216.degree. C., .sup.1H
NMR(DMSO-d6) .delta. 11.1 (s, 1 H), 8.48 (s, 1 H), 6.98 (s, 2 H),
6.73 (brs, .sup.1H), 6.38 (s, 1 H), 3.36 (m, 1 H), 2.28 (s, 3 H),
2.19 (s, 3 H), 2.08 (s, 6 H), 1.54 (m, 4 H), 0.88 (t, 6 H) ppm.
EXAMPLE 94
2-(4-Chloro-2,6-dimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyl-pyridine-3,-
4-diamine
[0642] A mixture of
(1-ethyl-propyl)-[6-methyl-3-nitro-2-(4-chloro-2,6-dim-
ethyl-phenoxy)-pyridin-4-yl]-amine (100 mg, 0.265 mmol) and iron
(73 mg, 1.33 mmol) in 12 ml of AcOH/H.sub.2O (1:1) was heated at
60.degree. C. for 3 hours. The mixture was concentrated to dryness.
The residue was diluted with water and extracted with ethyl
acetate. The organic layer was dried and concentrated to give the
title compound. .sup.1H NMR (CDCl.sub.3) .delta. 7.04 (s, 2 H),
6.12 (s, 1 H), 3.60 (brs, 2 H), 3.28 (m, 1 H), 2.14 (s, 3 H), 2.10
(s, 6 H), 1.45-1.80 (m, 4 H), 0.97 (t, 6 H) ppm.
EXAMPLE 95
N-(1-Ethyl-propyl)-2-methyl-5-nitro-N'-(2,4,6-trimethyl-pyridin-3-yl)-pyri-
midine-4,6-diamine
[0643] To a cooled solution of
(6-chloro-2-methyl-5-nitro-pyrimidin-4-yl)--
(2,4,6-trimethyl-pyridin-3-yl)-amine (88 mg, 0.29 mmol) in 1 ml of
dry THF was added 1-ethyl-propyl-amine (80 mg, 0.92 mmol) at
-78.degree. C. The mixture was stirred at that temperature for 3
hrs, then warmed to -10.degree. C. for 1 hour. The mixture was
quenched with water andextracted with ethyl acetate. The organic
layer was dried and concentrated to give the title compound (88 mg,
86%) as an orange solid, mp 151-152.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 9.16 (d, 1 H), 6.92 (s, 1 H), 4.35 (m, 1 H),
2.50 (s, 3 H), 2.39 (s, 3 H), 2.18 (s, 3 H), 2.16 (s, 3 H),
1.5-1.80 (m, 4 H), 0.94 (t, 6 H) ppm.
EXAMPLE 96
(1-Ethyl-propyl)-[2-methyl-5-nitro-6-(2,4,6-trimethyl-pyridin-3-yloxy)-pyr-
imidin-4-yl]-amine
[0644] A solution of 3-hydroxy-2,4,6-trimethylpyridine (41 mg, 0.3
mmol) in 1 ml of dry THF was treated with 60% sodium hydride in oil
(13 mg, 0.3 mmol) at rt. The reaction mixture was cooled to
-78.degree. C. and a solution of
(6-chloro-2-methyl-5-nitro-pyrimidin-4-yly(l-ethyl-propylyami- ne
(78 mg, 0.3 mmol) in 1 ml of dry THF was added. The reaction was
stirred at -78.degree. C for 1 hour, quenched with water and
extracted with ethyl acetate. The organic layer was dried and
concentrated to give 91 mg (84%) of white solid of the title
compound, mp 134-135C. .sup.1H NMR (CDCl.sub.3) .delta. 8.30 (d, 1
H), 6.89 (s, 2 H), 4.30 (m, 1 H), 2.31 (s, 3 H), 2.26 (s, 3 H),
2.10 (s, 6 H), 1.5-1.8 (m, 4 H), 0.97 (t, 6 H) ppm.
EXAMPLE 97
2-(4-Chloro-2,6-dimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyl-pyridine-3,-
4-diamine
[0645] A mixture of
[2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-py-
ridin-4-yl]-(1-ethyl-propyl)-amine (810 mg, 2.14 mmol) and iron
(Fe) (594 mg, 10.72 mmol) in 96 ml of 1:1 of AcOH:H.sub.2O was
heated at reflux for 2 hours. Additional Fe (600 mg) was added. The
mixture was heated for an additional 1.5 hours. The reaction
mixture was concentrated to dryness. The residue was quenched with
water, basified to pH 9.0 and filtered through celite. The filtrate
was extracted with ethyl acetate. The organic layer was washed with
brine, dried and concentrated to give the title compound as a
yellow oil. The oil was purified through silica gel column
chromatography using chloroform as eluent to give 570 mg of
2-(4chloro-2,6-dimethyl-phenoxy)-N
4-(1-ethyl-propyl)-6-methyl-pyridine-3- ,4-diamine as a tan solid,
mp 72-74.degree. C. .sup.1H NMR(CDCl.sub.3) .delta. 7.04(s,2 H),
6.11(s,1 H), 4.03(d,1 H), 3.30(m,1 H), 3.07(s,1 H), 2.14(s,3 H),
2.10(s,6 H), 1.4-1.75(m,4 H), 0.97(t,6 H)ppm. The corresponding
di-HCl salt was prepared as a white solid, mp 208-210.degree.
C.
EXAMPLE 98
N-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3--
yl]-acetamide
[0646] A mixture of
2-(2,4,6-trimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-meth-
yl-pyridine-3,4-diamine (250 mg, 0.763 mmol), acetic anhydride (72
mg, 0.763 mmol) and triethylamine (77 mg, 0.763 mmol) in 5 ml of
methylene chloride was stirred at room temperature for 3 hours. The
mixture was quenched with water and extracted with ethyl acetate.
The organic layer was dried and concentrated to dryness to give 310
mg of the crude material. The crude material was purified through
silica gel column chromatography using 2% methanol in chloroform as
eluent to give 250 mg (89% yield) of
N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phe-
noxy)-pyridin-3-yl]-acetamide as tan solid, mp 154-156.degree. C.
.sup.1H NMR(CDCl.sub.3) .delta. 6.97(0.64 H), 6.86(s,2 H),
6.26(0.36 H), 6.14(o.64 H), 6.12(s,0.36 H), 4.80(d,0.64 H),
4.40(d,0.36 H), 3.2-3.4(m,1 H), 2.29(s,3 H), 2.26(s,1.9 H),
2.17(s,1.1 H), 2.16(s,1.9 H), 2.06(s,6 H), 1.99(s,1.1 H),
1.4-1.75(m,4 H), 0.97(t,6 H)ppm.
EXAMPLE 99
N-[2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyri-
din-3-yl]-acetamide
[0647] The title compound (35 mg) was isolated as a side product
from the reduction experiment described in the Example 97. Compound
can be prepared by standard acylation method by reacting
2-(4-chloro-2,6-dimethy-
l-phenoxy)-N4-(1-ethyl-propyl)-6-methyi-pyridine-3,4-diamine with
acetic anhydride and triethylamine in methylene chloride. A tan
solid was prepared, mp 161-164.degree. C. .sup.1H NMR(CDCl.sub.3)
.delta. 7.04(s,2 H), 6.88(s,0.6 H), 6.26(s,0.4 H), 6.15(s,1 H),
4.75(d,0.6 H), 4.40(d,0.4 H), 3.30(m,1 H), 2.27(s,1.8 H), 2.15(s,3
H), 2.06(s,6 H), 1.98(s,1.2 H), 1.4-1.8(m,4 H), 0.97(t,6 H)ppm.
EXAMPLE 100
1-Ethyl-3-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-py-
ridin-3-yl]-urea
[0648] .sup.1H NMR(CDCl.sub.3) .delta. 6.85(s,2 H), 6.11(s,1 H),
5.38(s,1 H), 4.68(s,1 H), 4.65(m,1 H), 3.2-3.4(m,3 H), 2.28(s,3 H),
2.16(s,3 H), 2.08(s,6 H), 1.4-1.7(m,4 H), 1.10(t,3 H), 0.93(t,6
H)ppm.
EXAMPLE 101
N-[4-Ethyl-propyl)-2-methyl-N"-(2,4,6-trimethyl-pyridin-3-yl)-pyrimidine-4-
,5,6-triamine
[0649] The title compound was prepared by hydrogenation of
N-(1-ethyl-propyl)-2-methyl-5-nitro-N"-(2,
4,6-trimethyl-pyridin-3-yl)-py- rimidine-4,6-diamine by the method
analogous to that described in Example 93. .sup.1H NMR(CDCl.sub.3)
.delta. 6.9(s,1 H), 6.25(brs,1 H), 4.7(d,1 H), 4.08(m,1 H), 2.5(s,3
H), 2.45(s,3 H), 2.30(s,3 H), 2.20(s,3 H), 1.45-1.7(m,4 H),
0.98(t,6 H) ppm.
EXAMPLE 102
N4-(1-Ethyl-propyl)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine-4,5-di-
amine
[0650] The title compound was prepared by hydrogenation of
(1-ethyl-propyl)-[2-methyl-5-nitro-6-(2,
4,6-trimethyl-phenoxy)-pyrimidin- -4-yl]-amine by the method
analogous to that described in Example 93. .sup.1H NMR(CDCl.sub.3)
.delta. 6.88(s,2 H), 4.52(d,1 H), 4.10(m,1 H), 2.94(brs,2 H),
2.30(s,3 H), 2.23(s,3 H), 2.09(s,6 H), 1.4-1.8(m,4 H), 0.95(t,6 H)
ppm. The corresponding HCl salt, mp 248-250.degree. C. .sup.1H
NMR(CD.sub.3OD) .delta. 6.91(s,2 H), 4.00(m,1 H), 2.39(s,3 H),
2.28(s,3 H), 2.07(s,6 H), 1.6-1.8(m,4 H), 1.00(t,6 H) ppm.
EXAMPLE 103
[6-(1-Ethyl-propoxy)-2-methyl-5-nitro-pyrimidin-4-yl]-(2,4,6-trimethyl-phe-
nyl)-amine
[0651] A mixture of 3-pentanol (0.5 ml) and 60% sodium hydride
(NaH) in oil (89 mg, 2.22 mmol) in 2 ml of dry THF was stirred for
2 min, then treated with a solution of
6-(chloro-2-methyl-5-nitropyrimidin-4-yl)-(2,4-
,6-trimethylphenyl)-amine (350 mg, 1.14 mmol) in 3 ml of dry THF at
-78.degree. C. and stirred at that temperature for 1 hour, then
stirred at room temperature overnight. The mixture was quenched
with water and extracted with ethyl acetate. The organic layer was
dried and concentrated to give the crude material which was
purified through silica gel column chromatography using 2:1 of
hexane/CHCl.sub.3 as eluent to give 331 mg (85%) of the title
compound as a yellow solid, mp 112-113.degree. C. .sup.1H
NMR(CDCl.sub.3) .delta. 9.48(brs,1 H), 6.49(s,2 H), 5.37(m,1 H),
2.33(s,3 H), 2.29(s,3 H), 2.18(s,6 H), 1.7-1.9(m,4 H), 0.99(t,6 H)
ppm.
EXAMPLE 104
N-(1-Ethyl-propyl)-2-methyl-5-nitro-N'-(2,4,6-trimethyl-phenyl)-pyrimidine-
-4,6-diamine
[0652] The title compound was prepared by the method analogous to
that described in Example 5 using 1-ethylpropylamine. .sup.1H
NMR(CDCl.sub.3) .delta. 10.48(s,1 H), 9.25(d,1 H), 6.94(s,2 H),
4.37(m,1 H), 2.32(s,3 H), 2.21(s,3 H), 2.18(s,6 H), 1.5-1.8(m,4 H),
0.97(t,6 H) ppm.
EXAMPLE 105
6-(1-Ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-di-
amine
[0653] The title compound was prepared by the method analogous to
that described in Example 93 starting from
[6-(1-ethyl-propoxy)-2-methyl-5-nit-
ro-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine. .sup.1H
NMR(CDCl.sub.3) .delta. 6.92(s,2 H), 5.96(s,1 H), 5.12(m,1 H),
2.85(brs,1 H), 2.31(s,3 H), 2.30(s,3 H), 2.19(s,6 H), 1.70(m,4 H),
0.94(t,6 H) ppm.
EXAMPLE 106
6-(1-Ethyl-propoxy)-2-methyl-5-nitro-pyrimidin-4-yl]-(2,4,6-trimethyl-pyri-
din-3-yl)-amine
[0654] The title compound was prepared by the method analogous to
that described in Example 103 starting from
(6-chloro-2-methyl-5-nitropyrimidi-
n-4-yl)-(2,4,6-trimethyl-pyridin-3-yl)-amine and sodium
3-pentanoxide. .sup.1H NMR(CDCl.sub.3) .delta. 9.45(s,1 H),
6.95(s,1 H), 5.35(m,1 H), 2.53(s,3 H), 2.41(s,3 H), 2.29(s,3 H),
2.18(s,3 H),1.7-1.9(m,4 H), 0.98(t,6 H) ppm.
EXAMPLE 107
N-(1-Ethyl-propyl)-2-methyl-N"-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5,6-t-
riamine
[0655] The title compound was prepared by the method analogous to
that described in Example 93 starting from
N-(1-ethyl-propyl)-2-methyl-5-nitro-
-N'-(2,4,6-trimethyl-phenylpyrimidine-4,6-diamine. .sup.1H
NMR(CDCl.sub.3) .delta. 6.90(s,2 H), 6.10(s,1 H), 4.78(d,1 H),
4.03(m,1 H), 2.31(s,3 H), 2.29(s,3 H), 2.20(s,6 H), 1.4-1.6(m,4 H),
0.91 (t,6 H) ppm.
EXAMPLE 108
6-(1-Ethyl-propoxy)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin--
6-one
[0656] A mixture of
6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-pheny-
l)-pyrimidine-4,5-diamine (182 mg, 0.554 mmol), triethylamine (39
mg, 0.388 mmol) and triphosgene (58 mg, 0.196 mmol) in 6 ml of dry
THF was stirred at room temperature for 30 min. The mixture was
quenched with water and extracted with chloroform. The organic
layer was dried and concentrated to give 177 mg (90%) of the title
compound as a white solid, mp 159-160.degree. C. .sup.1H
NMR(CDCl.sub.3) .delta. 8.50(s,1 H), 6.99(s,2 H), 5.30(m,1 H),
2.47(s,3 H), 2.32(s,3 H), 2.08(s,6 H), 1.73(m,4 H), 0.94(t,6 H)
ppm.
EXAMPLE 109
6-(1-Ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-pyridin-3-yl)-pyrimidine--
4,5-diamine
[0657] The title compound was prepared by the method analogous to
that described in Example 93 starting from
6-(1-ethyl-propoxy)-2-methyl-5-nitr-
o-pyrimidin-4-yl]-(2,4,6-trimethyl-pyridin-3-yl)-amine. .sup.1H
NMR(CDCl.sub.3) .delta. 6.89(s,1 H), 5.97(s,1 H), 5.29(m,1 H),
2.90(brs,1 H), 2.48(s,3 H), 2.41(s,3 H), 2.26(s,3 H), 2.17(s,3 H),
1.68(m,4 H), 0.93(t,6 H)popm.
EXAMPLE 110
6-(1-Ethyl-propylamino)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-pu-
rin-8-one
[0658] The title compound was prepared by the method analogous to
that described in Example 108 starting from
N-(1-ethyl-propyl)-2-methyl-N'-(2,-
4,6-trimethyl-phenyl)-pyrimidine-4,5,6-triamine. .sup.1H
NMR(CDCl.sub.3) .delta. 6.59(s,2 H), 5.28(d,1 H), 3.92(m,1 H),
2.40(s,3 H), 2.32(s,3 H), 2.08(s,6 H), 1.25-1.45(m,4 H), 0.80(t,6
H)ppm.
EXAMPLE 111
[0659]
N4-(1-Ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-p-
yridine-3,4-diamine and
N4-(1-Ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimeth-
yl-phenoxy)-pyridine-3,4-diamine
[0660] To a solution of
N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-ph-
enoxy)-pyridine-3,4-diamine (0.250 g, 0.763 mmol) in dry THF (6 ml)
was treated with 1M LiN(SiMe.sub.3).sub.2 in THF (1.0 ml, 1.0 mmol)
at -78.degree. C. and stirred for 10 min. an excess of methyl
iodide was added and the resulting mixture was stirred at room
temperature overnight. The mixture was quenched with water and
extracted with ethyl acetate. The organic layer was dried and
concentrated to give a crude material. The crude material was
purified through silica gel column chromatography using 5% ethyl
acetate in hexane as eluent to give
N4-(1-ethyl-propyl)-6,N3,N3-trimethyl-2-(2,
4,6-trimethyl-phenoxy)-pyridi- ne-3,4-diamine and
N4-(1-ethyl-propyl)-6,N3-dimethyl-2-(2,
4,6-trimethyl-phenoxy)-pyridine-3,4-diamine.
[0661]
N4-(1-Ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-p-
yridine-3,4-diamine: .sup.1H NMR(CDCl.sub.3) .delta. 6.88(s,2 H),
6.02(s,1 H), 5.55(d,1 H), 3.21(m,1 H), 2.79(s,6 H), 2.30(s,3 H),
2.10(s,3 H), 2.09(s,6 H), 1.4-1.75(m,4 H), 0.95(t,6 H) ppm.
[0662]
N4-(1-Ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyrid-
ine-3,4-diamine: .sup.1H NMR(CDCl.sub.3) .delta. 6.89(s,2 H),
6.10(s,1 H), 4.84(d,1 H), 3.30(m,1 H), 2.98(s,1 H), 2.72(s,3 H),
2.32(s,3 H), 2.16(s,3 H), 2.12(s,6 H), 1.45-1.70(m,4 H), 0.99(t,6
H) ppm.
EXAMPLE 112
N4-(1-Ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyrimidine-3chlor-
o-4-amine
[0663] The title compound was prepared by the method analogous to
those of Examples 33-39 starting from
3,4-dichloro-6methyl-2-(2,4,6-trimethyl-phen- oxy)-pyrimidine and
1-ethyl-propylamine. .sup.1H NMR(CDCl.sub.3) .delta. 6.87(s,2 H),
4.97(d,1 H), 4.12(m,1 H), 2.30(s,3 H), 2.25(s,3 H), 2.10(s,6 H),
1.4-1.8(m,4 H), 0.96(t,6 H) ppm.
EXAMPLE 113
Butyl-(2,8-dimethyl-9-(2,4,6-trimethyl-phenyl)-9H-purin-6-yl)-ethyl-amine
[0664] A mixture of
N-butyl-N-ethyl-2-methyl-N'-(2,4,6-trimethylphenyl)-py- rimidine-4,
5,6-triamine (105 mg, 0.63 mmol) and triethyl orthoacetate (0.204
g,1.25 mmol) and 10 mg of p-TsOH in toluene was heated reflux
overnight. The mixture was concentrated to dryness and the residue
was quenched with water and extracted with ethyl acetate. The
organic layer was dried and concentrated to give yellow oil. The
oil was purified through silica gel column chromatography using 1:1
of hexane:chloroform as eluent to give the title compound. .sup.1H
NMR(CDCl.sub.3) .delta. 7.01(s,2 H), 3.9-4.1(m,4 H), 2.45(s,3 H),
2.35(s,3 H), 2.20(s,3 H), 1.91(s,6 H), 1.6-1.8(m,2 H), 1.35-1.5(m,2
H), 1.29(t,3 H), 0.99(t,3 H) ppm.
EXAMPLE 114
[0665] The compounds below were prepared by reacting of
(2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(alkyl- or dialkyl)-amine
with substituted phenol by a method analogous to the following: To
a mixture of (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(alkyl- or
dialkyl)-amine (1 mmol) and 2,4,6-trimethylphenol (1 mmol) in dry
THF was added potassium tert-butoxide (1 mmol) and the resulting
mixture was stirred at room temperature until all starting material
was consumed. The mixture was quenched with water and extracted
with ethyl acetate. The organic layer was dried and concentrated to
give the title compound after purification through silica gel
column chromatography:
[0666]
2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-(S)-
-ylamino]-butan-1-ol
[0667] 1H NMR(CDCl.sub.3) d 7.69(,1 H), 6.289s,1 H), 3.65-3.80(m,2
H), 3.60(m,1 H), 2.12(s,3 H), 2.08(s,6 H), 1.8(brs,1 H),
1.5-1.8(m,2 H), 1.01(t,3 H) ppm.
[0668] (1
-Methoxymethyl-propyl)-[6-methyl-3-nitro-2-(4-trifluoromethoxy-p-
henoxy) pyridin-4-yl]-amine
[0669] yellow solid, mp. 75-76.degree. C., Anal. For
C.sub.18H.sub.20N.sub.3O.sub.5F.sub.3, calc. C52.05; H, 4.85; N,
10.12; found, C, 52.14; H, 5.04; N, 10.13
[0670]
2-(2-Amino-4,6-dichloro-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1--
methoxymethyl-propyl)-amine
[0671] 1H NMR (CDCl.sub.3) d 9.55(d,1 H), 7.23(d,1 H), 7.00(d,1 H),
6.05(s,1 H), 3.69(m,1 H), 3.49(m,2 H), 3.38(s,3 H), 2.35(s,3 H),
1.78(m,1 H), 1.65(m,1 H), 0.99(t,3 H) ppm.
[0672]
3-Methoxy-2-[4-(1-methoxymethyl-propylamino)-6-methyl-3-nitro-pyrid-
in-2-yloxy]-benzaldehyde
[0673] yellow solid, mp. 126.5-130.5.degree. C., Anal. For
C.sub.19H.sub.23N.sub.3O.sub.6, calc. C58.60; H, 5.95; N, 10.79;
found, C, 58.45; H, 6.11; N, 10.32
[0674]
[2-(2,6-Dibromo-4-trifluoromethoxy-phenoxy)-6-methyl-3-nitro-pyridi-
n-4-yl]-( 1 -methoxymethyl-propyl)-amine
[0675] yellow solid, 1H NMR(CDCl.sub.3) d 8.00(d,1 H), 7.49(,2 H),
6.35(s,1 H), 3.64(m,1 H), 3.53(m,2 H), 3.43(s,3 H), 2.20(s,3 H),
1.6-1.9(m,4 H), 1.04(t,3 H)ppm.
[0676]
[2-(2-Bromo-4-chloro-6-methoxy-phenoxy)-6-methyl-3-nitro-pyridin-4--
yl]-(1-methoxymethyl-propyl)-amine
[0677] yellow solid, mp. 111.8-113.6.degree. C., Anal. For
C.sub.15H.sub.21N.sub.3O.sub.5BrCl, calc, C, 45.54; H, 4.46; N,
8.85; found, C, 45.94; H, 4.32; N, 8.68
[0678]
[2-(2,4-Dichloro-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxy-
methyl-propyl)-amine
[0679] 1H NMR (CDCl.sub.3) d 7.183(d,1 H), 7.46(d,1 H), 7.30(dd,1
H), 7.15(dd,1 H), 6.33(s,1 H), 3.65(m,1 H), 3.51(m,2 H), 3.42(s,3
H), 2.21(s,3 H), 1.82(m,1 H), 1.66(m,1 H), 1.03(t,3 H) ppm.
[0680]
[2-(2-Bromo-6-chloro-4-methoxy-phenoxy)-6-methyl-3-nitro-pyridin-4--
yl]-(1-methoxymethyl-propyl)-amine
[0681] 1H NMR(CDCl.sub.3) d 7.88(d,1 H), 7.04(d,1 H), 6.93(d,1 H),
6.27(s,1 H), 3.79(s,3 H), 3.60(m,1 H), 3.4-3.5(m,2 H), 3.38(s,3 H),
2.15(s,3 H), 1.78(m,1 H), 1.64(m,1 H), 0.99(t,3 H)
[0682]
(1-Methoxymethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethoxy-phen-
oxy)-pyridin-4-yl]-amine
[0683] mp. 126.8-129.5.degree. C.; Anal. For
C.sub.20H.sub.27N.sub.3O.sub.- 7 calc. C, 57.00; H, 6.46; N, 9.97;
found C, 56.94; H, 6.85; N, 9.66.
EXAMPLE 115
2-Chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-p-
yridin-3-yl]-acetamide
[0684] To a solution of
N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-ph-
enoxy)-pyridine-3,4-diamine (250 mg, 0.763 mmol) in dry THF was
added chloroacetyl chloride (86 mg, 0.763 mmol) and triethylamine
(77 mg, 0.763 mmol) at 0.degree. C. The resulting mixture was
warmed to room temperature and stirred for 1 hr. The mixture was
quenched with water and extracted with ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate, filtered, and
concentrated to dryness to give the title compound as a solid. The
solid was purified through silica gel column chromatography to give
280 mg(91%) of tan crystals, mp. 152-154.degree. C.
[0685] 1H NMR(CDCl.sub.3) d 8.07(brs,1 H), 6.88(s,2 H), 6.16(s,1
H), 4.75(m,1 H), 4.25(s,2 H), 3.33(m,1 H), 2.30(s,3 H), 2.18(s,3
H), 2.08(s,6 H), 1.4-1.75(m,4 H), 0.97(t,6 H) ppm.
[0686] The following compounds were prepared by an analogous method
to that in the preceding paragraph:
[0687]
3-Chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phe-
noxy)-pyridin-3-yl]-propionamide
[0688] tan solid,mp. 183-185.degree. C. Anal. For
C.sub.23H.sub.32ClN.sub.- 3O.sub.2 calc, C, 66.09; H, 7.72; N,
10.05; found, C, 66.27; H, 7.87; N, 9.99.
[0689]
2-Chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phe-
noxy)-pyridin-3-yl]-propionamide
[0690] mp. 170-172.degree. C., Anal. For
C.sub.23H.sub.32ClN.sub.3O.sub.2 calc. C, 66.09; H, 7.72; N, 10.05;
found C, 66.20; H, 7.52; N, 10.09.
EXAMPLE 116
N3-Allyl-N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-
-3,4-diamine
[0691] To a solution of
N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-ph-
enoxy)-pyridine-3,4-diamine (500 mg, 1.52 mmol) in dry THF was
added 1 M in THF of lithium bis(trimethylsilyl)amide (1.6 ml, 1.6
mmol) at -78.degree. C., After stirring at -78.degree. C. for 10
min, allyl bromide (0.13 ml, 1.52 mmol) was added and the resulting
mixture was stirred at that temperature for 20 min, then warmed to
room temperature overnight. The mixture was quenched with water and
extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate, filtered, and concentrated to dryness to
give the title compound as a green-blue oil. The oil was purified
through silica gel column chromatography using 5% ethyl acetate in
hexane as eluent to give a yellow crystal, mp. 86-88.degree. C.
[0692] 1H NMR(CDCl.sub.3) d 6.87(s,2 H), 6.0(m,2 H), 5.2-5.35(m,2
H), 4.8(d,1 H), 3.54(d,2 H), 3.3(m,1 H), 3.05(s,1 H), 2.30(s,3 H),
2.14(s,3 H), 2.09(s,6 H), 1.4-1.6(m,4 H), 0.96(t,6 H) ppm.
[0693] The following compounds were prepared by an analogous
method:
[0694]
N3-(3-Chloro-propyl)-N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-pyridine-3,4-diamine
[0695] 1H NMR(CDCl.sub.3) d 6.85(s,2 H), 6.05(s,1 H), 4.9(d,1 H),
3.8(m,2 H), 3.3(m,1 H), 3.1(m,2 H), 2.3(s,3 H), 2.159s,3 H),
2.04(s,6 H), 1.79m,2 H), 1.5(m,2 H), 1.0(m,6 H) ppm.
[0696]
N4-(1-Ethyl-propyl)-6-methyl-N3-propa-1,2-dienyl-2-(2,4,6-trimethyl-
-phenoxy)-pyridine-3,4-diamine
[0697] 1H NMR(CDCl.sub.3) d 8.93(d,1 H), 6.86(s,2 H), 6.66(m,1 H),
6.09(s,1 H), 5.4-5.6(m,2 H), 5.54(d,1 H), 3.27(m,1 H), 2.27(s,3 H),
2.12(s,3 H), 2.05(s,6 H), 1.6(m,4 H), 0.94(t,6 H) ppm.
EXAMPLE 117
2-[3-Amino-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamin-
o]-butan-1-ol
[0698] A mixture of
2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-nitro--
pyridin-4-(S)-ylamino]-butan-1-ol (120 mg) and Fe (73 mg) in 12 ml
of 1:1 of AcOH:H2O was heated at reflux for 2 hr. The reaction
mixture was to dryness. The residue was quenched with water,
basified to pH 12 and filtered through celite. The filtrate was
extracted with chloroform. The organic layer was washed with brine,
dried and concentrated to give the title compound as a yellow
solid. The solid was purified through silica gel column
chromatography using 1:1 EtOAc:hexane as eluent to give the title
compound as a white solid, mp. 161-162.degree. C.
[0699] 1H NMR(CDCl.sub.3) d 7.03(s,2 H), 6.15(s,1 H), 3.75(m,2 H),
3.47(m,1 H), 2.25(brs,3 H), 2.08(s,6 H), 1.5-1.8(m,2 H), 0.98t,3 H)
ppm
EXAMPLE 118
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotin-
ic acid methyl ester
[0700] A mixture of
4chloro-6-methyl-2-(4-Chloro-2,6-dimethyl-phenoxy)-nic- otinic acid
methyl ester (77 mg, 0.226 mmol) and 1-ethyl-propyl-amine in DMSO
was heated at 120.degree. C. for 4 hr. The mixture was quenched
with sat. ammonium chloride, water, brine and extracted with ethyl
acetate. The organic layer was dried and concentrated to give 140
mg of yellow solid. 1HNMR(CDCl.sub.3) d 8.10(d,1 H), 7.03(s,2 H),
6.09(s,1 H), 3.88(s,3 H), 3.35(m,1 H), 2.10(s,3 H), 2.08(s,6 H),
1.5-1.7(m,4 H), 0.96(t,6 H) ppm.
EXAMPLE 119
2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotini-
c acid methyl ester
[0701] A mixture of
4-chloro-6-methyl-2-(4-bromo-2,6-dimethyl-phenoxy)-nic- otinic acid
methyl ester and 1-ethyl-propyl-amine in DMSO was heated at
120.degree. C. for 16 hr. The mixture was quenched with water,
brine and extracted with ethyl acetate. The organic layer was dried
and concentrated to dryness. The residue was purified through
silica gel column chromatography using hexane to 3% ethyl acetate
in hexane as eluent to give the title compound as a white solid. 1H
NMR(CDCl.sub.3) d 8.1(d,1 H), 7.18(s,2 H), 6.08(s,1 H), 3.87(s,3
H), 3.35(m,1 H), 2.10(s,3 H), 2.08(s,6 H), 1.4-1.7(m,4 H), 0.96(t,6
H) ppm.
EXAMPLE 120
4-(1-Ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotini-
c acid methyl ester
[0702] A mixture of
4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotini- c acid
methyl ester and 1-ethyl-propyl-amine in DMSO was heated at
130.degree. C. overnight. The mixture was quenched with water,
brine and extracted with ethyl acetate. The organic layer was dried
and concentrated to dryness. The residue was purified through
silica gel column chromatography to give the title compound. 1H
NMR(CDCl.sub.3) d 8.26(d,1 H), 6.87(s,2 H), 6.26(s,1 H), 4.11(m,1
H), 3.87(s,3 H), 2.324(m, 1 H), 2.30(s,3 H), 2.17s,3 H), 2.08(s,6
H), 1.92(q,2 H), 1.16(t,3 H) ppm.
EXAMPLE 121
4-(s)-(1-Hydroxymethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-n-
icotinic acid methyl ester
[0703] A mixture of
4-chloro-2-(2,4,6-trimethyl-phenoxy)-6-methyl-nicotini- c acid
methyl ester (500 mg, 1.56 mmol) and (S)-2-amino-1-butanol (696 mg,
7.82 mmol) in DMSO was heated in 130.degree. C. oil bath for 24 hr.
The mixture cooled to rt and quenched with water and extracted with
ethyl acetate. The organic layer was separated, washed with water,
dried over anhydrous sodium sulfate, filtered, and concentrated to
dryness to give 610 mg of crude product as an oil. The oil was
purified through silica gel column chromatography using 30% ethyl
acetate in hexane as eluent to give the title compound. Anal. calc.
for C.sub.21H.sub.28N.sub.2O.sub.4. 1/2H.sub.2O: C, 66.11; H, 7.66;
N, 7.34; found: C, 66.27; H, 7.60; N, 7.21.
EXAMPLE 122
4-(1-Ethyl-2-hydroxy-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nic-
otinic acid methyl ester
[0704] A mixture of
4-chloro-2-(2,4,6-trimethyl-phenoxy)-6-methyl-nicotini- c acid
methyl ester (250 mg, 0.78 mmol) and 3-amino-pentan-2-ol (320 mg,
3.13 mmol) in DMSO was heated in 130.degree. C. oil bath for 24 hr.
The mixture cooled to rt and quenched with water and extracted with
ethyl acetate. The organic layer was separated, washed with water,
dried over anhydrous sodium sulfate, filtered, and concentrated to
dryness to give 280 mg of crude product as an oil. The oil was
purified through silica gel column chromatography using 20% ethyl
acetate in hexane as eluent to give the title compound as a yellow
solid, mp 116-120.degree. C.
[0705] 1H NMR(CDCl3) d 8.17(m,1 H), 6.87(s,2 H), 6.21&6.14(two
s, 1 H), 3.88(s,3 H), 3.8-4.0(m,2 H), 3.5(m,1 H), 3.3(m,1 H),
2.30(s,3 H), 2.12(s,3 H), 2.09(s,6 H), 1.8(d,1 H), 1.5-1.8(m,2 H),
1.26(d,3 H), 0.99(t,3 H) ppm.
EXAMPLE 123
2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-met-
hyl-nicotinic acid methyl ester
[0706] A mixture of
4-chloro-2-(4-bromo-2,6-trimethyl-phenoxy)-6-methyl-ni- cotinic
acid methyl ester (850 mg) and (S)-2-amino-1-butanol in DMSO was
heated in 130.degree. C. oil bath for 24 hr. The mixture cooled to
rt and quenched with water and extracted with ethyl acetate. The
organic layer was separated, washed with water, dried over
anhydrous sodium sulfate, filtered, and concentrated to dryness to
give 764 mg of crude product as an oil. The oil was purified
through silica gel column chromatography to give the title
compound. 1H NMR (CDCl.sub.3) d 8.15(d,1 H), 7.16(s,2 H), 6.18(s,1
H), 3.86(s,3 H), 3.72(m,1 H), 3.70(m,1 H), 3.54(m,1 H), 2.10(s,3
H), 2.06(s,6 H), 1.5-1.8(m,2 H), 1.00(t,3 H) ppm.
EXAMPLE 124
2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-methoxymethyl-propylamino)-6-met-
hyl-nicotinic acid methyl ester
[0707] A mixture of
4-chloro-2-(4-bromo-2,6-trimethyl-phenoxy)-6-methyl-ni- cotinic
acid methyl ester and 1-methoxymethyl-propylamine in DMSO was
heated in 130.degree. C. oil bath for 24 hr. The mixture cooled to
rt and quenched with water and extracted with ethyl acetate. The
organic layer was separated, washed with water, dried over
anhydrous sodium sulfate, filtered, and concentrated to dryness to
give crude product. The cude compound was purified through silica
gel column chromatography to give the title compound.
EXAMPLE 125
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-
-nicotinic acid methyl ester
[0708] A mixture of
4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-ni- cotinic
acid methyl ester (9.000 g, 26.45 mmol) and (S)-2-amino-1-butanol
(12.7 ml) in 1-methyl-2-pyrrolidinone was heated at 130.degree. C.
for 2 hr, then at 100.degree. C. overnight. The mixture cooled to
rt and poured into ice-water and diluted with ethyl acetate. The
organic layer was separated, washed with water, dried over
anhydrous sodium sulfate, filtered, and concentrated to dryness to
give 13.6 g of crude product as a light yellow oil. The oil was
purified through silica gel column chromatography using chloroform
to 2% MeOH in chloroform as eluent to give 6.6839 g (64%) of the
title compound as a white glass foam. The glass foam was triturated
with hexane to give a white solid. The solid was recrystallized
from di-iso-propyl ether to give a white crystals, mp
122.5-124.degree. C. Anal. calc. for
C.sub.20H.sub.25ClN.sub.2O.sub.4: C, 61.14; H, 6.41; N, 7.13;
found: C, 60.98; H, 6.43; N, 6.95.
EXAMPLE 126
2-(4-Chloro-2-methoxy-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methy-
l-nicotinic acid methyl ester
[0709] A mixture of
4-chloro-2-(4-Chloro-2-methoxy-phenoxy)-6-methyl-nicot- inic acid
methyl ester and (S)-2-amino-1-butanol in 1-methyl-2-pyrrolidinone
was heated at 130.degree. C. overnight. The mixture cooled to room
temperature and poured into ice-water and diluted with ethyl
acetate. The organic layer was separated, washed with water, dried
over anhydrous sodium sulfate, filtered, and concentrated to
dryness. The residue was purified through silica gel column
chromatography to give the title compound as a solid mp.
92.8-93.8.degree. C., Anal. For C.sub.19H.sub.23N.sub.2O.sub.5Cl
calc. C, 57.80; H, 5.87; 7.09; found, C, 57.70; H, 5.89; 7.02.
EXAMPLE 127
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-meth-
yl-nicotinic acid methyl ester
[0710] A mixture of
4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-ni- cotinic
acid methyl ester (500 mg, 1.47 mmol) and 3-amino-pentan-2-ol (758
mg, 7.35 mmol) in 1-methyl-2-pyrrolidinone was heated in
130.degree. C. oil bath for 24 hr. The mixture cooled to rt and
quenched with water and extracted with ethyl acetate. The organic
layer was separated, washed with water, dried over anhydrous sodium
sulfate, filtered, and concentrated to dryness to give an oil. The
oil was purified through silica gel column chromatography using 20%
ethyl acetate in hexane as eluent to give the title compound as a
white crystal, mp 133-135.degree. C.
[0711] 1H NMR(CDCl.sub.3) d 8.19(m,1 H), 7.00(s,2 H),
6.20&6.14(two sets of s,1 H), 3.8-3.9(m,1 H), 3.86(s,3 H),
3.3&3.5(two sets of m,1 H), 2.07(s,3 H), 2.06(s,6 H), 1.75(m,1
H), 1.55(m,1 H), 1.24(d,3 H), 0.96(t,3 H)ppm.
EXAMPLE 128
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methoxy-propylamino)-6-meth-
yl-nicotinic acid methyl ester
[0712] To a solution of
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hyd-
roxy-propylamino)-6-methyl-nicotinic acid methyl ester (50 mg,
0.123 mmol) in dry THF was added NaH and stirred for 20 min. An
excess of MeI was added and the resulting mixture was stirred at rt
overnight. The mixture cooled to rt and quenched with water and
extracted with ethyl acetate. The organic layer was separated,
washed with water, dried over anhydrous sodium sulfate, filtered,
and concentrated to dryness to give an oil. The oil was purified
through silica gel column chromatography using 20% ethyl acetate in
hexane asan eluent to give the title compound as a clear oil. 1H
NMR(CDCl3) d 8.20(d,1 H), 7.00(s,2 H), 6.14&6.10(two sets of
s,1 H), 3.859s,3 H), 3.47(m,1 H), 3.39&3.37(two sets of s,3 H),
2.08(s,3 H), 2.06(s,6 H), 1.75(m,1 H), 1.58(m,1 H), 1.14(t,3 H),
0.95(t,3 H)ppm.
EXAMPLE 129
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-n-
icotinic acid methyl ester
[0713] The title compound was prepared by Dess-Martin oxidation of
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-met-
hyl-nicotinic acid methyl ester. A white solid was obtained after
silica gel column chromatography. 1H NMR(CDCl.sub.3) d 8.6(d,1 H),
7.01(s,2 H), 5.899s,1 H), 3.9-4.0(m,1 H), 3.90(s,3 H), 2.17(s,3 H),
2.07(s,3 H), 2.05(s,3 H), 1.859m,1 H), 1.93(m, 1 H), 1.00(t,3 H)
ppm.
EXAMPLE 130
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicoti-
nic acid methyl ester
[0714] The title compound was prepared by Dess-Martin oxidation of
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methy-
l-nicotinic acid methyl ester. The title compound was obtained
after column chromatography. 1H NMR (CDCl3) 9.54(d,1 H), 8.56(d,1
H), 7.01(s,2 H), 5.93(s,1 H), 3.92(m,1 H), 3.89(s,3 H), 2.08(s,3
H), 2.05(s,6 H), 1.05(t,3 H) ppm.
EXAMPLE 131
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(4-ethyl-2-oxo-oxazolidin-3-yl)-6--
methyl-nicotinic acid methyl ester
[0715] A mixture of
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-p-
ropylamino)-6-methyl-nicotinic acid methyl ester (106 mg, 0.27
mmol) , triphosgene )27 mg, 0.090 mmol), triethylamine (27 mg, 0.27
mmol) in dry THF was stirred at room temperature for 2 hr. The
mixture was quenched with water and extracted with ethyl acetate.
The organic layer was separated, washed with water, dried over
anhydrous sodium sulfate, filtered, and concentrated to dryness to
give 13.6 g of crude product as a white glass foam. The foam was
triturated with hexane/diethyl ether to give a white solid, mp.
144-145.5.degree. C., Anal. For C.sub.21H.sub.23ClN.sub.2O.sub.5
calc.: C, 60.22; H, 5.53; N, 6.69; found: C, 60.10, H, 5.79; N,
6.66.
EXAMPLE 132
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-[(2-hydroxy-ethylamino)-methyl]-
-propylamino)-6-methyl-nicotinic acid methyl ester
[0716] To a solution of
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-prop-
ylamino)-6-methyl-nicotinic acid methyl ester in dichloroethane was
added 2-amino-ethanol, sodium cyanoborohydride, acetic acid,
anhydrous sodium sulfate. The resulting mixture was heated at
reflux and cooled to rt. The mixture was quenched with water and
extracted with chloroform. The organic layer was separated, washed
with water, dried over anhydrous sodium sulfate, filtered, and
concentrated to dryness. After chromatography, the title compound
was obtained as a white glass foam. 1H NMR(CDCl.sub.3) d 8.3(d,1
H), 7.0(s,2 H), 6.1(s,1 H), 3.9(s,3 H), 3.64(m,2 H), 3.57(m,1 H),
2.90(m,2 H), 2.83(m,2 H), 2.5(brs,2 H), 2.09(s,3 H), 2.06(s,6 H),
1.65(m,2 H), 0.97(t,3 H) ppm.
EXAMPLE 133
4-[Ethyl-(2-hydroxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nic-
otinic acid methyl ester
[0717] A mixture of
4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotini- c acid
methyl ester and 1-ethyl-propyl-amine in 1-methyl-2-pyrrolidinone
was heated at 130.degree. C. until starting material was consumed.
The mixture was quenched with water, brine and extracted with ethyl
acetate. The organic layer was dried and concentrated to dryness.
The residue was purified through silica gel column chromatography
to give the title compound. 1H NMR(CDCl.sub.3) d 6.85(s,2 H),
6.40(s,1 H), 3.88(s,3 H), 3.73(t,2 H), 3.43(t,2 H), 3.31(q,2 H),
2.27(s,3 H), 2.22(s,3 H), 2.06(s,6 H), 1.15(t,3 H) ppm.
EXAMPLE 134
4-[Ethyl-(2-methanesulfonyloxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-p-
henoxy)-nicotinic acid methyl ester
[0718] A mixture of
4-[ethyl-(2-hydroxy-ethyl)-amino]-6-methyl-2-(2,4,6-tr-
imethyl-phenoxy)-nicotinic acid methyl ester, methanesulfonyl
chloride and triethylamine in methylene chloride was stirred at rt
until all starting material were consumed. The mixture was quenched
with water, brine and extracted with methylene chloride. The
organic layer was dried and concentrated to dryness. The residue
was purified through silica gel column chromatography to give the
title compound. 1H NMR(CDCl.sub.3) d 6.83(s,2 H), 6.25(s,1 H),
4.34(t,2 H), 3.86(s,3 H), 3.6(t,2 H), 3.38(t,2 H), 3.09s,3 H),
2.25(s,3 H), 2.20(s,3 H), 2.04(s,6 H), 1.18(t,3 H) ppm.
EXAMPLE 135
4-[(2-Hydroxy-ethyl)-thiophen-2-ylmethyl-amino]-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-nicotinic acid methyl ester
[0719] A mixture of
4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotini- c acid
methyl ester and 2-[(thiophen-2-ylmethyl)-amino]-ethanol in
1-methyl-2-pyrrolidinone was heated at 130.degree. C. overnight.
The mixture was quenched with water, brine and extracted with ethyl
acetate. The organic layer was dried and concentrated to dryness.
The residue was purified through silica gel column chromatography
to give the title compound. 1H NMR (CDCl.sub.3) d 7.22(m,1 H),
6.94m,2 H), 6.84(s,2 H), 6.44(s,1 H), 4.52(s,2 H), 3.91(s,3 H),
3.679t,2 H), 3.369t,2 H), 2.279s,3 H), 2.20(s,3 H), 2.07(s,6 H)
ppm.
EXAMPLE 136
[0720] The following compounds were prepared by the method
analogous to that in Example 118, starting with an appropriate
4-chloro-6-methyl-2-(su- bstituted-phenoxy)-nicotinic acid alkyl
ester with an appropriate alkyl- or dialkyl-amine.
[0721]
4-(2,2-Dimethyl-4-phenyl-[1,3]dioxan-5-ylamino)-6-methyl-2-(2,4,6-t-
rimethyl-phenoxy)-nicotinic acid methyl ester
[0722] 1H NMR (CDCl.sub.3) d 8.71(d,2 H), 7.1-7.4(m,5 H), 6.82(s,2
H), 5.55(s,1 H), 5.229s,1 H), 4.29(d,1 H), 3.97(d,1 H), 3.869s,3
H), 3.61(d,1 H), 2.25(s,3 H), 2.01(s,6 H), 1.91(s,3 H), 1.65(s,3
H), 1.61 (s,3 H) ppm.
[0723]
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamin-
o)-6-methyl-nicotinic acid ethyl ester
[0724] 1H NMR(CDCl.sub.3) d 8.01(d,1 H), 7.02(s,2 H), 6.17(s,1 H),
4.33(q,2 H), 3.71(m,1 H), 3.66(m,1 H), 3.54m,1 H), 2.10(s,3 H),
2.07(s,6 H), 1.5-1.8(m,2 H), 1.33(t,3 H), 1.00(t,3 H) ppm.
[0725]
4-[Ethyl-(2-methoxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-pheno-
xy)-nicotinic acid methyl ester
[0726] 1H NMR(CDCl.sub.3) d 6.83(s,2 H), 6.19(s,1 H), 3.869s,3 H),
3.35-3.6(m,4 H), 3.35(s,3 H), 2.26(s,3 H), 2.15(s,3 H), 2.06(s,6
H), 1.179t,3 H) ppm.
[0727]
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S,R)-&(S,S)-(1-ethyl-2-hydroxy-
-propylamino)-6-methyl-nicotinic acid methyl ester
[0728] 1H NMR(CDCl.sub.3) d 8.2(d,1 H), 7.01(s2 H), 6.20(s, 0.2 H),
6.15(s,0.8 H), 3.92(m,1 H), 3.87(s,3 H), 3.48(m,0.2 H), 3.31 (m,0.8
H), 2.08(s,3 H), 2.06(s,6 H), 1.5-1.8(m,2 H), 1.25(d,3 H), 0.96(t,3
H) ppm.
[0729]
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(R)-(1-hydroxymethyl-propylamin-
o)-6-methyl-nicotinic acid methyl ester
[0730] 1H NMR(CDCl.sub.3) 8.12(d,1H), 7.00(s,2 H), 6.16(s,1 H),
3.85(s,3 H), 3.6-3.8(m,2 H), 3.53(m,1 H), 2.08(s,3 H), 2.05(s,6 H),
1.5-1.8(m,2 H), 0.98(t,3 H)ppm.
[0731]
4-(2-Hydroxy-1-hydroxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-nicotinic acid methyl ester
[0732] 1H NMR(CDCl.sub.3) d 8.44(d,1 H), 6.84(s,2 H), 6.17(s,1 H),
3.8-4.0(m,4 H), 3.85(s,3 H), 3.70(m,1 H), 2.60(s,3 H), 2.27(s,3 H),
2.11(s,2 H), 2.05(s,6 H) ppm.
[0733]
4-(2-Methoxy-1-methoxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-nicotinic acid methyl ester
[0734] 1H NMR(CDCl.sub.3) d 8.38(d,1 H), 6.88(s,2 H), 6.18(s,1 H),
3.88(s,3 H), 3.78(m,1 H), 3.56(m,2 H), 3.44(s,6 H), 2.31(s,3 H),
2.15(s,3 H), 2.09(s,6 H) ppm.
[0735]
4-(1-Hydroxymethyl-2-methoxy-ethylamino)-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-nicotinic acid methyl ester
[0736] 1H NMR(CDCl.sub.3) d 8.44(d,1 H), 6.88(s,2 H), 6.21(s,1 H),
3.89(s,3 H), 3.80(m,1 H), 3.5-3.7(m,2 H), 3.45(s,3 H), 2.31(s,3 H),
2.16(s,3 H), 2.09(s,6 H) ppm.
[0737]
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-butylamino)--
6-methyl-nicotinic acid methyl ester
[0738] 1H NMR (CDCl.sub.3) d 8.34(d,1 H), 7.069s,2 H), 6.16(s,1 H),
3.91(s,3 H), 3.70(m,1 H), 3.5(m,1 H), 2.13(s,3 H), 2.11(s,6 H),
1.5-1.9(m,4 H), 1.01(m,6 H) ppm.
EXAMPLE 137
[2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridi-
n-3-yl]-methanol
[0739] A mixture of
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-ph-
enoxy)-nicotinic acid methyl ester (130 mg, 0.332 mmol) and an
excess of 1 M diisobutyl aluminum hydride in THF in dry THF was
stirred at -78.degree. C. for 10 min, then warmed to rt. The
mixture was quenched with methanol and stirred at room temperature
for 20 min, filtered through celite and washed with methanol and
chloroform. The filtrate was concentrated to dryness. The residue
was purified through silica gel column chromatography to. give the
title compound. 1HNMR(CDCl.sub.3) d 7.03(s,2 H), 6.11(s,1 H),
5.03(d,1 H), 4.96(s,2 H), 3.32(m,1 H), 2.14(s,3 H), 2.07(s,6 H),
1.4-1.7(m,4 H), 0.96(t,6 H) ppm.
[2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-
-3-yl]-methanol
[0740] The title compound was prepared by the method analogous to
that in the preceding paragraph. 1H NMR(CDCl.sub.3) d 7.18(s,2 H),
6.11(s,1 H), 5.05(d,1 H), 4.91(d,2 H), 3.31(m,1 H), 2.14(s,3 H),
2.07(s,6 H), 1.4-1.7(m,4 H), 0.96(t,6 H) ppm.
EXAMPLE 138
2-[3-Hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-ylam-
ino]-butan-1-ol
[0741] A mixture of
4-(s)-(1-hydroxymethyl-propylamino)-6-methyl-2-(2,4,6--
trimethyl-phenoxy)-nicotinic acid methyl ester and 1M lithium
aluminum hydride and aluminum chloride in THF in dry THF was heated
at reflux. The mixture was cooled and quenched with water, 2N NaOH,
then of water and stirred at room temperature for 10 min. White
solid formed and was filtered through celite, washed with THF. The
filtrate was concentrate to dryness to give the title compound as
white solid after column chromatography,
[0742] mp. 135-137.degree. C.; Anal. For
C.sub.20H.sub.28N.sub.2O.sub.3 calc. C, 69.74; H, 8.19; N, 8.13;
found C, 69.42; H, 8.34; N, 7.95
[0743] The following compounds were prepared by the method
analogous to that in the preceding paragraph, starting with the
corresponding ester with lithium aluminum hydride and aluminum
chloride.
[0744]
3-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyrid-
in-4-ylamino]-pentan-2-ol
[0745] mp. 180-182.degree. C. 1H NMR(CDCl.sub.3) 7.0(s,2 H),
6.18&6.15(two sets of s,1 H), 5.1and 5.22(m,1 H), 4.92(m,2 H),
3.80-4.0(m,1 H), 3.20-3.5(m,1 H), 2.11(s,3 H), 2.04(s,6 H),
1.4-1.8(m,2 H), 1.23(m,3 H), 0.98(m,3 H) ppm.
[0746]
2-[2-(2,6-Dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylam-
ino]-butan-1-ol
[0747] 1H (CDCl.sub.3) d 7.05(m,3 H), 6.20(s,1 H), 4.8-5.0(m,2 H),
3.74(m,1 H), 3.66(m,1 H), 3.50(m,1 H), 2.0-2.29m,9 H),
1.55-1.75(m,2 H), 0.99(t,3 H) ppm.
[0748]
3-[3-Hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-y-
lamino]-pentan-2-ol
[0749] 1H NMR(CDCl.sub.3) d 6.86(s,2 H), 6.17(s, 1 H), 4.0(d,1 H),
3.9(m,1 H), 3.3(m,1 H), 2.29(s,3 H), 2.14(s,3 H), 2.13(s,3 H),
2.07(s,6 H), 1.8(d,1 H), 1.4-1.8(m,2 H), 1.25(d,3 H), 0.99(t,3 H)
ppm.
[0750]
2-[2-(4-Chloro-2-methoxy-phenoxy)-3-hydroxymethyl-6-methyl-pyridin--
4-ylamino]-butan-1-ol
[0751] 1H NMR(CDCl.sub.3) 6.8-7.0(m,3 H), 6.2(s,1 H), 5.02(d,1 H),
4.7(ABq,2 H), 3.74(m,5 H), 3.350-3.5(m,2 H), 2.9(brs,2 H), 2.18(s,3
H), 1.4-1.7(m,2 H), 1.23(m,3 H), 0.95(t,3 H) ppm.
EXAMPLE 139
2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-yl-
amino]-butan-1-ol
[0752] A mixture of
4-(s)-(1-hydroxymethyl-propylamino)-6-methyl-2-(4-chlo-
ro-2,6-dimethyl-phenoxy)-nicotinic acid methyl ester and 1M lithium
aluminum hydride in THF was stirred at rt for 2 hr. The mixture was
cooled and quenched with water, 2N NaOH, then of water and stirred
at room temperature for 10 min. White solid formed and was filtered
through celite, washed with THF. The filtrate was concentrate to
dryness to give the title compound as white solid after column
chromatography, mp 133-135.degree. C., 1H NMR(CDCl.sub.3) 7.00(s,2
H), 6.17(s,1 H), 5.12(d,1 H), 4.90(m,2 H), 3.4-3.8(m,3 H), 2.12(s,3
H), 2.04(s,6 H), 1.4-1.6(m,2 H), 0.99(t,3 H) ppm.
[0753] The following compounds were prepared by the method
analogous to that in the preceding paragraph, starting with the
corresponding methyl ester with lithium aluminum hydride:
[0754]
2{Ethyl-[3-hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyrid-
in-4-yl]-amino}-ethanol
[0755] 1H NMR(CDCl.sub.3) d 1H NMR(CDCl3) 6.86(s,2 H), 6.53(s,1 H),
4.94(s,2 H), 3.67(m,2 H), 3.1-3.3 (m,4 H), 2.28(s,3 H), 2.20(s,3
H), 2.04(s,6 H), 1.09(t,3 H) ppm.
[0756]
4-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyrid-
in-4-ylamino]-hexan-3-ol
[0757] mp. 145-148.degree. C. 1H NMR(CDCl3) d 1 H NMR(CDCl3)
7.05(s,2 H), 6.16(s,1 H), 5.3(d,1 H), 4.94(s,2 H), 3.67(m,1 H),
3.40 (m,1 H), 2.151(s,3 H), 2.09(s,6 H), 1.4-1.8(m,4 H), 1.23(m,3
H), 1.02(m,6 H) ppm.
[0758]
2-[2-(4-Chloro-2-methoxy-phenoxy)-3-hydroxymethyl-6-methyl-pyridin--
4-(S)-ylamino]-butan-1-ol
[0759] 1H NMR (CDCl.sub.3) d 7.8-7.95(m,2 H), 5.02(d,1 H),
4.74(ABq,2 H), 3.74(s,3 H), 3.72(m,2 H), 3.45m,1 H), 2.98(brs,1 H),
2.18(s,3 H), 1.4-1.7(m,2 H), 0.95(t,3 H) ppm.
[0760]
4-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyrid-
in-4-ylamino]-hexan-3-ol
[0761] 1H NMR (CDCl.sub.3) d 7.05(s,2 H), 6.16(s,1 H), 5.30(d,1 H),
4.94(s,2 H), 3.67(m,1 H), 3.4(m,1 H), 2.15(s,3 H), 2.09(s,6 H),
1.5-1.9(m,4 H), 1.01 (m,6 H) ppm.
[0762]
[2-(2,4-Dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-
-pyridin-3-yl]-methanol
[0763] 1H NMR(CDCl.sub.3) d 6.90(d,1 H), 6.42(s,1 H), 6.40(d,1 H),
5.91(s,1 H), 4.42(m,1 H), 4.28(s,2 H), 3.79(s,3 H), 3.76(s,3 H),
3.56(m,2 H), 3.40(s,3 H), 2.33(s,3 H), 1.5-1.85(m,2 H), 1.02(t,3 H)
ppm.
EXAMPLE 140
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-me-
thyl-nicotinic acid
[0764] A mixture of
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymeth-
yl-propylamino)-6-methyl-nicotinic acid methyl ester (113 mg) and
lithium hydroxide in dioxane/THF/water was stirred at room
temperature over night. The mixture was quenched with ammonium
chloride and extracted with chloroform. The organic layer was dried
and concentrated to give 78 mg of the title compound as a white
solid. 1H NMR(CDCl.sub.3) d 10.55(brs,1 H), 9.2(d,1 H), 7.06(s,2
H), 6.3(s,1 H), 3.5-3.8(m,3 H), 2.11(s,3 H), 2.09(s,3 H), 2.08(s,3
H), 1.78(m,1 H), 1.62(m,1 H), 1.00(t,3 H) ppm.
4-(1-Ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotini-
c acid
[0765] mp. 131-133.degree. C., 1H NMR(CDCl.sub.3) d 11.29(brs,1 H),
9.35(d,1 H), 6.91(s,2 H), 6.38(s,1 H), 4.12(m,1 H), 2.88(m,1 H),
2.32(s,3 H), 2.19(s,3 H), 2.09(s,6 H), 1.96(m,2 H), 1.17(t,6 H)
ppm.
[0766]
2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-methoxymethyl-propylamino-
)-6-methyl-nicotinic acid
[0767] 1H NMR (CDCl.sub.3) d 10.5(brs, 1 H), 8.6(d,1 H), 7.15(d,2
H), 6.25(s,1 H), 3.3-3.6(m,3 H), 3.38(s,3 H), 2.11 (s,3 H),
2.09(s,3 H), 2.08(s,3 H), 1.5-1.85(m,2 H), 0.91 (t,3 H) ppm.
[0768]
4-(2-Methoxy-1-methoxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-nicotinic acid
[0769] 1H NMR(CDCl.sub.3) d 9.44(d,1 H), 6.92(s,2 H), 6.30(s,1 H),
3.80(m,1 H), 3.58(m,2 H), 3.44(s,6 H), 2.33(s,3 H), 2.16(s,3 H),
2.10(s,6 H) ppm.
EXAMPLE 141
[0770] The following compounds were prepared by reacting the
corresponding
[2-(substituted-phenoxy)-3-chloromethyl-6-methyl-pyridin-4-yl]-(alkyl)-am-
ine with an appropriate amine.
[0771]
[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-isobutoxymethyl-6-methyl-pyrid-
in-4-yl]-(1-ethyl-propyl)-amine
[0772] 1H NMR(CDCl.sub.3) d 6.94(s,2 H), 6.0(s,1 H), 5.13(d,1 H),
4.7(s,2 H), 3.2(m,1 H), 3.16(d,2 H), 2.02(s,3 H), 1.96(s,6 H),
1.8(m,1 H), 1.3-1.6(m,4 H), 0.82(t,6 H), 0.8(d,6 H) ppm.
[0773]
[3-Ethoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]--
(1-ethyl-propyl)-amine
[0774] 1 H NMR (CDCl.sub.3) d 6.86(s,2 H), 6.03(s,1 H), 5.30(d,1
H), 4.83(s,2 H), 3.58(q,2 H), 3.35(m, 1 H), 2.29(s,3 H), 2.15(s,3
H), 2.06(s,6 H), 1.5-1.78(m,4 H), 1.23(t,3 H), 0.967(t,6 H)ppm.
[0775]
2-[3-Butoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl-
amino]-butan-1-ol
[0776] 1 H NMR(CDCl.sub.3) d 6.85(s,2 H), 6.179s,1 H), 5.3(d,1 H),
4.82(Abq,2 H), 3.5-3.8(m,2 H), 3.5(t,2 H), 2.3(s,3 H), 2.15(s,3 H,
2.02(s,6 H),1.75(brs,1 H), 1.5-1.8(m,4 H), 1.3-1.5(m,2 H), 1.02(t,3
H), 0.9(t,3 H) ppm.
EXAMPLE 142
[0777]
1-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyr-
idin-3-yl]-ethanol
[0778] The title compound was prepared by reacting
4-(1-ethyl-propylamino)-
-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-carbaldehyde with
methyllithium lithium in THF at -78.degree. C. The desired product
was isolated after silica gel column chromatography to give 60.1%
of colorless oil. 1 H NMR(CDCl.sub.3) d 6.87(s,2 H), 6.06(s,1 H),
5.7(q,1 H), 3.3(m,1 H), 2.29(s,3 H), 2.12(s,6 H), 2.069s,3 H),
1.4-1.7(m,4 H), 1.59(d,3 H), 0.8-1.0(m,6 H) ppm.
EXAMPLE 143
Acetic acid
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-p-
yridin-3-ylmethyl ester
[0779] The title compound was obtained by acetylation of
[2-(2,4,6-trimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-yl]-(1-et-
hyl-propyl)-amine.
[0780] 1H NMR(CCl.sub.3) d 6.84(s,2 H), 6.04(s,1 H), 5.35(s,2 H),
5.23(d,1 H), 3.32(m,1 H), 2.28(s,3 H), 2.12(s,3 H), 2.08(s,3 H),
2.07(s,6 H), 1.4-1.7(m,4 H), 0.93(t,6 H) ppm.
EXAMPLE 144
2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-(1-hydroxy-1-methyl-ethyl)-6-methyl-
-pyridin-4-(S)-ylamino]-butan-1-ol
[0781] The title compound was prepared by reacting
2-(4-chloro-2,6-dimethy-
l-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic acid
methyl ester with an excess of 1M methyl magnesium bromide in THF
at room temperature overnight. Standard work-up procedure to give
the title compound after silica gel chromatography.
[0782] 1 H NMR(CDCl.sub.3) d 7.4(brs,1 H), 7.01(s,2 H), 6.13(s,1
H), 3.7(m,1 H), 3.6(m,1 H), 3.45(m,1 H), 2.04(s,3 H), 2.03(s,3 H),
2.02(s,3 H), 1.5-1.7(m,2 H), 0.98(t,3 H) ppm.
EXAMPLE 145
[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-pro-
pyl)-amine
[0783] To a solution of
[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-chloromethyl--
6-methyl-pyridin-4-yl]-(1-ethyl-propylyamine (75 mg, 0.196 mmol) in
dry THF was added 1.0M BH.sub.3 in THF (0.59 ml, 0.59 mmol) and
stirred for 2 hr. The mixture was quenched with dilute HCl and
stirred for 5 min. The reaction mixture was neutralized with 2N
NaOH, water and extracted with ethyl acetate. The organic layer was
separated, dried and concentrated to dryness. The residue was
purified through silica gel column chromatography to give the title
compound as a colorless oil.
[0784] 1H NMR(CDCl.sub.3) d 7.03(s,2 H), 6.08(s,1 H), 3.73(d,1 H),
3.3(m,1 H), 2.15(s,3 H), 2.12(s,3 H), 2.08(s,6 H), 1.4-1.6(m,4 H),
0.96(t,6 H) ppm.
EXAMPLE 146
[2-(2,6-Dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amin-
e
[0785] To a solution of
[2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propy-
lamino)-6-methyl-pyridin-3-yl]-methanol (43 mg, 0.106 mmol) in dry
THF was added 1.0M lithium aluminium hydride in diethyl ether (0.25
ml) and aluminum chloride (28 mg). The resulting mixture was
stirred at room temperature overnight. The mixture was quenched
with water, 2NaOH, then water. Solid formed and filtered through
celite, washed with THF, then chloroform. The filtrate was
concentrated to dryness. The residue was diluted with water and
ethyl acetate. The organic layer was separated, dried and
concentrated to give the crude material. The title compound was
isolated after silica gel chromatography. 1H NMR(CDCl.sub.3) d
6.9-7.1(m,3 H), 6.07(s,1 H), 3.35(d,1 H), 3.33(m,1 H), 2.14(s,3 H),
2.13(s,3 H), 2.12(s,6 H), 1.5-1.8(m,4 H), 0.97(t,6 H) ppm.
EXAMPLE 147
[2-(4-Bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-prop-
yl)-amine
[0786] The title compound was prepared by the method analogous to
that in Example 145 as a white solid. 1H NMR(CDCl.sub.3) d 7.19(s,2
H), 6.09(s,1 H), 3.36(d,1 H), 3.33(m,1 H), 2.15(s,3 H), 2.12(s,3
H), 2.09(s,6 H), 1.4-1.8(m,4 H), 0.97(t,6 H) ppm.
EXAMPLE 148
4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benz-
aldehyde
[0787] To a solution of
[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyr-
idin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added
n-butyllithium at -78.degree. C. After stirring at -78.degree. C.
for 10 min, n,N-dimethylformamide was added and the resulting
mixture was stirred at -78.degree. C. for 20 min, the dry-ice bath
was removed. After stirring for 5 min, the mixture was quenched
with diluted HCl, water and adjusted to pH7.5 and extracted with
ethyl acetate. The organic layer was separated, dried, and
concentrated to dryness. The residue was purified through silica
gel chromatography to give the title compound. 1H NMR(CDCl.sub.3) d
9.93(s,1 H), 7.60(s,2 H), 6.10(s,1 H), 3.75(d,1 H), 3.35(m1H),
2.17(s,6 H), 2.13(s,3 H), 2.12(s,3 H), 1.4-1.8(m,4 H), 0.97(t,6 H)
ppm.
EXAMPLE 149
{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phe-
nyl}-methanol
[0788] A mixture of
4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-ylox-
y]-3,5-dimethyl-benzaldehyde and sodium borohydride in methanol was
stirred at room temperature. After standard work-up procedure and
purification, the title compound was obtained as a solid. 1H
NMR(CDCl.sub.3) d 7.06(s,2 H), 6.08(s,1 H), 4.64(s,2 H), 3.74(d,1
H), 3.33(m,1 H), 2.14(s,3 H), 2.13(s,3 H), 2.11 (s,6 H) ppm.
EXAMPLE 150
(1-Ethyl-propyl)-[2-(4-methoxymethyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-py-
ridin-4-yl]-amine
[0789] To a solution of
(4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-
-yloxy]-3,5-dimethyl-phenyl}-methanol in dry THF was added 60% NaOH
in oil and stirred for 5 min. Excess of MeI was added and stirred
at room temperature for 2 hr. After standard worked up procedure
and purification, the title compound was obtained as a clear golden
oil. 1H NMR(CDCl.sub.3) d 7.02(s,2 H), 6.06(s,1 H), 4.40(s,3 H),
3.72(d,lH), 3.39(s,3 H), 3.36(m,1 H), 2.12(s,3 H), 2.11(s,3 H),
2.10(s,6 H), 1.4-1.7(m,4 H), 0.95(t,6 H) ppm.
EXAMPLE 151
[2-(4-Ethyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-prop-
yl)-amine
[0790] To a solution of
[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyr-
idin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added
n-butyllithium at -78.degree. C. After stirring at -78.degree. C.
for 10 min, ethyl iodide was added and the resulting mixture was
stirred at -78.degree. C. for 30 min, the dry-ice bath was removed.
After stirring for 5 min, the mixture was quenched with brine and
extracted with ethyl acetate. The organic layer was separated,
dried, and concentrated to dryness. The residue was purified
through silica gel chromatography to give the title compound. 1H
NMR(CDCl.sub.3) d 6.89(s,2 H), 6.07(s,1 H), 3.72(d,1 H), 3.34(m,1
H), 2.58(q,2 H), 2.16(s,3 H), 2.12(s,3 H), 2.09(s,6 H), 1.4-1.7(m,4
H), 1.25(t,3 H), 0.96(t,6 H) ppm.
EXAMPLE 152
2-{4-[4-(1
-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl--
phenyl}-propan-2-ol
[0791] To a solution of
[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyr-
idin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added
n-butyllithium at -78.degree. C. After stirring at -78.degree. C.
for 10 min, acetone was added and the resulting mixture was stirred
at -78.degree. C. for 30 min, the dry-ice bath was removed. After
stirring for 5 min, the mixture was quenched with brine and
extracted with ethyl acetate. The organic layer was separated,
dried, and concentrated to dryness. The residue was purified
through silica gel chromatography to give the title compound.1H
NMR(CDCl.sub.3) d 7.17(s,2 H), 6.08(s,1 H), 3.73(d,1 H), 3.33(m,1
H), 2.19(s,3 H), 2.15(s,3 H), 2.12(s,6 H), 1.4-1.7(m,4 H), 1.26(s,6
H), 0.96(t,6 H) ppm.
EXAMPLE 153
1-{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-p-
henyl}-ethanol
[0792] To a solution of
[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyr-
idin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added
n-butyllithium at -78.degree. C. After stirring at -78.degree. C.
for 10 min, acetaldehyde was added and the resulting mixture was
stirred at -78.degree. C. for 30 min, the dry-ice bath was removed.
After stirring for 5 min, the mixture was quenched with brine and
extracted with ethyl acetate. The organic layer was separated,
dried, and concentrated to dryness. The residue was purified
through silica gel chromatography to give the title compound. 1H
NMR(CDCl.sub.3) d 7.06(s,2 H), 4.84(m,1 H), 6.08(s,1 H), 3.73(d,1
H), 3.35(m,1 H), 2.14(s,3 H), 2.12(s,3 H), 2.11 (s,6 H),
1.4-1.7(m,4 H), 1.51 (d,3 H), 0.96(t,6 H) ppm.
EXAMPLE 154
(1-Ethyl-propyl)-[2-(4-isopropenyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyri-
din-4-yl]-amine
[0793] The title compound was prepared by reacting of
2-{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl--
phenyl}-propan-2-ol with Burgess Inner salt
(Et.sub.3NS(O).sub.2NCOOMe in benzene at reflux for 30 min. 1H
NMR(CDCl.sub.3) d 7.17(s,2 H), 6.08(s,1 H), 5.34(s,1 H), 5.02(s,1
H), 3.72(d,1 H), 3.32(m,1 H), 2.12 and 2.15 (two sets of s, 12 H),
1.4-1.6(m,4 H), 0.97(t,6 H) ppm.
EXAMPLE 155
(1-Ethyl-propyl)-[2-(4-isopropyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridi-
n-4-yl]-amine
[0794] The title compound was prepared by hydrogenation of
(1-ethyl-propyl)-[2-(4-isopropenyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyr-
idin-4-yl]-amine using 10% Pd/C as catalyst in ethyl acetate at 55
psi until all starting material were consumed. The title compound
was obtained as an oil after purification. 1H NMR(CDCl.sub.3) d
6.93(s,2 H), 6.10(s,1 H), 3.73(brs,1 H), 3.36(m,1 H), 2.18(s,3 H),
2.14(s,3 H), 2.12(s,6 H), 1.4-1.8(m,4 H), 1.27(d,6 H), 0.98(t,6 H)
ppm.
EXAMPLE 156
[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-
allyl)-amine
[0795] The title compound was prepared as a clear oil by reduction
of 4-(1-Ethyl-prop-2-ynylamino)-6-methyl-2-(2,
4,6-trimethyl-phenoxy)-nicoti- nic acid with lithium aluminum
hydride and aluminum chloride. 1H NMR(CDCl.sub.3) d 6.87(s,2 H),
6.08(s,1 H), 5.7-5.9(m,1 H), 5.1-5.3(m,2 H), 3.75-4.0(m,2 H),
2.30(s,3 H), 2.16(s,3 H), 2.15(s,3 H), 2.08(s,6 H), 1.70(m,2 H),
1.03(t,3 H)ppm.
EXAMPLE 157
(1-Ethyl-propyl)-[2-(4-fluoro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-
-yl]-amine
[0796] To a solution of
[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyr-
idin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added
n-butyllithium at -78.degree. C. After stirring at -78.degree. C.
for 10 min, (PhSO2)2NF was added and the resulting mixture was
stirred at -78.degree. C. for 30 min, the dry-ice bath was removed.
After stirring for 5 min, the mixture was quenched with brine and
extracted with ethyl acetate. The organic layer was separated,
dried, and concentrated to dryness. The residue was purified
through silica gel chromatography to give the title compound. 1H
NMR(CDCl.sub.3) d 6.77(s,1 H), 6.73(s,1 H), 6.08(s,1 H), 3.3(m,1
H), 2.12(s,3 H), 2.09(s,6 H), 2.08(s,3 H), 1.4-1.8(m,4 H), 0.97(t,6
H)ppm.
EXAMPLE 158
2-[2-(2,6-Dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-butan-1-ol
[0797] The title compound was prepared by the method analogous to
that in Example 146.
[0798] 1H NMR(CDCl.sub.3) d 7.05(m,3 H), 6.24(s,1 H), 3.4-3.8(m,3
H), 2.24(s,3 H), 2.16(s,3 H), 2.10(s,6 H), 1.5-1.8(m,2 H), 0.99(t3
H)ppm.
EXAMPLE 159
2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-ylamino]-butan-1-
-ol
[0799] To a solution of
2-(2,4,6-trimethyl-phenoxy)-4-(1-hydroxymethyl-pro-
pylamino)-6-methyl-nicotinic acid methyl ester in dry THF was added
1.0M lithium aluminium hydride in diethyl ether (0.25 ml) and
aluminum chloride. The resulting mixture was heated at reflux for 2
hr. The mixture was quenched with of water, 2NaOH, then water and
stirred. Solid formed and was filtered through celite, washed with
water and ethyl acetate. The organic layer was separated, dried,
concentrated, and purification to give the title compound as a
white solid. Anal. For C.sub.20H.sub.28N.sub.2O.sub.2.1/2H.sub.2O
calc. C, 70.90; H, 8.52; N, 8.01; found C, 71.18; H, 8.66; N,
8.30
[0800] The following compounds were prepared by the method
analogous to that in the preceding paragraph, using the
corresponding 2-(substituted
phenoxy)-4-(alkyl-amino)-6-methyl-nicotinic acid methyl ester with
lithium aluminum hydride and aluminum chloride.
[0801]
3-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-pent-
an-2-ol
[0802] 1H NMR(CDCl.sub.3) d 6.86(s,2 H), 6.17&6.13(two sets of
s, 1 H), 5.0-5.2(m,1 H), 4.9(s,2 H), 3.9-4.1(m,1 H), 3.5(m,1 H),
3.3(m,1 H), 2.29(s,3 H), 2.14(s,3 H), 2.08(s,6 H), 1.4-1.8(m,2 H),
1.27(m,3 H), 0.98(m,3 H) ppm.
[0803]
3-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino-
]-pentan-2-ol
[0804] 1H NMR(CDCl.sub.3) d 7.01(s,2 H), 6.14&6.11(two sets of
s,1 H), 4.04&3.82(two sets of d,1 H), 3.92(m,1 H),
3.4&3.2(m,1 H), 2.13(s,3 H), 2.11(s,3 H), 2.05(s,6 H),
1.4-1.8(m,2 H), 1.25(two sets of d, 3 H), 0.98&0.96(two sets of
t,3 H) ppm.
EXAMPLE 160
Benzyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine
[0805] A mixture of
4-bromo-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyrid- ine (250
mg, 0.78 mmol), benzylethylamine (127 mg, 0.937 mmol), Pd(OAc)2(3.6
mg, 0.0156 mmol), (S)-2,2'-bis (diphenylphosphino)-1,1'-bina-
phthyl (BINAP) (9.7 mg, 0.0156 mmol), potassium t-butoxide (105 mg,
0.781 mmol) in 25 ml of toluene was heated at reflux for 2 hr. The
mixture was cooled to rt, quenched with water and extracted with
ethyl acetate. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give a brown oil.
The crude material was purified through silica gel column
chromatography to give the title compound. 1H NMR(CDCl.sub.3) d
7.2-7.4(m,5 H), 6.86(s,2 H), 6.41(s,1 H), 4.23(s,2 H), 3.07(q,2 H),
2.31(s,3 H), 2.29(s,3 H), 2.16(s,3 H), 2.06(s,6 H), 1.05(t,3 H)
ppm.
[0806] The following compounds were prepared by the method
analogous to that in the preceding paragraph, using an appropriate
4-bromo-2-(substituted phenoxy)-3-methyl-6-alkyl or alkoxy-pyridine
with an appropriate amine.
[0807]
[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-me-
thoxymethyl-propyl)-amine
[0808] 1H NMR(CDCl.sub.3) d 7.06(s,2 H), 6.13(s,1 H), 4.14(d,1 H),
3.3-3.6(m,3 H), 3.42(s,3 H), 2.16(s,3 H), 2.14(s,3 H), 2.09(s,6 H),
1.5-1.8(m,2 H0, 1.03(t,3 H) ppm.
[0809]
2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-3-ph-
enyl-propan-1-ol
[0810] 1H NMR(CDCl.sub.3) d 8.6(d,1 H), 7.2-7.4(m5 H), 6.84(s,2 H),
6.169s,1 H), 4.099d,1 H), 3.82(m,1 H), 3.5-3.7(m,2 H), 2.95(d,2 H),
2.96(s,3 H), 2.27(s,3 H), 2.14(s,3 H), 2.05(s,6 H) ppm.
[0811]
[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-me-
thoxymethyl-propyl)-amine
[0812] 1H NMR(CDCl.sub.3) d 7.06(s,2 H), 6.13(s,1 H), 4.2(m,1 H),
3.53(m,2 H), 3.42(s,3 H), 2.19(s,3 H), 2.14(s,3 H), 2.10(s,6 H),
1.5-1.8(m,2 H), 1.03(t,3 H) ppm.
[0813]
[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-et-
hoxymethyl-propyl)-amine
[0814] 1H NMR(CDCl.sub.3) d 7.06(s,2 H), 6.14(s,1 H), 4.24(d,1 H),
4.4-4.65(m,5 H), 2.19(s,3 H), 2.14(s,3 H), 2.10(s,6 H), 1.8(m,1 H),
1.65(m,1 H), 1.25(t,3 H), 1.03(t,3 H) ppm.
[0815]
[3,6-Dimethyl-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-(1-methoxy-
methyl-propyl)-amine
[0816] 1H NMR(CDCl.sub.3) d 6.20(s,2 H), 6.08(s,1 H), 3.80(s,3 H),
3.73(s,6 H), 3.8(m,2 H), 3.39(m,1 H), 3.36(s,3 H), 2.23(brs,3 H),
2.10(s,3 H), 1.74(m,1 H), 1.59(m,1 H), 0.969t,3 H) ppm.
[0817]
[2-(4-Bromo-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]--
(1-ethy-propyl)-amine
[0818] 1H NMR(CDCl.sub.3) d 7.18(s,2 H), 6.09(s,1 H), 4.43(d,1 H),
3.89(s,3 H), 3.25(m,1 H), 2.10(s,9H), 1.4-1.8(m,4 H), 0.95(t,6 H)
ppm.
[0819]
(1-Ethyl-propyl)-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-py-
ridin-4-yl]-amine
[0820] 1H NMR(CDCl.sub.3) d6.85(s,2 H), 6.07(s,1 H), 4.44(m,1 H),
3.89(s,3 H), 3.23(m,1 H), 2.27(s,3 H), 2.09(s,6 H), 2.08(s,3 H),
1.65(m,2 H), 1.45(m,2 H), 0.93(m,6 H) ppm.
[0821]
[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-propyl-pyridin-4-yl]--
(1-ethyl-propyl)-amine
[0822]
[2-(4-Bromo-2,6-dimethyl-phenoxy)-6-methyl-3-propyl-pyridin-4-yl]-(-
1-ethyl-propyl)-amine
[0823] 1H NMR(CDCl.sub.3) d 7.03(s,2 H), 6.13(s,1 H), 3.8(m,1 H),
3.74(s,2 H), 3.38(m,1 H), 2.15(s,3 H), 2.05(s,6 H), 1.50-1.7(m,4
H), 0.97(t,6 H) ppm.
[0824]
(1-Ethyl-propyl)-[6-methyl-3-propyl-2-(2,4,6-trimethyl-phenoxy)-pyr-
idin-4-yl]-amine
[0825]
[2-(2,4-Dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-
-(1-ethyl-propyl)-amine
[0826] 1H NMR(CDCl.sub.3) 7.24(d,1 H), 7.1(d,1 H), 6.1(s,1 H),
4.47(d,1 H), 3.9(s,3 H), 3.22(m,1 H), 2.12(s,3 H), 2.08(s,3 H),
1.4-1.7(m,4 H), 0.9(t,6 H) ppm.
[0827]
[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-
-(1-ethyl-propyl)-amine
[0828] 1H NMR(CDCl.sub.3) 7.02(s,2 H), 6.07(s,1 H), 4.44(brs,1 H),
3.8-3.95(m,3 H), 3.23(m,1 H), 2.09(s,6 H), 2.08(s,3 H), 1.4-1.7(m,4
H), 0.93(t,6 H)ppm.
[0829]
[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-
-(1-methoxymethyl-propyl)-amine
[0830] 1H NMR(CDCl.sub.3) d 7.02(s,2 H), 6.11(s,1 H), 4.71(d,1 H),
3.88(s,3 H), 3.45(m,2 H), 3.37(s,3 H), 2.10(s,3 H), 2.09(s,6 H),
1.73(m,1 H), 1.59(m,1 H), 0.98(m,3 H) ppm.
[0831]
[2-(2,4-Dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-
-(1-methoxymethyl-propyl)-amine
[0832] 1H NMR (CDCl.sub.3) d 7.1-7.25(m,2 H), 6.13(s,1 H), 4.74(d,1
H), 3.91(s,3 H), 3.47(m,1 H), 3.39(m,2 H), 3.37(s,3 H), 2.14(s,3
H), 2.1 0(s,3 H), 1.78(m, 1 H), 1.59(m, 1 H), 0.98(t,3 H)ppm.
[0833]
[2-(4-Chloro-2-methoxy-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-
-methoxymethyl-propyl)-amine
[0834] 1H NMR (CDCl.sub.3) d 6.8-7.0(m,3 H), 6.17(s,1 H), 4.76(d,1
H), 3.82(s,3 H), 3.75(s,3 H), 3.3-3.5(m,3 H), 3.35(s,3 H), 2.19(s,3
H), 1.73(m,1 H), 1.56(m,1 H), 0.96(t,3 H) ppm.
[0835]
[2-(3-Chloro-2,6-dimethoxy-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl-
]-(1-methoxymethyl-propyl)-amine
[0836] 1H NMR(CDCl.sub.3) d 7.12(d,1 H), 6.64(d,1 H), 6.12(s,1
H)<4.73(d,1 H), 3.88(s,3 H), 3.78(s,3 H), 3.70(s,3 H),
3.3-3.5(m,3 H), 3.35(s,3 H), 2.11 (s,3 H), 1.5-1.8(m,2 H), 0.96(t,3
H) ppm.
[0837]
(1-Methoxymethyl-propyl)-[3-methoxy-6-methyl-2-(2,4,6-trimethoxy-ph-
enoxy)-pyridin-4-yl]-amine
[0838] 1H NMR(CDCl.sub.3) d 6.19(s,2 H), 6.10s,1 H), 4.75(m,1 H),
3.87(s,3 H), 3.80(s,3 H), 3.73(s,6 H), 3.3-3.5(m,2 H), 3.35(s,3 H),
2.17(s,3 H), 1.78(m,1 H), 1.5(m,1 H), 0.96(t,3 H) ppm.
[0839]
[3-Methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-yl-
]-(1-ethoxymethyl-propyl)-amine
[0840] 1H NMR(CDCl.sub.3) d 6.59(s,2 H), 6.10(s,1 H), 4.70(d,1 H),
3.89s,3 H), 3.77(s,3 H), 3.48(m,1 H), 3.39(m,2 H), 3.37(s,3 H),
2.11(s,3 H), 2.10(s,6 H), 1.74(m,1 H), 1.57(m,1 H), 0.98(t,3 H)
ppm.
[0841]
[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-ethoxy-6-methyl-pyridin-4-yl]--
(1-methoxymethyl-propyl)-amine
[0842] 1H NMR(CDCl.sub.3) d 7.07(s,2 H), 6.16(s,1 H), 4.82(d,1 H),
4.20(q,2 H), 3.54(m,1 H), 3.43(m,2 H), 3.42(s,3 H), 2.15(s,3 H),
2.13(s,6 H), 1.5-1.9(m,2 H), 1.439t,3 H), 1.02(t,3 H) ppm.
EXAMPLE 161
2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-(S)-ylamino]-b-
utan-1-ol
[0843] To a solution of
[1-(tert-butyl-dimethyl-silanyloxymethyl)-propyl]--
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine
in dry THF was added 1 M tetrabutylammonium fluoride in THF at room
temperature. The mixture was stirred at room temperature for 2 hr,
quenched with water, extracted with ethyl acetate. The organic
layer was separated, dried and concentrated to dryness. The residue
was purified by Biotage using 15% ethyl acetate in hexane as eluent
to give the title compound as a white solid. 1H NMR(CDCl.sub.3) d
7.06(s,2 H), 6.18(s,1 H), 4.04(d,1 H), 3.74(m,1 H), 3.69(m,1 H),
3.53(m,1 H), 2.18(s,3 H), 2.16(s,3 H), 2.10(s,6 H), 1.6-1.8(m,2 H),
1.04(t,3 H) ppm.
[0844] The following compounds were prepared by the method
analogous to that in the preceding paragraph, starting with the
corresponding tert-butyl-dimethyl-silanyloxymethyl derivative with
tetrabutylammonium fluoride.
[0845]
2-[3-Methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-yla-
mino]-butan-1-ol
[0846] 1H NMR (CDCl.sub.3) d 6.85(s,2 H), 6.15(s,1 H), 4.57(d,1 H),
3.91(s,3 H), 3.72(m,1 H), 3.61(m,1 H), 3.41(m,1 H), 2.27(s,3 H),
2.10(s,3 H), 2.07(s,6 H), 1.5-1.8(m,3 H), 0.98(t,3 H) ppm.
[0847]
2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-y-
lamino]-butan-1-ol
[0848] 1H NMR(CDCl.sub.3) d 7.02(s,2 H), 6.16(s,1 H), 4.60(d,1 H),
3.91(s,3 H), 3.71(m,1 H), 3.61(m,1 H), 3.40(m,1 H), 2.10(s,3 H),
2.08(s,6 H), 1.8(brs,1 H), 1.71(m,1 H), 1.68(m,1 H), 0.99(t,3 H)
ppm.
[0849]
4-[4-(1-Hydroxymethyl-propylamino)-3-methoxy-6-methyl-pyridin-2-ylo-
xy]-3,5-dimethyl-benzonitrile
[0850] 1H NMR(CDCl.sub.3) d 7.35(s,2 H), 6.19(s,1 H), 4.7(brs,1 H),
3.88(s,3 H), 3.731(m,1 H), 3.64(m,1 H), 3.43(m,1 H), 2.14(m,9 H),
1.8(brs,1 H), 1.71(m,1 H), 1.58(m,1 H), 0.99(t,3 H) ppm.
EXAMPLE 162
3-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-penta-
n-2-ol
[0851] The title compound was prepared by Dess Martin oxidation of
2-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-(S)-ylamino]--
butan-1-ol methylene chloride at room temperature, followed by
Gringard reaction using methyl magnesium bromide in THF.1H
NMR(CDCl.sub.3) d 7.07(s,2 H), 6.18(s,1 H), 4.3(brs,1 H), 4.0(m,1
H), 3.32(m,1 H), 2.22(s,3 H), 2.17(s,3 H), 2.11 (s,6 H),
1.6-1.8(m,2 H), 1.30(d,3 H), 1.01 (t,3 H)ppm.
EXAMPLE 163
2-[2-Methyl-6-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-butan-1-ol
[0852] The title compound was prepared as an oil by heating
2-(2,4,6-trimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl--
nicotinic acid in 160.degree. C. until all starting material were
consumed. Anal. For C.sub.19OH.sub.26N.sub.2O.sub.2 H.sub.2O calc.
C, 68.65; H. 8.49; N, 8.42; found C, 69.04; H, 8.14; N, 8.91
EXAMPLE 164
(1-Ethyl-prop-2-ynyl)-[2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]--
amine
[0853] The title compound was prepared by the method analogous to
that in Example 163.
[0854] 1H NMR(CDCl.sub.3) d 6.89(s,2 H), 6.12(d,1 H), 5.41(d,1 H),
3.9-4.2(m,2 H), 2.37s,3 H), 2.30(s,3 H), 2.27(m,1 H), 1.76(m,2 H),
1.05(t,3 H) ppm.
EXAMPLE 165
2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin--
3-ol
[0855] To a solution of
[2-(4-bromo-2,6-dimethyl-phenoxy)-3-methoxy-6-meth-
yl-pyridin-4-yl]-(1-ethy-propyl)-amine in methylene chloride was
added BBr.sub.3 at 0.degree. C. and stirred for hr. The mixture was
quenched with water and extracted with chloroform. The organic
layer was separated, dried, and concentrated to give the title
compound. 1H NMR(CDCl.sub.3) d 7.20(s,2 H), 6.12(s,1 H), 4.77(d,1
H), 3.27(m,1 H), 2.13(s,3 H), 2.1 0(s,6 H), 1.4-1.8(m, 4 H),
0.97(t,6 H) ppm.
[0856] The following compounds were prepared by the method
analogous to that in the preceding paragraph, starting with an
appropriate [2-(substituted
phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(alkyl)-amine with
BBr.sub.3 or BCl.sub.3.
[0857]
4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridi-
n-3-ol
[0858] 1H NMR(CDCl.sub.3) d6.85(s,2 H), 6.10(s,1 H), 5.12(brs,1 H),
4.21(m,1 H), 3.27(m,1 H), 2.28(s,3 H), 2.09(s,9 H), 1.5-1.8(m,4 H),
0.96(m,6 H) ppm.
[0859]
4-(S)-(1-Hydroxymethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phe-
noxy)-pyridin-3-ol
[0860] 1H NMR (CDCl.sub.3) d 6.85(s,2 H), 6.17(s,1 H), 5.13(brs,1
H), 4.28(d,1 H), 3.73(m,1 H), 3.60(m,1 H), 3.50(m,1 H), 2.27(s,3
H), 2.12(s,3 H), ?.07(s,6 H), 1.75(brs,1 H), 1.5-1.7(m,2 H),
0.99(t,3 H) ppm.
[0861]
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-
-methyl-pyridin-3-ol
[0862] 1H NMR(CDCl.sub.3) d 7.032(s,2 H), 6.10(s,1 H), 5.2(brs,1
H), 4.35(brs,1 H), 3.71(m,1 H), 3.61 (m,1 H), 3.40(m,1 H), 2.07(s,9
H), 1.8(brs, 1 H), 1.71 (m,1 H), 1.60(m,1 H), 0.99(m,3 H) ppm.
[0863]
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl--
pyridin-3-ol
[0864] 1H NMR(CDCl.sub.3) d 7.02(s,2 H), 6.10(s,1 H), 5.02(brs,1
H), 4.22(brs,1 H), 3.25(brs,1 H), 2.08(brs,9 H), 1.62(m,2 H),
1.52(m,2 H), 0.95(brs,6 H) ppm.
EXAMPLE 166
Chloro-acetic acid
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phe-
noxy)-pyridin-3-yl ester
[0865] The title compound was prepared by reacting
4-(1-ethyl-propylamino)-
-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ol with
chloroacetyl chloride /triethylamine in THF at 0.degree. C. to rt.
1H NMR(CDCl.sub.3) d 6.84(s,2 H), 6.15(s,1 H), 4.3(s,2 H), 4.0(d,1
H), 3.3(m,1 H), 2.28(s,3 H), 2.17(s,3 H), 2.08(s,6 H), 1/6-1.7(m,4
H), 0.9(t,6 H) ppm.
EXAMPLE 167
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-[(1-ethyl-propyl)-methyl-amino]-6-meth-
yl-pyridin-3-ol
[0866] 1H NMR(CDCl.sub.3) d 7.03(s,2 H), 6.25(s,1 H), 5.4(brs,1 H),
3.93(m,1 H), 2.70(s,3 H), 2.12(s,3 H), 2.08(s,6 H),1.55(m,4 H),
0.89(t,6 H) ppm.
EXAMPLE 168
[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl-
]-acetonitrile
[0867] 1H NMR(CDCl.sub.3) d 6.87(s,2 H), 6.13(s,1 H), 3.83(d,1 H),
3.79(S,2 H), 3.38(m,1 H), 2.30(s,3 H), 2.27(s,3 H), 2.21 (s,6 H),
1.4-1.8(m,4 H), 1.00(t,6 H) ppm.
EXAMPLE 169
4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-ca-
rbaldehyde
[0868] 1H NMR(CDCl.sub.3) d 10.52(s,1 H), 9.26(d,1 H), 6.89(s,2 H),
6.11(s,1 H), 3.42(m,1 H), 2.31 (s,3 H0, 2.15(s,3 H), 2.11 (s,6 H),
1.45-1.75(m,4 H), 0.97(t,6 H) ppm.
EXAMPLE 170
(1-Ethyl-propyl)-[3-[(1-ethyl-propylimino)-methyl]-6-methyl-2-(2,4,6-trime-
thyl-phenoxy)-pyridin-4-yl]-amine
[0869] 1H NMR(CDCl.sub.3) d 10.33(d,1 H), 8.94(s,1 H), 6.89(s,2 H),
6.10(s,1 H), 3.41(m,1 H), 2.86(m,1 H), 2.99(s,3 H), 2.14(s,3 H),
2.10(s,6 H), 1.4-1.89m,8 H), 0.94(t,6 H), 0.87(t,6 H) ppm.
EXAMPLE 171
2-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3--
ylmethyl]-malonic acid dimethyl ester
[0870] To a solution of dimethylmalonate (60 mg, 0.44 mmol) and 60%
NaH in oil (20 mg, 0.44 mmol) in dry THF was added the title
compound of Example 85 (50 mg, 0.146 mmol) at room temperature for
1 hr. The mixture was quenched with water and extracted with ethyl
acetate. The organic layer was separated, dried and concentrated to
dryness. The residue was purified through silica gel column
chromatography to give the title compound as a clear oil. 1H NMR
(CDCl.sub.3) d 6.88(s,2 H), 6.03(s,1 H), 4.85(m,1 H), 4.03(t,1 H),
3.73(s,6 H), 3.26(m,1 H), 3.18(d,2 H), 2.30(s,3 H), 2.13s,3 H),
2.07(s,6 H), 1.5-1.8(m,4 H), 0.97(t,6 H)ppm.
EXAMPLE 172
2-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3--
ylmethyl]-malonic acid diisopropyl ester
[0871] The title was prepared by the method analogous to that in
Example 171. 1H NMR (CDCl.sub.3) d 6.87(s,2 H), 6.03(s,1 H),
5.10(m,2 H), 4.90(d,1 H), 3.94(t,1 H), 3.31(m,1 H), 3.16(d,2 H),
2.30(s,3 H), 2.13s,3 H0, 2.08(s,6 H), 1.5-1.8(m,4 H), 1.1-1.3(two
sets of d, 6 H), 0.97(t,6 H)ppm.
EXAMPLE 173
4-(1-Ethyl-propoxy)-6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridine
[0872] To a mixture of
2-chloro-4-(1-ethyl-propoxy)-6-methyl-3-nitro-pyrid- ine (500 mg,
1.93 mmol) and 2,4,6-trimethylphenol (289 mg, 2.13 mmol) in dry THF
was added potassium t-butoxide. The resulting mixture was stirred
at rt. overnight. The mixture was quenched with water, brine and
extracted 3 times with ethyl acetate. The organic layer was
separated, dried (MgSO.sub.4) and concentrated to dryness. After
silica gel column chromatography purification, the title compound
was obtained as a light yellow crystal, mp 106-109.degree. C. Anal.
For C.sub.20H.sub.26N.sub.2O.- sub.4 calc. C, 67.02; H, 7.31; N,
7.82; found, C, 67.34; H, 7.40; N, 7.42.
EXAMPLE 174
4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylamine
[0873] A mixture of
4-(1-ethyl-propoxy)-6-methyl-3-nitro-2-(2,4,6-trimethy-
l-phenoxy)-pyridine (150 mg, 0.418 mmol) and 10% Pd/C (23 mg) in
ethanol was hydrogenated at 50 psi for 15 hours. An additional 10
Pd/C was added and the resulting mixture was hydrogenated for an
additional 24 hr. The mixture was filtered through celite and the
filtrate was concentrated to dryness to give 200 mg of the crude
material. After column chromatography, the title compound was
prepared as a the corresponding HCl salt as a white solid, mp
96-98.degree. C.
EXAMPLE 175
[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-
3-yl]-dimethyl-amine
[0874] To a solution of
4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-ph-
enoxy)-pyridin-3-ylamine in dry THF was added lithium
bis(trimethylsilyl)amide at -78.degree. C. After stirring at
-78.degree. C. for 10 minutes, an excess of methyl iodide was
added. The title compound was isolated after quenching with water
and extracting with ethyl acetate. The crude material was purified
by silica gel column chromatography to give the title compound as a
tan foam.
EXAMPLE 176
N-[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]--
succinamic acid
[0875] A mixture of
4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenox-
y)-pyridin-3-ylamine (100 mg, 0.304 mmol), succinic anhydride 31
mg,0.304 mmol) and triethylamine in methylene chloride was stirred
at rt. overnight. The mixture was quenched with water, and
extracted with methylene chloride. The organic layer was separated,
dried and concentrated to give a solid. The title compound was
isolated as a white crystal after silica gel column
chromatography.
[0876] 1H NMR(CDCl.sub.3) d 6.90(brs,1 H), 6.84(s,2 H), 6.37(s,1
H), 4.2(m,1 H), 2.6-2.8(m,4 H), 2.28(s,3 H), 2.22(s,3 H), 2.03(s,6
H), 1.69(m,4 H), 0.94(t,6 H) ppm.
EXAMPLE 177
4-(1-Ethyl-propoxy)-3,6-dimethyl-2-[3-(2,4,6-trimethyl-pyridinoxy)]-pyridi-
ne
[0877] To a solution of 3-pentanol (0.11 ml) in dry THF was added
sodium hydride (60% in oil, 20 mg). After stirring for 5 min, a
solution of 4-chloro-2,5-dimethyl-6-[3-(
2,4,6-trimethyl-pyridinoxy)]-pyridine (92 mg, 0.332 mmol) in THF
was added. DMSO was added and the resulting mixture was heated at
130.degree. C. oil bath overnight. The mixture was quenched with
water, brine and extracted 3 times with ethyl acetate. The organic
layer was separated, dried (MgSO.sub.4) and concentrated to
dryness. After silica gel column chromatography purification, the
title compound was obtained as a clear oil. 1H NMR (CDCl.sub.3) d
6.88 (s,1 H), 6.37(s,1 H), 4.21(m,1 H), 2.5(s,3 H), 2.29(s,3 H),
2.19(s,3 H), 2.18(s,3 H), 2.07(s,3 H), 1.70(m,4 H), 0.98(t,6 H)
ppm. The oil was prepared as the corresponding HCl salt to give a
white solid (63 mg).
[0878] The title compounds of the following Examples 178 and 179
were prepared by the methods analogous to that in Example 177,
starting with an appropriate 6-alkyl-4-chloro-or
bromo-3-methyl-2-(2,4,6-trimethyl-phen- oxy)-pyridine with
3-pentanol/NaH:
EXAMPLE 178
6-Ethyl-4-(1-ethyl-propoxy)-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine
[0879] 1H NMR(CDCl.sub.3) d 6.87(s,2 H), 6.28(s,1 H), 4.20(m,1 H),
2.46(q,2 H), 2.30(s,3 H), 2.20(s,3 H), 2.07(s,6 H), 1.72(m,4 H),
1.05(t,3 H), 0.99(t,6 H) ppm.
EXAMPLE 179
4-(1-Ethyl-propoxy)-2-(4-fluoro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-
e
[0880] colorless oil. Anal. For C.sub.20H.sub.26FNO.sub.2 calc. C,
72.48; H, 7.91; N, 4.23; found C, 72.39; H, 7.77; N, 4.10.
EXAMPLE 180
[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-a-
mine
[0881] To a solution of
4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-ph-
enylamino)-nicotinic acid (240 mg, 0.673 mmol) in dry THF was added
lithium aluminum hydride and aluminum chloride. The resulting
mixture was heated at reflux for 3 hours. The mixture was quenched
with 0.1 ml water and 0.1 ml 2N NaOH , then quenched with water and
ethyl acetate. The organic layer was separated, dried and
concentrated to give 250 mg of brown oil. After silica gel column
chromatography, 170 mg(78%) of the title compound was obtained
which was prepared as a HCl salt as a white solid, mp.
132-133.degree. C. 1H NMR(CDCl.sub.3) d 6.87(s,2 H), 6.09(s,1 H),
5.399brs,1 H), 4.13(m,1 H), 2.27(s,3 H), 2.22(s,3 H), 2.15(s,6 H),
1.98(s,3 H), 1.67(m,4 H), 0.94(t,6 H) ppm.
EXAMPLE 181
[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl-
]-methanol
[0882] To a solution of
4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-ph-
enylamino)-nicotinic acid (100 mg, 0.281 mmol) in dry THF was added
BH.sub.3.DMS. The resulting mixture was heated at reflux overnight.
The mixture was quenched with dilute HCl and stirred for 30
minutes, adjusted pH to 7.5-8.5, then extracted with ethyl acetate.
The organic layer was separated, dried and concentrated to give 100
mg of brown oil. After silica gel column chromatography, 91 mg(95%)
of the title compound was obtained as a white foam. Anal. For
C.sub.21H.sub.30N.sub.2O.sub.2.1/2H.s- ub.2O cal. C, 71.76; H,
8.89; N, 7.97; found: C, 71.97; H, 8.90; N, 7.69.
EXAMPLE 182
[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl-
]-oxo-acetonitrile
[0883] The title compound was prepared by reacting
[4-(1-ethyl-propoxy)-6--
methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol with
thionyl chloride in benzene, concentrated to dryness, followed by
reacting with diethylaluminum cyanide. After standard workup
procedure and silica gel column chromatography, compound was
obtained as a yellow crystal, mp. 108-110.degree. C.
[0884] 1H NMR(CDCl.sub.3) d 8.57(s,1 H), 6.97(s,2 H), 6.37(s,1 H),
4.46(m,1 H), 2.35(s,3 H), 2.34(s,3 H), 2.09(s,6 H), 1.6-1.8(m,4 H),
0.99(t,6 H) ppm.
EXAMPLE 183
[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl-
]-imidazol-1-yl-methanone
[0885] To a solution of
4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-ph-
enylamino)-nicotinic acid (250 mg, 0.701 mmol) in 2 ml of DMF was
added carbonyldiimidazole (190 mg, 1.19 mmol) and the resulting
mixture was stirred at room temperature overnight. After standard
workup procedure and silica gel column chromatography, 260
mg(91.2%) of the title compound was obtained as a golden-crystal,
mp. 120-122.degree. C., Anal. For
C.sub.24H.sub.30N.sub.4O.sub.2.1/4H.sub.2O calc: C, 70.13; H, 7.48;
N, 13.63; Found: C, 70.06; H, 7.69; N, 13.37.
EXAMPLE 184
2-[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3--
yl]-propan-2-ol
[0886] The title compound was prepared by reacting
[4-(1-ethyl-propoxy)-6--
methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-imidazol-1-yl-methano-
ne with an excess MeMgBr in THF at rt. After standard workup
procedure and silica gel column chromatography, the title compound
was obtained as a tan solid, mp. 81-83.degree. C.; Anal. For
C.sub.22H.sub.30N.sub.2O.sub.2- . 1.5 H.sub.2O calc.: C,69.49; H,
9.38; N, 7.04; found: C, 69.49; H, 9.27; N, 6.86
EXAMPLE 185
2-[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3--
ylmethyl]-malonic acid dimethyl ester
[0887] The title compound was prepared by reacting
[4-(1-ethyl-propoxy)-6--
methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol with
thionyl chloride in benzene, concentrated to dryness, followed by
reacting with methyl malonate/NaH in DMSO. After standard workup
procedure and silica gel column chromatography, the title compound
was obtained as a solid, mp. 96-98.degree. C.; Anal. For
C.sub.26H.sub.36N.sub.2O.sub.5. 1/3H.sub.2O calc.: C,67.51; H,
7.99; N, 6.04; found: C, 67.48; H, 7.99; N, 6.02.
EXAMPLE 186
3-[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3--
yl]-propionic acid
[0888] Hydrolysis of
2-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-ph-
enylamino)-pyridin-3-ylmethyl]-malonic acid dimethyl ester with
phosphoic/water at reflux to give the title compound as a white
foam. Anal. For C.sub.23H.sub.32N.sub.2O.sub.3. 3/4H.sub.2O calc.:
C,69.40; H, 8.48; N, 7.04; found: C, 69.17; H, 8.62; N, 6.90.
EXAMPLE 187
[3-Aminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-
-phenyl)-amine
[0889] The title compound was prepared by reacting
[4-(1-ethyl-propoxy)-6-- methyl-2-(2,4,6-trimethyl-phenylamino)
-pyridin-3-yl]-methanol with thionyl chloride in benzene,
concentrated to dryness, followed by reacting with NH.sub.3(g) at
room temperature. After standard workup procedure and silica gel
column chromatography, the title compound was obtained as a golden
oil (80%), Anal. For C.sub.21H.sub.31N.sub.3O. calc.: C,73.86; H,
9.15; N, 12.3; found: C, 73.50; H, 9.25; N, 11.39.
EXAMPLE 188
2-Chloro-N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-p-
yridin-3-ylmethyl]-acetamide
[0890] The title compound was prepared by acylation of
3-aminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,
4,6-trimethyl-phenyl)-amine with chloroacetyl chloride. After
standard workup procedure and silica gel column chromatography, the
title compound was obtained as an off-white crystal, mp.
142-144.degree. C.; Anal. For C.sub.23H.sub.32ClN.sub.3O.sub.2.
calc.: C,66.09; H, 7.72; N, 10.05; found: C, 65.81; H, 7.64; N,
9.86.
EXAMPLE 189
[3-Dimethylaminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-t-
rimethyl-phenyl)-amine hydrochloride salt
[0891] The title compound was prepared by reacting
[4-(1-ethyl-propoxy)-6--
methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol with
thionyl chloride in benzene, concentrated to dryness, followed by
reacting with dimethylamine at room temperature. After standard
work-up procedure and silica gel column chromatography, the title
compound was obtained as an oil. The corresponding HCl salt was
prepared as a white solid, mp. 85-88.degree. C.; Anal. For
C.sub.23H.sub.35N.sub.3O.2HCl. 1.5 H.sub.2O calc.: C,58.83; H,
8.588; N, 8.94; found: C, 58.32; H, 8.5327; N, 8.64.
EXAMPLE 190
Dithiocarbonic acid O-ethyl ester
S-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-
-trimethyl-phenylamino)-pyridin-3-ylmethyl] ester
[0892] The title compound was prepared by reacting
[4-(1-ethyl-propoxy)-6--
methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol with
thionyl chloride in benzene, concentrated to dryness, followed by
reacting with NaSCSOEt at room temperature. After standard work-up
procedure and silica gel column chromatography, the title compound
was obtained as a white solid, mp. 55-57.degree. C.; Anal. For
C.sub.24H.sub.34N.sub.2O.sub.2S.su- b.2. calc.: C,64.54; H, 7.67;
N, 6.27; found: C, 64.67; H, 7.78; N, 6.26.
EXAMPLE 191
4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide
[0893] The title compound was prepared by reacting
4-(1-ethyl-propoxy)-6-m-
ethyl-2-(2,4,6-trimethyl-phenylamino)-nicotinic acid with thionyl
chloride in benzene, concentrated to dryness, followed by reacting
with NH.sub.3(g) at room temperature. After standard work-up
procedure and silica gel column chromatography, the title compound
was obtained an oil. The corresponding HCl salt was prepared as an
off-white solid, mp 185-187.degree. C.; Anal. For
C.sub.21H.sub.29N.sub.3O.sub.2. calc.: C,70.96; H, 8.22; N, 11.82;
found: C, 71.30; H, 8.33; N, 11.78.
EXAMPLE 192
4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinonitri-
le
[0894] The title compound was prepared by reacting
4-(1-ethyl-propoxy)-6-m-
ethyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide with
triphosgen/triethylamine in THF. mp 105-107.degree. C., 1H
NMR(CDCl.sub.3) d 6.90(s,2 H), 6.26(brs,1 H), 6.05(s,1 H), 4.24(m,1
H), 2.28(s,3 H), 2.25(s,3 H), 2.17(s,6 H), 1.72(m,4 H), 0.97(t,6 H)
ppm.
EXAMPLE 193
4-(1-Ethyl-propoxy)-6,N,N-trimethyl-2-(2,4,6-trimethyl-phenylamino)-nicoti-
namide
[0895] The title compound was prepared by reacting
4-(1-ethyl-propoxy)-6-m-
ethyl-2-(2,4,6-trimethyl-phenylamino)-nicotinic acid with thionyl
chloride in benzene, concentrated to dryness, followed by reacting
with dimethylamine at room temperature. After standard work-up
procedure and silica gel column chromatography, the title compound
was obtained an oil. The corresponding HCl salt was prepared as a
white solid, mp. 197-200.degree. C.; Anal. For
C.sub.23H.sub.33N.sub.3O.sub.2.H.sub.2O. calc.: C,63.07; H, 8.28;
N, 9.59; found: C, 63.24; H, 8.07; N, 9.61.
EXAMPLE 194
[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethy!-phenylamino)-pyridin-3-yl-
]-acetonitrile
[0896] The title compound was prepared by reacting
[4-(1-ethyl-propoxy)-6--
methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol with
thionyl chloride in benzene, concentrated to dryness, followed by
reacting with potassium cyanide in DMSO at room temperature. After
standard work-up procedure and silica gel column chromatography,
the title compound was obtained as a pale orange solid, mp.
112-115.degree. C., 1H NMR(CDCl.sub.3) d 6.9(s,2 H), 6.14(s,1 H),
5.6(brs,1 H), 4.22(m,1 H), 3.49(s,2 H), 2.28(s,3 H), 2.22(s,3 H),
2.16(s,6 H), 1.71(m,4 H), 0.95(t,6 H) ppm.
EXAMPLE 195
[2-(4-Bromo-2,6-dimethyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-
-3-yl]-methanol
[0897] To a solution of
4-(1-ethyl-propoxy)-6-methyl-2-(4-bromo-2,6-dimeth-
yl-phenylamino)-nicotinic acid (130 mg, 0.309 mmol) in dry THF was
added BH.sub.3.DMS. The resulting mixture was heated at reflux
overnight. The mixture was quenched with dilute HCl and stirred for
30 min, adjusted pH to 7.5-8.5, then extracted with ethyl acetate.
The organic layer was separated, dried and concentrated to give 100
mg of brown oil. After silica gel column chromatography, 110
mg(87.3%) of the title compound was obtained as a white semi-solid.
1H NMR(CDCl.sub.3) d 7.25(s,2 H), 6.85(brs,1 H), 4.8(brs,2 H),
4.18(m,1 H), 2.2(s,3 H), 2.07(s,6 H), 1.7(m,4 H), 0.95(t,6 H)
ppm.
EXAMPLE 196
[2-(4-chloro-2,6-dimethyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridi-
n-3-yl]-methanol
[0898] To a solution of
4-(1-ethyl-propoxy)-6-methyl-2-(4-chloro-2,6-dimet-
hyl-phenylamino)-nicotinic acid in dry THF was added BH.sub.3.DMS.
The resulting mixture was heated at reflux overnight. The mixture
was quenched with dilute HCl and stirred for 30 minutes, adjusted
pH to 7.5-8.5, then extracted with ethyl acetate. The organic layer
was separated, dried and concentrated to give a brown oil. After
silica gel column chromatography, the title compound was obtained
as a green oil. 1H NMR(CDCl.sub.3) d 7.02(s,2 H), 6.83(brs,1 H),
4.78(s,2 H), 4.14(m, 1 H), 2.2(s,3 H), 2.13(s,6 H), 1.66(m,4 H),
0.93(9t,6 H) ppm.
EXAMPLE 197
[2-(2,4-Dichloro-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-m-
ethanol
[0899] To a solution of
4-(1-ethyl-propoxy)-6-methyl-2-(2,4-dichloro-pheny-
lamino)-nicotinic acid in dry THF was added BH.sub.3.DMS. The
resulting mixture was heated at reflux overnight. The mixture was
quenched with dilute HCl and stirred for 30 min, adjusted pH to
7.5-8.5, then extracted with ethyl acetate. The organic layer was
separated, dried and concentrated to give a golden oil. After
silica gel column chromatography, the title compound was obtained
as a golden oil. 1H NMR(CDCl.sub.3) d 8.44(d,1 H), 8.18(s,1 H),
7.32(d,1 H), 7.179d,1 H), 6.28(s,1 H), 4.82(s,2 H), 4.21 (m,1 H),
2.42(s,3 H), 1.6-1.8(m,4 H), 0.94(t,6 H) ppm.
EXAMPLE 198
[2-(2,4-Dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-pyridi-
n-3-yl]-methanol
[0900] The title compound was prepared by a method analogous to
that described for Example 197, starting with the corresponding
nicotinic acid with BH.sub.3.DMS. 1H NMR(CDCl.sub.3) d 6.91(d,1 H),
6.50(m,2 H),5.91(s,1 H), 4.42(m,1 H), 4.281(s,2 H), 3.79(s,3 H),
3.76(s,3 H), 3.56(m,2 H), 3.40(s,3 H), 2.33(s,3 H), 1.6-1.8(m,2 H),
1.02(t,3 H) ppm.
EXAMPLE 199
[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl-
]-imidazol-1-yl-methanone
[0901] The title compound was prepared by a method analogous to
that described for Example 183, starting with the corresponding
nicotinic acid with carbonyldiimidazole. 1HNMR(CDCl.sub.3) d
8.1(s,1 H), 7.52(s,1 H), 7.05(s,1 H), 6.78(s,2 H), 6.17(s,1 H),
5.97(d,1 H), 3.3(m, 1 H), 2.23(s,3 H), 2.18(s,3 H), 2.00(s,6 H),
1.4-1.7(m,4 H), 0.93(t,6 H) ppm.
EXAMPLE 200
1-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3--
yl]-ethanone
[0902] The title compound was prepared by reacting
[4-(1-Ethyl-propylamino- )6-methyl-2-(2,
4,6-trimethyl-phenoxy)-pyridin-3-yl]-imidazol-1-yl-methano- ne with
methylmagnesium bromide/ethyl ether in methylene chloride. 1H
NMR(CDCl.sub.3) d 9.7(d,1 H), 6.88(s,2 H), 6.10(s,1 H), 3.32(m,1
H), 2.73(s,3 H), 2.31(s,3 H), 2.10(s,3 H), 2.09(s,6 H), 1.5-1.7(m,4
H), 0.95(t,6 H)ppm.
EXAMPLE 201
(1-Ethyl-propyl)-[6-methyl-3-propyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4--
yl]-amine
[0903] 1H NMR(CDCl.sub.3) d 6.84(s,2 H), 6.04(s,1 H), 3.81(d,1 H),
3.31(m,1 H), 2.56(t,2 H), 2.27(s,3 H), 2.12(s,3 H), 2.04(s,6 H),
1.4-1.7(6 H), 1.02(t,3 H), 0.93(t,6 H) ppm.
EXAMPLE 202
2-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3--
ylmethyl]-2-methyl-malonic acid dimethyl ester
[0904] The title compound was prepared by a method analogous to
that described for Example 185. 1H NMR(CDCl.sub.3) 6.87(s,2 H),
6.01(s,1 H), 5.05(m,1 H), 3.70(s,6 H), 3.4(s,2 H), 3.3(m,1 H),
2.27(s,3 H), 2.12(s,3 H), 2.07(s,6 H), 1.4-1.7(m,4 H), 1.48(s,3 H),
0.949t,6 H) ppm.
EXAMPLE 203
[4-(1
-Ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenylyamine
[0905] The title compound was prepared by decarboxylation of the
corresponding nicotinic acid af 160.degree. C. oil bath. mp.
98-100.degree. C.; Anal. For C.sub.20H.sub.28N.sub.2O calc. C,
76.88; H, 9.03; N, 8.97; found: C, 76.97; H, 9.21; N, 8.99.
[0906] The following title compounds of Examples 204 and 205 were
prepared by reacting of
3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-4--
carbaldehyde with alkyl-magnesium bromide in THF:
EXAMPLE 204
2-Ethyl-1-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-bu-
tan-1-ol
[0907] 1H NMR(CDCl.sub.3) 6.87(s,2 H), 6.72(s,1 H), 4.90(t,1 H),
4.00(s,3 H), 2.29(s,3 H), 2.19(s,3 H), 2.06(s,6 H), 1.2-1.6(m,5 H),
0.92(t,3 H), 0.88(t,3 H) ppm.
EXAMPLE 205
1-[3-Methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-2-methyl-b-
utan-1-ol
[0908] 1H NMR(CDCl.sub.3) 6.88(s,2 H), 6.74(s,1 H), 5.00(m,1 H),
4.00(s,3 H), 2.29(s,3 H), 2.19(s,3 H), 2.06(s,6 H), 1.4-1.9(m,3 H),
0.992(t,3 H), 0.989(d,3 H) ppm.
EXAMPLE 206
1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-ol
[0909] To a -78.degree. C. solution of
4-bromo-3,6-dimethyl-2-(2,4,6-trime- thyl-phenoxy)-pyridine in dry
THF was added nBuLi and stirred at that temperature for 20 minutes.
Excess propionaldehyde was added and stirred for 2 hours at
-78.degree. C. The mixture was quenched with water, extracted with
ethyl acetate. The organic layer was washed with brine, dried and
concentrated. After column chromatography, an off-white solid was
obtained, mp. 119-120.degree. C.1H NMR(CDCl.sub.3) d 6.86(s,3 H),
4.90(m,1 H), 2.281(s,3 H), 2.28(s,3 H), 2.21(s,3 H), 2.02(s,6 H),
1.65-1.8(m,2 H), 1.00(t,3 H) ppm.
EXAMPLE 207
4-(1-Methoxy-propyl-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine
[0910] The title compound was prepared by reaction of
1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-ol
with sodium hydride, followed by quenching with methyl iodide. 1H
NMR(CDCl.sub.3) d 6.87(s,2 H), 6.74(s,1 H), 4.33(m,1 H), 3.25(s,3
H), 2.28(s,3 H), 2.27(s,3 H), 2.21 (s,3 H), 2.03(s,6 H), 1.6-1
.8(m,2 H), 0.94(t,3 H) ppm.
EXAMPLE 208
4-(1-Ethoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine
[0911] The title compound was prepared by reaction of
1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-ol
with sodium hydride, followed by quenching with ethyl iodide.
[0912] 1H NMR(CDCl.sub.3) d 6.86(s,2 H), 6.77(s,1 H), 4.41(m,1 H),
3.22-3.45(m,2 H), 2.28(s,3 H), 2.27(s,3 H), 2.21 (s,3 H), 2.03(s,6
H), 1.6-1.8(m,2 H), 1.20(t,3 H), 0.95(t,3 H) ppm.
EXAMPLE 209
4-(1-Allyloxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine
[0913] The title compound was prepared by reaction of
1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-ol
with sodium hydride, followed by quenching with allyl bromide.
[0914] 1H NMR(CDCl.sub.3) d 6.87(s,2 H), 6.78(s,1 H), 5.93(m,1 H),
5.1-5.3(m,2 H), 4.48(m,1 H), 3.95(m,1 H), 3.76(m,1 H), 2.29(s,3 H),
2.26(s,3 H), 2.21(s,3 H), 2.03(s,6 H), 1.6-1.8(m,2 H), 0.96(t,3 H)
ppm.
EXAMPLE 210
4-(1-Butoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine
[0915] The title compound was prepared by reacting of
1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-ol
with sodium hydride, followed by quenching with butyl iodide.
[0916] 1H NMR(CDCl.sub.3) d 6.86(s,2 H), 6.76(s,1 H), 4.37(m,1 H),
3.35(m,1 H), 3.25(m,1 H), 2.28(s,3 H), 2.26(s,3 H), 2.20(s,3 H),
2.03(s,6 H), 1.6-1.8(m,2 H), 1.5-1.65(m,2 H), 1.3-1.5(m,2 H),
0.96(t,3 H), 0.89(t,3 H) ppm.
[0917] The title compounds of the following Examples 211 through
215 were prepared by a method analogous to that described in 206
starting with an appropriate
4-bromo-2-(substituted-phenoxy)-pyridine derivative with nBuLi,
followed by quenching with an appropriate aldehyde.
EXAMPLE 211
1-[2-(2,4-Dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-et-
hyl-butan-1-ol
[0918] one racemate 1H NMR(CDCl.sub.3) d 7.28(d,1 H), 7.14(d,1 H),
6.80(s,1 H), 4.92(d,1 H), 4.00(s,3 H), 2.21(s,3 H), 2.13(s,3 H),
1.3-1.65(m,5 H), 0.93(t,3 H), 0.87(t,3 H) ppm.
[0919] The other racemate 1H NMR (CDCl.sub.3) d 7.18(s,1 H),
7.08(d,1 H), 6.74(d,1 H), 5.17(m,1 H), 3.93(s,3 H), 2.75(m,1 H),
2.1-2.25(m,1 H), 2.16(s,3 H), 2.13(s,3 H), 1.6-1.8(m,2 H),
1.0-1.3(m,2 H), 0.93(t,3 H), 0.72(t,3 H) ppm.
EXAMPLE 212
1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-2,2,2-trifluoro--
ethanol
[0920] mp. 134-139.degree. C., Anal. For
C.sub.18H.sub.20F.sub.3NO.sub.2 calc.: C, 63.71; H, 5.94; N, 4.13;
found: C, 63.59; H, 6.00; N, 4.02.
EXAMPLE 213
1-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-2,2,2-trif-
luoro-ethanol
[0921] 1H NMR(CDCl.sub.3) d 6.979s,2 H), 6.19(s,1 H), 2.14(s,6 H),
2.06(s,6 H) ppm.
EXAMPLE 214
[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-pyridin-2-yl-
-methanol
[0922] 1H NMR(CDCl.sub.3) d 8.61 (d, 1 H), 7.71 (m,1 H), 7.30(m, 1
H), 7.10(m, 1 H), 7.03(s,2 H),6.70(s,1 H), 6.03(s,1 H), 2.37(s,3
H), 2.16(s,3 H), 2.03(s,6 H), ppm.
EXAMPLE 215
1-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-et-
hyl-butan-1-ol
[0923] 1H NMR(CDCl.sub.3) d 7.05(s,2 H), 6.759s,1 H), 4.90(t,1 H),
3.98(s,3 H), 2.19(s,3 H), 2.06(s,6 H), 2.13(d,1 H), 1.25-1.65(m,5
H), 0.92(t,3 H), 0.87(t,3 H) ppm.
[0924] The title compounds of the following Examples 216 through
219 were prepared by oxidation of the corresponding alcohol with
Dess Martin reagent in DMSO/methylene chloride or pyridinium
chlorochromate in methylene chloride.
EXAMPLE 216
1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-one
[0925] mp. 82-85.5.degree. C., Anal. For C.sub.19H.sub.25NO.sub.2
calc.: C, 76.74; H, 7.80; N, 4.71; Found: C, 76.61; H, 7.94; N,
4.66.
EXAMPLE 217
1-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-2,2,2-trif-
luoro-ethanone
[0926] 1H NMR(CDCl3) d 7.06(s,2 H), 6.99(s,1 H), 2.42(s,3 H),
2.30(s,3 H), 2.03(s,6 H) ppm.
EXAMPLE 218
[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-pyridin-2-yl-
-methanone
[0927] 1H NMR(CDCl.sub.3) d 8.72(d,1 H), 8.17(d,1 H), 7.95(m,1 H),
7.52(m,1 H), 7.05(s,2 H),6.75(s,1 H), 2.25(s,3 H), 2.22(s,3 H),
2.07(s,6 H) ppm.
EXAMPLE 219
1-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-et-
hyl-butan-1-one
[0928] 1H NMR(CDCl.sub.3) d 7.05(s,2 H), 6.67(s,1 H), 3.98(s,3 H),
3.09(m,1 H), 2.61(s,3 H), 2.06(s,6 H), 1.76(m,2 H), 1.51 (m,2 H),
0.92(t,6 H) ppm.
EXAMPLE 220
4-(1-Ethoxy-2,2,2-trifluoro-ethyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy-
)-pyridine
[0929] The title compound was prepared by reacting the
corresponding alcohol with NaH, followed by quenching with ethyl
iodide.
[0930] 1H NMR(CDCl.sub.3) d 6.92(s,1 H), 6.87(s,2 H), 4.92(m,1 H),
3.60(m2 H), 2.349s,3 H), 2.29(s,3 H), 2.26(s,3 H), 2.03(s,6 H),
1.26(t,3 H) ppm.
[0931] The title compounds of the following Examples 221 through
222 were prepared by reacting of the corresponding ketone with
alkyl lithium or alkyl magnesium.
EXAMPLE 221
2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butan-2-ol
[0932] 1H NMR(CDCl.sub.3) d 6.86(m,3 H), 2.48(s,3 H), 2.28(s,3 H),
2.21(s,3 H), 2.02(s,6 H), 1.8-2.1(m,2 H), 1.61(s,3 H), 0.84(t,3 H)
ppm.
EXAMPLE 222
3-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-pentan-3-ol
[0933] 1H NMR(CDCl.sub.3) d 6.87(s,1 H), 6.86(s,2 H), 2.43(s,3 H),
2.28(s,3 H0, 2.21(s,3 H), 2.0-2.2(m,2 H), 2.02(s,6 H), 1.7-1.9(m,2
H), 1.69(brs,1 H), 0.8(t,6 H) ppm.
EXAMPLE 223
1-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxy-6-methyl-pyridin-4-yl]-2-et-
hyl-butan-1-one
[0934] The title compound was prepared by reacting
1-[2-(4-Chloro-2,6-dime-
thyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-one
with BBr.sub.3 or BCl.sub.3 in THF or methylene chloride.
[0935] 1H NMR (CDCl.sub.3) d 7.04(s,2 H), 7.01(s,1 H), 3.26(m,1 H),
2.24(s,3 H), 2.08(s,6 H), 1.80(m,2 H), 1.63(m,2 H), 0.91(t,6 H)
ppm.
EXAMPLE 224
4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinamide
[0936] To a solution of
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethy-
l-phenoxy)-nicotinic acid in anhydrous methylene chloride was added
thionyl chloride. After stirring for 1 hr. the reaction mixture was
concentrated to dryness. The residue was dissolved in dry THF and
NH3(g) was bubbled in. The reaction mixture was quenched with water
and extracted with ethyl acetate. The organic layer was separated,
dried and concentrated to give a light yellow solid. The solid was
purified through silica gel column chromatography using 1% methanol
in chloroform as eluent to give the title compound as a white
solid, mp. 85-88.degree. C. 1H NMR(CDCl.sub.3) d 9.69(brs,1 H),
8.01(brs,1 H), 6.87(s,2 H), 6.11(s,1 H), 5.48(brs,1 H), 3.31(m,1
H), 2.29(s,3 H), 2.10(s,3 H), 2.07(s,6 H), 1.60(m,4 H), 0.95(t,6 H)
ppm.
[0937] The title compounds of the following Examples 225 through
231 were prepared by a method analogous to that described in the
preceding paragraph, starting with the corresponding nicotinic acid
or pyrimidine-5-carboxylic derivative and quenching with an
appropriate nucleophile.
EXAMPLE 225
4-(1-Ethyl-propylamino)-6,N-dimethyl-2-(2,4,6-trimethyl-phenoxy)-nicotinam-
ide
[0938] 1H NMR(CDCl.sub.3) d 9.8(brs,1 H), 8.21(brs,1 H), 6.88(s,2
H), 6.11(s,1 H), 3.31(m,1 H), 2.92(d,3 H), 2.30(s,3 H), 2.10(s,3
H), 2.07(s,6 H), 1.60(m,4 H), 0.95(t,6 H) ppm.
EXAMPLE 226
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-me-
thyl-nicotinamide
[0939] 1H NMR(CDCl.sub.3) d 9.7(d,1 H), 7.9(brs,1 H), 7.0(s,2 H),
6.2(s,1 H), 5.6(brs,1 H), 3.7(m,1 H), 3.66(m, 1 H), 3.54(m, 1 H),
2.07(s,3 H), 2.068(s,3 H), 2.06(s,3 H), 1.7(m, 1 H), 1.6(m, 1 H),
0.99(t,3 H) ppm.
EXAMPLE 227
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-me-
thyl-nicotinic acid hydrazide
[0940] 1H NMR(CDCl.sub.3) d 9.15(s,1 H), 7.04(s,2 H), 6.23(s,1 H),
3.6-3.8(m,2 H), 3.53(m,1 H), 2.08(s,6 H), 2.05(s,3 H), 2.04(s,3 H),
1.5-1.8(m,2 H), 1.01 (t,3 H) ppm.
EXAMPLE 228
2-(4-Chloro-2,6-dimethyl-phenoxy)-N-ethyl-4-(S)-(1-hydroxymethyl-propylami-
no)-6-methyl-nicotinamide
[0941] 1H NMR(CDCl.sub.3) d 9.74(d,1 H), 8.12(s,1 H), 7.05(s,2 H),
6.23(s,1 H), 3.5-3.8(m,3 H), 3.43(m,2 H), 2.06(s,9 H), 1.8(brs, 1
H), 1.5-1.7(m,2 H), 1.1 9(t,3 H), 1.00(t,3 H) ppm.
EXAMPLE 229
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6,N--
dimethyl-nicotinamide
[0942] 1H NMR(CDCl.sub.3) d 9.80(d,1 H), 8.12(s,1H), 7.04(s,2 H),
6.22(s,1 H), 3.5-3.8(m,3 H), 2.93(d,3 H),2.06(s,9 H), 1.8(brs,1 H),
1.5-1 .7(m,2 H), 0.99(t,3 H) ppm.
EXAMPLE 230
2-(4-Chloro-2,6-dimethyl-phenoxy)-N-cyclopentyl-4-(S)-(1-hydroxymethyl-pro-
pylamino)-6-methyl-nicotinamide
[0943] 1H NMR(CDCl.sub.3) d 9.69(d,1 H), 8.13(d,1 H), 7.04(s,2 H),
6.22(s,1 H), 4.35(m,1 H), 3.4-3.8(m,3 H), 2.056(s,9 H), 1.4-2.0(m,
10 H), 0.99(t,3 H) ppm.
EXAMPLE 231
2-(4-Chloro-2,6-dimethyl-phenoxy)-N-cyclopropylmethyl-4-(S)-(1-hydroxymeth-
yl-propylamino)-6-methyl-nicotinamide
[0944] 1H NMR(CDCl.sub.3) d 9.71(d,1 H), 8.24(s,1 H), 7.05(s,2 H),
6.23(s,1 H), 3.5-3.8(m,3 H), 3.27(t,2 H), 2.08(s,6 H), 2.07(s,3 H),
1.8(brs,1 H), 1.5-1.75(m,2 H), 0.99(t,3 H), 0.46(m,2 H), 0.21(m,2
H) ppm.
[0945] The title compounds of the following Examples 232 through
236 were prepared by a method analogous to that described for
Example 224.
EXAMPLE 232
4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinam-
ide
[0946] A brown solid, mp. 204-206.degree. C.
EXAMPLE 233
4-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5--
carboxic acid amide
[0947] Mp. 174-176.degree. C.; Anal. For
C.sub.20H.sub.28N.sub.4O.sub.2 calc.: C, 67.39; H, 7.92; N, 15.72;
found: C, 67.90; H, 8.19; N, 14.66. 1H NMR(CDCl.sub.3) d 7.95(s,1
H), 6.89(s,2 H), 5.58(s,1 H), 5.4(m,1 H), 2.28(s,3 H), 2.25(s,3 H),
2.15(s,6 H), 1.75(m,4 H), 0.96(t,6 H) ppm.
EXAMPLE 234
4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinonitri-
le
[0948] 1H NMR(CDCl.sub.3) d 6.85(s,2 H), 6.06(s,1 H), 4.72(d,1 H),
3.36(m,1 H), 2.28(s,3 H), 2.17(s,3 H), 2.09(s,6 H), 1.5-1.8(m,4 H),
0.96(t,6 H) ppm.
EXAMPLE 235
[4-(1-Ethyl-propoxy)-6-methyl-3-nitro-pyridin-2-yl]-(2,4,6-trimethyl-pheny-
l)-amine
[0949] The title compound was prepared by heating 2-bromo (or
chloro)-4-(1-ethyl-propoxy)-6-methyl-3-nitro-pyridine with
2,4,6-trimethylaniline in DMSO at 130.degree. C. The reaction
mixture was quenched with water and extracted with ethyl acetate.
The organic layer was separated, dried and concentrated to give
crude material. The material was purified through silica gel column
chromatography to give the title compound as a yellow solid. 1H
NMR(CDCl.sub.3) d 8.52(s,1 H), 6.92(s,2 H), 6.12(s,1 H), 4.31(m,1
H), 2.32(s,3 H), 2.24(s,3 H), 2.18(s,6 H), 1.77(m,4 H0, 1.01(t,6 H)
ppm.
EXAMPLE 236
4-(1-Ethyl-propoxy-6-methyl-N2-(2,4,6-trimethyl-phenyl(pyridine-2,3-diamin-
e
[0950] The title compound was prepared by hydrogenation of the
corresponding 3-nitro derivative with 10% Pd/C in ethanol at 50
psi. A pale gray solid was obtained in 97% yield, mp. 73-75.degree.
C. 1H NMR(CDCl.sub.3) d 6.89(s,2 H), 6.18(s,1 H), 4.22(m,1 H),
3.2(brs,2 H), 2.29(s,3 H), 2.19(s,6 H), 1.7(m,4 H), 0.97(t,6 H)
ppm.
EXAMPLE 237
2-Chloro-N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-p-
yridin-3-yl]-acetamide
[0951] The title compound was prepared by acylation of
4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenylypyridine-2,3-diam-
ine with chloroacetyl chloride, NEt.sub.3 in THF at room
temperature. A tan solid was isolated, mp. 79-82.degree. C. Anal.
For C.sub.22H.sub.30ClN.sub.3O.sub.2 calc. C, 65.41; H, 7.49; N,
10.40; found: C, 65.56; H, 7.62; N, 10.98.
EXAMPLE 238
N-Butyl-N-ethyl-6-methyl-3-nitro-N-(2,4,6-trimethyl-phenyl)-pyridine-2,4-d-
iamine
[0952] A mixture of
butyl-(2-chloro-6-methyl-3-nitro-pyridin-4-yl)-ethyl-a- mine (700
mg, 2.58 mmol) and 2,4,6-trimethylaniline in DMSO was heated in
140.degree. C. oil bath for overnight. An additional 0.75 ml of
2,4,6-trimethylaniline was added and the resulting mixture was
heated for an additional 48 hours. The mixture was quenched with
water, brine and extracted 3 times with ethyl acetate. The organic
layer was separated, dried (MgSO.sub.4) and concentrated to
dryness. After silica gel column chromatography purification, the
title compound was obtained as an oil.
EXAMPLE 239
4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinic
acid
[0953] The title compound was prepared by heating
2-chloro-4-(1-ethyl-prop- ylamino)-6-methyl-nicotinic acid and
trimethylaniline in the presence of potassium carbonate and copper
in DMF. The desired product was isolated by silica gel column
chromatography using 5% methanol in chloroform as solvent to give a
tan solid, mp. 130-135.degree. C.
EXAMPLE 240
4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinic
acid methyl ester
[0954] A mixture of
2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid methyl
ester, trimethylaniline, potassium carbonate, copper in DMF was
heated at reflux. The mixture was quenched with ammonium chloride
and stirred for 20 min, filtered through celite and washed with
ethyl, acetate. The filtrate was extracted with ethyl acetate. The
organic layer was separated, dried and concentrated to dryness. The
residue was purified through silica gel column chromatography using
2% methanol in chloroform as eluent to give the title compound as a
solid.
[0955] 1H NMR(CDCl.sub.3) d 8.9(s,1 H), 8.0(d,1 H), 6.91(s,2 H),
5.79s,1 H), 3.92(s,3 H), 3.37(m,1 H), 2.30(s,3 H), 2.17(s,3 H),
2.10(s,6 H), 1.5-1.7(m,4 H), 0.96(t,6 H) ppm.
EXAMPLE 241
N4-(1-Ethyl-propyl)-3,6dimethyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-d-
iamine
[0956] The title compound was prepared by reduction of
4-(1-ethyl-propylamino)-6-methyl-2-(2,
4,6-trimethyl-phenylamino)-nicotin- ic acid with 1 M of lithium
aluminium hydride in diethyl ether and aluminium trichloride at
reflux. 1H NMR(CDCl.sub.3)6.9(s,2 H), 6.0(s,1 H). 5.4(brs,1 H),
3.6(d,1 H), 3.3(m,1 H), 2.32(s,3 H), 2.2(s,3 H), 2.15(s,6 H),
1.4-1.7(m,4 H), 1.0(t,6 H) ppm.
EXAMPLE 242
2-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylaminoypyridin-
-3-ylmethyl]-malonic acid dimethyl ester
[0957] Mp. 136-138.degree. C.; Anal. For
C.sub.26H.sub.37N.sub.3O.sub.43/4- H.sub.2O calc.: C,66.57; H,
8.27; N, 8.96; found: C, 66.67; H, 7.95; N, 8.88.
EXAMPLE 243
[2-(4-Bromo-2,6-dimethyl-phenylamino)-4-(1-ethyl-propylamino)-6-methyl-pyr-
idin-3-yl-methanol
[0958] The title compound was prepared by reduction of the
corresponding nicotinic acid derivative with BH.sub.3.DMS in THF at
reflux. Standard work-up procedure to give the title compound as a
white foam. 1H NMR(CDCl.sub.3) 7.15(s,2 H), 6.2(brs,1 H), 5.92(s,1
H), 4.479m,1 H), 4.43(s,2 H), 3.25(m,1 H), 2.17(s,3 H), 2.10(s,6
H), 1.58(m,2 H), 1.47(m,2 H), 0.90(t,6 H) ppm.
EXAMPLE 244
N2-(2,4-Dichloro-phenyl)-N4-(1-ethyl-propyl)-3,6-dimethyl-pyridine-2,4-dia-
mine
[0959] The title compound was prepared by a method analogous to
that described for Example 146. 1H NMR(CDCl.sub.3) d 7.79(dd,1 H),
7.30(d,1 H), 7.10(dd,1 H), 6.53(brs,1 H), 6.13(s,1 H), 3.79(d,1 H),
3.2-3.4(m,1 H), 2.36(s,3 H), 1.92(s,3 H), 1.4-1.6(m,4 H), 0.93(t,6
H) ppm.
EXAMPLE 245
[2-(2,4-Dichloro-phenylamino)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-y-
l]-methanol
[0960] The title compound was prepared by reduction of the
corresponding nicotinic acid derivative with BH.sub.3.DMS in THF at
reflux. 1H NMR(CDCl.sub.3) d 7.22(d,1 H), 7.07(d,1 H), 7.00(d,1 H),
6.10(s,1 H), 5.7(brs,1 H), 4.4(s,2 H), 3.3 (m,1 H), 2.35(s,3 H),
2.02(s,3 H), 1.4-1.6(m,4 H), 0.92&0.91 (two sets of t,6 H)
ppm.
EXAMPLE 246
2-[6-Methyl-3-nitro-2-(2,4,6-trimethyl-phenylamino)-pyridin-4-ylamino]-but-
an-1-ol
[0961] The title compound was prepared by heating
2-[6-methyl-3-nitro-2chl- oro-pyridin-4-ylamino]-butan-1-ol with
trimethylaniline in DMSO at 130.degree. C. 1H NMR(CDCl.sub.3) d
9.38(brs,1 H), 6.93(s,3 H), 3.7-3.8(m,3 H), 2.30(s,3 H), 2.12(s,6
H), 1.8(m,1 H), 1.65(m,1 H), 1.02(t,3 H) ppm
EXAMPLE 247
2-[4-(1-Ethyl-propylamino-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-5-
-yl]-propionic acid ethyl ester
[0962] 1H NMR(CDCl.sub.3) d 6.85(s,2 H,1 H), 4.49(q,1 H),
4.04.2(m,3 H), 2.289s,3 H0, 2.20(s,3 H), 2.06(s,6 H), 1.4-1.7(m,4
H), 1.44(d,3 H), 1.21(t,3 H), 0.93(t,3 H), 0.87(t,3 H) ppm.
EXAMPLE 248
[3-Aminomethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-
-propyl)-amine
[0963] The title compound was prepared by a method analogous to
that described for Example 188. mp. 117-119.degree. C.; Anal. For
C.sub.21H.sub.31N.sub.3O. 1/3H.sub.2O calc.: C,72.58; H, 9.18; N,
12.09; found: C, 72.93; H, 9.28; N, 12.02.
[0964] The following title compounds of Examples 249-251 were
prepared by reacting
[4-(1-ethyl-propylamino)-6-methyl-2-(4-halo-2,6-dimethyl-phenoxy-
)-pyridin-3-yl]-methanol with thionyl chloride in benzene,
concentrated to dryness, followed by reacting with potassium
cyanide in DMSO at room temperature.
EXAMPLE 249
(2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-
-3-yl]-acetonitrile
[0965] 1H NMR(CDCl.sub.3) d 7.2(s,2 H), 6.1(S,1 H), 3.82(d,1 H),
3.7(s,2 H), 3.34(m,1 H), 2.1(s,3 H), 2.03(s,6 H), 1.45-1.7(m,4 H),
0.99(t,6 H) ppm.
EXAMPLE 250
[2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridi-
n-3-yl]-acetonitrile hydrogen chloride
[0966] 1H NMR(CDCl.sub.3) d 7.08(s,2 H), 6.2(s,1 H), 4.92(d,1 H),
3.45(m,1 H), 2.71(s,3 H), 2.549m,2 H), 2.14(s,6 H), 1.7(m,2 H),
1.40-1.6(m,4 H), 0.95(t,6 H) ppm.
EXAMPLE 251
[6-(1-Ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-ami-
ne
[0967] MP. 149-151.degree. C., Anal. For C.sub.20H.sub.26N.sub.4O
calc.: C, 72.81; H, 8.68; N, 13.41; found: C, 72.70; H, 8.86; N,
13.14
EXAMPLE 252
2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-
-1-ol
[0968] The title compound was prepared by heating the corresponding
nicotinic acid derivative at 160-170.degree. C. oil bath. 1H NMR
(CDCl3) d 7.05(s,2 H), 6.09(s,1 H), 5.35(s,1 H), 4.43(s,1 H),
3.68(m,1 H), 3.64(m,1 H), 3.29(m,1 H), 2.30(s,3 H), 2.09(s,6 H),
1.60(m,1 H), 1.47(m,1 H), 0.89(t,3 H) ppm.
EXAMPLE 253
[3-Aminomethyl-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-yl-
]-(1-chloromethyl-propyl)-amine
[0969] The title compound was prepared by reacting
[2-[2-(4-chloro-2,6-dim-
ethyl-phenoxy)-3-pyridin-4-(S)-ylamino]-butan-1-ol with thionyl
chloride in benzene, concentrated to dryness, followed by reacting
with NH.sub.3(g) at room temperature. After standard workup
procedure and silica gel column chromatography, the title compound
was obtained. 1H NMR(CDCl.sub.3) d 7.00(s,2 H), 6.3(brs,1 H),
6.07(s,1 H), 4.0-4.2(m,2 H), 3.9(brs,2 H), 3.5-3.8(m,3 H), 2.12(s,3
H), 2.03(s,6 H), 1.6-1.9(m,2 H), 1.00(t,3 H) ppm
[0970] The following title compounds of Examples 254 and 255 were
prepared by reacting [2-(2-(4-chloro-2,6-dimethyl-phenoxy>3-
pyridin-4-(S)ylamino]-butan-1-ol with thionyl chloride in benzene,
concentrated to dryness, followed by reacting with an appropriate
amine in THF at room temperature. After standard workup procedure
and silica gel column chromatography, the title compound was
obtained.
EXAMPLE 254
2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-methylaminomethyl-pyridin--
4-(S)-ylamino]-butan-1-ol
[0971] 1H NMR(CDCl.sub.3) d 7.01(s,2 H), 6.14(s,1 H), 4.55(brs,1
H), 3.6-3.8(m,2 H), 3.4(m,1 H), 2.6(s,3 H), 2.11 (s,3 H),
2.02(brs,6 H), 1.65(m,2 H), 0.97(t,3 H)ppm.
EXAMPLE 255
2-[3-Aminomethyl-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)--
ylamino]-butan-1-ol
[0972] 1H NMR(CDCl.sub.3) d 6.999s,2 H), 6.10(s,1 H), 4.4.00(Abq,2
H), 3.5-3.75(m,2 H), 3.4(m, 1 H), 2.73(brs,4 H), 2.08(s,3 H),
2.00(s,6 H), 1.58(m,4 H), 0.94(t,3 H) ppm.
[0973] The title compounds of the following Examples 256 through
262 were prepared by bromination or chlorination of
2-[2-(substituted-phenoxy)-6-m- ethyl-pyridin-4-alkylamine with NBS
or NCS in methylene chloride or chloroform at room temperature.
EXAMPLE 256
[3-Bromo-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propy-
l)-amine
[0974] 1H NMR(CDCl.sub.3) d 6.85(s,2 H), 6.04(s,1 H), 4.62(d,1 H),
3.33(m,1 H), 2.27(s,3 H), 2.13(s,3 H), 2.08(s,6 H), 1.5-1.7(m,2 H),
0.95(t,3 H) ppm.
EXAMPLE 257
2-[3,5-Dibromo-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-ylamin-
o]-butan-1-ol
[0975] 1H NMR(CDCl.sub.3) d 7.02(s,2 H), 4.34(m,1 H), 3.6-3.8(m,2
H), 2.30(s,3 H), 2.05(s,6 H), 1.5-1.8(m,2 H), 0.98(t,3 H) ppm.
EXAMPLE 258
2-[3-Bromo-6-(4-chloro-2,6-dimethyl-phenoxy)-2-methyl-pyridin-4-(S)-ylamin-
o]-butan-1-ol
[0976] 1H NMR(CDCl.sub.3) d 7.05(s,2 H), 5.62(s,1 H), 4.86(d,1 H),
3.55-3.7(m,2 H), 3.3(m,1 H), 2.428(s,3 H), 2.09(s,6 H), 1.4-1.7(m,3
H), 0.91(t,3 H) ppm.
EXAMPLE 259
2-[3-Bromo-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamin-
o]-butan-1-ol
[0977] 1H NMR(CDCl.sub.3) d 7.02(s,2 H), 6.14(s,1 H), 4.81(d,lH),
3.6-3.8(m,2 H), 3.45(m,1 H), 2.12(s,3 H), 2.08(s,6 H), 1.5-1.8(m,2
H), 1.00(t,3 H) ppm.
EXAMPLE 260
2-[3-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylami-
no]-butan-1-ol
[0978] 1H NMR(CDCl.sub.3) d 7.02(s,2 H), 6.18(s,1 H), 4.76(d,1 H),
3.6-3.8(m,2 H), 3.45(m,1 H), 2.13(s,3 H), 2.07(s,6 H), 1.5-1.8(m,2
H), 0.99(t,3 H) ppm.
EXAMPLE 261
2-[3,5-Dichloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-ylami-
no]-butan-1-ol
[0979] 1H NMR(CDCl.sub.3) d 7.03(s,2 H), 4.34(m,1 H), 3.6-3.8(m,2
H), 2.40(s,3 H), 2.05(s,6 H), 1.5-1.8(m,2 H), 0.99(t,3 H) ppm.
EXAMPLE 262
2-[3-Chloro-6-(4-chloro-2,6-dimethyl-phenoxy)-2-methyl-pyridin-4-(S)-ylami-
no]-butan-1-ol
[0980] 1H NMR(CDCl.sub.3) d 7.05(s,2 H), 5.66(s,1 H), 4.86(brs,1
H), 3.5-3.8(m,2 H), 3.3(m,1 H), 2.38(s,3 H), 2.09(s,6 H),
1.4-1.7(m,3 H), 0.91(t,3 H) ppm.
EXAMPLE 263
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(4-ethyl-2-oxo-oxazolidin-3-yl)-6--
methyl-nicotinonitrile
[0981] The title compound was prepared by reacting with
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methy-
l-nicotinic acid with triphosgene/NEt.sub.3 in THF. 1H
NMR(CDCl.sub.3) d 7.18(s,1 H), 7.06(s,2 H), 5.00(m,1 H), 4.64(t,1
H), 4.23(dd,1 H), 2.339s,3 H), 2.08(s,6 H), 1.5-1.8(m,2 H),
0.949t,3 H) ppm.
EXAMPLE 264
2-(2,4-Dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-nicotin-
ic acid
[0982] 1H NMR(CDCl.sub.3) d 8.3(brs,1 H), 6.5(m,3 H), 6.26(s,1 H),
4.66(m,1 H), 3.92(s,3 H), 3.85(s,3 H), 3.66(m,2 H), 3.43(s,3 H),
2.52(s,3 H), 1.91 (m,2 H), 1.07(t,3 H) ppm.
EXAMPLE 265
4-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5--
carbonitrile
[0983] 1H NMR(CDCl.sub.3) d 6.92(s,2 H), 6.45(s,1 H), 5.22(m,1 H),
2.29(s,6 H), 2.16(s,6 H), 1.70(m,4 H), 0.93(t,6 H) ppm.
EXAMPLE 266
N-(1-Ethyl-propyl)-2,5-dimethyl-N'-(2,4,6-trimethyl-phenyl)-pyrimidine-4,6-
-diamine
[0984] 1H NMR(CDCl.sub.3) d 8.9(s,1 H), 6.85(s,2 H), 4.95(d,1 H),
4.21(m,1 H), 2.5(s,3 H). 2.25(s,3 H), 2.13(s,6 H), 1.4-1.7(m,4 H),
1.3(s,3 H), 0.85(t,6 H) ppm
EXAMPLE 267
5-Chloro-N4-(1-ethyl-propyl)-2-methyl-N6-(2,4,6-trimethyl-phenyl)-pyrimidi-
ne-4,6-diamine
[0985] 1H NMR(CDCl.sub.3) d 6.85(s,2 H), 6.0(s,1 H), 4.D(m,1 H),
4.2(m,1 H), 2.3(s,3 H), 2.22(,3 H), 2.17(s,6 H), 1.4-1.70(m,4 H),
0.97(t,6 H) ppm.
EXAMPLE 268
5-Bromo-N-(1-ethyl-propyl)-2-methyl-N'-(2,4,6-trimethyl-phenyl)-pyrimidine-
-4,6-diamine
[0986] MP. 117-119.degree. C., Anal. For C.sub.19H.sub.21BrN.sub.4
calc.: C, 58.31; H, 6.95; N, 14.32; found: C, 58.43; H, 7.08; N,
14.23.
EXAMPLE 269
4-(1-Ethyl-propylamino)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-
e-5-carboxylic acid
[0987] 1H NMR(CDCl.sub.3) d 12.2(brs,1 H), 11.1(brs,1 H), 6.84(s,2
H), 4.18(m,1 H), 2.38(s,3 H), 2.18(s,3 H), 2.15(s,6 H), 1.56(m,4
H), 0.90(t,6 H) ppm.
EXAMPLE 270
[4-(Cyclopropylmethyl-propyl-amino)-2-methyl-6-(2,4,6-trichloro-phenylamin-
o)-pyrimidin-5-yl]-methanol
[0988] 1H NMR(CDCl.sub.3) d 7.49s,2 H), 4.95(s,2 H), 4.92(s,1 H),
3.28(brs,4 H), 2.359s,3 H), 1.54(m,2 H), 0.95(m,1 H), 0.81(t,3 H),
0.44(m,2 H), 0.19(m,2 H) ppm.
EXAMPLE 271
6-(1-Ethyl-propoxy)-2,N5,N5-trimethyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidi-
ne-4,5-diamine
[0989] The title compound was prepared by methylation of
6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-d-
iamine with lithium bis(trimethylsilyl)amide in THF, followed by
quenching with methyl iodide. 1 H NMR(CDCl.sub.3) d 7.35(s,1 H),
6.90(s,2 H), 5.16(m,1 H), 2.73(s,6 H), 2.29(s,3 H), 2.27(s,3 H),
2.18(s,6 H), 1.6-1.8(m,4 H), 0.96(t,6 H) ppm.
EXAMPLE 272
[5-Bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phe-
nyl)-amine
[0990] The title compound was prepared by reacting
(5-bromo-6-(1-ethyl-pro- poxy)-2-methyl-pyrimidin-4-yl]-(2,
4,6-trimethyl-phenyl)-amine with 3-pentanol/NaH in THF at reflux
overnight. After standard work-up and purification, the title
compound was obtained as a white solid, mp. 94-96.degree. C. 1H
NMR(CDCl.sub.3) d 6.91(s,2 H), 6.41(s,1 H), 5.13(m,1 H), 2.29(s,3
H), 2.26(,3 H), 2.17(s,6 H), 1.70(m,4 H), 0.95(t,6 H) ppm.
EXAMPLE 273
4-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5--
carboxylic acid
[0991] To a solution of n-BuLi in THF was added a solution of
[5-bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,
4,6-trimethyl-phenylamine in THF at -78.degree. C. After stirring
for 10 minutes, CO.sub.2(g) was added at -78.degree. C. and stirred
at that temperature for 1 hour, then gradually warmed to room
temperature. The resulting mixture was quenched with water and
adjusted to pH 2 to 3 and extracted with chloroform. The organic
layer was separated, dried and concentrated to dryness. The residue
was purified through silica gel column chromatography to give the
title compound as a solid, mp. 118-120.degree. C., Anal. For
C.sub.20H.sub.27N.sub.3O.sub.3 calc.: C, 67.20; H, 7.61; N, 11.76;
found: C, 67.25; H, 7.87; N, 11.48.
EXAMPLE 274
[4-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-5--
yl]-methanol
[0992] To a solution of
4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-ph-
enylamino)-pyrimidine-5-carboxylic acid in dry THF was added
BH.sub.3.DMS. The resulting mixture was heated at reflux. The
mixture was quenched with dilute HCl and stirred for 30 minutes,
adjusted pH to 7.5-8.5, then extracted with ethyl acetate. The
organic layer was separated, dried and concentrated to give a crude
material. The crude material was purified through silica gel column
chromatography to give the title compound as a solid, mp.
121-123.degree. C., Anal. For C.sub.20H.sub.29N.sub.3O.sub.2 calc.
C, 69.94; H, 8.51; N, 12.23; found: C, 69.73; H, 8.47; N,
11.99.
EXAMPLE 275
[6-(1-Ethyl-propoxy)-5-methoxymethyl-2-methyl-pyrimidin-4-yl]-(2,4,6-trime-
thyl-phenyl)-amine
[0993] The title compound was prepared by reacting
[4-(1-ethyl-propoxy)-2--
methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-5-yl]-methanol
with NaH, followed by quenching with MeI. 1H NMR(CDCl.sub.3) d
7.0(s,1 H), 6.89(s,2 H), 5.12(m,1 H), 4.62(s,2 H), 3.33(s,3 H),
2.28(s,3 H0, 2.27(s,3 H), 2.14(s,6 H), 1.66(m,4 H), 0.91(t,6 H)
ppm.
EXAMPLE 276
(5-Aminomethyl-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimeth-
yl-phenyl)-amine
[0994] To a solution of
[4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-p-
henylamino)-pyrimidin-5-yl]-methanol in anhydrous methylene
chloride was added thionyl chloride. After stirring for 1 hour, the
reaction mixture was concentrated to dryness. The residue was
dissolved in dry THF and NH.sub.3(g) was bubbled in. The reaction
mixture was quenched with water and extracted with ethyl acetate.
The reaction was worked-up and purified by standard procedure to
give the title compound.
[0995] 1H NMR(CDCl.sub.3) d 8.50(s,1 H), 6.88(s,2 H), 5.08(m,1 H),
3.97(s,2 H), 2.279s,3 H), 2.25(s,3 H), 2.159s,6 H), 1.74(brs,2 H),
1.65(m,4 H), 0.91(t,6 H) ppm.
EXAMPLE 277
7-(1-Ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]p-
yridin-2-ylamine
[0996] The title compound was prepared by reacting
4-(1-ethyl-propoxy)-6-m-
ethyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine with BrCN in
acetonitrile at room temperature overnight.
[0997] The mixture was quenched with water and adjusted to pH 8.0
with saturated sodium bicarbonate and extracted with ethyl acetate.
The organic layer was separated, dried and concentrated to give
crude material. The material was purified through silica gel column
chromatography to give the title compound as a white solid, mp.
159-161.degree. C. 1H NMR(CDCl.sub.3) d 7.05(s,2 H), 6.5(s,1 H),
4.6(m,1 H), 4.3(m,2 H), 2.45(s,3 H), 2.35(s,3 H), 2.0(s,6 H),
1.7(m,4 H), 1.0(t,6 H) ppm.
EXAMPLE 278
7-(1-Ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3
H-imidazo[4,5-b]pyridine
[0998] A mixture of
4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-pheny-
l)-pyridine-2,3-diamine, trimethyl orthoformate, p-toluenesulfonic
acid monohydrate in toluene was heated at reflux using Dean-Stark
apparatus for 24 hours. The mixture was heated at reflux overnight.
The mixture was quenched with water, sat. NaHCO.sub.3, extracted
with ethyl acetate. The organic layer was separated, dried
(MgSO.sub.4) and concentrated to dryness. After purification, the
title compound was isolated. Anal. For
C.sub.21H.sub.29N.sub.3O.1/4H.sub.2O calc. C, 73.76; H, 8.10; N,
12.29; found: C, 73.22; H, 7.96; N, 12.42.
EXAMPLE 279
7-(1-Ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-imidaz-
o[4,5-b]pyridin-2-one
[0999] The title compound was prepared by reacting
4-(1-ethyl-propoxy)-6-m-
ethyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine with
triphosgene, NEt.sub.3 in THF at room temperature. A white solid
was isolated, mp. 184-186.degree. C. Anal. For
C.sub.21H.sub.27N.sub.3O.sub.2 calc. C, 71.36; H, 7.70; N, 11.89;
found: C, 71.09; H, 7.75; N, 11.63.
EXAMPLE 280
7-(1-Ethyl-propoxy)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-im-
idazo[4,5-b]pyridin-2-one
[1000] The title compound was prepared by reacting
7-(1-ethyl-propoxy)-5-m-
ethyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-imidazo
[4,5-b]pyridin-2-one with lithium bis(trimethylsilyl)amide,
followed by quenching with methyl iodide. Mp. 151-153.degree. C.
Anal. For C.sub.22H.sub.29N.sub.3O.sub.2. 1/4H.sub.2O calc. C,
71.03; H, 7.99; N, 11.30; found: C, 71.29; H, 8.01; N, 11.03.
EXAMPLE 281
(1-Ethyl-propyl[-5-methyl-3-(2,4,6-trimethyl-phenyl)-3
H-imidazo[4,5-b]pyridin-7-yl]-amine
[1001] A mixture of
N-4-(1-ethyl-propyl)-6-methyl-N-2-(2,4,6-trimethyl-phe-
nyl)-pyridine-2,3,4-triamine (250 mg, 0.77 mmol) , trimethyl
orthoformate (0.081 g, 0.766 mmol), p-toluenesulfonic acid
monohydrate (0.01 g) in benzene was heated at reflux using
Dean-Stark apparatus for 24 hours. Benzene was removed and toluene
was added and an excess of trimethyl orthoformate (0.084 ml) was
added to the reaction mixture. The mixture was heated at reflux
overnight. The mixture was quenched with water, sat. NaHCO.sub.3,
extracted with ethyl acetate. The organic layer was separated,
dried (MgSO.sub.4) and concentrated to dryness. After purification,
the title compound was isolated as a white crystal, mp
78-80.degree. C.
EXAMPLE 282
[2,5-Dimethyl-3-(2,4,6-trimethyl-phenyl )-3
H-imidazo[4,5-b]pyridin-7-yl]-- (1-ethyl-propyl)-amine
[1002] A mixture of
N-4-(1-ethyl-propyl)-6-methyl-N-2-(2,4,6-trimethyl-phe-
nyl)-pyridine-2,3,4-triamine (250 mg, 0.77 mmol), trimethyl
orthoacetate (0.184 g, 1.532 mmol), p-toluenesulfonic acid
monohydrate (0.01 g) in toluene was heated at reflux using
Dean-Stark apparatus for 3 hours. The mixture was quenched with
water, brine, extracted with ethyl acetate. The organic layer was
separated, dried (MgSO.sub.4) and concentrated to dryness. After
purification, the title compound was obtained as a white crystal,
mp 101-103.degree. C. Anal. For C.sub.22H.sub.30N.sub.4 calc. C,
75.39; H, 8.63; N, 15.98; found, C, 75.44; H. 8.95; N, 15.95.
EXAMPLE 283
N7-(1-Ethyl-propyl)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3
H-imidazo[4,5-b]pyridine-2,7-diamine
[1003] The title compound was prepared by reacting
N4-(1-ethyl-propyl)-6-m-
ethyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine with BrCN
in acetonitrile at room temperature overnight. The mixture was
quenched with water and adjusted to pH 8.0 with saturated sodium
bicarbonate and extracted with ethyl acetate. The organic layer was
separated, dried and concentrated to give crude material. The
material was purified through silica gel column chromatography to
give the title compound as a brown solid, mp. 158-160.degree. C.;
Anal. For C.sub.21H.sub.29N.sub.5 1/4H.sub.2O calc. C, 70.85; H,
8.35; N, 19.67; found: C, 71.07; H, 8.30; N, 19.63.
EXAMPLE 284
6-(1-Ethyl-propylamino)-2,7-dimethyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydr-
o-purin-8-one
[1004] The title compound was prepared by methylation of
6-(1-ethyl-propylamino)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-p-
urin-8-one with lithium bis(trimethylsilyl)amide in THF, followed
by quenching with methyl iodide. 1H NMR(CDCl.sub.3) d 6.98(s,2 H),
4.45(d,1 H), 4.3(m,1 H), 3.7(s,3 H), 2.4(s,3 H), 2.3(s,3 H),
2.1(s,6 H), 1.5-1.8(m,4 H), 1.0(t,6 H) ppm.
EXAMPLE 285
6-(1-Ethyl-propoxy)-2,7-dimethyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-pu-
rin-8-one
[1005] The title compound was prepared by methylation of
6-(1-Ethyl-propoxy)-2-methyl-9-(2,
4,6-trimethyl-phenyl)-7,9-dihydro-puri- n-8-one with lithium
bis(trimethylsilyl)amide in THF, followed by quenching with methyl
iodide. 1H NMR(CDCl.sub.3) d7.00(s,2 H), 5.31(m,1 H), 3.66(s,3 H),
2.479s,3 H), 2.33(s,3 H), 2.06(s,6 H), 1.79(m,4 H), 1.01(t,6 H)
ppm.
EXAMPLE 286
[2-(4-Methoxy-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-meth-
oxymethyl-propylyamine
[1006] 1H NMR(CDCl.sub.3) d 7.71(d,1 H), 6.57(s,2 H), 6.21(s,1 H),
3.76(s,3 H), 3.59(m,1 H), 3.48(m,1 H), 3.45(m,1 H), 3.37(s,3 H),
2.13(s,3 H), 2.08(s,6 H), 1.6-1.8(m,4 H), 0.86(t,3 H) ppm.
EXAMPLE 287
(1-Ethyl-propyl)-[2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin--
4-yl]-amine
[1007] 1H NMR(CDCl.sub.3) d 6.64(s,2 H), 6.12(s,1 H), 3.82(s,3 H),
3.36(m,1 H), 2.26(s,3 H), 2.13(s,6 H), 2.10(s,3 H), 1.5-1.8m,4 H),
0.99(t,6 H).
EXAMPLE 288
2-[2-(4-Methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-buta-
n-1-ol
[1008] 1H NMR(CDCl.sub.3) d 6.64(s,2 H), 6.13(s,1 H), 4.10(m,1 H),
3.76(s,3 H), 3.7-3.8(m,21 H), 3.57(m,1 H), 2.21(s,3 H), 2.19(s,6
H), 2.12(s,3 H), 1.6-1.8(m,2 H), 1.04(t,3 H) ppm.
EXAMPLE 289
sec-Butyl-[3-methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-
-yl]-amine
[1009] 1H NMR(CDCl.sub.3) d 6.64(s,2 H), 6.13(s,1 H), 4.51(d,1 H),
3.92(s,3 H), 3.82(s,3 H), 3.469m,1 H), 2.18(s,3 H), 2.15(s,6 H),
1.60(m,2 H), 1.26(d,3 H), 1.00(t,3 H) ppm.
EXAMPLE 290
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(4-ethyl-oxazolidin-3-yl)-3,6-dimethyl-
-pyridine
[1010] 1H NMR(CDCl.sub.3) d 7.07(s,2 H), 6.36(s,1 H), 4.98(m,1 H),
4.78(m,1 H), 4.23(m,1 H), 3.83(m,1 H), 3.71(m,1 H), 2.28(s,3 H),
2.20(s,3 H), 2.09(s,6 H), 1.81(m,1 H), 1.58(m,1 H), 0.98(t,3 H)
ppm.
EXAMPLE 291
4-(4-Ethyl-oxazolidin-3-yl)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethy-
l-pyridine
[1011] 1H NMR(CDCl.sub.3) d 6.65(s,2 H), 6.36(s,1 H), 4.98(m,1 H),
4.77(m,1 H), 4.23(m,1 H), 3.83(s,3 H), 3.71(m,1 H), ), 2.29(s,3 H),
2.22(s,3 H), 2.119(s,6 H), 1.82(m,1 H), 1.56(m,1 H), 0.99(t,3 H)
ppm
EXAMPLE 293
2-(4-Methoxy-2,6-dimethyl-phenoxy)-N%4&-(1-methoxymethyl-propyl)-6-methyl--
pyridine-3,4-diamine
[1012] 1H NMR(CDCl.sub.3) d 6.64(s,2 H), 6.16(s,1 H), 4.3(m,1 H),
3.82(s,3 H), 3.6-3.8(m,2 H), 3.42(s,3 H), 3.2(brs,2 H), 2.18(s,3
H), 2.13(s,6 H), 1.6-1.8(m,2 H), 1.03(t,3 H) ppm.
EXAMPLE 294
3-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-yl-
amino]-pentan-2-ol
[1013] 1H NMR(CDCl.sub.3) d 7.01(s,2 H), 6.16(s,1 H), 5.19(d,1 H),
4.94(m,2 H), 3.88(m,1 H), 3.27(m,1 H), 2.11(s,3 H), 2.05(s,6 H),
1.73(m,1 H), 1.57(m,1 H), 1.24(d,3 H), 0.97(t,3 H)ppm.
EXAMPLE 295
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-n-
icotinic acid methyl ester
[1014] 1H NMR(CDCl.sub.3) d 8.63(d,1 H), 7.01(s,2 H), 5.90(s,1 H),
3.95(m,1 H), 3.90(s,3 H), 2.08(s,3 H), 2.05(s,3 H), 2.03(s,6 H),
1.8-2.0(m,2 H), 1.00(t,3 H) ppm.
EXAMPLE 296
3-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxymethyl-6-methyl-pyridin-4-yl-
amino]-pentan-2-ol
[1015] 1H NMR(CDCl.sub.3) d 7.08(s,2 H), 6.21(s,1 H), 5.40(brs,1
H), 4.83(q,2 H), 3.91(m,1 H), 3.40(s,3 H), 3.33(m,1 H), 2.20(s,3
H), 2.10(s,6 H), 1.78(m,1 H), 1.58(m,1 H), 1.29(d,3 H), 1.01(t,3 H)
ppm.
EXAMPLE 297
3-[2-(4-Methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-pent-
an-2-ol
[1016] 1H NMR(CDCl.sub.3) d 6.66(s,2 H), 6.27(s,1 H), 4.05(m,1 H),
3.82(s,3 H), 3.38(m,1 H), 2.35(s,3 H), 2.21(s,3 H), 2.14(s,6 H),
1.6-1.9(m,2 H), 1.30(m,3 H), 1.01(t,3 H)ppm.
EXAMPLE 298
4-sec-Butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinic
acid methyl ester
[1017] 1 H NMR(CDCl.sub.3) d 8.01(d,1 H), 6.58(s,2 H), 6.06(s,1 H),
3.85(s,3 H), 3.77(s,3 H), 2.10(s,3 H), 2.07(s,6 H), 1.21(d,3 H0,
0.97(t,3 H) ppm.
EXAMPLE 299
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-2-methyl-propylamin-
o)-6-methyl-nicotinic acid methyl ester
[1018] 1H NMR(CDCl.sub.3) d 8.28(d,1 H), 7.06(s,2 H), 6.32(s,1 H),
3.92(s,3 H), 3.41(m,1 H), 2.14(s,3 H), 2.12(s,6 H), 1.91(m,1 H),
1.44(m,1 H), 1.33(s,3 H), 1.30(s,3 H0, 0.99(s,3 H) ppm.
EXAMPLE 300
4-(1-Hydroxymethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methy-
l-nicotinic acid methyl ester
[1019] 1H NMR(CDCl.sub.3) d 8.13(d,1 H), 6.63(s,2 H), 6.21(s,1 H),
3.91(s,3 H0, 3.82(s,3 H0, 3.81(m,2 H), 3.59(m,1 H), 2.16(s,3 H),
2.12(s,6 H), 1.6-1.859m,2 H), 1.05(t,3 H) ppm.
EXAMPLE 301
2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-3-methylsulfanyl-prop-
ylamino)-6-methyl-nicotinic acid methyl ester
[1020] 1H NMR(CDCl.sub.3) d 8.25(d,1 H), 7.02(s,2 H), 6.30(s,1 H),
3.85(s,3 H), 3.6-3.9(m,3 H), 2.5-2.7(m,2 H), 2.14(s,3 H), 2.10(s,3
H), 2.06(s,6 H), 1.8-2.1(m,2 H)ppm.
EXAMPLE 301
2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)--
nicotinic acid methyl ester
[1021] 1H NMR(CDCl.sub.3) d 8.25(d,1 H), 7.01(s,2 H), 6.05(s,1 H),
4.11(m,1 H), 3.9-4.1(m,2 H), 3.8-3.9(m,1 H), 3.86(s,3 H), 3.73(m,1
H), 2.2-2.4(m,1 H), 2.11(s,3 H), 2.05(s,6 H), 1.95(m,1 H) ppm.
EXAMPLE 302
{3-[2-(4-Chloro-2,6-dimethyl-phenoxy
)-3-methoxycarbonyl-6-methyl-pyridin--
4-ylamino]-4-hydroxy-butyl)-dimethyl-sulfonium iodide
[1022] 1H NMR(CD.sub.3OD) d 7.11(s,2 H), 6.61(s,1 H), 4.00(m,1 H),
3.86(s,3 H), 3.6-3.9(m,3 H), 2.95(d,6 H), 2.5-2.7(m,2 H), 2.22(s,3
H), 2.07(s,6 H), 1.8-2.1(m,2 H)ppm.
EXAMPLE 303
4-(1-Hydroxymethyl-3-methylsulfanyl-propylamino)-2-(4-methoxy-2,6-dimethyl-
-phenoxy)-6-methyl-nicotinic acid methyl ester
[1023] 1H NMR(CDCl.sub.3) d 8.15(d,1 H), 6.58(s,2 H), 6.28(s,1 H),
3.85(s,3 H), 3.76(s,3 H), 3.6-3.9(m,3 H), 2.5-2.7(m,2 H), 2.12(s,3
H), 2.09(s,3 H), 2.07(s,6 H), 1.8-2.1(m,2 H)ppm.
EXAMPLE 304
4-(1-Hydroxymethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dim-
ethyl-nicotinamide
[1024] 1HNMR(CDCl.sub.3) d 9.84(d,1 H), 8.31(m,1 H), 6.66(s,2 H),
6.29(s,1 H), 3.81(s,3 H), 3.5-3.9(m,3 H), 2.98(d,3 H), 2.15(s,3 H),
2.12(s,6 H), 1.6-1.8(m,2 H), 1.05(t,3 H)ppm.
EXAMPLE 305
4-sec-Butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinam-
ide
[1025] 1H NMR(CDCl.sub.3) d 9.77(brs,1 H), 8.22(brs,1 H), 6.61(s,2
H), 6.11(s,1 H), 3.78(s,3 H), 3.45(m,1 H), 2.93(d,3 H), 2.10(s,3
H), 2.07(s,6 H), 1.5-1.7(m,2 H), 1.23(m,3 H), 0.98(t,3 H)ppm.
EXAMPLE 306
2-(4-Methoxy-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-
-nicotinic acid methyl ester
[1026] 1H NMR(CDCl.sub.3) d 8.28(d,1 H), 6.63(s,2 H), 6.09(s,1 H),
4.15(m,1 H), 3.98-4.1(m,2 H), 3.8-3.98(m,1 H), 3.90(s,3 H),
3.81(s,3 H), 3.76(m,1 H), 2.32-2.36(m,1 H), 2.19(s,3 H), 2.11(s,6
H), 1.95(m,1H) ppm.
EXAMPLE 307
4-sec-Butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinamide
[1027] 1H NMR(CDCl.sub.3) d 9.74(ds,1 H), 8.05(brs,1 H), 6.65(s,2
H), 6.16(s,1 H), 5.55(brs,1 H), 3.83(s,3 H), 3.51 (m,1 H), 2.16(s,3
H), 2.12(s,6 H), 1.5-1.7(m,2 H), 1.26(d,3 H), 1.02(t,3 H)ppm.
Preparation A
[1028]
(6-Chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-amine
[1029] A mixture of 2,5-dimethyl-4,6-dichloropyrimidine (1.77 g, 10
mmol) and trimethylaniline (2.70 g, 20 mmol) in 5 ml of DMSO was
heated in an oil bath of 160.degree. C. for 4 hours. The mixture
was quenched with water and extracted with ethyl acetate. The
organic layer was separated, dried and concentrated to give the
crude material. After silica gel column purification, and titration
with hexane, white crystals (790 mg) were obtained; high MS calc,
275.1185, found 275.11667; IR(KBr) 3290, 3240, 2900, 1540 cm-1. 1H
NMR (CDCl.sub.3) .delta. 6.91 (s, 2 H), 5.85 (s, 1 H), 2.33 (s, 3
H), 2.87 (s, 3 H), 2.24 (s, 3 H), 2.12 (s, 6 H) ppm.
Preparation B
[1030]
(6-Chloro-2,5-dimethylpyrimidin-4-ylymethyl-(2,4,6-trimethylphenyl)-
-amine
[1031] A solution of
(6-chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethy-
lphenyl)-amine (276 mg, 1 mmol) in dry THF (2 ml) was treated with
sodium hydride (60% in oil, 60 mg, 1.5 mmol) at room temperature.
After stirring for 2 minutes, an excess of methyl iodide (0.5 ml)
was added and the resulting mixture was stirred at room temperature
for 20 minutes. The mixture was quenched with saturated ammonium
chloride and extracted with ethyl acetate. The organic layer was
separated, dried and concentrated to give a pale yellow solid (255
mg). .sup.1H NMR (CDCl.sub.3) .delta. 6.85 (s, 2 H), 3.26 (s, 3 H),
2.50 (s, 3 H), 2.27 (s, 3 H), 2.03 (s,. 6 H), 1.39 (s, 3 H)
ppm.
Preparation C
[1032]
4-Chloro-2,5-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyrimidine
[1033] A solution of 2,4,6-trimethylphenol (2.720 g, 20 mmol) in 60
ml of dry THF was treated with NaH (60% in oil, 1.200 g, 30 mmol)
at room temperature. After stirring at room temperature for 15
minutes, 2,5-dimethyl-4,6-dichloropyrimidine (3.34 g, 20 mmol) was
added and the resulting mixture was heated at reflux for 15 hours.
The mixture was quenched with saturated ammonium chloride and
extracted with ethyl acetate. The organic layer was dried and
concentrated to give 5.4528 g of beige solid. The solid was
recrystallized from isopropanol to give 5.1345 g of pale yellow
solid, mp 86-87.degree. C.; high MS (C.sub.15H.sub.17ClN.sub.20)
calc. 276.1025, found 276.10359. .sup.1H NMR (CDCl.sub.3) .delta.
6.87 (s, 2 H), 2.37 (s, 6 H), 2.28 (s, 3 H), 2.01 (s, 6 H) ppm.
Preparation D
[1034] 2,4-Dichloro-3,6-dimethylpyridine
[1035] A mixture of 2,4-dihydroxy-3,6-dimethylpyridine (2.86 g,
20.58 mmol), POCl.sub.3 (15 ml) and N,N-diethylaniline (3.6 ml,
22.64 mmol) was heated at reflux for 3 hours. The mixture was
cooled, poured into ice water and extracted with diethyl ether. The
organic layer was dried and concentrated to give 3.02 g of the
crude material. After silica gel column chromatography using
chloroform as eluent, 1.3102 g of the title compound was obtained
as a yellow oil. .sup.1H NMR (CDCl.sub.3) .delta. 7.07 (s, 1 H),
2.43 (s, 3 H), 2.39 (s, 3 H) ppm.
Preparation E
[1036]
4-Chloro-3,6-dimethyl-2-(2,4,6-trimethyl-phenyoxy)-pyridine
[1037] A solution of 2,4,6-trimethylphenol (450 mg, 3.31 mmol) in 2
ml of DMSO was treated with NaH (60% in oil, 180 mg, 4.5 mmol).
After 5 min, 2,4-Dichloro-3,6-dimethyl-pyridine (528 mg, 3 mmol)
was added. The mixture was heated in the oil bath of 130.degree. C.
for 6 hours. The mixture was quenched with water and extracted with
EtOAc. The organic layer was dried and concentrated to give 812.5
mg of crude material with two regioisomers. After silica gel column
chromatography using 1:1 of CHCl.sub.3:hexane as eluent, the title
compound was isolated as white crystals (141 mg), mp 57-62.degree.
C.; high MS for C.sub.16H.sub.18ClNO: calc, 275.1072, found
275.70172; IR(KBr) 2951, 2920, 1592, 1564 cm-1; .sup.1H NMR
(CDCl.sub.3) .delta. 6.87 (s, 2 H), 6.77 (s, 1 H), 2.39 (s, 3 H),
2.29 (s, 3 H), 2.18 (s, 3 H), 2.03 (s, 6 H) ppm. The regiochemistry
was determined by X-ray structural analysis of the undesired
regioisomer,
2-chloro-3,6-dimethyl-4-(2,4,6-trimethyl-phenyoxy)-pyridine.
[1038] To a solution of
4-chloro-2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-- pyridine
1-oxide (34 mg) in 1 ml dry methylene chloride was added 2M
PCl.sub.3 in methylene chloride (0.022 ml). After addition, the
mixture was heated at reflux for 0.5 hours, cooled and concentrated
to dryness. The residue was poured into ice-water and extracted
with methylene chloride. The organic layer was washed with brine,
neutralized with sat. sodium carbonate, dried and concentrated to
give 47 mg of the crude material. The crude material was
crystallized out upon standing to give 31 mg (95%) of white
crystals of the title compound.
Preparation F
[1039]
(6-Chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-aceto-
nitrile
[1040] To a solution of mesitylacetonitrile (0.900 g, 5.65 mmol) in
8 ml dry THF was added sodium hydride (60% in oil, 0.250 g, 6.21
mmol) and the mixture was stirred at room temperature for 40
minutes. 2,5-Dimethyl-4,6-dichloropyrimidine (1.000 g, 5.65 mmol)
was added and the resulting mixture was heated at reflux for 5
hours. The mixture was quenched with water and extracted with ethyl
acetate. The organic layer was dried and concentrated to give 1.800
g of a yellow oil. The oil residue was purified through silica gel
column chromatography using 10% ethyl acetate in hexane as eluent
to give 0.986 g (58.3%) of the title compound as a white solid, mp
100-102.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 6.86 (s, 2 H),
5.60 (s, 1 H), 2.69 (s, 3 H), 2.25 (s, 3 H), 2.18 (s, 6 H), 1.92
(s, 3 H) ppm.
Preparation G
[1041]
2-(6-Chloro-2,5-dimethylpyrimidin-4-yl)-2-(2,4,6-trimethylphenyl)-p-
ropionitrile
[1042] A solution of
(6-chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethy-
lphenyl)-acetonitrile (0.250 g, 0.834 mmol) in 4 ml of dry THF was
cooled to -78.degree. C. and treated with lithium
bistrimethylsilylamide (1.0 M in THF, 0.92 ml) and stirred at that
temperature for 45 minutes. Methyl iodide (0.426 g, 3.00 mmol) was
added. The reaction mixture was gradually warmed to room
temperature and stirred for 1 hour. The reaction mixture was
quenched with water and extracted with ethyl acetate. The organic
layer was dried and concentrated to give a yellow oil. The oil
residue was purified through silica gel chromatotron using ethyl
acetate/hexane (4:6) as eluent to give 161 mg (62%) of yellow
solid, mp 181-183.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 6.980
(s, 2 H), 3.45 (s, 3 H), 2.40 (s, 3 H), 2.24 (s, 3 H), 2.21 (s, 6
H), 1.25 (s, 3 H) ppm.
Preparation H
[1043]
4-Hydroxy-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine
[1044] A mixture of
6-chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylp-
henyl)-acetonitrile (1.5 g, 5.0 mmol) and 60 ml of 85% phosphoric
acid was heated at reflux for 2 hours. The mixture was cooled at rt
and diluted with water and extracted with chloroform. The organic
layer was washed with brine, dried and concentrated to give 1.21 g
(95%) of the title compound as a white solid, mp 260-262.degree.
C.
Preparation I
[1045]
4-Chloro-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine
[1046] A mixture of
4-hydroxy-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyri- midine (1.2
g, 4.68 mmol) and POCl.sub.3 (25 ml) was heated at reflux for 1
hour. The mixture was cooled and evaporated to dryness. The residue
was poured into ice-water and extracted with ethyl acetate. The
organic layer was washed with brine, dried and concentrated to
dryness to give 1.24 g (97%) of golden crystals, mp 82-84.degree.
C.
Preparation J
[1047] The following compounds were prepared by the methods
analogous to that in Preparation C starting with
5-substituted-4,6-dichloro-2-methyl-p- yrimidine and substituted
phenol in tetrahydrofuran in the presence of a base (sodium
hydride) at the temperature indicated below.
[1048]
5tert-Butyl-4-chloro-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-
e
[1049] The reaction was carried out at reflux in THF to give white
crystals, mp 70-72.degree. C., .sup.1H NMR (CDCl.sub.3) .delta.
6.82 (s, 2 H), 2.28 (s, 3 H), 2.24 (s, 3 H), 1.96 (s, 6 H), 1.60
(s, 9H) ppm.
[1050]
4-Chloro-5-isopropyl-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-
e
[1051] The reaction was carried at reflux in THF to give white
crystals, mp 68-70.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 6.88
(s, 2 H), 3.60 (m, 1 H), 2.36 (s, 3 H), 2.29 (s, 3 H), 2.00 (s, 6
H), 1.43 (s, 3 H), 1.41 (s, 3 H) ppm.
[1052]
4,5-Dichloro-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine
[1053] The reaction run at room temperature to give white crystals,
mp 68-70.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 6.88 (s, 2 H),
2.41 (s, 3 H), 2.29 (s, 3 H), 2.04 (s, 6 H) ppm.
[1054]
4-Chloro-5-bromo-2-methyl-4-(2,4,6-trimethyl-phenoxy)-pyrmidine
[1055] The reaction was run at 0.degree. C. to room temperature.
.sup.1H NMR (CDCl.sub.3) .delta. 6.88 (s, 2 H), 2.41 (s, 3 H), 2.29
(s, 3 H), 2.03 (s, 6 H) ppm.
[1056]
4-Chloro-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine-5-carbonit-
rile
[1057] The reaction was run at -40.degree. C. to give yellow
crystals, mp 89-91.degree. C. .sup.1H NMR (CDCl.sub.3) .delta. 6.89
(s, 2 H), 2.51 (s, 3 H), 2.29 (s, 3 H), 2.04 (s, 6 H) ppm.
Preparation K
[1058] 2,4-Dichloro-3,6-diemthyl-pyridine 1-oxide
[1059] A mixture of 2,4-dichloro-3,6-dimethyl-pyridine (790 mg,
4.49 mmol) and 50% m-chloro-perbenzoic acid (1.544 g, 4.49 mmol) in
10 ml of chloroform was stirred at room temperature for 20 hours.
The mixture was quenched with water, washed with saturated sodium
thiosulfate and saturated sodium carbonate, brine and extracted
with chloroform. The organic layer was dried and concentrated to
give 954 mg of crude material. The material was purified through
silica gel to give 662 mg of the title compound as a white
crystals, mp 131-132.degree. C. .sup.1H NMR (CDCl.sub.3) .delta.
7.22 (s, 1 H), 2.51 (s, 3 H), 2.47 (s, 3 H) ppm.
Preparation L
[1060] The following compounds were prepared by the method
analogous to that described in Preparation K starting with an
appropriate 2,4-dichloro-pyridine and an oxidizing agent.
[1061] 2,4-Dichloro-6-methyl-1-oxy-nicotinic acid methyl ester
[1062] M.p. 90-91.5.degree. C. .sup.1H NMR (CDCl.sub.3) .delta.
7.26 (s, 1 H), 3.98 (s, 3 H), 2.54 (s, 3 H) ppm.
[1063] (2,4-Dichloro-6-methyl-1-oxy-pyridin-3-yl)methanol
[1064] M.p. 188-191.degree. C. .sup.1H NMR (CDCl.sub.3) .delta.
7.13 (s, 1 H), 4.87 (d, 2 H), 2.47 (s, 3 H), 2.38 (t, 1 H, OH)
ppm.
[1065] 2,4-Dichloro-3,5,6-trimethyl-pyridine 1-oxide
[1066] M.p. 146-148.degree. C. .sup.1H NMR (CDCl.sub.3) .delta.
2.57 (s, 3 H), 2.49 (s, 3 H), 2.38 (s, 3 H)) ppm.
[1067] 2,4-Dichloro-6-methyl-pyridine 1-oxide
[1068] M.p. 100-102.degree. C. .sup.1H NMR (CDCl.sub.3) .delta.
7.42 (d, 1 H), 7.22 (d, 1 H), 2.55 (s, 3 H) ppm.
Preparation M
[1069]
4-Chloro-2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyridine-1-oxide
[1070] To a solution of 2,4,6-trimethylphenol (415 mg, 3.05 mmol)
in dry THF (20 ml) was treated with 60% sodium hydride in oil (122
mg, 3.05 mmol) at room temperature. After all H.sub.2 was evolved,
2,4-dichloro-3,6-dimethyl-pyridine 1-oxide (585.4 mg, 3.05 mmol)
was added and the resulting mixture was heated at reflux for 2
hours. The mixture was quenched with saturated ammonium chloride
and extracted with ethyl acetate. The organic layer was dried and
concentrated to dryness to give solid. The solid was recrystallized
from pet ether to give 802 mg (90%) of the title compound as white
crystals, mp 106-107.degree. C. .sup.1H NMR (CDCl.sub.3) 6 7.04 (s,
1 H), 6.78 (s, 2 H), 2.41 (s, 3 H), 2.36 (s, 3 H), 2.22 (s, 3 H),
2.06 (s, 6 H) ppm.
Preparation N
[1071] The following compounds were prepared by the method
analogous to that described in Preparation M starting with an
appropriate 2,4-dichloro-pyridine-1-oxide with an appropriate
phenol or thiophenol in the presence of a base (potassium
tert-buoxide, sodium hydride, or potassium hydride) at temperature
between room temperature to reflux in dry THF.
[1072]
2-(4-Bromo-2,6-dimethyl-phenoxy)-4-chloro-3,6-dimethyl-pyridine
1-oxide
[1073] White crystals, mp 137-139.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 7.12 (s, 2 H), 7.08 (s, 1 H), 2.42 (s, 6 H),
2.09 (s, 6 H) ppm.
[1074]
4-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine
1-oxide
[1075] .sup.1H NMR (CDCl.sub.3) .delta. 7.08 (s, 1 H), 6.97 (s, 2
H), 2.42 (s, 6 H), 2.09 (s, 6 H) ppm,
[1076]
4-Chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-1-oxy-nicotinic acid
methyl ester
[1077] .sup.1H NMR (CDCl.sub.3) .delta. 7.04 (s, 1 H), 6.78 (s, 2
H), 3.48 (s, 3 H), 2.52 (s, 3 H), 2.22 (s, 3 H), 2.08 (s, 6 H)
ppm.
[1078] 4-Chloro-2,3,5trimethyl-6-(2,4,6-trimethyl-phenoxy)-pyridine
1-oxide
[1079] White crystals, mp 132-134.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 6.75 (s, 2 H), 2.47 (s, 3 H), 2.38 (s, 3 H),
2.35 (s, 3 H), 2.20 (s, 3 H), 2.04 (s, 6 H) ppm.
[1080] 4-Chloro-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridine
1-oxide
[1081] White crystals, mp 191-193.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 6.96 (s, 1 H), 6.95 (s, 2 H), 2.62 (s, 3 H),
2.32 (s, 3 H), 2.13 (s, 6 H) ppm.
[1082]
4-Chloro-2-(2,4-dimethyl-phenylsulfanyl)-3,6-dimethyl-pyridine
1-oxide white crystals, mp 148-151.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 7.23 (s, 1 H), 7.02 (s, 1 H), 6.88 (s, 2 H),
2.46 (s, 3 H), 2.41 (s, 3 H), 2.39 (s, 3 H), 2.27 (s, 3 H) ppm.
[1083]
4-Chloro-2-(2,4,6-trimethyl-phenylsulfanyl)-3,6-dimethyl-pyridine
1-oxide
[1084] White crystals, mp 132-134.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 7.13 (s, 1 H), 6.91 (s, 2 H), 2.46 (s, 3 H),
2.31 (s, 6 H), 2.27 (s, 3 H), 2.10 (s, 3 H) ppm.
Preparation O
[1085] The following compounds were prepared by the method
analogous to that described in Preparation E, second paragraph,
starting with an appropriate 4-chloro-6-substituted
phenoxy-pyridine 1-oxide and phosphorous trichloride.
[1086]
2-(4-Bromo-2,6-dimethyl-phenoxy)-4-chloro-3,6-dimethyl-pyridine
[1087] White crystals. .sup.1H NMR (CDCl.sub.3) .delta. 7.22 (s, 2
H), 6.81 (s, 1 H), 2.40 (s, 3 H), 2.20 (s, 3 H), 2.05 (s, 6 H)
ppm.
[1088]
4-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine
[1089] White crystals. .sup.1H NMR (CDCl.sub.3) .delta. 7.07 (s, 2
H), 6.81 (s, 1 H), 2.41 (s, 3 H), 2.20 (s, 3 H), 2.06 (s, 6 H)
ppm.
[1090] 4-Chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid
methyl ester
[1091] Yellow crystals, mp 122-125.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 6.84 (s, 2 H), 6.82 (s, 1 H), 3.94 (s, 3 H),
2.27(s, 3 H), 2.25 (s, 3 H), 2.04 (s, 6 H) ppm.
[1092]
4-Chloro-2,3,5-trimethyl-(2,4,6-trimethyl-phenoxy)-pyridine
[1093] White crystals, mp 101-103.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 6.85 (s, 2 H), 2.39 (s, 3 H), 2.28 (s, 3 H),
2.22 (s, 3 H), 2.20 (s, 3 H), 2.01 (s, 6 H) ppm.
[1094] 4-Chloro-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridine
[1095] White crystals, mp 46-48.degree. C. .sup.1H NMR (CDCl.sub.3)
.delta. 6.92 (s, 2 H), 6.84 (s, 1 H), 2.62 (s, 3 H), 2.32 (s, 3 H),
2.13 (s, 6 H) ppm.
[1096]
4-Chloro-2-(2,4-dimethyl-phenylsulfanyl)-3,6-dimethyl-pyridine
[1097] White crystals, mp 148-151.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 7.23 (s, 1 H), 7.02 (s, 1 H), 6.88 (s, 2 H),
2.46 (s, 3 H), 2.41 (s, 3 H), 2.39 (s, 3 H), 2.27 (s, 3 H) ppm.
[1098]
4-Chloro-2-(2,4,6-trimethyl-phenylsulfanyl)-3,6-dimethyl-pyridine
[1099] White crystals, mp 132-134.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 7.13 (s, 1 H), 6.91 (s, 2 H), 2.46 (s, 3 H),
2.31 (s, 6 H), 2.27 (s, 3 H), 2.10 (s, 3 H) ppm.
Preparation P
[1100] 2-Chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid
methyl ester
[1101] A mixture of 2,4-dichloro-6-methyl-nicotinic acid methyl
ester (2.228 g, 10.13 mmol) and 1-ethyl-propyl amine (1.762 g,
20.26 mmol) in DMSO (4 ml) was heated at 110.degree. C. for 5
hours, then at room temperature overnight. The mixture was quenched
with water and extracted with ethyl acetate. The organic layer was
dried and concentratd to give 1.796 g of crude material. The crude
material was purified through silica gel column chromatography
using chloroform to 5% methanol in chloroform as eluent to give
1.167 g (43%) of the title compound as a colorless oil. .sup.1H NMR
(CDCl.sub.3) .delta. 7.14 (brs, 1 H), 6.27 (s, 1 H), 3.86 (s, 3 H),
3.27 (m, 1 H), 2.33 (s, 3 H), 1.3-1.6 (m, 4 H), 0.88 (t, 6 H)
ppm.
Preparation Q
[1102]
(2-Chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine
[1103] A mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine (250 mg,
1.21 mmol) and 1-ethyl-propyl amine (105 mg, 1.21 mmol) in DMSO (4
ml) was stirred at room temperature for 15 hours. The mixture was
quenched with water and extracted with ethyl acetate. The organic
layer was dried and concentratd to give 280 mg of yellow oil. The
oil was purified through silical gel column chromatography using
65% chloroform in hexane as eluent to give 110 mg (35%) of the
title compound as a yellow crystal, mp 82-84.degree. C. .sup.1H NMR
(CDCl.sub.3) .delta. 6.57 (d, 1 H), 6.46 (s, 1 H), 3.39 (m, 1 H),
2.42 (s, 3 H), 1.4-1.8 (m, 4 H), 0.94 (t, 6 H) ppm
Preparation R
[1104]
(6-Chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine
[1105] A mixture of 2-methyl-5-nitro-4,6-dichloro-pyrimidine (208
mg, 1.00 mmol) and 1-ethyl-propyl-amine (87 mg, 1.03 mmol) in 2 ml
of dry THF was stirred at -78.degree. C. for 4 hours. The mixture
was quenched with water and extracted with ethyl acetate. The
organic layer was washed with brine, dried and concentrated to give
a green oil. The oil was purified through silica gel column
chromatography using chloroform to 1:1 hexane/chloroform as eluent
to give the title compound (93 mg, 35%). .sup.1H NMR (CDCl.sub.3)
.delta. 7.50 (brs, 1 H), 4.29 (m, 1 H), 2.51 (s, 3 H), 1.4-1.8 (m,
4 H), 0.92 (t, 6 H) ppm.
Preparation S
[1106]
(6-Chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(2,4,6-trimethyl-pyridin-
-3-yl)-amine
[1107] A solution of 2-methyl-5-nitro-4,6-dichloro-pyrimidine (208
mg, 1.00 mmol) in 2.5 ml of acetonitrile was treated with
2,4,6-trimethyl-3-amino-pyridine (273 mg, 2 mmol) stirred at room
temperature 2 hours. The mixture was quenched with water and
extracted with ethyl acetate. The organic layer was washed with
brine, dried and concentrated to give red residue. The residue was
purified through silica gel column chromatography using chloroform
to 6% methanol in chloroform as eluent to give the title compound
(110 mg, 36%) as an orange oil. .sup.1H NMR (CDCl.sub.3) .delta.
8.78 (brs, 1 H), 6.97 (s, 1 H), 2.54 (s, 3 H), 2.43 (s, 3 H), 2.40
(s, 3 H), 2.17 (s, 3 H) ppm.
Preparation T
[1108] 2-Chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid
[1109] The title compound was prepared by reaction of
2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid methyl
ester with LiOH.H.sub.2O in a mixture of water and dioxane at room
temperature. The desired product was acidified to pH 3 and
extracted with ethyl acetate. The organic layer was dried and
concentrated to dryness. The title compound was obtained as white
crystals after titration with ethyl acetate. mp. 164-165.degree.
C.; anal. For C.sub.12H.sub.17Cl.sub.2O.sub.- 2 cacl. C, 56.14; H,
6.67; N, 10.91; found: C, 56.40; H, 6.53; H, 10.93.
Preparation U
[1110]
4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine
1-oxide
[1111] To a solution of 2,4,6-trimethylphenol in dry THF was added
NaH and stirred at room temperature for 20 minutes. A solution of
2,4-dichloro-6-ethyl-3-methyl-pyridine 1-oxide was added and the
resulting mixture was heated at reflux for 1.5 hour. The mixture
was cooled to room temperature, quenched with water, extracted with
ethyl acetate. The organic layer was separated, dried and
concentrated to give the title compound which was used directly for
the next step reaction.
Preparation V
[1112]
4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine
[1113] To a solution of
4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-pheno- xy)-pyridine
1-oxide in methylene chloride was added PCl.sub.3 and the resulting
mixture was heated at reflux for 20 min, cooled to rt. The mixture
was concentrated to dryness. The residue was worked-up using
standard procedure to give the title compound. After silica gel
purification, the title compound was prepared as a white solid, mp.
42-44.degree. C. Anal. For C.sub.17H20CO calc. C, 70.46; H, 6.96;
N, 4.83; found, C, 70.35; H, 7.13; N, 4.58.
Preparation W
[1114]
2-[4-Chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl-
]-malonic acid dimethyl ester
[1115] The title compound was prepared by reacting
4-chloro-3-chloromethyl-
-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine with dimethyl
malonate/NaH in methanol. The title compound was isolated as a
colorless oil.
Preparation X
[1116]
4-Chloro-3,6-dimethyl-2-(2,4,6-trimethyl-3-pyridyl)-pyridine
Preparation Y
[1117] 2-Chloro-4-(1-methoxymethyl-propoxy)-6-methyl-nicotinic acid
ethyl ester
[1118] 1H NMR(CDCl.sub.3) d 6.72(s,1 H), 4.5(m,1 H), 4.4(q,2 H),
3.49(d,2 H), 3.31(s,3 H), 2.46(s,3 H), 1.68(m,2 H), 1.34(t,3 H),
0.93(t,3 H) ppm.
Preparation Z
[1119] 2-Chloro-4-(1-methoxymethyl-propoxy)-6-methyl-nicotinic
acid
[1120] 1H NMR(CDCl.sub.3) d 6.81(s,2 H), 4.51(m,1 H), 3.60(m,2 H),
3.40(s,3 H), 2.55(s,3 H), 1.77(m,2 H), 1.02(t,3 H)ppm.
Preparation AA
[1121]
(2-Chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-methoxymethyl-propyl)-a-
mine mp. 63-65.degree. C., Anal. For C.sub.11H16N3O3Cl calc. C,
48.27; H, 5.89, N, 15.35; found C, 48.65; H, 6.03, N, 15.11.
Preparation BB
[1122]
(5-Bromo-6-chloro-2-methyl-pyrimidin-4-yl)-(2,4-dichloro-phenyl)-am-
ine
[1123] Mp. 165-167.degree. C.; Anal. For C11H7BrCl3 calc.: C,
35.95; H, 1.92; N, 11.43; found: C, 36.41; H, 1.91; N, 11.05.
Preparation CC
[1124]
(6-Chloro-2-methyl-pyrimidin-4-yl)-(2,4-dichloro-phenyl)-amine
[1125] Mp. 134-136.degree. C.; Anal. For
C.sub.11H.sub.8Cl.sub.3N.sub.3 calc.: C, 45.79; H, 2.79; N, 14.56;
found: C, 45.91; H, 2.69; N, 14.50.
Preparation DD
[1126]
[4-Chloro-6-(1-ethyl-propylamino)-2-methyl-pyrimidin-5-yl]-acetic
acid ethyl ester
[1127] Mp. 78-80.degree. C., anal. For
C.sub.14H.sub.22ClN.sub.3O.sub.2 calc.: C, 56.09; H, 7.40; N,
14.02; found: C, 56.31; H, 7.60; N,13.94.
Preparation EE
[1128]
2-[4-Bromo-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-5-yl-prop-
ionic acid ethyl ester
[1129] 1H NMR(CDCl.sub.3) d 6.86(s,2 H), 4.2-4.359m,2 H),
4.0-4.15(m,1 H), 2.4(s,3 H), 2.28(s,3 H), 1.99(s,3 H), 1.97(s,3 H),
1.58(d,3 H), 1.22(t,3 H) ppm.
Preparation FF
[1130] 2-(4,6-Dibromo-2-methyl-pyriman -5-yl)-propionic acid ethyl
ester
[1131] 1 H NMR(CDCl3)4.36(m,1 H), 4.19(m,2 H), 2.68(s,3 H),
1.549d,3 H), 1.22(t,3 H) ppm.
Preparation GG
[1132]
4-Bromo-3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine
[1133] 1H NMR(CDCl.sub.3) d 6.92(s,1 H), 6.87(s,2 H), 4.00(s,3 H),
2.299s,3 H), 2.18(s,3 H), 2.059s,6 H) ppm.
Preparation HH
[1134]
4-Bromo-2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine
[1135] 1H NMR(CDCl.sub.3) d 7.04(s,2 H), 6.97(s,1 H), 2.42(s,3 H),
2.17(s,3 H), 2.03(s,6 H) ppm.
Preparation II
[1136]
4-Bromo-2-(2,4-dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridi-
ne
[1137] 1H NMR(CDCl.sub.3) d 7.3(d,1 H), 7.18(d,1 H), 4.0(s,3 H),
2.2(s,3 H), 2.15(s,3 H) ppm.
Preparation JJ
[1138]
4-Bromo-2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridi-
ne
[1139] Anal. For C.sub.15H.sub.15BrClNO.sub.2 calc.: C, 50.52; H,
4.24; N, 3.93; found: C, 50.52; H, 4.37; N, 3.91.
Preparation KK
[1140]
4-Bromo-2-(4-chloro-2-methoxy-phenoxy)-3-methoxy-6-methyl-pyridine
[1141] 1H NMR(CDCl.sub.3) d 6.9-7.1(m,4 H), 3.94(s,3 H), 3.71(s,3
H), 2.21s,3 H) ppm.
Preparation LL
[1142]
4-Bromo-2-(3-chloro-2,6-dimethoxy-phenoxy)-3-methoxy-6-methyl-pyrid-
ine
[1143] 1H NMR(CDCl.sub.3) d 7.17(d,1 H), 6.96(s,1 H), 6.66(d,1 H),
3.97(s,3 H), 3.79(s,3 H), 3.70(s,3 H), 2.18(s,3 H) ppm.
Preparation MM
[1144]
4-Bromo-3-methoxy-6-methyl-2-(2,4,6-trimethoxy-phenoxy)-pyridine
[1145] 1H NMR(CDCl.sub.3) d 6.90(s,1 H), 6.19(s,2 H), 3.968(s,3 H),
3.80(s,3 H), 3.71(s,6 H), 2.18(s,3 H) ppm.
Preparation NN
[1146]
4-Bromo-3-methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyrid-
ine
[1147] 1H NMR(CDCl.sub.3) d 6.92(s,1 H), 6.60(s,2 H), 3.98(s,3 H),
3.78(s,3 H), 2.18(s,3 H), 2.07(s,6 H) ppm.
Preparation OO
[1148]
4-Bromo-2-(4-chloro-2,6-dimethyl-phenoxy)-3-ethoxy-6-methyl-pyridin-
e
[1149] 1H NMR(CDCl.sub.3) d 7.099s,2 H), 7.00(s,1 H), 4.28(q,2 H),
2.22(s,3 H), 2.10(s,6 H), 1.51(t,3 H) ppm.
Preparation PP
[1150]
4-Bromo-3,6-dimethyl-2-(2,4,6-trimethoxy-phenoxy)-pyridine
[1151] 1H NMR(CDCl.sub.3) d 6.99(s,1 H), 6.25(s,2 H), 3.86(s,3 H),
3.77(s,6 H), 2.47(s,3 H), 2.25(s,3 H) ppm.
Preparation QQ
[1152]
4-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-1-oxy-nicotinic
acid methyl ester
Preparation RR
[1153]
4-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acid
methyl ester
[1154] 1H NMR(CDCl.sub.3) d 7.03(s,2 H), 6.869s,1 H), 3.969s,3 H),
2.259s,3 H), 2.05(s,6 H) ppm.
Preparation SS
[1155]
4-Chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-carbaldehy-
de
[1156] The title compound was prepared by oxidation of
4-chloro-4-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl-methanol
with pyridinium chlorochromate in methylene chloride at room
temperature. The desired product was isolated after column
chromatography to give a green solid (80% yield). 1H
NMR(CDCl.sub.3) d 10.66(s,1 H), 6.91(s,3 H), 2.31(s,3 H), 2.07(s,3
H) ppm.
Preparation TT
[1157] 2-(4-Bromo-2,6-dimethyl-phenoxy)-4-chloro-6-methyl-nicotinic
acid methyl ester
[1158] mp. 108-110.degree. C.; Anal. For
C.sub.16H.sub.15BrClNO.sub.3 calc., 49.96; H, 3.93; N, 3.64; found:
C, 50.07; H, 4.10; N, 3.57.
Preparation UU
[1159]
4-Chloro-2-(4-chloro-2-methoxy-phenoxy)-6-methyl-1-oxy-nicotinic
acid methyl ester
[1160] mp. 117-120.degree. C., Anal. For
C.sub.15H.sub.13NO.sub.5Cl.sub.2 calc.: C, 50.30; H, 3.66; N, 3.91;
Found: C, 50.41; H, 3.55; N, 4.00.
Preparation VV
[1161] 4-Chloro-2-(4-chloro-2-methoxy-phenoxy)-6-methyl-nicotinic
acid methyl ester
[1162] mp. 92-93.degree. C., Anal. For
C.sub.15H.sub.13NO.sub.4Cl.sub.2 calc.: C, 52.65; H, 3.83; N, 4.09;
found: C, 52.34; H, 3.85; N, 4.13.
Preparation WW
[1163]
[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[2-(4-chloro-2,6--
dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine
[1164] 1H NMR(CDCl.sub.3) d 7.06(s,2 H), 6.12(s,1 H), 4.3(d,1 H),
3.6-3.8(m,2 H), 3.4(m,1 H), 2.16(s,3 H), 2.14(s,3 H), 2.10(s,6 H),
1.5-1.8(m,2 H), 1.03(t,3 H), 0.95(s,9 H), 0.09(m,6 H) ppm.
[1165] The following compounds were prepared by a method analogous
to that described in Example 160, using an appropriate
4-bromo-2-(substituted phenoxy)-6-alkyl or alkoxy-pyridine with
1-(tert-Butyl-dimethyl-silanylox- ymethyl)-propylamine.
Preparation XX
[1166]
[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[3-methoxy4-methy-
l-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-yl]-amine
[1167] 1H NMR (CDCl.sub.3) d 6.84(s,2 H), 6.08(s,1 H), 4. 8(d,1 H),
3.88(s,3 H), 3.5-3.7(m,2 H), 3.3(m,1 H), 2.27(s,3 H), 2.099s,3 H),
2.07(s,6 H), 1.75(m,1 H), 1.55(m,1 H), 0.97(t,3 h), 0.89(s,9 H),
0.04(s,6 H) ppm.
Preparation YY
[1168]
[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[2-(4-chloro-2,6--
dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-amine
[1169] 1H NMR(CDCl.sub.3) d 7.02(s,2 H), 6.10(s,1 H), 4.80(d,1 H),
3.87(s,3 H), 3.6-3.7(m,2 H), 3.30(m,1 H), 2.09(s,3 H), 2.08(s,6 H),
1.75(m,1 H), 1.55(m,1 H), 0.97(t,3 H), 0.89(s,9 H), 0.03(s,6 H)
ppm.
Preparation ZZ
[1170]
4-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propylamino]-2-(4chloro-
-2,6-dimethyl-phenoxy)-6-methyl-pyridin-3-ol
[1171] 1H NMR(CDCl.sub.3) d 7.01 (s,2 H), 6.15(s,1 H), 4.46(d,1 H),
3.7(m,1 H), 3.6(m,1 H), 3.4(m,1 H), 2.09(s,3 H), 2.08(s,6 H),
1.5-1.8(m,2 H), 1.06(s,9H), 0.98(t,3 H), 0.24(s,6 H) ppm.
Preparation AAA
[1172]
[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[3-methoxy-6-meth-
yl-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-amine
[1173] 1H NMR(CDCl.sub.3) d 6.19(s,2 H), 6.09(s,1 H), 3.86(s,3 H),
3.80(s,3 H), 3.73(s,6 H), 3.3(m,1 H), 2.16(s,3 H), 1.75(m,1 H),
1.5(m,1 H), 0.95(t,3 H), 0.89(s,9 H), 0.04(s,6 H) ppm.
Preparation BBB
[1174]
4-{4-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propylamino]-3-metho-
xy-6-methyl-pyridin-2-yloxy}-3,5-dimethyl-benzonitrile
[1175] 1H NMR(CDCl.sub.3) d 7.40(s,2 H), 6.19(s,1 H), 4.90(brs,1
H), 3.87(s,3 H), 3.70(m,2 H), 3.3(m,1 H), 2.19(m,9 H), 1.5-1.8(m,2
H), 1.02(t,3 H), 093(s,9 H), 0.09(s,6 H) ppm.
* * * * *