U.S. patent application number 14/884826 was filed with the patent office on 2016-02-04 for heteroaromatic compounds as btk inhibitors.
The applicant listed for this patent is Boehringer Ingelheim International GmbH. Invention is credited to Joerg Martin BENTZIEN, Angela Kay BERRY, Todd BOSANAC, Michael Jason BURKE, Darren Todd DISALVO, Joshua Courtney HORAN, Shuang LIANG, Can MAO, Wang MAO, Yue SHEN, Fariba SOLEYMANZADEH, Renee M. ZINDELL.
Application Number | 20160031872 14/884826 |
Document ID | / |
Family ID | 49029216 |
Filed Date | 2016-02-04 |
United States Patent
Application |
20160031872 |
Kind Code |
A1 |
BENTZIEN; Joerg Martin ; et
al. |
February 4, 2016 |
HETEROAROMATIC COMPOUNDS AS BTK INHIBITORS
Abstract
The present invention encompasses compounds of the formula (I)
##STR00001## wherein the groups A, Cy, X1 and Y are defined herein,
which are suitable for the treatment of diseases related to BTK,
process of making, pharmaceutical preparations which contain
compounds and their methods of use.
Inventors: |
BENTZIEN; Joerg Martin;
(White Plains, NY) ; BERRY; Angela Kay;
(Gaylordsville, CT) ; BOSANAC; Todd; (New Milford,
CT) ; BURKE; Michael Jason; (Newtown, CT) ;
DISALVO; Darren Todd; (New Milford, CT) ; HORAN;
Joshua Courtney; (Danbury, CT) ; LIANG; Shuang;
(Danbury, CT) ; MAO; Can; (Philadelphia, PA)
; MAO; Wang; (Milford, CT) ; SHEN; Yue;
(Berlin, CT) ; SOLEYMANZADEH; Fariba; (Danbury,
CT) ; ZINDELL; Renee M.; (New Milford, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim International GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
49029216 |
Appl. No.: |
14/884826 |
Filed: |
October 16, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13962260 |
Aug 8, 2013 |
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14884826 |
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61681684 |
Aug 10, 2012 |
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Current U.S.
Class: |
514/210.18 ;
514/236.5; 514/278; 514/326; 514/406; 514/407; 544/130; 546/15;
546/16; 546/211; 548/147; 548/357.5 |
Current CPC
Class: |
C07D 231/38 20130101;
C07D 231/40 20130101; A61P 37/08 20180101; C07D 417/02 20130101;
C07D 401/04 20130101; A61P 11/06 20180101; C07D 403/08 20130101;
C07D 231/14 20130101; C07D 403/04 20130101; C07D 405/14 20130101;
A61P 17/00 20180101; C07D 401/14 20130101; A61P 27/02 20180101;
C07D 417/06 20130101; C07D 417/04 20130101; A61P 19/02 20180101;
A61P 19/00 20180101; A61P 43/00 20180101; A61P 11/00 20180101; C07D
401/02 20130101; A61P 1/04 20180101; C07D 403/06 20130101; C07D
413/14 20130101; A61P 11/02 20180101; C07D 401/06 20130101; A61P
29/00 20180101; A61P 37/06 20180101; C07D 277/56 20130101; A61P
17/04 20180101; A61P 35/02 20180101; C07D 417/08 20130101 |
International
Class: |
C07D 417/08 20060101
C07D417/08; C07D 401/02 20060101 C07D401/02; C07D 231/40 20060101
C07D231/40; C07D 231/38 20060101 C07D231/38; C07D 401/04 20060101
C07D401/04; C07D 403/08 20060101 C07D403/08 |
Claims
1. A compound of the formula (I) ##STR00280## wherein A ring is:
##STR00281## R.sub.1 is N(R.sub.3).sub.2 or hydrogen; Cy is aryl or
heteroaryl each is substituted by R.sub.2 and optionally
substituted by halogen, halo C.sub.1-4 alkyl, C.sub.1-4 alkyl and
C.sub.1-4 alkoxy; R.sub.2 is chosen from: L-Ar, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy, each Ar, C.sub.1-6 alkyl and C.sub.1-6 alkoxy are
optionally substituted by halogen, halo C.sub.1-4 alkyl, C.sub.1-4
alkyl, R.sub.3--S(O).sub.m--, --CN, --C(O)--N(R.sub.3).sub.2 or
C.sub.1-4 alkoxy; L is a linker chosen from a bond, O, >C(O),
--(CH.sub.2).sub.n--, --O--(CH.sub.2).sub.n--, --N(R.sub.3)--,
--N(R.sub.3)--(CH.sub.2).sub.n--, --(CH.sub.2).sub.n--N(R.sub.3)--,
--C(O)--N(R.sub.3)--, --C(O)--N(R.sub.3)--(CH.sub.2).sub.n--,
--N(R.sub.3)--C(O)--N(R.sub.3)--, --N(R.sub.3)--C(O)--,
--S(O).sub.m--N(R.sub.3)-- and --N(R.sub.3)--S(O).sub.m--, wherein
the --CH.sub.2-- in each L can have 1-2 hydrogens replaced by
C.sub.1-3 alkyl, said C.sub.1-3 alkyl groups can optionally cyclize
to form a C.sub.3-6 cycloalkyl ring; Ar is carbocycle, heterocycyl
or heteroaryl; X.sub.1 is a linker chosen from a bond,
--(CH.sub.2).sub.n--; Y is chosen from C.sub.7-C.sub.10 spirocycle
optionally containing 0-1 ring nitrogen atoms, a nitrogen
containing mono- or bi-cyclic heterocycle, carbocycle, aryl, each
substituted by one R.sub.4, R.sub.4 is ##STR00282## wherein R.sub.5
cannot be hydrogen, ##STR00283## each n is independently 1-4; each
m is independently 0-2; each R.sub.3 is independently chosen from
hydrogen or C.sub.1-4 alkyl; each R.sub.5 is independently chosen
from hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylC.sub.1-4 alkoxy, --(CH.sub.2).sub.n-heterocycle and
heterocycle each heterocycle optionally substituted by halogen, OH
or R.sub.3--S(O).sub.m--; each group defined above for Cy,
R.sub.1-R.sub.5, X.sub.1 and Y can be where possible partially or
fully halogenated; or a pharmaceutically acceptable salt
thereof.
2. The compound according to claim 1 and wherein A ring is:
##STR00284## or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 and wherein Cy is phenyl,
pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl each is
substituted by R.sub.2 and optionally substituted by F, Cl or
C.sub.1-4 alkoxy; R.sub.2 is chosen from: L-Ar and C.sub.1-3
alkoxy, each Ar and C.sub.1-3 alkoxy are optionally substituted by
F, Cl, C.sub.1-4 alkyl, R.sub.3--S(O).sub.2--, --CN,
--C(O)--NH(R.sub.3) or C.sub.1-3 alkoxy; L is a linker chosen from
a bond, O, >C(O), --CH.sub.2--, --O--CH.sub.2--, --NH--,
--NH--CH.sub.2--, --CH.sub.2--NH--, --C(O)--NH--CH.sub.2--,
--NH--C(O)--NH-- and --N(R.sub.3)--S(O).sub.m--; Ar is phenyl,
pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl,
indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzothiazolyl,
piperidinyl, piperazinyl or pyrrolidinyl or a pharmaceutically
acceptable salt thereof.
4. The compound according to claim 3 and wherein Cy is phenyl or
pyridinyl, each is substituted by R.sub.2 and optionally
substituted by F, Cl or C.sub.1-2 alkoxy; R.sub.2 is chosen from:
L-Ar and C.sub.1-3 alkoxy, each Ar and C.sub.1-3 alkoxy are
optionally substituted by F, Cl, C.sub.1-4 alkyl,
CH.sub.3--S(O).sub.2--, --CN, --C(O)--NH(R.sub.3) or C.sub.1-2
alkoxy; L is a linker chosen from a bond, O, >C(O),
--CH.sub.2--, --O--CH.sub.2--, --NH--, --NH--CH.sub.2--,
--CH.sub.2--NH--, --C(O)--NH--CH.sub.2--, --NH--C(O)--NH-- and
--N(R.sub.3)--S(O).sub.m--; Ar is phenyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, benzoxazolyl, indolyl, isoindolyl,
benzofuranyl, benzimidazolyl, benzothiazolyl or piperidinyl or a
pharmaceutically acceptable salt thereof.
5. The compound according to claim 4 and wherein Cy is phenyl or
pyridinyl, each is substituted by R.sub.2 and optionally
substituted by F, Cl or C.sub.1-2 alkoxy; R.sub.2 is chosen from:
L-Ar and C.sub.1-3 alkoxy, each Ar and C.sub.1-3 alkoxy are
optionally substituted by F, Cl, C.sub.1-4 alkyl,
CH.sub.3--S(O).sub.2--, --CN, --C(O)--NH(CH.sub.3) or C.sub.1-2
alkoxy; L is a linker chosen from a bond, O, >C(O),
--CH.sub.2--, --O--CH.sub.2--, --NH--, --NH--CH.sub.2--,
--CH.sub.2--NH--, --C(O)--NH--CH.sub.2--, --NH--C(O)--NH-- and
--N(H)--S(O).sub.2--; Ar is phenyl, pyridinyl, benzoxazolyl or
piperidinyl or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5 and wherein X.sub.1 is a
linker chosen from a bond and --(CH.sub.2).sub.n--; Y is chosen
from: a spirocycle chosen from ##STR00285## a heterocycle chosen
from piperidinyl and pyrrolidinyl; and phenyl each heterocycle or
phenyl substituted by one R.sub.4; R.sub.4 is ##STR00286## wherein
R.sub.5 cannot be hydrogen, ##STR00287## each R.sub.4 is optionally
halogenated; each R.sub.5 is independently chosen from hydrogen,
C.sub.1-3 alkyl, halo C.sub.1-3 alkyl, C.sub.1-3 alkylC.sub.1-3
alkoxy, --CH.sub.2-heterocycle and heterocycle each heterocycle
optionally substituted by F, Cl, OH and CH.sub.3--S(O).sub.2-- and
each heterocycle chosen from pyrrolidinyl, piperidinyl, morpholinyl
and 1,4-oxazepane, or a pharmaceutically acceptable salt
thereof.
7. The compound according to claim 6 and wherein X.sub.1 is a
linker chosen from a bond and --(CH.sub.2).sub.n--; Y is chosen
from: a spirocycle chosen from ##STR00288## a heterocycle chosen
from piperidinyl and pyrrolidinyl; and phenyl each heterocycle or
phenyl substituted by one R.sub.4; R.sub.4 is ##STR00289##
X.sub.3=halogen or hydrogen, ##STR00290## each R.sub.5 is
independently chosen from hydrogen, C.sub.1-3 alkyl, --CF.sub.3,
C.sub.1-3 alkylC.sub.1-3 alkoxy, --CH.sub.2-heterocycle and
heterocycle each heterocycle optionally substituted by F, Cl, OH
and CH.sub.3--S(O).sub.2-- and each heterocycle chosen from
pyrrolidinyl, piperidinyl and 1,4-oxazepane, or a pharmaceutically
acceptable salt thereof.
8. The compound according to claim 1 and wherein Cy is ##STR00291##
##STR00292## ##STR00293## or a pharmaceutically acceptable salt
thereof.
9. The compound according to claim 8 and wherein X--Y= ##STR00294##
##STR00295## ##STR00296## a pharmaceutically acceptable salt
thereof.
10. The compound according to claim 9 and wherein A ring is:
##STR00297## or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 9 and wherein A ring is:
##STR00298## or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 9 and wherein A ring is:
##STR00299## or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 9 and wherein A ring is:
##STR00300## or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 2 and wherein R.sub.2 is L-Ar;
L is a linker chosen from a bond, O, and --O--(CH.sub.2).sub.n--; n
is 1-3; Ar is carbocycle or heterocycle.
15. The compound according to claim 14 and wherein Ar is C.sub.3-5
cycloalkyl or tetrahydrofuranyl; n=1.
16. The compound according to claim 15 and wherein L-Ar is
##STR00301##
17. The compound according to claim 2 and wherein R.sub.2 is:
##STR00302## --OCH.sub.2CH.sub.3, --OCH.sub.2CH.sub.2CH.sub.3,
--OCH.sub.3--OCF.sub.3 or --OCH.sub.2CF.sub.3.
18. A compound chosen from: ##STR00303## ##STR00304## ##STR00305##
##STR00306## ##STR00307## ##STR00308## ##STR00309## ##STR00310##
##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315##
##STR00316## ##STR00317## ##STR00318## ##STR00319## ##STR00320##
##STR00321## ##STR00322## ##STR00323## ##STR00324## ##STR00325##
##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330##
##STR00331## ##STR00332## ##STR00333## or the pharmaceutically
acceptable salts thereof.
19. A compound chosen from: ##STR00334## ##STR00335## ##STR00336##
##STR00337## ##STR00338## ##STR00339## ##STR00340## ##STR00341##
##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346##
##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351##
##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356##
##STR00357## ##STR00358## ##STR00359## or the pharmaceutically
acceptable salts thereof.
20. A pharmaceutical composition comprising a therapeutically
effective amount of a compound according to claim 1 or a
pharmaceutically acceptable salt thereof.
21. A method of treating a disease chosen from rheumatoid
arthritis, systemic lupus erythromatosis, scleroderma, asthma,
allergic rhinitis, allergic eczema, B cell lymphoma, multiple
sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic
arthritis, inflammatory bowel disease, graft versus host disease,
psoriatic arthritis, ankylosing spondylitis and uveitis, comprising
administering to a patient a therapeutically effective amount of a
compound according to claim 1 or a pharmaceutically acceptable salt
thereof.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Technical Field
[0002] The present invention relates to novel compounds which
inhibit BTK and their use as medicaments.
[0003] 2. Background Information
[0004] Members of the protein kinase family of human enzymes play
important regulatory roles in a multitude of distinct signal
transduction processes due to their post-translational modification
of specific proteins via the addition of a phosphate group (Hunter,
Cell, 1987 50, 823-829). Bruton's tyrosine kinase (BTK) is a member
of the Tec family of tyrosine kinases and plays a critical role in
B cell development, activation and antibody production.
[0005] The contribution of BTK to B cell biology is exemplified in
the X-linked agammaglobulinemia (XLA) immunodeficiency in humans
(reviewed in Lindvall, Immunol Rev 2005, 203, 200-215 that display
attenuated calcium signaling upon BCR engagement, lack mature B
cells in periphery due to block between pro- and pre-B cells stage
and have lower levels of circulating antibodies than normal healthy
subjects. The outcome of recent clinical trials with B cell
depleting anti-CD20 molecules in diseases such as rheumatoid
arthritis (RA) and multiple sclerosis (MS) support the hypothesis
that B cells offer an important intervention node for controlling
autoimmune disorders (Townsend et al. 2010). As such, attenuation
of B cell activation and proliferation via inhibition of BTK may
offer similar therapeutic benefit and is consistent with the
demonstrated resistance of BTK-deficient mice to collagen induced
arthritis (Jansson, 1993, Clin Exp Immunol 94, 459-xxx) and
experimental autoimmune encephalitis (Svensson et al. 2002 and
Mangla et al 2004). Similarly, the clinical efficacy observed with
a neutralizing antibody to the B cell stimulating factor BlyS
supports a role for B cells in the pathophysiology of systemic
lupus erythematosus (SLE) (La Cava 2010). Given the necessity for
BTK for the production of autoantibodies, including anti-DNA
antibodies, in murine models of SLE (Steinberg et al., 1982;
Golding et al., 1983; Scribner et al., 1987; Seldin et al., 1987;
Satterthwaite et al., 1998; Takeshita et al., 1998; Whyburn et.
al., 2003), BTK inhibitors may offer therapeutic benefit to SLE
patients.
[0006] Within myeloid cells, BTK signal transduction is necessary
for the stimulated release of inflammatory cytokines such as TNF
from stimulated monocytes (Horwood, J Exp Med, 2003, 1603-xxx) and
for optimal actin cytoskeletal organization and lacunar bone
resorption in isolated osteoclasts (Danks, 2011, J Bone and Mineral
Research, 26, 182-192). Bone marrow derived mast cells lacking BTK
exhibit impaired activation-induced degranulation and cytokine
release (ref). Given the role of BTK in signal transduction
processes across multiple cell types implicated in the pathogenesis
of autoimmune and allergic disorders, inhibition of BTK activity
may provide clinical benefit in diseases such as RA, MS, SLE,
asthma and allergic disorders.
SUMMARY OF THE INVENTION
[0007] The invention comprises a novel class of heteroaromatic
compounds and methods for making and using the same. These
compounds are useful for the treatment of autoimmune and allergic
disorders in that they exhibit good inhibitory effect upon BTK.
DETAILED DESCRIPTION OF THE INVENTION
[0008] In a first generic embodiment, there is provided a compound
of the formula (I)
##STR00002##
A ring is:
##STR00003##
R.sub.1 is N(R.sub.3).sub.2 or hydrogen; Cy is aryl or heteroaryl
each is substituted by R.sub.2 and optionally substituted by
halogen, halo C.sub.1-4 alkyl, C.sub.1-4 alkyl and C.sub.1-4
alkoxy; R.sub.2 is chosen from: L-Ar, C.sub.1-6 alkyl and C.sub.1-6
alkoxy, each Ar, C.sub.1-6 alkyl and C.sub.1-6 alkoxy are
optionally substituted by halogen, halo C.sub.1-4 alkyl, C.sub.1-4
alkyl, R.sub.3--S(O).sub.m--, --CN, --C(O)--N(R.sub.3).sub.2 or
C.sub.1-4 alkoxy; L is a linker chosen from a bond, O, >C(O),
--(CH.sub.2).sub.n--, --O--(CH.sub.2).sub.n--, --N(R.sub.3)--,
--N(R.sub.3)--(CH.sub.2).sub.n--, --(CH.sub.2).sub.n--N(R.sub.3)--,
--C(O)--N(R.sub.3)--, --C(O)--N(R.sub.3)--(CH.sub.2).sub.n--,
--N(R.sub.3)--C(O)--N(R.sub.3)--, --N(R.sub.3)--C(O)--,
--S(O).sub.m--N(R.sub.3)-- and --N(R.sub.3)--S(O).sub.m--, wherein
the --CH.sub.2-- in each L can have 1-2 hydrogens replaced by
C.sub.1-3 alkyl, said C.sub.1-3 alkyl groups can optionally cyclize
to form a C.sub.3-6 cycloalkyl ring; Ar is carbocycle, heterocycyl
or heteroaryl; X.sub.1 is a linker chosen from a bond,
--(CH.sub.2).sub.n--; Y is chosen from C.sub.7-C.sub.10 spirocycle
optionally containing 0-1 ring nitrogen atoms, a nitrogen
containing mono- or bi-cyclic heterocycle, carbocycle, aryl, each
substituted by one R.sub.4,
R.sub.4 is
##STR00004##
[0009] wherein R.sub.5 cannot be hydrogen,
##STR00005##
each n is independently 1-4; each m is independently 0-2; each
R.sub.3 is independently chosen from hydrogen or C.sub.1-4 alkyl;
each R.sub.5 is independently chosen from hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylC.sub.1-4 alkoxy,
--(CH.sub.2).sub.n-heterocycle and heterocycle each heterocycle
optionally substituted by halogen, OH and R.sub.3--S(O).sub.m--;
each group defined above for Cy, R.sub.1-R.sub.5, X.sub.1 and Y can
be where possible partially or fully halogenated; or a
pharmaceutically acceptable salt thereof.
[0010] In a further embodiment, there is provided a compound of the
formula (I) according to the embodiment herein-above and
wherein
A ring is:
##STR00006##
or a pharmaceutically acceptable salt thereof.
[0011] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
Cy is phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl each
is substituted by R.sub.2 and optionally substituted by F, Cl or
C.sub.1-4 alkoxy; R.sub.2 is chosen from: L-Ar and C.sub.1-3
alkoxy, each Ar and C.sub.1-3 alkoxy are optionally substituted by
F, Cl, C.sub.1-4 alkyl, R.sub.3--S(O).sub.2--, --CN,
--C(O)--NH(R.sub.3) and C.sub.1-3 alkoxy; L is a linker chosen from
a bond, O, >C(O), --CH.sub.2--, --O--CH.sub.2--, --NH--,
--NH--CH.sub.2--, --CH.sub.2--NH--, --C(O)--NH--CH.sub.2--,
--NH--C(O)--NH-- and --N(R.sub.3)--S(O).sub.m--; Ar is phenyl,
pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl,
indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzothiazolyl,
piperidinyl, piperazinyl or pyrrolidinyl or a pharmaceutically
acceptable salt thereof.
[0012] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
Cy is phenyl or pyridinyl, each is substituted by R.sub.2 and
optionally substituted by F, Cl or C.sub.1-2 alkoxy; R.sub.2 is
chosen from: L-Ar and C.sub.1-3 alkoxy, each Ar and C.sub.1-3
alkoxy are optionally substituted by F, Cl, C.sub.1-4 alkyl,
CH.sub.3--S(O).sub.2--, --CN, --C(O)--NH(R.sub.3) and C.sub.1-2
alkoxy; L is a linker chosen from a bond, O, >C(O),
--CH.sub.2--, --O--CH.sub.2--, --NH--, --NH--CH.sub.2--,
--CH.sub.2--NH--, --C(O)--NH--CH.sub.2--, --NH--C(O)--NH-- and
--N(R.sub.3)--S(O).sub.m--; Ar is phenyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, benzoxazolyl, indolyl, isoindolyl,
benzofuranyl, benzimidazolyl, benzothiazolyl or piperidinyl or a
pharmaceutically acceptable salt thereof.
[0013] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
Cy is phenyl or pyridinyl, each is substituted by R.sub.2 and
optionally substituted by F, Cl or C.sub.1-2 alkoxy; R.sub.2 is
chosen from: L-Ar and C.sub.1-3 alkoxy, each Ar and C.sub.1-3
alkoxy are optionally substituted by F, Cl, C.sub.1-4 alkyl,
CH.sub.3--S(O).sub.2--, --CN, --C(O)--NH(CH.sub.3) and C.sub.1-2
alkoxy; L is a linker chosen from a bond, O, >C(O),
--CH.sub.2--, --O--CH.sub.2--, --NH--, --NH--CH.sub.2--,
--CH.sub.2--NH--, --C(O)--NH--CH.sub.2--, --NH--C(O)--NH-- and
--N(H)--S(O).sub.2--; Ar is phenyl, pyridinyl, benzoxazolyl or
piperidinyl or a pharmaceutically acceptable salt thereof.
[0014] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
X.sub.1 is a linker chosen from a bond and --(CH.sub.2).sub.n--; Y
is chosen from: a spirocycle chosen from
##STR00007##
a heterocycle chosen from piperidinyl and pyrrolidinyl; and phenyl
each heterocycle or phenyl substituted by one R.sub.4;
R.sub.4 is
##STR00008##
[0015] wherein R.sub.5 cannot be hydrogen,
##STR00009##
each R.sub.4 is optionally halogenated; each R.sub.5 is
independently chosen from hydrogen, C.sub.1-3 alkyl, halo C.sub.1-3
alkyl, C.sub.1-3 alkylC.sub.1-3 alkoxy, --CH.sub.2-heterocycle and
heterocycle each heterocycle optionally substituted by F, Cl, OH
and CH.sub.3--S(O).sub.2-- and each heterocycle chosen from
pyrrolidinyl, piperidinyl, morpholinyl and 1,4-oxazepane, or a
pharmaceutically acceptable salt thereof.
[0016] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
X.sub.1 is a linker chosen from a bond and --(CH.sub.2).sub.n--; Y
is chosen from: a spirocycle chosen from
##STR00010##
a heterocycle chosen from piperidinyl and pyrrolidinyl; and phenyl
each heterocycle or phenyl substituted by one R.sub.4;
R.sub.4 is
##STR00011##
[0017] X.sub.3=halogen or hydrogen,
##STR00012##
each R.sub.5 is independently chosen from hydrogen, C.sub.1-3
alkyl, --CF.sub.3, C.sub.1-3 alkylC.sub.1-3 alkoxy,
--CH.sub.2-heterocycle and heterocycle each heterocycle optionally
substituted by F, Cl, OH and CH.sub.3--S(O).sub.2-- and each
heterocycle chosen from pyrrolidinyl, piperidinyl and
1,4-oxazepane, or a pharmaceutically acceptable salt thereof.
[0018] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
Cy is
##STR00013## ##STR00014## ##STR00015##
[0019] or a pharmaceutically acceptable salt thereof.
[0020] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
X--Y=
##STR00016## ##STR00017## ##STR00018##
[0021] or a pharmaceutically acceptable salt thereof.
[0022] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
A ring is:
##STR00019##
or a pharmaceutically acceptable salt thereof.
[0023] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
A ring is:
##STR00020##
or a pharmaceutically acceptable salt thereof.
[0024] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
A ring is:
##STR00021##
or a pharmaceutically acceptable salt thereof.
[0025] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
A ring is:
##STR00022##
or a pharmaceutically acceptable salt thereof.
[0026] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
R.sub.2 is
L-Ar;
[0027] L is a linker chosen from a bond, O, and
--O--(CH.sub.2).sub.n--; n is 1-3; Ar is carbocycle or heterocycle;
or a pharmaceutically acceptable salt thereof.
[0028] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments hereinabove and
wherein
Ar is C.sub.3-5 cycloalkyl or tetrahydrofuranyl; n=1; or a
pharmaceutically acceptable salt thereof.
[0029] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
L-Ar is
##STR00023##
[0030] or a pharmaceutically acceptable salt thereof.
[0031] In a further embodiment, there is provided a compound of the
formula (I) according to any of the embodiments herein-above and
wherein
R.sub.2 is:
##STR00024##
[0032]--OCH.sub.2CH.sub.3, --OCH.sub.2CH.sub.2CH.sub.3,
--OCH.sub.3, --OCF.sub.3 or --OCH.sub.2CF.sub.3;
[0033] or a pharmaceutically acceptable salt thereof.
[0034] In another embodiment, the invention provides made compounds
in Table I which can be made in view of the general schemes,
examples and methods known in the art.
TABLE-US-00001 TABLE of compounds and Biological activity HPLC RT
Example Structure BTK IC50 (nM) Method (min) m/z[M + H].sup.+ 1
##STR00025## 2600 A 4.13 401.2 2 ##STR00026## 33 A 4.08 431.3 3
##STR00027## 810 A 4.06 431.3 4 ##STR00028## -- A 2.56 382.4 5
##STR00029## -- A 2.59 438.4 6 ##STR00030## -- A 2.75 405.4 7
##STR00031## -- A 2.83 417.3 8 ##STR00032## -- A 2.61 391.2 9
##STR00033## 14 A 4.11 415.3 10 ##STR00034## -- A 4.14 494.3 11
##STR00035## 5500 A 2.80 494.2 12 ##STR00036## -- A 2.67 422.3 13
##STR00037## -- A 2.56 409.3 14 ##STR00038## 7800 A 2.81 419.4 15
##STR00039## -- A 2.89 394.4 16 ##STR00040## 580 A 2.77 365.3 17
##STR00041## 4800 A 2.60 418.4 18 ##STR00042## -- A 2.72 371.4 19
##STR00043## -- A 2.84 433.3 20 ##STR00044## 30 A 3.03 515.2 21
##STR00045## 98 A 2.85 466.3 22 ##STR00046## 7.6 A 2.91 447.3 23
##STR00047## 10 A 2.97 435.3 24 ##STR00048## 9.4 A 3.02 451.3 25
##STR00049## 5.1 A 3.03 527.3 26 ##STR00050## 22 A 3.03 560.3 27
##STR00051## 300 A 2.84 457.3 28 ##STR00052## 3.5 A 2.85 429.3 29
##STR00053## 3.2 A 2.83 417.3 30 ##STR00054## 57 A 2.54 474.35 31
##STR00055## 80 A 2.86 429.35 32 ##STR00056## 150 A 2.81 429.35 33
##STR00057## 9.7 A 2.83 417.35 34 ##STR00058## 21 A 2.78 394.35 35
##STR00059## 0.77 A 2.96 444.3 36 ##STR00060## 230 A 2.67 474.3 37
##STR00061## 38 A 2.51 500.3 38 ##STR00062## 13 A 2.84 455.3 39
##STR00063## 290 A 2.65 377.2 40 ##STR00064## 4.9 A 2.89 443.2 41
##STR00065## 0.73 A 2.99 456.3 42 ##STR00066## 64 A 2.92 417.4 43
##STR00067## 51 A 2.93 429.4 44 ##STR00068## 1 A 2.68 392.4 45
##STR00069## 10 A 2.83 431.4 46 ##STR00070## 1.2 A 2.85 417.4 47
##STR00071## 10 A 2.84 431.4 48 ##STR00072## 90 A 2.97 443.4 49
##STR00073## 180 A 2.96 443.4 50 ##STR00074## 3 A 2.98 434.3 51
##STR00075## 1.7 A 3.00 434.3 52 ##STR00076## 18 A 3.02 446.3 53
##STR00077## 14 A 3.00 446.3 54 ##STR00078## 0.73 A 3.00 432.4 55
##STR00079## 6.6 A 2.93 417.4 56 ##STR00080## 15 A 2.95 429.4 57
##STR00081## 3.2 A 2.99 446.3 58 ##STR00082## 1.1 A 3.01 458.3 59
##STR00083## 8.9 A 2.75 429.4 60 ##STR00084## 41 A 2.82 473.4 61
##STR00085## 780 A 2.86 548.1 62 ##STR00086## 93 A 2.97 435.3 63
##STR00087## 660 A 3.08 485.3 64 ##STR00088## 6500 A 2.79 495.1 65
##STR00089## 330 B 0.65 495.1 66 ##STR00090## 43 A 3.10 469.2 67
##STR00091## 38 A 2.95 447.3 68 ##STR00092## 41 A 3.08 451.4 69
##STR00093## 43 A 3.20 485.3 70 ##STR00094## 45 A 3.07 451.3 71
##STR00095## 14 A 3.04 431.4 72 ##STR00096## 4 A 3.04 431.4 73
##STR00097## 9.3 A 3.00 435.3 74 ##STR00098## -- A 2.89 453.3 75
##STR00099## 6600 A 2.91 442.3 76 ##STR00100## 61 A 2.92 442.4 77
##STR00101## 1.9 A 2.72 543.3 78 ##STR00102## 2.1 A 2.95 472.2 79
##STR00103## 6.4 A 3.05 460.2 80 ##STR00104## 0.93 A 3.04 458.4 81
##STR00105## 0.79 A 2.91 458.3 82 ##STR00106## 2 A 2.95 472.2 83
##STR00107## 2.1 A 2.99 484.3 84 ##STR00108## 52 A 3.10 474.2 85
##STR00109## 300 A 3.11 486.2 86 ##STR00110## 95 A 3.03 457.4 87
##STR00111## 4.3 A 2.87 469.3 88 ##STR00112## 21 A 2.96 443.4 89
##STR00113## 34 A 2.98 455.3 90 ##STR00114## 90 B 0.55 460.1 91
##STR00115## 0.79 A 2.94 470.3 92 ##STR00116## 0.89 A 2.88 470.3 93
##STR00117## 33 A 2.80 514.3 94 ##STR00118## 8200 A 2.75 436.3 95
##STR00119## 1600 A 2.71 399.3 96 ##STR00120## 4.8 A 2.95 435.3 97
##STR00121## 0.8 A 2.93 458.3 98 ##STR00122## 0.7 A 2.69 515.4 99
##STR00123## 3.2 A 2.76 557.3 100 ##STR00124## 0.8 A 2.63 501.3 101
##STR00125## 9.2 A 2.71 445.4 102 ##STR00126## 2.7 A 2.83 457.3 103
##STR00127## 2.8 A 3.13 445.2 104 ##STR00128## 19 A 2.79 422.4 105
##STR00129## 13 A 2.77 410.3 106 ##STR00130## 13 A 2.81 422.4 107
##STR00131## 3.3 A 2.81 422.4 108 ##STR00132## 14 A 2.75 448.3 109
##STR00133## 24 A 2.86 436.3 110 ##STR00134## 0.87 A 3.09 457.3 111
##STR00135## 16 A 2.77 410.4 112 ##STR00136## 6.7 A 2.82 408.4 113
##STR00137## 4.3 A 2.85 420.4 114 ##STR00138## 3.4 A 2.87 459.3 115
##STR00139## 3.5 A 2.82 462.3 116 ##STR00140## 12 A 2.78 450.3 117
##STR00141## 1.1 A 3.52 459.2 118 ##STR00142## 0.5 A 3.49 471.2 119
##STR00143## 11 A 3.25 471.3 120 ##STR00144## 3.5 A 3.29 459.2 121
##STR00145## 0.2 A 3.13 472.2 122 ##STR00146## 17 A 2.91 471.3
123 ##STR00147## 9.1 A 2.88 459.3 124 ##STR00148## 10 B 1.73 444.1
125 ##STR00149## 7.5 B 0.85 424.0 126 ##STR00150## 28 A 2.98 424.3
127 ##STR00151## 15 B 0.86 436 128 ##STR00152## 0.9 A 3.02 446.4
129 ##STR00153## 29 B 0.85 446.1 130 ##STR00154## 6.4 A 3 434.4 131
##STR00155## 28 B 0.80 433.9 132 ##STR00156## 1.9 B 1.02 451.5 133
##STR00157## 8.4 A 2.64 368.3 134 ##STR00158## 120 B 0.59 438.3 135
##STR00159## 26 A 2.83 454.3 136 ##STR00160## 14 B 0.91 466 137
##STR00161## 1.6 B 0.89 494.1 138 ##STR00162## 2.2 B 0.86 440.1 139
##STR00163## 16 B 0.56 428.1 140 ##STR00164## 0.9 B 0.90 436.2 141
##STR00165## 14 B 0.87 450.0 142 ##STR00166## 29 B 0.82 438.0 143
##STR00167## 37 B 0.85 450.0 144 ##STR00168## 72 B 0.80 438.1 145
##STR00169## 3.5 A 3.17 458.4 146 ##STR00170## 22 A 2.95 482.4 147
##STR00171## 9.2 B 0.84 432.0 148 ##STR00172## 3.0 A 3.03 456.3 149
##STR00173## 100 B 0.78 480.4 150 ##STR00174## 0.8 B 0.83 471.2 151
##STR00175## 0.7 B 0.78 471.3 152 ##STR00176## 1.5 B 0.73 459.3 153
##STR00177## 2.3 B 0.68 396.1 154 ##STR00178## 0.6 B 0.71 408.3 155
##STR00179## 7.3 B 0.69 396.2 156 ##STR00180## 16 B 0.70 420.4 [M -
H]+ 157 ##STR00181## 2.0 B 0.86 434.6 158 ##STR00182## 6.3 B 0.80
442.1 159 ##STR00183## 20 B 0.75 430.2 160 ##STR00184## 1.4 B 0.87
462.1 161 ##STR00185## 1.1 B 0.87 454.462.8 162 ##STR00186## 9.2 B
0.91 450.2 163 ##STR00187## 4.8 B 0.86 464.5 164 ##STR00188## 0.5 B
0.90 476.2 165 ##STR00189## 15 B 0.89 440.2 [M - H]+443.2 166
##STR00190## 6.6 B 1.06 420.3 167 ##STR00191## 0.9 B 0.75 422.2 168
##STR00192## 1.2 B 0.84 436.3
or the pharmaceutically acceptable salts thereof.
[0035] The present invention further relates to metabolites, and
prodrugs of compounds of the formula (I).
[0036] The present invention further relates to a pharmaceutically
acceptable salt of a compound of the formula (I) with inorganic or
organic acids or bases.
[0037] In another aspect the invention relates to compounds of
formula (I)--or the pharmaceutically acceptable salts thereof--as
medicaments.
[0038] In another aspect the invention relates to compounds of
formula (I)--or the pharmaceutically acceptable salts thereof--for
use in a method for treatment of a patient.
[0039] In another aspect the invention relates to compounds of
formula (I)--or the pharmaceutically acceptable salts thereof--for
use in the treatment of autoimmune diseases and allergic
disorders.
[0040] In another aspect the invention relates to the use of
compounds of formula (I)--or the pharmaceutically acceptable salts
thereof--for preparing a pharmaceutical composition for the
treatment of autoimmune diseases and allergic disorders.
[0041] In another aspect the invention relates to a method for the
treatment of autoimmune diseases and allergic disorders comprising
administering a therapeutically effective amount of a compound of
formula (I)--or one of the pharmaceutically acceptable salts
thereof--to a patient.
[0042] In another aspect the invention relates to a pharmaceutical
preparation containing as active substance one or more compounds of
formula (I)--or the pharmaceutically acceptable salts
thereof--optionally in combination with conventional excipients
and/or carriers.
DEFINITIONS
[0043] Terms that are not specifically defined here have the
meanings that are apparent to the skilled man in the light of the
overall disclosure and the context as a whole.
[0044] As used herein, the following definitions apply, unless
stated otherwise:
[0045] The use of the prefix C.sub.x-y, wherein x and y each
represent a natural number, indicates that the chain or ring
structure or combination of chain and ring structure as a whole,
specified and mentioned in direct association, may consist of a
maximum of y and a minimum of x carbon atoms.
[0046] Alkyl denotes monovalent, saturated hydrocarbon chains,
which may be present in both straight-chain (unbranched) and
branched form. If an alkyl is substituted, the substitution may
take place independently of one another, by mono- or
polysubstitution in each case, on all the hydrogen-carrying carbon
atoms.
[0047] For example, the term "C.sub.1-5alkyl" includes for example
H.sub.3C--, H.sub.3C--CH.sub.2--, H.sub.3C--CH.sub.2--CH.sub.2--,
H.sub.3C--CH(CH.sub.3)--, H.sub.3C--CH.sub.2--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--CH(CH.sub.3)--,
H.sub.3C--CH(CH.sub.3)--CH.sub.2--, H.sub.3C--C(CH.sub.3).sub.2--,
H.sub.3C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--CH.sub.2--CH(CH.sub.3)--,
H.sub.3C--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
H.sub.3C--CH(CH.sub.3)--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--C(CH.sub.3).sub.2--,
H.sub.3C--C(CH.sub.3).sub.2--CH.sub.2--,
H.sub.3C--CH(CH.sub.3)--CH(CH.sub.3)-- and
H.sub.3C--CH.sub.2--CH(CH.sub.2CH.sub.3)--.
[0048] Further examples of alkyl are methyl (Me; --CH.sub.3), ethyl
(Et; --CH.sub.2CH.sub.3), 1-propyl (n-propyl; n-Pr;
--CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr; iso-propyl;
--CH(CH.sub.3).sub.2), 1-butyl (n-butyl; n-Bu;
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (iso-butyl;
i-Bu; --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (sec-butyl; sec-Bu;
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (tert-butyl;
t-Bu; --C(CH.sub.3).sub.3), 1-pentyl (n-pentyl;
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 3-methyl-1-butyl (iso-pentyl;
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 2,2-dimethyl-1-propyl
(neo-pentyl; --CH.sub.2C(CH.sub.3).sub.3), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl (n-hexyl;
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3),
2,3-dimethyl-1-butyl (--CH.sub.2CH(CH.sub.3)CH(CH.sub.3)CH.sub.3),
2,2-dimethyl-1-butyl (--CH.sub.2C(CH.sub.3).sub.2CH.sub.2CH.sub.3),
3,3-dimethyl-1-butyl (--CH.sub.2CH.sub.2C(CH.sub.3).sub.3),
2-methyl-1-pentyl (--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3),
3-methyl-1-pentyl (--CH.sub.2CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3),
1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl,
2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl,
2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl,
2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl),
1-nonyl (n-nonyl); 1-decyl (n-decyl) etc.
[0049] By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl,
nonyl, decyl etc. without any further definition are meant
saturated hydrocarbon groups with the corresponding number of
carbon atoms, wherein all isomeric forms are included.
[0050] The above definition for alkyl also applies if alkyl is a
part of another (combined) group such as for example
C.sub.x-yalkylamino or C.sub.x-yalkoxy.
[0051] Unlike alkyl, alkenyl consists of at least two carbon atoms,
wherein at least two adjacent carbon atoms are joined together by a
C--C double bond and a carbon atom can only be part of one C--C
double bond. If in an alkyl as hereinbefore defined having at least
two carbon atoms, two hydrogen atoms on adjacent carbon atoms are
formally removed and the free valencies are saturated to form a
second bond, the corresponding alkenyl is formed.
[0052] Alkenyl may optionally be present in the cis or trans or E
or Z orientation with regard to the double bond(s).
[0053] Unlike alkyl, alkynyl consists of at least two carbon atoms,
wherein at least two adjacent carbon atoms are joined together by a
C--C triple bond. If in an alkyl as hereinbefore defined having at
least two carbon atoms, two hydrogen atoms in each case at adjacent
carbon atoms are formally removed and the free valencies are
saturated to form two further bonds, the corresponding alkynyl is
formed.
[0054] Haloalkyl (haloalkenyl, haloalkynyl) is derived from the
previously defined alkyl (alkenyl, alkynyl) by replacing one or
more hydrogen atoms of the hydrocarbon chain independently of one
another by halogen atoms, which may be identical or different. If a
haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted,
the substitutions may take place independently of one another, in
the form of mono- or polysubstitutions in each case, on all the
hydrogen-carrying carbon atoms.
[0055] Examples of haloalkyl (haloalkenyl, haloalkynyl) are
--CF.sub.3, --CHF.sub.2, --CH.sub.2F, --CF.sub.2CF.sub.3,
--CHFCF.sub.3, --CH.sub.2CF.sub.3, --CF.sub.2CH.sub.3,
--CHFCH.sub.3, --CF.sub.2CF.sub.2CF.sub.3,
--CF.sub.2CH.sub.2CH.sub.3, --CF.dbd.CF.sub.2, --CCl.dbd.CH.sub.2,
--CBr.dbd.CH.sub.2, --C.ident.C--CF.sub.3, --CHFCH.sub.2CH.sub.3,
--CHFCH.sub.2CF.sub.3 etc.
[0056] Halogen relates to fluorine, chlorine, bromine and/or iodine
atoms.
[0057] Cycloalkyl is made up of the subgroups monocyclic
hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon
rings. The systems are saturated. In bicyclic hydrocarbon rings two
rings are joined together so that they have at least two carbon
atoms together.
[0058] If a cycloalkyl is to be substituted, the substitutions may
take place independently of one another, in the form of mono- or
polysubstitutions in each case, on all the hydrogen-carrying carbon
atoms. Cycloalkyl itself may be linked as a substituent to the
molecule via every suitable position of the ring system.
[0059] Examples of cycloalkyl are cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl.
[0060] Corresponding groups are an example:
##STR00193##
[0061] Spirocycle is a spiro-hydrocarbon ring one carbon atom
(spiroatom) belongs to two rings together.
[0062] Aryl denotes mono-, bi- or tricyclic carbocycles with at
least one aromatic carbocycle. Preferably, it denotes a monocyclic
group with six carbon atoms (phenyl) or a bicyclic group with nine
or ten carbon atoms (two six-membered rings or one six-membered
ring with a five-membered ring), wherein the second ring may also
be aromatic or, however, may also be saturated or partially
saturated.
[0063] If an aryl is to be substituted, the substitutions may take
place independently of one another, in the form of mono- or
polysubstitutions in each case, on all the hydrogen-carrying carbon
atoms. Aryl itself may be linked as a substituent to the molecule
via every suitable position of the ring system.
[0064] Examples of aryl are phenyl and naphthyl.
[0065] The above definition of aryl also applies if aryl is part of
another (combined) group as for example in arylamino, aryloxy or
arylalkyl.
[0066] Heterocyclyl denotes ring systems, which are derived from
the previously defined cycloalkyl or spirocycle by replacing one or
more of the groups --CH.sub.2-- independently of one another in the
hydrocarbon rings by the groups --O--, --S-- or --NH--, wherein a
total of not more than five heteroatoms may be present, at least
one carbon atom may be present between two oxygen atoms and between
two sulphur atoms or between one oxygen and one sulphur atom and
the ring as a whole must have chemical stability. Heteroatoms may
optionally be present in all the possible oxidation stages
(sulphur.fwdarw.sulphoxide --SO--, sulphone --SO.sub.2--;
nitrogen.fwdarw.N-oxide).
[0067] If a heterocyclyl is substituted, the substitutions may take
place independently of one another, in the form of mono- or
polysubstitutions in each case, on all the hydrogen-carrying carbon
and/or nitrogen atoms. Heterocyclyl itself may be linked as a
substituent to the molecule via every suitable position of the ring
system.
[0068] Examples of heterocyclyl are tetrahydrofuranyl,
tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl,
morpholinyl,
or the following heterocyclic spirocycles
##STR00194##
[0069] Heteroaryl denotes monocyclic heteroaromatic rings or
polycyclic rings with at least one heteroaromatic ring, which
compared with the corresponding aryl or cycloalkyl, instead of one
or more carbon atoms, one or more identical or different
heteroatoms, selected independently of one another from among
nitrogen, sulphur and oxygen, wherein the resulting group must be
chemically stable. The prerequisite for the presence of heteroaryl
is a heteroatom and a heteroaromatic system.
[0070] If a heteroaryl is to be substituted, the substitutions may
take place independently of one another, in the form of mono- or
polysubstitutions in each case, on all the hydrogen-carrying carbon
and/or nitrogen atoms. Heteroaryl itself may be linked as a
substituent to the molecule via every suitable position of the ring
system, both carbon and nitrogen.
[0071] Examples of heteroaryl are, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, benzoxazolyl, indolyl, isoindolyl,
benzofuranyl, benzimidazolyl, benzothiazolyl, and the like.
[0072] Heteroatoms may optionally be present in all the possible
oxidation stages (sulphur.fwdarw.sulphoxide --SO--, sulphone
--SO.sub.2--; nitrogen.fwdarw.N-oxide).
[0073] Carbocycles include hydrocarbon rings containing from three
to twelve carbon atoms. These carbocycles may be either aromatic
either aromatic or non-aromatic ring systems. The non-aromatic ring
systems may be mono- or polyunsaturated. Preferred carbocycles
include but are not limited to cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,
cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl,
benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl,
decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl.
[0074] All cyclic and acyclic systems defined in this section
hereinabove shall be understood to be optionally partially or fully
halogenated where possible and unless otherwise indicated.
[0075] Stereochemistry/Solvates/Hydrates:
[0076] Unless specifically indicated, throughout the specification
and appended claims, a given chemical formula or name shall
encompass tautomers and all stereo, optical and geometrical isomers
(e.g. enantiomers, diastereomers, E/Z isomers, etc.) and racemates
thereof as well as mixtures in different proportions of the
separate enantiomers, mixtures of diastereomers, or mixtures of any
of the foregoing forms where such isomers and enantiomers exist, as
well as salts, including pharmaceutically acceptable salts thereof.
The compounds and salts of the invention can exist in unsolvated as
well as solvated forms with pharmaceutically acceptable solvents
such as water, ethanol and the like. In general, the solvated forms
such as hydrates are considered equivalent to the unsolvated forms
for the purposes of the invention.
[0077] Salts:
[0078] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgement,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, and commensurate with a
reasonable benefit/risk ratio.
[0079] As used herein "pharmaceutically acceptable salts" refers to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines;
alkali or organic salts of acidic residues such as carboxylic
acids; and the like.
[0080] For example, such salts include acetates, ascorbates,
benzenesulphonates, benzoates, besylates, bicarbonates,
bitartrates, bromides/hydrobromides, Ca-edetates/edetates,
camsylates, carbonates, chlorides/hydrochlorides, citrates,
edisylates, ethane disulphonates, estolates esylates, fumarates,
gluceptates, gluconates, glutamates, glycolates,
glycollylarsnilates, hexylresorcinates, hydrabamines,
hydroxymaleates, hydroxynaphthoates, iodides, isothionates,
lactates, lactobionates, malates, maleates, mandelates,
methanesulphonates, mesylates, methylbromides, methylnitrates,
methylsulphates, mucates, napsylates, nitrates, oxalates, pamoates,
pantothenates, phenyl acetates, phosphates/diphosphates,
polygalacturonates, propionates, salicylates, stearates,
subacetates, succinates, sulphamides, sulphates, tannates,
tartrates, teoclates, toluenesulphonates, triethiodides, ammonium,
benzathines, chloroprocaines, cholines, diethanolamines,
ethylenediamines, meglumines and procaines.
[0081] Further pharmaceutically acceptable salts can be formed with
cations from metals like aluminium, calcium, lithium, magnesium,
potassium, sodium, zinc and the like (also see Pharmaceutical
salts, Birge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).
[0082] The pharmaceutically acceptable salts of the present
invention can be synthesised from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base form of these compounds with a sufficient amount of the
appropriate base or acid in water or in an organic diluent like
ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a
mixture thereof.
[0083] Salts of other acids than those mentioned above which for
example are useful for purifying or isolating the compounds of the
present invention (e.g. trifluoroacetates), also comprise a part of
the invention.
[0084] Some abbreviated notations and their structure
correspondences are listed below: In a representation such as for
example
##STR00195##
the solid line means that the ring system may be attached to the
molecule via the carbon atom 1, 2 or 3, and is thus equivalent to
the following representation
##STR00196##
[0085] By a therapeutically effective amount for the purposes of
this invention is meant a quantity of substance that is capable of
obviating symptoms of illness or alleviating these symptoms, or
which prolong the survival of a treated patient.
LIST OF ABBREVIATIONS
TABLE-US-00002 [0086] Ac Acetyl ACN Acetonitrile aq Aqueous ATP
adenosine triphosphate Bn Benzyl Bu Butyl Boc tert-butyloxycarbonyl
cat Catalyst conc concentrated d day(s) TLC thin layer
chromatography DIEA N,N-diisopropylethylamine DMAP
4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMF
N,N-dimethylformamide DMSO Dimethylsulphoxide dppf
1.1'-bis(diphenylphosphino)ferrocene EDC
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI electron spray
ionization Et Ethyl Et.sub.2O diethyl ether EtOAc ethyl acetate
EtOH Ethanol h hour(s) HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium
hexafluorophosphate Hep Heptane HPLC high performance liquid
chromatography i Iso LC liquid chromatography LiHMDS lithium
bis(trimethylsilyl)amide sln. Solution mCPBA 3-Chloroperoxbenzoic
acid Me Methyl MeOH Methanol min Minutes MPLC medium pressure
liquid chromatography MS mass spectrometry NBS N-bromo-succinimide
NIS N-iodo-succinimide NMM N-methylmorpholine NMP
N-methylpyrrolidone NP normal phase n.a. not available PBS
phosphate-buffered saline Ph Phenyl Pr Propyl Pyr Pyridine rac
Racemic Rf (R.sub.f) retention factor RP reversed phase RT
Retention time (HPLC) rt ambient temperature TBAF
tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl TBME
tert-butylmethylether TBTU
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium
tetrafluoroborate tBu tert-butyl TEA Triethylamine temp.
Temperature tert Tertiary Tf Triflate TFA trifluoroacetic acid THF
Tetrahydrofuran TMS Trimethylsilyl TRIS
tris(hydroxymethyl)-aminomethane Ts p-Tosyl TsOH p-toluenesulphonic
acid UV Ultraviolet
[0087] Features and advantages of the present invention will become
apparent from the following detailed examples which illustrate the
fundamentals of the invention by way of example without restricting
its scope:
Preparation of the Compounds According to the Invention
General Synthetic Methods
[0088] Optimum reaction conditions and reaction times may vary
depending on the particular reactants used. Unless otherwise
specified, solvents, temperatures, pressures and other reaction
conditions may be readily selected by one of ordinary skill in the
art. Specific procedures are provided in the Synthetic Examples
section. Intermediates and products may be purified by
chromatography on silica gel, recrystallization and/or reverse
phase HPLC (RHPLC). Discrete enantiomers may be obtained by
resolution of racemic products using chiral HPLC. RHPLC
purification methods used anywhere from 0-100% acetonitrile in
water containing 0.1% formic acid or 0.1% TFA and used one of the
following columns:
a) Waters Sunfire OBD C18 5 .mu.m 30.times.150 mm column b) Waters
XBridge OBD C18 5 .mu.m 30.times.150 mm column c) Waters ODB C8 5
.mu.m 19.times.150 mm column d) Waters Atlantis ODB C18 5 .mu.m
19.times.50 mm column. e) Waters Atlantis T3 OBD 5 .mu.m
30.times.100 mm column f) Phenomenex Gemini Axia C18 5 .mu.m
30.times.100 mm column
HPLC Methods:
Analytical LC/MS Analysis Method A:
[0089] Column: Thermo Scientific, Aquasil C18, 50.times.2.1 mm, 5
.mu.m column
Gradient:
TABLE-US-00003 [0090] Time 0.1% Formic Acid in 0.1% Formic Acid
(min) Water in CAN Flow (ml/min) 0 90 10 0.5 0.5 90 10 0.5 1.5 1 99
0.5 2.5 1 99 0.5 3.3 90 10 0.5 4.0 90 10 0.5
Analytical LC/MS Analysis Method B:
[0091] Column: Waters BEH 2.1.times.50 mm C18 1.7 .mu.m column
Gradient:
TABLE-US-00004 [0092] 95% Water/5% Time (min) ACN (0.05% TFA) ACN
(0.05% TFA) Flow (ml/min) 0 90 10 0.8 1.19 0 100 0.8 1.7 0 100
0.8
[0093] The compounds according to the invention are prepared by the
methods of synthesis described hereinafter in which the
substituents of the general formulae have the meanings given
hereinbefore. These methods are intended as an illustration of the
invention without restricting its subject matter and the scope of
the compounds claimed to these examples. Where the preparation of
starting compounds is not described, they are commercially
obtainable or may be prepared analogously to known compounds or
methods described herein. Substances described in the literature
are prepared according to the published methods of synthesis.
[0094] Compounds of formula I may be prepared as shown in Scheme Ia
and Ib below.
##STR00197##
[0095] In scheme Ia, a heterocycle A is treated with a suitable
base and reacted with an X.sub.1--Y group containing a leaving
group (LG) B to afford the compound of general formula (I).
##STR00198##
[0096] In scheme Ib, C (where X=O, N, S, or NH.sub.2) is condensed
with D to afford the compound of general formula (I).
SYNTHETIC EXAMPLES
Method 1
Synthesis of Intermediate I-1
##STR00199##
[0098] A solution of R-1 (5.0 g, 23 mmol) in CH.sub.2Cl.sub.2 is
treated with TEA (6.5 mL, 47 mmol) and DMAP (0.57 g, 4.7 mmol). The
mixture is stirred for 24 h then concentrated in vacuo. The residue
is dissolved in EtOAc and washed with saturated aqueous ammonium
chloride and brine. The organics are collected and volatiles are
removed in vacuo. The crude residue is triturated with Et.sub.2O
and solid filtered and collected to afford I-1 (5.6 g, 65%) m/z
367.9 [M+].
[0099] The following intermediates were prepared in a similar
manner
TABLE-US-00005 Structure Intermediate m/z ##STR00200## I-2 396.3 [M
+ H] ##STR00201## I-3 356.0 [M + H]
Method 2
Synthesis of Intermediate I-4 and Separation of Diastereomers I-5
and I-6
##STR00202##
[0101] To a solution of PPh.sub.3CH.sub.3Br (578 g, 1.62 mol) in
THF (3.5 L) is added a solution of n-BuLi (600 mL, 1.5 mol) at
-78.degree. C. under N.sub.2. The mixture is stirred at 0.degree.
C. for 1 h then R-2 (200 g, 1.08 mol) in THF (2.0 L) is added to
the reaction mixture at 0.degree. C. The mixture is allowed to warm
to ambient temperature, stirred for 1 h, then poured into H.sub.2O
and extracted with EtOAc. The organic layers are washed with brine,
dried with Na.sub.2SO.sub.4, concentrated and purified by flash
chromatography (SiO.sub.2, Hep to 25% EtOAc in Hep) to give
compound R-3 (70 g, 36%).
[0102] To a solution of R-3 (20 g, 109 mmol) in Et.sub.2O (150 mL)
is added Zn--Cu (56.2 g, 436 mmol) at 10.degree. C. under N.sub.2.
Trichloroacetyl chloride (39.7 g, 218 mmol) in DME (150 mL) is
added. The mixture is allowed to warm to ambient temperature and
stirred for 2 days. The mixture is treated with aqueous NaHCO.sub.3
and extracted with EtOAc. The organic layers are washed with brine,
dried with Na.sub.2SO.sub.4, concentrated and purified by flash
chromatography (SiO.sub.2, Hep to 25% EtOAc in Hep) to give R-4 (11
g, 34%).
[0103] To a solution of R-4 (35.5 g, 121 mmol) in saturated
NH.sub.4Cl (64.7 g, 1.21 mol) in MeOH (400 mL) is added Zn (79.1 g,
1.21 mol). The mixture is stirred at ambient temperature for 8 h.
The mixture is treated with H.sub.2O and extracted with EtOAc. The
organic layers are washed with brine, dried with Na.sub.2SO.sub.4,
concentrated and purified by flash chromatography (SiO.sub.2, Hep
to 25% EtOAc in Hep) to afford R-5 (19 g, 69%).
[0104] To the mixture of R-5 (19 g, 84.3 mmol) in THF (200 mL) is
added NaBH.sub.4 (12.8 g, 337.2 mmol) at 0.degree. C. and then
stirred at ambient temperature for 6 h. The mixture is treated with
MeOH and H.sub.2O, then extracted with EtOAc. The organic layers
are washed with brine, dried with Na.sub.2SO.sub.4, concentrated
and purified by flash chromatography (SiO.sub.2, Hep to 50% EtOAc
in Hep) to yield R-6 (12 g, 63%).
[0105] To the mixture of R-6 (22 g, 96.8 mmol) and pyridine (23.2
g, 290.4 mmol) in CH.sub.2Cl.sub.2 (300 mL) is added TsCl (27.7 g,
145.2 mmol) at 0.degree. C. and then stirred at ambient temperature
overnight. The mixture is treated with H.sub.2O and extracted with
EtOAc. The organic layers are washed with brine, dried with
Na.sub.2SO.sub.4, concentrated and purified by flash chromatography
(SiO.sub.2, Hep to 40% EtOAc in Hep) to give I-4 (26.6 g, 72%) m/z
382.2 [M+H]. I-4 is separated by flash chromatography (SiO.sub.2,
Hep to 40% EtOAc in Hep) to give diastereomers I-5 (m/z 382.2
[M+H]) and I-6 (m/z 382.2 [M+H]).
Method 3
Synthesis of Intermediate I-8
##STR00203##
[0107] To a solution of R-7 (15.0 g, 97 mmol) in CH.sub.2I.sub.2
(350 mL) is added isoamylnitrite (58.7 g, 580 mmol). The solution
is stirred for 15 min at ambient temperature then heated at
70.degree. C. for 2 h. The mixture is cooled to ambient temperature
then partitioned between EtOAc and aqueous sodium bisulfite. The
organics are collected, dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The crude is purified by flash
chromatography (SiO.sub.2, Hep to 50% EtOAc in Hep) to give the I-7
(13.1 g, 51%) m/z 266.8 [M+H].
[0108] A solution of I-7 (2.0 g, 7.5 mmol), 4-phenoxyphenylboronic
acid (2.0 g, 9.3 mmol), and
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(1.5 g, 2.1 mmol) in DMF (20 mL) and 2M aqueous Cs.sub.2CO.sub.3
(10 mL) is heated at 120.degree. C. for 2 h. The mixture is cooled
to ambient temperature then partitioned between EtOAc and aqueous
NH.sub.4Cl. The organics are collected, dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The crude is purified by flash
chromatography (SiO.sub.2, 10-30% EtOAc in Hep) to give I-8 (1.6 g,
69%). m/z 309.1 [M+H]
Method 4
Synthesis of Intermediate I-9
##STR00204##
[0110] To malonitrile (7.55 g, 114 mmol) in THF (200 mL) at
0.degree. C. is added sodium hydride (60% dispersion in mineral
oil, 4.57 g, 114 mmol) slowly under a stream of nitrogen. After 10
min R-8 (27 g, 115 mmol) is added and the ice bath removed. The
mixture is stirred at ambient temperature for 1.5 h then
dimethylsulfate is added then heated at reflux for 2 h. The mixture
is cooled to ambient temperature then triethylamine and hydrazine
are added.
[0111] The mixture is heated at reflux for 2 h then concentrated in
vacuo, diluted with water, and extracted with 10% MeOH in EtOAc.
The organics are collected, dried over MgSO.sub.4, filtered and
concentrated. The crude is purified by flash chromatography
(SiO.sub.2, 0-100% EtOAc in Hep) to afford I-9 (5.7 g, 18%). m/z
277.5 [M+H]
Method 5
Synthesis of Intermediate I-10
##STR00205##
[0113] To a solution of I-1 (200 mg, 0.54 mmol) in DMSO (2.5 mL)
was added KCN (71 mg, 1.1 mmol). The mixture was heated at
100.degree. C. for 18 h then cooled to ambient temperature and
partitioned between EtOAc and water. The organics were collected,
dried over MgSO.sub.4, filtered and concentrated in vacuo to afford
I-10 (quant, 120 mg). m/z 223.1 [M+H]
[0114] The following intermediates were prepared in a similar
manner
TABLE-US-00006 Structure Intermediate m/z ##STR00206## I-11 181.0
[M - tBu] ##STR00207## I-12 211.1 [M + H] ##STR00208## I-13 195.4
[M - tBu]
Method 6
Synthesis of Intermediate I-14
##STR00209##
[0116] To a solution of I-10 (250 mg, 1.1 mmol) in DMF (2 mL) is
added 20% (w/w) aqueous (NH.sub.4).sub.2S (2 mL, 5.9 mmol). The
mixture is stirred at ambient temperature for 17 h then diluted
with water. The resulting white solid is filtered and collected to
give I-14 (160 mg, 55%). m/z 257.0 [M+H]
[0117] The following intermediates were prepared in a similar
manner
TABLE-US-00007 Structure Intermediate m/z ##STR00210## I-15 271.1
[M + H] ##STR00211## I-16 189.0 [M - tBu] ##STR00212## I-17 245.0
[M + H] ##STR00213## I-18 285.1 [M + H]
Method 7
Synthesis of Intermediate I-19
##STR00214##
[0119] A solution of I-13 (422 mg, 1.69 mmol) in EtOH (8.4 mL) is
treated with 50% (w/w) aqueous hydroxylamine (1.1 mL, 16.9 mmol).
The solution is heated at 70.degree. C. for 2 h then volatiles are
removed in vacuo to afford I-19 (478 mg, quant) m/z 284.1
[M+H].
[0120] The following intermediates were prepared in similar
manner
TABLE-US-00008 Structure Intermediate m/z ##STR00215## I-20 244.1
[M + H]
Method 8
Synthesis of Intermediate I-21
##STR00216##
[0122] To a solution of I-8 (200 mg, 0.65 mmol) and
Cs.sub.2CO.sub.3 (423 mg, 1.30 mmol) in DMF (3 mL) is added I-1
(262 mg, 0.71 mmol). The mixture is heated at 60.degree. C. for 18
h then concentrated in vacuo. The residue is purified by flash
chromatography (SiO.sub.2, Hep to 50% EtOAc in Hep) to give I-21
(217 mg, 66%) m/z 504.2 [M+H].
[0123] The following intermediates were prepared in similar
fashion:
TABLE-US-00009 Structure Intermediate m/z ##STR00217## I-22 492.2
[M + H] ##STR00218## I-23 518.2 [M + H] ##STR00219## I-24 518.2 [M
+ H] ##STR00220## I-25 NA
Method 9
Synthesis of Intermediate I-26
##STR00221##
[0125] To a solution of I-6 (800 mg, 2.6 mmol) in THF (40 mL) is
added R-8 (650 mg, 3.0 mmol), tri-n-octyl phosphine (3.0 g, 8.0
mmol), and ADDP (1,1'-(azodicarbonyl)dipiperidine) (2.1 g, 8.2
mmol). The mixture is stirred for 48 h then concentrated in vacuo.
The residue is partitioned between saturated aqueous NH.sub.4Cl and
EtOAc. The organics are washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude is
purified by flash chromatography (SiO.sub.2, Hep to 30% EtOAc in
Hep) to give I-24 (1.1 g, 84%) m/z 506.1 [M+H].
[0126] The following intermediates are prepared in similar
fashion:
TABLE-US-00010 Structure Intermediate m/z ##STR00222## I-25 NA
##STR00223## I-26 NA ##STR00224## I-27 417.9 [M + H] ##STR00225##
I-28 NA
Method 10
Synthesis of Intermediate I-30
##STR00226##
[0128] A solution of I-21 (260 mg, 0.52 mmol) in 1:1 dioxane/water
(8 mL) is treated with LiOH (120 mg, 5.0 mmol). The mixture is
heated at reflux for 2 h then volatiles are removed in vacuo. The
residue is acidified to pH=4 with 2M aqueous HCl, extracted with
EtOAc, washed with brine, dried over Na.sub.2SO.sub.4, filtered,
and concentrated in vacuo. The residue is dissolved in DMF (4 mL)
and treated with pyridine (80 uL, 1.0 mmol) and Boc anhydride (80
mg, 1.0 mmol). The solution is stirred for 10 min then ammonium
bicarbonate (95 mg, 1.2 mmol) is added. The mixture is stirred for
16 h then volatiles are removed in vacuo. The residue is
partitioned between EtOAc and saturated aqueous NH.sub.4Cl. The
organics are washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The residue is purified by
flash chromatography (SiO.sub.2, 20-80% EtOAc in Hep, then 20% MeOH
in CH.sub.2Cl.sub.2) to give I-29 (180 mg, 75%) m/z 475.0
[M+H].
[0129] To a stirred solution of I-29 (180 mg, 0.38 mmol) in
CH.sub.2Cl.sub.2 (3 mL) is added TFA (2 mL). The solution is
stirred at ambient temperature for 3 h then volatiles are removed
in vacuo. The residue is partitioned between saturated aqueous
NaHCO.sub.3 and EtOAc. The organics are collected, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford
I-30 (130 mg, 92%) m/z 375.0 [M+H].
[0130] The following intermediates were prepared in similar
fashion:
TABLE-US-00011 Structure Intermediate m/z ##STR00227## I-31
##STR00228## I-32 ##STR00229## I-33 ##STR00230## I-34 ##STR00231##
I-35 ##STR00232## I-36 ##STR00233## I-37 ##STR00234## I-38
##STR00235## I-39 NA
Method 11
Synthesis of Intermediate I-41
##STR00236##
[0132] To a solution of R-9 (5.00 g, 23.6 mmol) in THF (50 mL) is
added a 60% dispersion of sodium hydride in mineral oil (1.41 g,
35.1 mmol). The mixture is stirred for 5 min at ambient temperature
then diethyl carbonate (5.7 mL, 47.4 mmol). The reaction is stirred
for 30 min at ambient temperature then heated at reflux for 2 h.
The mixture is cooled to ambient temperature then partitioned
between saturated aqueous NH.sub.4Cl and EtOAc. The organics are
collected and concentrated in vacuo to afford a residue that is
purified by flash chromatography (SiO.sub.2, Hep to 70% EtOAc in
Hep) to give I-40 (6.2 g, 93%) m/z 285.1 [M+H].
[0133] To a cold (0.degree. C.) solution of I-40 (5.2 g, 18.3 mmol)
in CH.sub.2Cl.sub.2 (46 mL) is added SO.sub.2Cl.sub.2 (1.5 mL, 18.3
mmol). The mixture is allowed to warm to ambient temperature and
stirred for 30 min then treated with water, extracted with
CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo to afford I-41 (quant) m/z 318.9 [M+H].
Method 12
Synthesis of Intermediate I-43
##STR00237##
[0135] A solution of I-15 (400 mg, 1.48 mmol) and I-41 (943 mg,
2.96 mmol) in i-PrOH (15 mL) is treated with pyridine (0.36 mL,
4.44 mmol). The mixture is heated at 60.degree. C. for 3 days then
volatiles are removed in vacuo. The residue is purified by flash
chromatography (SiO.sub.2, Hep to 40% EtOAc in Hep) to give I-42
(240 mg, 30%) m/z 535.2 [M+H].
[0136] A solution of I-42 (240 mg, 0.45 mmol) in MeOH (3 mL), THF
(1 mL), and 5M aqueous NaOH (0.5 mL) is heated at 60.degree. C. for
3 h. The mixture is cooled to ambient temperature then acidified to
pH=1 with 6M aqueous HCl. The mixture is extracted with
CH.sub.2Cl.sub.2 then filtered through a phase Separator.RTM. then
volatiles are removed in vacuo. The residue is dissolved in DMF (2
mL) and treated with pyridine (324 mg, 4.1 mmol), Boc anhydride
(327 mg, 0.45 mmol), followed by ammonium bicarbonate (215 mg, 2.72
mmol). The mixture is stirred for 3 h then volatiles are removed in
vacuo to afford a residue that is purified by flash chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2 to 5% MeOH in CH.sub.2Cl.sub.2). The
purified material is dissolved in CH.sub.2Cl.sub.2 (5 mL) and
treated with 4.0M HCl in dioxane (1.1 mL). The mixture is stirred
for 1 h then volatiles are removed in vacuo to afford a residue
that is purified by flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2 to 20% MeOH in CH.sub.2Cl.sub.2 containing 2.5%
TEA) to give I-43 (134 mg, 73%) m/z 405.9 [M+H].
[0137] The following compounds are made in similar fashion:
TABLE-US-00012 Inter- Structure mediate m/z ##STR00238## I-44 380.8
[M + H] ##STR00239## I-45 380.4 [M + H] ##STR00240## I-46 NA
Method 13
Synthesis of Intermediate I-46
##STR00241##
[0139] To a solution of I-14 (160 mg, 0.62 mmol) and I-41 (298 mg,
0.94 mmol) in i-PrOH (6.2 mL) is added pyridine (0.15 mL, 1.9
mmol). The solution is heated at 70.degree. C. for 24 h then
volatiles are removed in vacuo. The crude is purified by flash
chromatography (SiO.sub.2, Hep to 40% EtOAc in Hep) to give I-46
(144 mg, 44%) m/z 521.2 [M+H].
[0140] A solution of I-46 (144 mg, 0.28 mmol) in MeOH (2 mL) and 3M
aqueous NaOH (2 mL) is heated at 65.degree. C. for 3 h then cooled
to ambient temperature. The solid is filtered, collected, and dried
then dissolved in DMF (2 mL) and treated with TBTU (71 mg, 0.22
mmol). The mixture is stirred for 15 min then treated with 7M
ammonia in MeOH (7 mL). The mixture is stirred for 20 min then
volatiles are removed in vacuo. The residue is partitioned between
water and EtOAc and organics are collected and concentrated. The
crude is purified by flash chromatography (Hep to EtOAc). The
resulting compound is dissolved in CH.sub.2Cl.sub.2 (2 mL) and
treated with TFA (1 mL). The reaction mixture is stirred for 2 h
then volatiles are removed in vacuo. The crude is partitioned
between CH.sub.2Cl.sub.2 and 10% (w/w) aqueous Na.sub.2CO.sub.3 and
CH.sub.2Cl.sub.2. The organics are collected and filtered through a
phase Separator.RTM. to afford after removal of the volatiles I-47
(58 mg, 53%) m/z 392.1 [M+H].
Method 14
Synthesis of Intermediate I-51
##STR00242## ##STR00243##
[0142] A solution of I-20 (500 mg, 2.1 mmol) and methyl propriolate
(0.35 mL, 4.1 mmol) in MeOH (10 mL) is heated at 65.degree. C. for
4 h. The mixture is concentrated in vacuo then dissolved in
diphenyl ether (2 mL) and heated at 200.degree. C. for 1 h. The
mixture is cooled to ambient temperature then purified by flash
chromatography (SiO.sub.2, Hep to EtOAc) to give I-48 (317 mg, 50%)
m/z 310.2 [M+H].
[0143] To a solution of I-48 (317 mg, 1.0 mmol) and p-TsOH Pyr (461
mg, 2.1 mmol) in CH.sub.2Cl.sub.2 (5 mL) is added NIS (461 mg, 2.1
mmol). The mixture is stirred in the dark at ambient temperature
for 24 h. The mixture is treated with saturated aqueous
Na.sub.2SO.sub.3 then filtered through a phase separator. The
organics are collected and concentrated in vacuo to afford a
residue that is purified by flash chromatography (SiO.sub.2, Hep to
80% EtOAc in Hep) to afford I-49 (339 mg, 76%) m/z 436.0 [M+H].
[0144] A mixture of I-49 (339 mg, 0.78 mmol),
4-phenoxylphenylboronic acid (333 mg, 1.56 mmol), and
tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.078 mmol), and
K.sub.3PO.sub.4 (827 mg, 3.89 mmol) in dioxane (4 mL) is heated at
100.degree. C. in the microwave for 45 min. The mixture is cooled
and concentrated in vacuo to afford a residue that is purified by
flash chromatography (SiO.sub.2, Hep to 80% EtOAc in Hep) to afford
I-50 (302 mg, 81%) m/z 478.2 [M+H].
[0145] A solution of I-50 (372 mg, 0.78 mmol) in MeOH (1.5 mL), THF
(1 mL), and 3M aqueous NaOH (3 mL) is heated at ambient temperature
for 20 h then acidified to pH=5 with concentrated aqueous HCl. The
volatiles are removed in vacuo and residue triturated with a
mixture of CH.sub.2Cl.sub.2 and MTBE. The solid is filtered,
collected, and dried. The solid is dissolved in DMF (2 mL) and
treated with pyridine (0.1 mL, 1.2 mmol), Boc anhydride (69 mg,
0.87 mmol), followed by ammonium bicarbonate (96 mg, 1.2 mmol). The
mixture is stirred for 16 h then partitioned between water and
CH.sub.2Cl.sub.2. The mixture is filtered through a phase
Separator.RTM. and organics are concentrated in vacuo to afford a
residue that is purified by flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2 to 5% MeOH in CH.sub.2Cl.sub.2). The purified
material is dissolved in CH.sub.2Cl.sub.2 (2 mL) and treated with
4.0M HCl in dioxane (4 mL). The mixture is stirred for 2 h then
volatiles are removed in vacuo to afford a residue that is purified
by trituration with MTBE:EtOAc to give I-51 (75 mg, 22%) m/z 393.1
[M+H].
[0146] The following intermediate is prepared in similar
fashion:
TABLE-US-00013 Inter- Structure mediate m/z ##STR00244## I-52 403.2
[M + H]
Method 15
Synthesis of Intermediate I-54
##STR00245##
[0148] To a solution of I-9 (1.50 g, 5.4 mmol) in DMF (20 mL) is
added sodium hydride (60% dispersion in mineral oil, 0.26 g, 6.5
mmol). The mixture is stirred for 5 min then I-1 (2.39 g, 6.5 mmol)
is added. The mixture is heated at 70.degree. C. for 18 h then
cooled to ambient temperature. The mixture is partitioned between
EtOAc and water then organics are collected, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue
is purified by flash chromatography (SiO.sub.2, Hep to 70% EtOAc in
Hep) to afford I-53 (1.2 g, 47%) m/z 472.2 [M+H].
[0149] A solution of I-53 (1.00 g, 2.2 mmol) in AcOH (5 mL) and
Concentrated aqueous HCl (1 mL) is heated at 90.degree. C. for 10
h. The mixture is cooled to ambient temperature then poured into
ice. The mixture is basified to pH 9-10 by addition of ammonium
hydroxide then extracted with EtOAc, washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue
is purified by RHPLC to afford I-54 (0.39 g, 48%) m/z 390.1
[M+H].
[0150] The following intermediates are prepared in similar
fashion:
TABLE-US-00014 Inter- Structure mediate m/z ##STR00246## I-54 378.1
[M + H] ##STR00247## I-55 418.2 [M + H] ##STR00248## I-56
##STR00249## I-57 404.1 [M + H] ##STR00250## I-58 404.1 [M + H]
Method 16
Synthesis of Example 9
##STR00251##
[0152] To a solution of I-7 (2.00 g, 7.5 mmol) in DMF (20 mL) is
added Cs.sub.2CO.sub.3 (4.9 g, 15 mmol) and I-3 (4.0 g, 11 mmol).
The reaction mixture is heated at 60.degree. C. for 24 h then
cooled to ambient temperature. The mixture is partitioned between
EtOAc and water. The organics are collected, washed with water,
dried over MgSO.sub.4, filtered, and concentrated in vacuo. The
crude is purified by flash chromatography (SiO.sub.2, Hep to 30%
EtOAc in Hep) to afford I-59 (2.10 g, 62%) m/z 445.0 [M+H].
[0153] To a solution of I-59 (7.00 g, 15.6 mmol) in 1:1
dioxane:water (50 mL) is added LiOH (3.00 g, 125 mmol). The
reaction mixture was heated at reflux for 2 h then volatiles are
removed in vacuo. The residue is acidified with aqueous 2 N HCl to
pH=4 then diluted with EtOAc, washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue
is dissolved in DMF (30 mL) and treated with Boc anhydride (2.22 g,
28 mmol) followed by ammonium bicarbonate (2.21 g, 28 mmol) and
pyridine (2.2 mL, 28 mmol). The mixture is stirred for 16 h then
volatiles are removed in vacuo. The residue is partitioned between
EtOAc and saturated aqueous NH.sub.4Cl then organics are collected,
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude is purified by flash
chromatography (SiO.sub.2, 20-80% EtOAc in Hep, then 20% MeOH in
CH.sub.2Cl.sub.2) to afford I-60 (3.8 g, 61%) m/z 421.0 [M+H]
[0154] To a solution of 4-benzylphenylboronic acid pinacol ester
(47 mg, 0.16 mmol) in DME (1 mL) is added a solution of I-19 (45
mg, 0.11 mmol) in DME (1 mL). To this solution is added aqueous 1 M
K.sub.2CO.sub.3 (1 mL) and SiliaCat DPP-Pd (50 mg, 0.01 mmol). The
mixture is heated at 100.degree. C. for 16 h then concentrated in
vacuo. The crude was purified by RHPLC to afford a residue that is
dissolved in DCE and treated with 4.0M HCl in dioxane (0.5 mL). The
mixture is stirred for 16 h then volatiles are removed in vacuo. To
the residue is added a solution of acrylic acid (7.7 mg, 0.11
mmol), EDC (23 mg, 0.12 mmol), and DIEA (35 uL, 0.20 mmol) in DMA
(0.8 mL). The reaction mixture is stirred for 4 h then volatiles
were removed in vacuo to afford a residue that was purified by
RHPLC to afford example 9 (12 mg, 26%).
[0155] The following compounds were prepared in a similar
manner:
Examples 1-8, 10-27, 94-96
Method 17
Synthesis of Example 28
##STR00252##
[0157] To a solution of I-30 (75 mg, 0.20 mmol) in DMF (2 mL) is
added DIEA (0.3 mL), TBTU (96 mg, 0.30 mmol), and acrylic acid (22
mg, 0.30 mmol). The mixture is stirred for 12 h at ambient
temperature then treated with water. The mixture is extracted with
EtOAc, dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo. The crude is purified by flash chromatography (30 to 90%
EtOAc in Hep) to give example 28 (36 mg, 42%).
[0158] The following compounds are prepared in similar fashion:
Examples 29, 33, 39, 42, 45, 47, 55, 88
Method 18
Synthesis of Example 38
##STR00253##
[0160] To a solution of I-32 (70 mg, 0.18 mmol) in DMF (3 mL) is
added DIEA (1 mL), TBTU (116 mg, 0.36 mmol), and R-10 (17 mg, 0.20
mmol). The mixture is stirred for 12 h at ambient temperature then
treated with water. The mixture is extracted with EtOAc, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude is
purified by RHPLC to give example 38 (38 mg, 46%).
[0161] The following compounds are prepared in similar fashion:
Examples 31, 32, 43, 48, 49, 56
Method 19
Synthesis of Example 37
##STR00254##
[0163] To a solution of I-32 (25 mg, 0.064 mmol) in DMF (2 mL) is
added DIEA (0.4 mL), TBTU (32 mg, 0.080 mmol), and R-11 (10 mg,
0.080 mmol). The mixture is stirred for 12 h at ambient temperature
then treated with water. The mixture is extracted with EtOAc, dried
over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The
crude is purified by flash chromatography (SiO.sub.2, 30 to 70%
EtOAc in Hep) to give example 37 (5 mg, 16%).
[0164] The following compounds are prepared in similar fashion:
Examples 30, 36
Method 20
Synthesis of Example 40
##STR00255##
[0166] To a solution of I-32 (100 mg, 0.26 mmol) in
CH.sub.2Cl.sub.2 (2 mL) is added EDC (60 mg, 0.31 mmol) followed by
acrylic acid (22 mg, 0.31 mmol). The mixture is stirred at ambient
temperature for 1 h then directly purified by flash chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2 to 5% MeOH in CH.sub.2Cl.sub.2) to
give example 40 (15 mg, 13%).
[0167] The following compounds were made in similar fashion:
Examples 86, 89
R-10 Used Instead of Acrylic Acid
Method 21
Synthesis of Example 60
##STR00256##
[0169] To a solution of I-60 (43 mg, 0.10 mmol) in DME (2 mL) is
added R-12 (65 mg, 0.18 mmol), SiliaCat DPP-Pd (50 mg, 0.01 mmol),
and potassium carbonate (500 mg). The mixture is heated at
140.degree. C. in a microwave for 2 h then concentrated in vacuo.
The crude is purified by flash chromatography (SiO.sub.2, 0 to 4%
MeOH in CH.sub.2Cl.sub.2) to give I-61 (38 mg, 72%) m/z 519.2
[M+H].
[0170] I-61 (38 mg, 0.073 mmol) is dissolved in CH.sub.2Cl.sub.2 (2
mL) and treated with 4.0M HCl in dioxane (3 mL). The mixture is
stirred for 2 h at ambient temperature then volatiles are removed
in vacuo. The residue is dissolved in CH.sub.2Cl.sub.2 (2 mL) and
treated with acrylic acid (5 mg, 0.073 mmol) and EDC (14 mg, 0.073
mmol). The mixture is stirred for 1 h at ambient temperature then
partitioned between water and CH.sub.2Cl.sub.2. The mixture is
filtered through a phase Separator.RTM. and organics are collected
and concentrated in vacuo. The crude is purified by flash
chromatography (SiO.sub.2, CH.sub.2Cl.sub.2 to 8% MeOH in
CH.sub.2Cl.sub.2) to give example 60 (13 mg, 57%).
[0171] The following compound was made in similar fashion:
Example 61
Method 22
Synthesis of Example 72
##STR00257##
[0173] A flask is charged with I-60 (4.0 g, 9.5 mmol),
4-hydroxyphenylboronic acid (1.9 g, 14 mmol),
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(0.67 g, 0.95 mmol), potassium carbonate (2.5 g, 18 mmol) and
treated with DMF (40 mL) and water (10 mL). The mixture is heated
in the microwave at 140.degree. C. for 90 min. The mixture is
cooled to ambient temperature then treated with saturated aqueous
NH.sub.4Cl, extracted with EtOAc, dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The crude is purified by flash
chromatography (SiO.sub.2, 20 to 50% EtOAc in Hep) to give I-62
(2.0 g, 54%) m/z [M+H].
[0174] To a solution of I-62 (90 mg, 0.23 mmol) in CH.sub.2Cl.sub.2
(7 mL) is added 3-tolylboronic acid (95 mg, 0.70 mmol),
Cu(OAc).sub.2 (300 mg), pyridine (1 mL), TEA (1 mL), and molecular
sieves (4 .ANG.). The mixture is stirred at ambient temperature
open to air for 12 h. The mixture was filtered through a silica gel
pad and volatiles from the filtrate are removed in vacuo. The crude
is purified by RHPLC to afford I-63 (61 mg, 55%) m/z 477.1
[M+H].
[0175] To a solution of I-63 (55 mg, 0.115 mmol) in
CH.sub.2Cl.sub.2 (3 mL) is added TFA (1 mL). The mixture is stirred
at ambient temperature for 2 h then treated with saturated aqueous
Na.sub.2CO.sub.3. The layers are separated and volatiles from the
organics are removed in vacuo to afford a residue. The residue is
dissolved in DMF (4 mL) and treated with acrylic acid (0.6 mL) and
EDC (38 mg, 0.25 mmol). The mixture is stirred at ambient
temperature 12 h then directly purified by RHPLC to give example 72
(17 mg, 34%).
[0176] The following compounds are prepared in similar fashion:
Examples 62-71, 73-76
Method 23
Synthesis of Example 90
##STR00258##
[0178] To a solution of I-31 (0.20 g, 0.55 mmol) in DMA (3 mL) is
added DIEA (0.15 mL, 0.86 mmol) and R-13 (0.12 g, 0.71 mmol). The
mixture is heated at 50.degree. C. for 18 h then cooled to ambient
temperature. The mixture is partitioned between water and EtOAc.
The organics are collected, dried over Na.sub.2SO.sub.4, filtered,
and concentrated in vacuo. The crude is purified by RHPLC to afford
I-64 (0.15 g, 62%) m/z 447.1 [M+H].
[0179] To a solution of I-64 (70 mg, 0.16 mmol) in DMF (2 mL) is
added TBTU (60 mg, 0.19 mmol) and DIEA (0.06 mL, 0.19 mmol). The
mixture is stirred for 5 min then treated with a 2.0M solution of
methylamine in THF (0.24 mL, 0.47 mmol). The mixture is stirred at
ambient temperature for 16 h then treated with saturated aqueous
ammonium chloride. The mixture is extracted with EtOAc, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude is
purified by RHPLC to afford example 90 (7 mg, 10%).
Method 24
Synthesis of Example 93
##STR00259##
[0181] To a solution of I-31 (100 mg, 0.28 mmol) in
CH.sub.2Cl.sub.2 (5 mL) is added TBTU (91 mg, 0.28 mmol) and R-14
(prepared according to J. Med. Chem. 2001, 44, 2719-2734, 70 mg,
0.41 mmol). The mixture is stirred at ambient temperature over
night then filtered and purified by flash chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2 to 10% MeOH with 1% ammonium
hydroxide) to give example 93 (58 mg, 41%).
Method 25
Synthesis of Example 58
##STR00260##
[0183] To a solution of I-47 (29 mg, 0.074 mmol) in
CH.sub.2Cl.sub.2 (2 mL) is added EDC (92 mg, 0.38 mmol) and R-10
(20 mg, 0.24 mmol). The mixture is stirred at ambient temperature
for 1 h then partitioned between water and CH.sub.2Cl.sub.2. The
mixture is filtered through a phase Separator.RTM. and organics are
collected and concentrated in vacuo. The crude is purified by flash
chromatography (SiO.sub.2, 20 to 100% EtOAc in Hep) to give example
58 (23 mg, 68%).
[0184] The following compounds are made in similar fashion:
Examples 78, 85, 52, 53
Method 26
Synthesis of Example 79
##STR00261##
[0186] To a solution of I-43 (65 mg, 0.16 mmol) in CH.sub.2Cl.sub.2
(2 mL) is added EDC (37 mg, 0.19 mmol) followed by acrylic acid (14
mg, 0.19 mmol). The mixture is stirred at ambient temperature for 1
h then directly purified by flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2 to 5% MeOH in CH.sub.2Cl.sub.2) to give example 79
(14 mg, 19%).
[0187] The following compounds were made in similar fashion:
Examples 34, 50, 51, 57, 84
Method 27
Synthesis of Example 77
##STR00262##
[0189] A solution of morpholine (35 mg, 0.4 mmol),
(E)-4-bromo-but-2-enoic acid (79 mg, 0.48 mmol), and Hunig's base
(0.21 mL, 1.2 mmol) in DMF (2 mL) is stirred for 18 h. To this
mixture is added EDC (71 mg, 0.37 mmol). The mixture is stirred for
5 min then treated with I-54 (120 mg, 0.31 mmol) and stirred for 18
h. Saturated aqueous ammonium chloride is added (4 mL) and mixture
is extracted with EtOAc, dried over sodium sulphate, concentrated,
and then purified by preparative TLC (SiO.sub.2, 30% MeOH in EtOAc)
to provide example 77 (64 mg, 38%).
[0190] The following compounds are made in similar fashion:
Examples 98-100
Method 28
Synthesis of Example 80
##STR00263##
[0192] To a solution of I-57 (200 mg, 0.51 mmol) in DMF (2 mL) is
treated with DIEA (150 mg, 1.1 mmol), EDC (130 mg, 0.67 mmol),
followed by acrylic acid (0.05 mL, 0.67 mmol). The solution is
stirred for 16 h then treated with saturated aqueous ammonium
chloride. The mixture is extracted with EtOAc, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude is
purified by flash chromatography (SiO.sub.2, EtOAc to 10% MeOH in
EtOAc) to afford example 80 (52 mg, 23%).
[0193] The following compounds are prepared in similar fashion:
Examples 35, 44, 54, 81, 82
Method 29
Synthesis of Example 41
##STR00264##
[0195] To a solution of I-53 (100 mg, 0.26 mmol) in DMF (2 mL) is
added EDC (54 mg, 0.28 mmol) and R-10 (23 mg, 0.28 mmol). The
mixture is stirred at ambient temperature for 16 h then partitioned
between saturated aqueous ammonium chloride and EtOAc. The organics
are collected, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude is purified by flash chromatography
(SiO.sub.2, EtOAc to 10% MeOH in EtOAc) to give example 41 (24 mg,
21%).
[0196] The following compounds are prepared in similar fashion:
Examples 83, 91, 92
Method 30
Synthesis of Example 87
##STR00265##
[0198] To a solution of the his HCl salt of I-51 (55 mg, 0.12 mmol)
in CH.sub.2Cl.sub.2 (1.7 mL) is added TEA (29 mg, 0.29 mmol), EDC
(34 mg, 0.17 mmol), and R-10 (15 mg, 0.17 mmol). The mixture is
stirred at ambient temperature for 2 h then partitioned between
water and CH.sub.2Cl.sub.2 then filtered through a phase
Separator.RTM.. The organics are collected and concentrated in
vacuo to afford a residue that is purified by flash chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2 to 45% MeOH in CH.sub.2Cl.sub.2) to
afford example 87 (25 mg, 46%).
[0199] The following compounds were prepared in similar
fashion:
Examples 59, 46
Acrylic Acid Used Instead of R-10
Method 31
Synthesis of Example 97
##STR00266## ##STR00267##
[0201] To a suspension of NaH (60% dispersion in mineral oil, 160
mg, 4.0 mmol) in DMF (5 mL) is added I-9 (0.93 g, 3.35 mmol). After
5 min of stirring, a solution of I-67 (1.28 g, 3.35 mmol) in DMF (5
mL) is added. The mixture is heated at 70.degree. C. overnight then
cooled to ambient temperature and partitioned between EtOAc and
water. The organics are collected and washed with water and brine,
dried, and concentrated in vacuo. The crude is purified by flash
chromatography (SiO.sub.2, 0-70% EtOAc in Heptane) to afford I-68
(0.59 g, 37%) m/z 486.7 [M+H].
[0202] I-68 (0.59 g, 1.22 mmol) is diluted with EtOH (1 mL) and
water (0.5 mL) and Hydrido(dimethylphosphinous acid kP) [hydrogen
bis(dimethylphosphinito-kP)]platinum (II) (0.07 g, 0.163 mmol) is
added. The mixture is heated at 80.degree. C. overnight then
concentrated in vacuo. The residue is dissolved in CH.sub.2Cl.sub.2
then filtered and concentrated to afford I-69 (0.28 g, 45%) m/z
504.7 [M+H].
[0203] I-69 (50 mg, 0.1 mmol) is dissolved in CH.sub.2Cl.sub.2 (0.8
mL) and TFA (0.08 mL). The mixture is stirred for 3 h then
partitioned between CH.sub.2Cl.sub.2 and aqueous saturated
NaHCO.sub.3. Organics are combined and concentrated to give a
residue that is treated with a prestirred (15 min) solution of
acrylic acid (10 .mu.L, 0.13 mmol), EDC (3.5 mg, 0.18 mmol), and
Hunig's base (70 .mu.L, 0.38 mmol) in DMF (1.0 mL). The mixture is
stirred overnight then diluted with aqueous saturated ammonium
chloride and extracted with EtOAc. The organics are combined,
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude is purified by flash
chromatography (SiO.sub.2) to afford example 97 (5 mg, 88%).
Method 32
Synthesis of Example 101
##STR00268## ##STR00269##
[0205] To a solution of 3-amino-4-cyanopyrazole (100 g, 0.9 mol) in
DMF (1 L) is added NBS (197.5 g, 1.1 mol) and mixture is stirred
for 10 h at ambient temperature. The mixture is concentrated in
vacuo then dissolved in EtOAc and washed with brine (8.times.). The
organics are collected and concentrated in vacuo to afford I-70 (50
g, 29%) m/z 187.0 [M+].
[0206] A vial is charged with I-70 (1.0 g, 5.35 mmol),
2-phenoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine
(2.07 g, 6.95 mmol), tetrakis(triphenylphosphine) palladium (0)
(0.62 g, 0.535 mmol) and dissolved in aqueous potassium carbonate
(10 mL, 2.0 M) and DME (6 mL). The mixture is heated at 130.degree.
C. for 3 h in a microwave. The mixture is filtered then diluted
with water, extracted with EtOAc, dried over sodium sulphate,
filtered, and concentrated in vacuo. The residue is purified by
flash chromatography (SiO.sub.2, 0-100% EtOAc in heptanes) to give
I-71 (1.18 g, 80%) m/z 278.0 [M+H].
[0207] Sodium hydride (60% dispersion in mineral oil, 100 mg, 2.5
mmol) is added to a solution of I-71 (530 mg, 1.9 mmol) in DMF (7.5
mL). The mixture is stirred for 5 min then treated with I-1 (840
mg, 2.3 mmol) and heated at 70.degree. C. for 18 h. The solution is
cooled to ambient temperature then partitioned between EtOAc and
water. Organics are collected, dried, filtered, and concentrated in
vacuo to afford a residue that is purified by flash chromatography
(SiO.sub.2, 0-100% EtOAc in heptanes) to give I-72 (310 mg, 35%)
m/z 473.2 [M+H].
[0208] I-72 (0.31 g, 0.66 mmol) is diluted with EtOH (5 mL) and
water (0.5 mL) and Hydrido(dimethylphosphinous acid kP) [hydrogen
bis(dimethylphosphinito-kP)]platinum (II) (28 mg, 0.066 mmol) is
added. The mixture is heated at 80.degree. C. overnight then
concentrated in vacuo. The residue is dissolved in CH.sub.2Cl.sub.2
then filtered and concentrated to afford a residue that is
dissolved in TFA (5 mL) and stirred for 3 h at ambient temperature
then concentrated in vacuo. The residue is dissolved in MeOH and
passed through an Agilent Stratospheres PL-HCO3 MP SPE cartridge
and concentrated in vacuo to afford I-73 (0.25 g, 98%) m/z 391.2
[M+H].
[0209] I-73 (110 mg, 0.28 mmol) is treated with a prestirred (15
min) solution of acrylic acid (21 .mu.L, 0.13 mmol) and EDC (65 mg,
0.34 mmol) in DMF (2.0 mL). The mixture is stirred overnight then
diluted with aqueous saturated ammonium chloride and extracted with
EtOAc. The organics are combined, washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude is
purified by flash chromatography (SiO.sub.2, 10% MeOH in EtOAc) to
afford example 101 (32 mg, 26%).
[0210] The following compounds are made in similar fashion:
Examples 102-103, 110
Method 33
Synthesis of Example 122
##STR00270## ##STR00271##
[0212] To a solution of I-71 (1.1 g, 3.97 mmol) in DMF (20 mL) is
added NaH (60% dispersion in mineral oil, 190 mg, 4.76 mmol). The
mixture is stirred for 5 min then treated with I-4 (1.82 g, 4.76
mmol) and heated at 70.degree. C. for 18 h. The mixture is cooled
then partitioned between EtOAc and water. Organics are collected,
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to
give a residue that is purified by flash chromatography (SiO.sub.2,
0-80% EtOAc in heptanes) to give I-74 (520 mg, 27%) m/z 487.3 [M+H]
and I-75 (500 mg, 26%) m/z 487.3 [M+H].
[0213] I-74 (250 mg, 0.514 mmol) is diluted with EtOH (5 mL) and
water (0.5 mL) and Hydrido(dimethylphosphinous acid kP) [hydrogen
bis(dimethylphosphinito-kP)]platinum (II) (22 mg, 0.051 mmol) is
added. The mixture is heated at 80.degree. C. overnight then
concentrated in vacuo. The residue is dissolved in CH.sub.2Cl.sub.2
then filtered and concentrated to afford a residue that is
dissolved in TFA (5 mL) and stirred for 3 h at ambient temperature
then concentrated in vacuo. The residue is dissolved in MeOH and
passed through an Agilent Stratospheres PL-HCO3 MP SPE cartridge
and concentrated in vacuo to afford I-76 (0.206 g, 98%) m/z 405.3
[M+H].
[0214] I-76 (254 mg, 0.63 mmol) is treated with a prestirred (15
min) solution of R-10 (69 mg, 0.82 mmol) and EDC (144 mg, 0.75
mmol) in DMF (2.0 mL). The mixture is stirred overnight then
diluted with aqueous saturated ammonium chloride and extracted with
EtOAc. The organics are combined, washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude is
purified by flash chromatography (SiO.sub.2, 10% MeOH in EtOAc) to
afford example 122 (48 mg, 16%).
[0215] The following compounds are made in similar fashion:
Examples 114, 117-120, 123, 150-152
Method 34
Synthesis of Example 104
##STR00272## ##STR00273##
[0217] A vial is charged with I-70 (0.50 g, 2.67 mmol),
4-isopropoxyboronic acid (0.58 g, 3.21 mmol),
tetrakis(triphenylphosphine)palladium (0) (0.43 g, 0.37 mmol) and
dissolved in aqueous potassium carbonate (4 mL, 2.0 M) and DME (3
mL). The mixture is heated at 130.degree. C. for 3 h in a
microwave. The mixture is filtered then diluted with water,
extracted with EtOAc, dried over sodium sulphate, filtered, and
concentrated in vacuo. The residue is purified by flash
chromatography (SiO.sub.2, 0-80% EtOAc in heptanes) to give I-77
(0.473 g, 73%) m/z 243.5 [M+H].
[0218] Sodium hydride (60% dispersion in mineral oil, 55 mg, 1.37
mmol) is added to a solution of I-77 (300 mg, 1.24 mmol) in DMF (5
mL). The mixture is stirred for 5 min then treated with I-1 (550
mg, 1.47 mmol) and heated at 70.degree. C. for 18 h. The solution
is cooled to ambient temperature then partitioned between EtOAc and
water. Organics are collected, dried, filtered, and concentrated in
vacuo to afford a residue that is purified by flash chromatography
(SiO.sub.2, 0-100% EtOAc in heptanes) to give I-78 (200 mg, 37%)
m/z 438.6 [M+H].
[0219] I-78 (190 mg, 0.43 mmol) is diluted with EtOH (4 mL) and
water (2 mL) and Hydrido(dimethylphosphinous acid kP) [hydrogen
bis(dimethylphosphinito-kP)]platinum (II) (11 mg, 0.026 mmol) is
added. The mixture is heated at 80.degree. C. overnight then
concentrated in vacuo. The residue is dissolved in CH.sub.2Cl.sub.2
then filtered and concentrated to afford a residue that is
dissolved in CH.sub.2Cl.sub.2 (5 mL) and TFA (1 mL) and stirred
overnight at ambient temperature then concentrated in vacuo. The
residue is dissolved in MeOH and passed through an Agilent
Stratospheres PL-HCO3 MP SPE cartridge and concentrated in vacuo to
afford I-79 (110 mg, 71%).
[0220] I-79 (40 mg, 0.11 mmol) and acrylic acid (10 mg, 0.14 mmol)
in DMF (5 mL) is treated with HATU (88 mg, 0.17 mmol) and Hunig's
base (60 .mu.L, 0.34 mmol) in DMF (2.0 mL). The mixture is stirred
overnight then concentrated in vacuo. The crude is purified by
RHPLC to afford example 105 (25 mg, 54%).
[0221] The following compounds are made in similar fashion:
Examples 104, 106-109, 111-113, 115-116, 124, 133, 134-136,
138-139, 141-144, 147-149, 166
Method 35
##STR00274## ##STR00275##
[0223] A vial is charged with I-70 (0.45 g, 2.41 mmol),
4-n-propoxyboronic acid (0.48 g, 2.65 mmol),
tetrakis(triphenylphosphine)palladium (0) (0.28 g, 0.24 mmol) and
dissolved in aqueous potassium carbonate (4.8 mL, 2.0 M) and
dioxane (2 mL). The mixture is heated at 130.degree. C. overnight.
The mixture is filtered then diluted with water, extracted with
EtOAc, dried over sodium sulphate, filtered, and concentrated in
vacuo. The residue is purified by flash chromatography (SiO.sub.2,
0-6% MeOH in CH.sub.2Cl.sub.2) to give I-80 (0.400 g, 69%) m/z
242.4 [M+].
[0224] Sodium hydride (60% dispersion in mineral oil, 33 mg, 0.82
mmol) is added to a solution of I-80 (200 mg, 0.74 mmol) in DMF (5
mL). The mixture is stirred for 5 min then treated with I-6 (318
mg, 0.82 mmol) and heated at 70.degree. C. for 18 h. The mixture is
concentrated in vacuo and purified by flash chromatography
(SiO.sub.2, 35% EtOAc in heptanes) to give I-81 (130 mg, 39%) m/z
452.9 [M+H].
[0225] I-81 (130 mg, 0.29 mmol) is diluted with EtOH (1.5 mL) and
water (0.5 mL) and Hydrido(dimethylphosphinous acid kP) [hydrogen
bis(dimethylphosphinito-kP)]platinum (II) (13 mg, 0.029 mmol) is
added. The mixture is heated at 80.degree. C. overnight then
concentrated in vacuo. The residue is dissolved in EtOAc then
filtered and concentrated to afford a residue that is dissolved in
CH.sub.2Cl.sub.2 (1 mL) and TFA (1 mL) and stirred for 1 h at
ambient temperature then concentrated in vacuo. The residue is
dissolved in MeOH and passed through an Agilent Stratospheres
PL-HCO3 MP SPE cartridge and concentrated in vacuo to afford I-82
(80 mg, 84%).
[0226] I-82 (130 mg, 0.35 mmol) is treated with a prestirred (15
min) solution of acrylic acid (30 mg, 0.42 mmol) and EDC (81 mg,
0.42 mmol) in DMF (2.0 mL). The mixture is stirred overnight then
diluted with aqueous saturated ammonium chloride and extracted with
EtOAc. The organics are combined, dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The crude is purified by RHPLC
to afford example 125 (30 mg, 20%).
[0227] The following compounds are made in similar fashion:
Examples 130, 132, 145-146, 153, 155-156, 159, 162-163, 165
Method 36
Synthesis of Example 126
##STR00276## ##STR00277##
[0229] Sodium hydride (60% dispersion in mineral oil, 80 mg, 2.02
mmol) is added to a solution of I-80 (445 mg, 1.84 mmol) in DMF (5
mL). The mixture is stirred for 5 min then treated with I-4 (770
mg, 2.02 mmol) and heated at 70.degree. C. for 18 h. The mixture is
diluted with saturated aqueous ammonium chloride, extracted with
EtOAc, dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo. The residue is purified by flash chromatography (SiO.sub.2,
0-6% MeOH in CH.sub.2Cl.sub.2) to give I-81 (200 mg, 24%) and I-84
(300 mg, 36%) m/z 452.5 [M+H].
[0230] I-84 (300 mg, 0.66 mmol) is diluted with EtOH (1.5 mL) and
water (0.5 mL) and Hydrido(dimethylphosphinous acid kP) [hydrogen
bis(dimethylphosphinito-kP)]platinum (II) (28 mg, 0.066 mmol) is
added. The mixture is heated at 80.degree. C. for 72 h then
concentrated in vacuo. The residue is dissolved in EtOAc then
filtered and concentrated to afford a residue that is dissolved in
CH.sub.2Cl.sub.2 (1 mL) and TFA (1 mL) and stirred for 1 h at
ambient temperature then concentrated in vacuo. The residue is
dissolved in MeOH and passed through an Agilent Stratospheres
PL-HCO3 MP SPE cartridge and concentrated in vacuo to afford I-85
(270 mg).
[0231] I-85 (80 mg, 0.22 mmol) is treated with a prestirred (15
min) solution of acrylic acid (19 mg, 0.26 mmol) and EDC (50 mg,
0.26 mmol) in DMF (2.0 mL). The mixture is stirred overnight then
diluted with aqueous saturated ammonium chloride and extracted with
EtOAc. The organics are combined, dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The crude is purified by RHPLC
to afford example 126 (7 mg, 8%).
[0232] The following compounds are made in similar fashion:
Examples 131
Method 37
Synthesis of Example 140
##STR00278##
[0234] I-82 (80 mg, 0.22 mmol) is treated with a prestirred (15
min) solution of R-10 (24 mg, 0.28 mmol) and EDC (50 mg, 0.26 mmol)
in DMF (2.0 mL). The mixture is stirred overnight then diluted with
aqueous saturated ammonium chloride and extracted with EtOAc. The
organics are combined, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude is purified by RHPLC to afford
example 140 (14 mg, 15%).
[0235] The following compounds are made in similar fashion:
Example 128, 137, 154, 157-158, 160-161, 164, 167-168
Method 38
Synthesis of Example 127
##STR00279##
[0237] I-85 (70 mg, 0.19 mmol) is treated with a prestirred (15
min) solution of R-10 (21 mg, 0.25 mmol) and EDC (44 mg, 0.23 mmol)
in DMF (2.0 mL). The mixture is stirred overnight then diluted with
aqueous saturated ammonium chloride and extracted with EtOAc. The
organics are combined, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude is purified by RHPLC to afford
example 127 (13 mg, 16%).
[0238] The following compounds are made in similar fashion:
Example 129
Description of Biological Properties
BTK Assay
[0239] An HTRF assay (Cisbio KinEASE-TK cat #62TK0PEC) was
performed to quantitate the ability of test compounds to inhibit
BTK mediated phosphorylation of substrate. Assays were assembled in
384 well plates where 6 nM of full-length human His-tagged BTK
(Life Technologies cat # PV3587) and test compound at varying
concentrations were preincubated for 15 minutes at 28.degree. C.
Then, 1 uM of TK substrate-biotin and 30 uM ATP were added and
incubated for an additional 30 minutes at 28.degree. C.
Phospohrylation was detected by adding 62.5 nM Streptavidin-XL665
and TK-Antibody Cryptate diluted 1:100 in HTRF detection buffer
(Cisbio cat #62SDBRDF) and incubated for 60 minutes at RT. The
plate was read on an Envision plate reader and the fluorescence is
measured at 620 nm (cryptate) and 665 nm (XL665). A ratio is
calculated (665/620) and converted to POC relative to control and
blank wells.
Assay Buffer:
[0240] 50 mM HEPES (Invitrogen #15630), 0.01% Brij-35 (sigma
#B4184), 10 mM MgCl2 (Sigma M1028), 1 mM EGTA (Ambion AM9262) and
100 uM sodium orthovanedate (Sigma S6508), 1 mM DTT (Sigma D5545)
and 10 nM supplement enzyme buffer (Cisbio cat#61SEBALB).
[0241] Preferred compounds for the treatment of autoimmune
disorders exhibit selective inhibition of BTK over other kinases
such as EGFR. The compounds described herein show a range of
selectivities against EGFR as measured in cellular assays (BTK
activity measured by CD69 expression in primary CD19.sup.+ cells;
EGFR activity measured by EGFR phosphorylation in A431 cells). See
Table II.
TABLE-US-00015 TABLE II Example B-cell CD69 IC.sub.50 (nM) A431
p-EGFR IC.sub.50 (nM) 54 1.2 6.6 46 2.0 120 161 2.1 400 164 1.5 420
41 1 430 81 0.9 790 160 4.5 1200 78 2.5 1800 165 10 3700 107 8.2
4200 28 9 4700 163 15 5200 112 41 5800 113 24 6300 115 7.8 6400 40
20 >10000 106 30 >10000 158 58 >10000
Inhibition of B-Cell Activation Measured by CD69 Expression
[0242] Primary CD19.sup.+ cells were purified from healthy frozen
peripheral blood mononuclear cells (AllCells, Emeryville, Calif.)
and negatively selected by magnetic separation, >97% purity
(Stemcell Technologies, Vancouver, CA). Cells were collected and
plated in a 96 flat bottom plate at a concentration of
2.times.10.sup.5/well in RPMI media containing 10% FBS, rested for
1 hour at 37.degree. c. Cells were treated with inhibitor in
duplicates or vehicle control in 1% DMSO final concentration for 1
hour at 37.degree. c., 5% CO.sub.2. Cells were then stimulated with
12.5 ug/ml Goat F(ab').sub.2 anti-human IgD (SouthernBiotech,
Birmingham, Ala.) for 18-24 hours at 37.degree. C., 5% CO.sub.2.
Cells were collected and stained for APC-CD19, clone HIB19 and
PE-CD69, clone FN50 (antibodies purchased from BD Bioscience, San
Jose, Calif.). B cells were analyzed by flow cytometry using a BD
LSRII or BD FACsCanto Flow Cytometer. Viable cells were gated, and
CD69 percentage was determined using FlowJo software.
Inhibition of EGFR Autophosphorylation in A431 Human Epithelial
Cells Stimulated with Epithelial Growth Factor
[0243] A431cells (ATCC # CRL-1555 FZ) are thawed and plated in DMEM
containing 10% FBS in a 384-well tissue culture treated plate at
15,000 cells/well. After incubating for 24 hours at 37.degree. C.,
5% CO.sub.2, the cells are treated with test compound (1% DMSO
final concentration) and incubated for 16 hours at 37.degree. C.,
5% CO.sub.2. EGF (Millipore, 01-107) is added at a final
concentration of 60 ng/mL and incubated for 10 minutes. The medium
is removed, the cells are lysed, and phospho EGFR is measured (Meso
Scale Diagnostics, N31CB-1).
Therapeutic Use
[0244] On the basis of their biological properties the compounds of
formula (I) according to the invention, or their tautomers,
racemates, enantiomers, diastereomers, mixtures thereof and the
salts of all the above-mentioned forms are suitable for treating
autoimmune and allergic disorders in that they exhibit good
inhibitory effect upon BTK.
[0245] Such diseases include for example: rheumatoid arthritis,
systemic lupus erythromatosis, scleroderma, asthma, allergic
rhinitis, allergic eczema, B cell lymphoma, multiple sclerosis,
juvenile rheumatoid arthritis, juvenile idiopathic arthritis,
inflammatory bowel disease, graft versus host disease, psoriatic
arthritis, ankylosing spondylitis and uveitis.
[0246] The compounds of formula (I) may be used on their own or in
combination with other active substances according to the
invention, optionally also in combination with other
pharmacologically active substances.
[0247] Suitable preparations include for example tablets, capsules,
suppositories, solutions--particularly solutions for injection
(s.c., i.v., i.m.) and infusion--elixirs, emulsions or dispersible
powders. The content of the pharmaceutically active compound(s)
should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50
wt.-% of the composition as a whole, i.e. in amounts which are
sufficient to achieve the dosage range specified below. The doses
specified may, if necessary, be given several times a day.
[0248] Suitable tablets may be obtained, for example, by mixing the
active substance(s) with known excipients, for example inert
diluents such as calcium carbonate, calcium phosphate or lactose,
disintegrants such as corn starch or alginic acid, binders such as
starch or gelatine, lubricants such as magnesium stearate or talc
and/or agents for delaying release, such as carboxymethyl
cellulose, cellulose acetate phthalate, or polyvinyl acetate. The
tablets may also comprise several layers.
[0249] Coated tablets may be prepared accordingly by coating cores
produced analogously to the tablets with substances normally used
for tablet coatings, for example collidone or shellac, gum arabic,
talc, titanium dioxide or sugar. To achieve delayed release or
prevent incompatibilities the core may also consist of a number of
layers. Similarly the tablet coating may consist of a number of
layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
[0250] Syrups or elixirs containing the active substances or
combinations thereof according to the invention may additionally
contain a sweetener such as saccharine, cyclamate, glycerol or
sugar and a flavour enhancer, e.g. a flavouring such as vanillin or
orange extract. They may also contain suspension adjuvants or
thickeners such as sodium carboxymethyl cellulose, wetting agents
such as, for example, condensation products of fatty alcohols with
ethylene oxide, or preservatives such as p-hydroxybenzoates.
[0251] Solutions for injection and infusion are prepared in the
usual way, e.g. with the addition of isotonic agents, preservatives
such as p-hydroxybenzoates, or stabilisers such as alkali metal
salts of ethylenediamine tetraacetic acid, optionally using
emulsifiers and/or dispersants, whilst if water is used as the
diluent, for example, organic solvents may optionally be used as
solvating agents or dissolving aids, and transferred into injection
vials or ampoules or infusion bottles.
[0252] Capsules containing one or more active substances or
combinations of active substances may for example be prepared by
mixing the active substances with inert carriers such as lactose or
sorbitol and packing them into gelatine capsules.
[0253] Suitable suppositories may be made for example by mixing
with carriers provided for this purpose such as neutral fats or
polyethyleneglycol or the derivatives thereof.
[0254] Excipients which may be used include, for example, water,
pharmaceutically acceptable organic solvents such as paraffins
(e.g. petroleum fractions), vegetable oils (e.g. groundnut or
sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or
glycerol), carriers such as e.g. natural mineral powders (e.g.
kaolins, clays, talc, chalk), synthetic mineral powders (e.g.
highly dispersed silicic acid and silicates), sugars (e.g. cane
sugar, lactose and glucose), emulsifiers (e.g. lignin, spent
sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone)
and lubricants (e.g. magnesium stearate, talc, stearic acid and
sodium lauryl sulphate).
[0255] The preparations are administered by the usual methods,
preferably by oral or transdermal route, most preferably by oral
route. For oral administration the tablets may of course contain,
apart from the above-mentioned carriers, additives such as sodium
citrate, calcium carbonate and dicalcium phosphate together with
various additives such as starch, preferably potato starch,
gelatine and the like. Moreover, lubricants such as magnesium
stearate, sodium lauryl sulphate and talc may be used at the same
time for the tabletting process. In the case of aqueous suspensions
the active substances may be combined with various flavour
enhancers or colourings in addition to the excipients mentioned
above.
[0256] For parenteral use, solutions of the active substances with
suitable liquid carriers may be used.
[0257] The dosage for intravenous use is from 1-1000 mg per hour,
preferably between 5 and 500 mg per hour.
[0258] However, it may sometimes be necessary to depart from the
amounts specified, depending on the body weight, the route of
administration, the individual response to the drug, the nature of
its formulation and the time or interval over which the drug is
administered. Thus, in some cases it may be sufficient to use less
than the minimum dose given above, whereas in other cases the upper
limit may have to be exceeded. When administering large amounts it
may be advisable to divide them up into a number of smaller doses
spread over the day.
[0259] All patent and non-patent documents or literature cited in
this application are herein incorporated by reference in their
entirety.
* * * * *