U.S. patent application number 11/255526 was filed with the patent office on 2006-03-16 for conjugated aromatic compounds with a pyridine substituent.
Invention is credited to Alexander Alanine, Bernd Buettelmann, Marie-Paule Heitz Neidhart, Emmanuel Pinard, Rene Wyler.
Application Number | 20060058354 11/255526 |
Document ID | / |
Family ID | 8179103 |
Filed Date | 2006-03-16 |
United States Patent
Application |
20060058354 |
Kind Code |
A1 |
Alanine; Alexander ; et
al. |
March 16, 2006 |
Conjugated aromatic compounds with a pyridine substituent
Abstract
The present invention relates to compounds of formulae ##STR1##
The compounds of the present invention are NMDA
(N-methyl-D-aspartate)-receptor subtype blockers and are used in
the treatment of diseases related to this receptor.
Inventors: |
Alanine; Alexander;
(Schlierbach, FR) ; Buettelmann; Bernd;
(Schopfheim, DE) ; Neidhart; Marie-Paule Heitz;
(Hagenthal le Bas, FR) ; Pinard; Emmanuel;
(Linsdorf, FR) ; Wyler; Rene; (Zuerich,
CH) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.;PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
US
|
Family ID: |
8179103 |
Appl. No.: |
11/255526 |
Filed: |
October 21, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10672950 |
Sep 26, 2003 |
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11255526 |
Oct 21, 2005 |
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10277002 |
Oct 21, 2002 |
6951875 |
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10672950 |
Sep 26, 2003 |
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Current U.S.
Class: |
514/337 ;
546/329; 546/339 |
Current CPC
Class: |
C07D 213/73 20130101;
C07D 213/74 20130101; A61P 25/14 20180101; C07D 213/53 20130101;
A61P 25/16 20180101; C07D 213/38 20130101; C07D 213/79 20130101;
A61P 43/00 20180101; A61P 25/24 20180101; C07D 213/84 20130101;
C07D 409/04 20130101; A61P 21/02 20180101; A61P 25/00 20180101;
A61P 25/28 20180101 |
Class at
Publication: |
514/337 ;
546/329; 546/339 |
International
Class: |
A61K 31/44 20060101
A61K031/44 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 29, 2001 |
EP |
01125765.6 |
Claims
1. A compound of formulae ##STR21## wherein R.sup.1 and R.sup.2 are
each independently selected from the group hydrogen, lower alkyl,
--(CH.sub.2).sub.nNR.sup.5R.sup.5 and --(CH.sub.2).sub.n+1OH;
R.sup.5 and R.sup.5' are each independently hydrogen or lower
alkyl; R.sup.3 and R.sup.4 are each independently selected from the
group hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl
and hydroxy; Ar is selected from the group phenyl and thiophenyl;
The dotted line is selected from the group two hydrogens not
forming a bridge, and --CH.sub.2--CHR'--, wherein R' is selected
from the group lower alkyl and hydrogen; and n is 0, 1 or 2; or a
pharmaceutically acceptable acid addition salt thereof, with the
proviso that when ar is unsubstituted phenyl and R.sup.2 is H,
R.sup.1 is not 2-amino.
2. A compound of formula ##STR22## wherein R.sup.1 and R.sup.2 are
each independently selected from the group hydrogen, lower alkyl,
--(CH.sub.2).sub.nNR.sup.5R.sup.5 and --(CH.sub.2).sub.n+1OH;
R.sup.5 and R.sup.5' are each independently hydrogen or lower
alkyl; and R.sup.3 and R.sup.4 are each independently selected from
the group of hydrogen, lower alkyl, lower alkoxy, halogen,
trifluoromethyl and hydroxy or a pharmaceutically acceptable acid
addition salt thereof.
3. A compound of formula IA-1 according to claim 2, selected from
the group trans-4-methyl-6-styryl-pyridin-2-yl-amine,
trans-2-styryl-pyridin-4-yl-amine and
trans-C-(6-styryl-pyridin-2-yl)-methylamine.
4. A compound of formula ##STR23## wherein R.sup.1 and R.sup.2 are
each independently selected from the group hydrogen, lower alkyl,
--(CH.sub.2).sub.nNR.sup.5R.sup.5 and --(CH.sub.2).sub.n+1OH;
R.sup.5 and R.sup.5' are each independently hydrogen or lower
alkyl; R.sup.3 and R.sup.4 are each independently selected from the
group hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl
and hydroxy; and R' is selected from the group lower alkyl and
hydrogen; or a pharmaceutically acceptable acid addition salt
thereof.
5. A compound of formula IA-2 according to claim 4, wherein R' is
hydrogen.
6. A compound of formula IA-2 according to claim 5, selected from
the group 2-(3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine,
2-(3,4-dihydro-naphthalen-2-yl)-6-methyl-pyridin-4-yl-amine,
[4-amino-6-(3,4-dihydro-naphthalen-2-yl)-pyridin-2-yl]-methanol,
2-(3,4-dihydro-naphthalen-2-yl)-5-methyl-pyridin-4-yl-amine,
2-(3,4-dihydro-naphthalen-2-yl)-6-ethyl-pyridin-4-yl-amine,
2-(3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl]-methyl-amine,
C-[6-(3,4-dihydro-naphthalen-2-yl)-pyridin-2-yl]-methylamine,
2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine,
2-(5,7-dimethyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine,
2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-6-ethyl-pyridin-4-yl-amine,
2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-6-methyl-pyridin-4-yl-amine
and
2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-5-methyl-pyridin-4-yl-amine.
7. A compound of formula IA-2 according to claim 4, wherein R' is
methyl.
8. A compound of formula IA-2 according to claim 7, selected from
the group
rac.-2-(4-methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine,
rac.-2-methyl-6-(4-methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine
and
rac.-5-methyl-2-(4-methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl--
amine.
9. A compound of formula ##STR24## wherein R.sup.1 and R.sup.2 are
each independently selected from the group hydrogen, lower alkyl,
--(CH.sub.2).sub.nNR.sup.5R.sup.5 and --(CH.sub.2).sub.n+1OH;
R.sup.5 and R.sup.5' are each independently hydrogen or lower
alkyl; and R.sup.3 and R.sup.4 are each independently selected from
the group hydrogen, lower alkyl, lower alkoxy, halogen,
trifluoromethyl and hydroxy; R' is selected from the group lower
alkyl and hydrogen; and n is 0, 1 or 2; or a pharmaceutically
acceptable acid addition salt thereof.
10. A compound of formula IA-4 according to claim 9, wherein R' is
hydrogen.
11. A compound of formula IA-4 according to claim 10, selected from
the group 2-(6,7-dihydro-benzo[b]thiophen-5-yl)-pyridin-4-yl-amine
and
2-(6,7-dihydro-benzo[b]thiophen-5-yl)-5-methyl-pyridin-4-yl-amine.
12. A compound of formula ##STR25## wherein R.sup.1 and R.sup.2 are
each independently selected from the group hydrogen, lower alkyl,
--(CH.sub.2).sub.nNR.sup.5R.sup.5' and --(CH.sub.2).sub.n+1OH;
R.sup.5 and R.sup.5' are each independently hydrogen or lower
alkyl; and R.sup.3 and R.sup.4 are each independently selected from
the group hydrogen, lower alkyl, lower alkoxy, halogen,
trifluoromethyl and hydroxy; or a pharmaceutically acceptable acid
addition salt thereof.
13. A compound of formula IB-1 according to claim 12, which is
trans-6-methyl-4-styryl-pyridin-2-yl-amine.
14. A compound of formula IA or IB according to claim 1, wherein
one of R.sup.1 or R.sup.2 is amino.
15. A pharmaceutical composition comprising a compound of formula
IA or IB of claim 1, combinations thereof or a pharmaceutically
acceptable salt thereof and a pharmaceutically acceptable
carrier.
16. A method of treatment of diseases responsive to therapeutic
indications for NMDA receptor subtype specific blockers, such as
Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS
(amyotrophic lateral sclerosis) and neurodegeneration associated
with bacterial or viral infections, and, in addition, depression
and chronic or acute pain comprising administering a
therapeutically effective amount of a compound of formulae 1A or IB
according to claim 1, combinations thereof or a pharmaceutically
acceptable salt thereof to a patient in need of such treatment.
17. A process for preparing a compound of formula IA-la comprising
a) reacting a compound of formula ##STR26## with diphenyl
phosphoryl azide, forming a compound of formula ##STR27## wherein
R.sup.2 is selected from the group hydrogen, lower alkyl,
--(CH.sub.2).sub.nNR.sup.5R.sup.5' and --(CH.sub.2).sub.n+1OH;
R.sup.5 and R.sup.5' are each independently hydrogen or lower
alkyl; and R.sup.3 and R.sup.4 are each independently selected from
the group hydrogen, lower alkyl, lower alkoxy, halogen,
trifluoromethyl and hydroxy; Ar is selected from the group phenyl
and thiophenyl and n is 0, 1 or 2.
18. A process for preparing a compound of formula IA-1b comprising
reacting the amino group of a compound of formula ##STR28## with a
compound of formula R.sup.5X, forming a compound of formula
##STR29## wherein R.sup.2 is selected from the group hydrogen,
lower alkyl, --(CH.sub.2).sub.nNR.sup.5R.sup.5' and
--(CH.sub.2).sub.n+1OH; R.sup.3 and R.sup.4 are each independently
selected from the group hydrogen, lower alkyl, lower alkoxy,
halogen, trifluoromethyl and hydroxy; Ar is selected from the group
phenyl and thiophenyl; R.sup.5 is lower alkyl; X is halogen; and; n
is 0, 1 or 2.
19. A process for preparing a compound of formulae IIB-1a,
comprising: reacting a compound of formula ##STR30## with diphenyl
phosphoryl azide forming a compound of formula ##STR31## wherein
R.sup.2 is selected from the group hydrogen, lower alkyl,
--(CH.sub.2).sub.nNR.sup.5R.sup.5 and --(CH.sub.2).sub.n+1OH;
R.sup.3 and R.sup.4 are each independently selected from the group
hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl and
hydroxy; Ar is selected from the group phenyl and thiophenyl;
R.sup.5 is lower alkyl; and; n is 0, 1 or 2.
20. A process for preparing a compound of formula IIB-1b
comprising: reacting the amino group of a compound of formula
##STR32## with a compound of formula R.sup.5X forming a compound of
formula ##STR33## wherein R.sup.1 is selected from the group
hydrogen, lower alkyl, --(CH.sub.2).sub.nNR.sup.5R.sup.5 and
--(CH.sub.2).sub.n+1OH; R.sup.5 and R.sup.5' are each independently
hydrogen or lower alkyl; R.sup.3 and R.sup.4 are each independently
selected from the group consisting of hydrogen, lower alkyl, lower
alkoxy, halogen, trifluoromethyl and hydroxy; Ar is selected from
the group phenyl and thiophenyl; X is halogen; and n is 0, 1 or
2.
21. A process for preparing a compound of formulae IA-2 comprising:
reacting a compound of formula ##STR34## with a compound of formula
##STR35## forming a compound of formula ##STR36## wherein R.sup.1
and R.sup.2 are each independently selected from the group
hydrogen, lower alkyl, --(CH.sub.2).sub.nNR.sup.5R.sup.5' and
--(CH.sub.2).sub.n+1OH; R.sup.5 and R.sup.5 are each independently
hydrogen or lower alkyl; and R.sup.3 and R.sup.4 are each
independently selected from the group hydrogen, lower alkyl, lower
alkoxy, halogen, trifluoromethyl and hydroxy; and n is 0, 1 or
2.
22. A process for preparing a compound of formula IB-2 comprising:
reacting a compound of formula ##STR37## with a compound of formula
##STR38## forming a compound of formula ##STR39## wherein R.sup.1
and R.sup.2 are each independently selected from the group
hydrogen, lower alkyl, --(CH.sub.2).sub.nNR.sup.5R.sup.5 and
--(CH.sub.2).sub.n+1OH; R.sup.5 and R.sup.5' are each independently
hydrogen or lower alkyl; and R.sup.3 and R.sup.4 are each
independently selected from the group hydrogen, lower alkyl, lower
alkoxy, halogen, trifluoromethyl and hydroxy; and n is 0, 1 or 2.
Description
PRIORITY TO RELATED APPLICATIONS
[0001] This application is a division of U.S. application Ser. No.
10/672,950, filed Sep. 26, 2003, now pending; which is a division
of U.S. application Ser. No. 10/277,002, filed Oct. 21, 2002 now
U.S. Pat. No. 6,951,875. The entire contents of the
above-identified applications are hereby incorporated by
reference.
FIELD OF INVENTION
[0002] The present invention is related to compounds of the general
formulae ##STR2## Compounds of formula IA or IB are NMDA
(N-methyl-D-aspartate)-receptor subtype selective blockers useful
in the treatment or prevention of CNS disorders.
BACKGROUND
[0003] Under pathological conditions of acute and chronic forms of
neurodegeneration overactivation of NMDA receptors is a key event
for triggering neuronal cell death. NMDA receptors are composed of
members from two subunit families, namely NR-1 (8 different splice
variants) and NR-2 (A to D) originating from different genes.
Members from the two subunit families show a distinct distribution
in different brain areas. Heteromeric combinations of NR-1 members
with different NR-2 subunits result in NMDA receptors displaying
different pharmaceutical properties. Possible therapeutic
indications for NMDA NR-2B receptor subtype specific blockers
include acute forms of neurodegeneration caused, e.g., by stroke
and brain trauma, and chronic forms of neurodegeneration such as
Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS
(amyotrophic lateral sclerosis), neurodegeneration associated with
bacterial or viral infections, and, in addition, depression and
chronic and acute pain.
SUMMARY
[0004] The present invention relates to a compound of formula
##STR3## [0005] wherein [0006] R.sup.1 and R.sup.2 are each
independently selected from the group hydrogen, lower alkyl,
--(CH.sub.2).sub.nNR.sup.5R.sup.5 and --(CH.sub.2).sub.n+1OH;
[0007] R.sup.5 and R.sup.5' are each independently selected from
the group hydrogen and lower alkyl; [0008] R.sup.3 and R.sup.4 are
each independently selected from the group hydrogen, lower alkyl,
lower alkoxy, halogen, trifluoromethyl and hydroxy; [0009] Ar is
phenyl or thiophenyl; [0010] the dotted line is selected from the
group consisting of two hydrogen atoms not forming a bridge and
--CH.sub.2--CHR'--, wherein R' is H or lower alkyl; and [0011] n is
0, 1 or 2; [0012] or a pharmaceutically acceptable acid addition
salt thereof, with the proviso that when Ar is unsubstituted phenyl
and R.sup.2 is H, R.sup.1 is not 2-amino.
[0013] 6-styryl-pyridin-2-yl-amine has been specifically described
in J. Med. Chem., 1984, 27, 125 for use as antiallergic agent and
in JACS, 1949, 71, 1186 as an intermediate in a condension reaction
of N-substituted pyridones.
[0014] Compounds of formulae IA and IB of the present invention may
have the following sub-structures: ##STR4## ##STR5## [0015]
R.sup.1, R.sup.2, R.sup.1, R.sup.4 and R' are as described
above.
[0016] The compounds of formulae IA or IB or pharmaceutically
acceptable salts thereof are distinguished by valuable therapeutic
properties. Compounds of the present invention are NMDA
(N-methyl-D-aspartate)-receptor subtype selective blockers, which
have a key function in modulating neuronal activity and plasticity
which makes them key players in mediating processes underlying
development of CNS as well as learning and memory formation.
[0017] The present invention relates to compounds of formulae IA
and IB or harmaceutically acceptable acid addition salts thereof
and the preparation of the compounds of formulae IA and IB or
pharmaceutically acceptable salts thereof. The invention also
relates to pharmaceutical compositions containing a compound of
formulae IA, IB, a combination thereof or a pharmaceutically
acceptable acid addition salt thereof and a pharmaceutically
acceptable vehicle and the manufacture of such pharmaceutical
compositions. The present invention additionly relates to a method
of treatment of acute forms of neurodegeneration caused, e.g., by
stroke and brain trauma, and chronic forms of neurodegeneration
such as Alzheimer's disease, Parkinson's disease, Huntington's
disease, ALS (amyotrophic lateral sclerosis), neurodegeneration
associated with bacterial or viral infections, and, in addition,
depression and chronic and acute pain comprising administering to a
patient in need of such treatment a therapeutically effective
amount of a compound of formulae Ia, lb or combinations thereof or
a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION
[0018] The following definitions of the general terms used in the
present description apply irrespective of whether the terms in
question appear alone or in combination.
[0019] As used herein, the term "lower alkyl" denotes a straight-
or branched-chain alkyl group containing from 1 to 7 carbon atoms,
for example, methyl, ethyl, propyl, isopropyl, butyl and the like.
Preferred lower alkyl groups contain from 1 to 4 carbon atoms.
[0020] The term "halogen" denotes chlorine, iodine, fluorine and
bromine.
[0021] The term "lower alkoxy" denotes a group wherein the alkyl
residue is as defined above and the alkyl group is connected via an
oxygen atom.
[0022] The term "pharmaceutically acceptable acid addition salt"
embraces salts with inorganic and organic acids, such as
hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,
citric acid, formic acid, fumaric acid, maleic acid, acetic acid,
succinic acid, tartaric acid, methane-sulfonic acid,
p-toluenesulfonic acid and the like.
[0023] Preferred compounds of formula IA-1, for example the
following compounds are selected from the group: [0024]
trans-4-methyl-6-styryl-pyridin-2-yl-amine, [0025]
trans-2-styryl-pyridin-4-yl-amine and [0026]
trans-C-(6-styryl-pyridin-2-yl)-methylamine.
[0027] Further preferred are compounds of formula IA-2, wherein R'
is hydrogen, for example compounds selected from the group: [0028]
2-(3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine, [0029]
2-(3,4-dihydro-naphthalen-2-yl)-6-methyl-pyridin-4-yl-amine, [0030]
[4-amino-6-(3,4-dihydro-naphthalen-2-yl)-pyridin-2-yl]-methanol,
[0031] 2-(3,4-dihydro-naphthalen-2-yl)-5-methyl-pyridin-4-yl-amine,
[0032] 2-(3,4-dihydro-naphthalen-2-yl)-6-ethyl-pyridin-4-yl-amine,
[0033] [2-(3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl]-methyl-amine,
[0034]
C-[6-(3,4-dihydro-naphthalen-2-yl)-pyridin-2-yl]-methylamine,
[0035] 2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine,
[0036]
2-(5,7-dimethyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine,
[0037]
2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-6-ethyl-pyridin-4-yl-amine,
[0038]
2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-6-methyl-pyridin-4-yl-am-
ine and [0039]
2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-5-methyl-pyridin-4-yl-amine.
[0040] Additional preferred compounds of formula IA-2 are further
those, wherein R' is methyl, for example the compounds selected
from the group: [0041]
rac.-2-(4-methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine,
[0042]
rac.-2-methyl-6-(4-methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-
-yl-amine and [0043]
rac.-5-methyl-2-(4-methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine-
.
[0044] Preferred compounds of formula IA-4 are those, wherein R' is
hydrogen, for example the compounds selected from the group [0045]
2-(6,7-dihydro-benzo[b]thiophen-5-yl)-pyridin-4-yl-amine and [0046]
2-(6,7-dihydro-benzo[b]thiophen-5-yl)-5-methyl-pyridin-4-yl-amine.
[0047] A preferred compound of formula IB-1 is, for example, the
following compound: [0048]
trans-6-methyl-4-styryl-pyridin-2-yl-amine.
[0049] A further preferred group of compounds of formulae IA and IB
are those, wherein one of R.sup.1 or R.sup.2 is amino.
[0050] The above-mentioned compounds of formulae IA and IB can be
prepared in accordance with the invention by [0051] reacting a
compound of formula ##STR6## [0052] with diphenyl phosphoryl azide
forming a compound of formula ##STR7## [0053] reacting the amino
group of a compound of formula IA-1a with a compound of formula
R.sup.5X to give a compound of formula ##STR8## [0054] wherein
R.sup.2-R.sup.4 and Ar have the significances given above, R.sup.5
is lower alkyl and X is halogen, or [0055] reacting a compound of
formula ##STR9## [0056] with diphenyl phosphoryl azide to a
compound of formula ##STR10## [0057] wherein R.sup.2-R.sup.4 and Ar
have the significances given above, or reacting the amino group of
a compound of formula IB-1a with a compound of formula R.sup.5X to
give a compound of formula ##STR11## [0058] wherein R.sup.1,
R.sup.3 and R.sup.4 and Ar have the significances given above,
R.sup.5 is lower alkyl and X is halogen, or [0059] reacting a
compound of formula ##STR12## [0060] with a compound of formula
##STR13## [0061] to a compound of formula ##STR14## [0062] wherein
R.sup.1 to R.sup.4 have the significances given above, or [0063]
reacting a compound of formula ##STR15## [0064] with a compound of
formula ##STR16## [0065] o a compound of formula ##STR17## [0066]
wherein R.sup.1 to R.sup.4 have the significances given above, or
if desired, converting the compound of formula I obtained into a
pharmaceutically acceptable salt.
[0067] In the following the preparation of compounds of formulae IA
and IB are described in more detail:
[0068] In accordance with the process variants, described above,
and with schemes 1-3, described below, compounds of formulae IA and
IB may be prepared by known procedures, for example the
following:
[0069] In accordance with schemes 1 and 2 a compound of formula IVA
or IVB may be prepared as follows:
[0070] To a refluxing solution of 2-picoline-1-oxide or
4-picoline-1-oxide and potassium tert.-butanolate in butanol is
added portionwise an aldehyde of formula VA. Reflux is maintained
for about 90 min. Then the mixture is cooled, diluted and
extracted. The combined organic phases are dried and concentrated
to provide a compound of formulae IVA or IVB. The obtained compound
is then reacted first with dimethylsulfate and then with NaCN.
After extraction and crystallization a compound of formulae IIIA or
IIIB is obtained, for example
6-(2-p-tolyl-vinyl)-pyridine-2-carbonitrile (IIIA) or
trans-6-methyl-4-styryl-pyridine-2-carbonitrile (IIIB). The
corresponding carbonitrile compounds and HCl are further refluxed
for 3 hr. All volatiles are distilled off and the residue is
stirred with H.sub.2O, filtered and dried to obtain a compound of
formulae IIA or IIB. The most preferred compounds of formulae IA-1a
or IB-1a, wherein one of R.sup.1 or R.sup.2 is amino, may then be
prepared as follows: A compound of formula IIA or IIB is brought to
reaction with triethylamine, diphenyl phosphoryl azide and butanol.
After extractive workup the residue is refluxed about 4 hr with HCl
and after a further workup a compound of formula IA-1a or IB-1a is
obtained. The amino group may then further modified by alkylation
to obtain compounds of formulae IA-1b or IB-1b.
[0071] In accordance with scheme 3, a compound of formula IA-2 or
IB-2 is obtained as follows: A compound of formula IX, for example
3-bromo-1,2-dihydro-naphthalene, is prepared in analogy to M.
Adamczyk and D. S. Watt, J. Org. Chem., 1984, 49, 422.6. This
compound is then solved in diethylether, cooled in a dry ice bath
and tert.-butyllithium solution in pentane is added. The solution
is stirred about for 30 min, then triisopropylborate is added. The
reaction mixture is brought to rt and treated with HCl. After 15
min the organic phase is dried, evaporated and precipitated with
pentane to provide a compound of formula X.
[0072] This compound is further treated with a compound of formula
XIA or XIB as follows: A solution of a compound of formula XIA or
XIB and palladium tetrakis(triphenylphosphine) in toluene is
stirred at room temperature (rt) for about 15 min. Then a compound
of formula X and an aqueous K.sub.2CO.sub.3 solution is added and
the resulting mixture is refluxed for about 30 min. Toluene is
added and the organic phase is dried and concentrated to obtain a
compound of formula IA-2 or IB-2.
[0073] Pharmaceutically acceptable salts can be manufactured
according to methods which are known in the art. The acid addition
salts of compounds of formulae IA and IB are especially well suited
for pharmaceutical use.
[0074] In the following schemes 1-3 are described processes for
preparation of compounds of formulae IA and IB, starting from known
compounds, from commercial products or from compounds, which can be
prepared in conventional manner.
[0075] The preparation of compounds of formulae IA and IB are
described in more detail in working examples 1-41 ##STR18##
[0076] The substitutents R.sup.1 to R.sup.4 and Ar are described
above and THF is tetrahydrofuran. ##STR19##
[0077] The substituents R.sup.1, R.sup.3 and R.sup.4 and Ar are
described above. ##STR20##
[0078] The substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 and
Ar are described above.
[0079] As mentioned earlier, the compounds of formulae IA and IB or
their pharmaceutically acceptable acid addition salts possess
valuable pharmacodynamic properties. They are NMDA-receptor subtype
2B selective blockers, which have a key function in modulating
neuronal activity and plasticity which makes them key players in
mediating processes underlying development of CNS as well as
learning and memory formation.
[0080] The compounds were investigated in accordance with the test
given hereinafter.
Test Method
.sup.3H-Ro 25-6981 binding (Ro 25-6981 is
[R--(R*,S*)]-.alpha.-(4-Hydroxy-phenyl)-.beta.-methyl-4-(phenyl-methyl)-1-
-piperidine propanol)
[0081] Male Fullinsdorf albino rats weighing between 150-200 g were
used. Membranes were prepared by homogenization of the whole brain
minus cerebellum and medulla oblongata with a Polytron (10.000 rpm,
30 seconds), in 25 volumes of a cold Tris-HCl 50 mM, EDTA 10 mM, pH
7.1 buffer. The homogenate was centrifuged at 48,000 g for 10
minutes at 4.degree. C. The pellet was resuspended using the
Polytron in the same volume of buffer and the homogenate was
incubated at 37.degree. C. for 10 minutes. After centrifugation the
pellet was homogenized in the same buffer and frozen at -80.degree.
C. for at least 16 hours but not more than 10 days. For the binding
assay the homogenate was thawed at 37.degree. C., centrifuged and
the pellet was washed three times as above in a Tris-HCl 5 mM, pH
7.4 cold buffer. The final pellet was resuspended in the same
buffer and used at a final concentration of 200 mg of
protein/ml.
[0082] .sup.3H-Ro 25-6981 binding experiments were performed using
a Tris-HCl 50 mM, pH 7.4 buffer. For displacement experiments 5 nM
of .sup.3H-Ro 25-6981 were used and non specific binding was
measured using 10 mM of tetrahydroisoquinoline and usually it
accounts for 10% of the total. The incubation time was 2 hours at
4.degree. C. and the assay was stopped by filtration on Whatmann
GF/B glass fiber filters (Unifilter-96, Packard, Zurich,
Switzerland). The filters were washed 5 times with cold buffer. The
radioactivity on the filter was counted on a Packard Top-count
microplate scintillation counter after addition of 40 mL of
microscint 40 (Can berra Packard S. A., Zuirich, Switzerland).
[0083] The above procedure was performed to determine data for
calculation of an IC.sub.50 value. The IC.sub.50 value is a
concentration expressed in micromoles (.mu.M) for a test compound
at which 50% of the ligand (in this determination, .sup.3H-Ro
25-6981) bonded to the receptor is displaced. The binding ability
of the compounds of the invention was measured in vitro using a
minimum of 10 concentrations and repeated at least once. The
specific binding at each concentration was then calculated as the %
of the maximum specific binding (100%) obtained in the same
experiment, in the absence of a test compound. Competitive
displacement of .sup.3H-Ro 25-6981 was observed, with complete
displacement of the radioligand from specific binding sites
(usually about 0% of specific binding at the highest concentrations
tested). An IC.sub.50 value was then calculated with all the ten
datapoints (% of specific bound) by plotting the data on a
semilogarithmic scale with a sigmoidal fit (Log of the molar
concentration on X-axis vs. % of specific bound on the Y-axis)
using Microsoft Excel fit software or Microcal Origin software. The
pooled normalized values were analyzed using a non-linear
regression calculation program which provide IC.sub.50 with their
relative upper and lower 95% confidence limits.
[0084] The IC.sub.50 (.mu.M) of preferred compounds of formulae IA
or IB, tested in accordance with the above mentioned methods, is
<0.1 .mu.M. In table I below representative IC.sub.50 values are
described. TABLE-US-00001 TABLE I Example No. IC.sub.50 (.mu.M) 14
0.01 16 0.04 18 0.08 19 0.018 22 0.032 24 0.011 26 0.038 27 0.052
28 0.038 30 0.02 34 0.057 36 0.023 37 0.082 13 0.03
[0085] The compounds of formulae IA, IB or combinations thereof and
their salts, as herein described, can be incorporated into standard
pharmaceutical dosage forms, for example, for oral or parenteral
application with the usual pharmaceutical adjuvant materials, for
example, organic or inorganic inert carrier materials, such as,
water, gelatin, lactose, starch, magnesium stearate, talc,
vegetalbe oils, gums, polyalkylene-glycols and the like. The
pharmaceutical preparations can be employed in a solid form, for
example, as tablets, suppositories, capsules, or in liquid form,
for example, as solutions, suspensions or emulsions. Pharmaceutical
adjuvant materials can be added and include preservatives
stabilizers, wetting or emulsifying agents, salts to change the
osmotic pressure or to act as buffers. The pharmaceutical
preparations can also contain other therapeutically active
substances.
[0086] The dosage can vary within wide limits and will, of course,
be fitted to the individual requirements in each particular case.
In the case of oral administration the dosage lies in the range of
about 0.1 mg per dosage to about 1000 mg per day of a compound of
general formula I although the upper limit can also be exceeded
when this is shown to be indicated.
[0087] The following examples illustrate the present invention in
more detail. However, they are not intended to limit its scope in
any manner. All temperatures are given in degree Celsius.
EXAMPLE 1
6-Styryl-pyridin-2-ylamine hydrochloride
[0088] Prepared according to the literature: Y. Honma et al., J.
Med. Chem., 1984, 27, 125.
EXAMPLE 2
6-(2-p-Tolyl-vinyl)-pyridin-2-yl-amine hydrochloride
a) 2-(2-p-Tolyl-vinyl)-pyridine 1-oxide
[0089] To a refluxing solution of 2-picoline-1-oxide (10.9 g, 100
mmol), potassium tert.-butanolate (11.2 g, 100 mmol) in butanol
(100 ml) was added portion-wise p-tolualdehyde (12.0 g, 100 mmol).
Reflux was maintained for 90 min. Then the mixture was cooled to
rt, diluted with H.sub.2O (100 ml) and extracted with
CH.sub.2Cl.sub.2. The combined organic phases were dried with
MgSO.sub.4, concentrated and chromatographed (SiO.sub.2 with
CH.sub.2Cl.sub.2/MeOH=95:5) to provide the title compound (11.6 g,
55%) as a yellow solid material. MS: m/e=211 (M.sup.+).
b) 6-(2-p-Tolyl-vinyl)-pyridine-2-carbonitrile
[0090] In a variation to the procedure referred to in example 1,
2-(2-p-tolyl-vinyl)-pyridine 1-oxide (9.8 g, 46 mmol) was reacted
first with dimethylsulfate (5.8 g, 46 mmol) and then with NaCN
(2.74 g, 56 mmol). After extraction and crystallization
6-(2-p-tolyl-vinyl)-pyridine-2-carbonitrile (5.8 g, 57%) was
obtained as a yellow crystalline material. Mp. 137-138.degree. C.
(isopropanol), MS: m/e=220 (M.sup.+)
c) 6-(2-p-Tolyl-vinyl)-pyridine-2-carboxylic acid
[0091] In a variation to the procedure referred to in examplel,
6-(2-p-tolyl-vinyl)-pyridine-2-carbonitrile (3.0 g, 14 mmol) and
37% HCl (70 ml) was refluxed for 3 hr. All volatiles were distilled
off and the residue stirred with H.sub.2O (100 ml), filtered and
dried over NaOH to obtain the title compound (2.81 g, 84%) as a
yellow crystalline material. MS: m/e=239 (M.sup.+).
d) 6-(2-p-Tolyl-vinyl)-pyridin-2-yl-amine 1:1 hydrochloride
[0092] In a variation to the procedure referred to in examplel,
6-(2-p-tolyl-vinyl)-pyridine-2-carboxylic acid (2.81 g, 11.7 mmol)
was brought to reaction with triethylamine (1.21 g, 12.0 mmol),
diphenyl phosphoryl azide (3.56 g, 12.9 mmol) and butanol (33 ml).
After extractive workup the residue was refluxed (4 hr) with 3N
HCl. Extractive workup and chromatography (SiO.sub.2 with
AcOEt/hexane/NEt.sub.3=10:20:1) afforded the title compound as an
oil which was crystallized as the yellow hydrochloride salt (0.95
g, 33%). Mp.>250.degree. C. (MeOH/Et.sub.2O), MS: m/e=210
(M.sup.+).
EXAMPLE 3
6-[2-(4-Methoxy-phenyl)-vinyl]-pyridin-2-yl-amine hydrochloride
a) 2-[2-(4-Methoxy-phenyl)-vinyl]-pyridine 1-oxide
[0093] Following the general method described in example 2a,
2-picoline-1-oxide was reacted with potassium tert.-butanolate and
p-anisaldehyde. After extraction and chromatography the title
compound was obtained as a yellow solid material. MS: m/e=227
(M.sup.+).
b) 6-[2-(4-Methoxy-phenyl)-vinyl]-pyridine-2-carbonitrile
[0094] Following the general method described in example 2b,
2-[2-(4-methoxy-phenyl)-vinyl]-pyridine l-oxide was reacted first
with dimethylsulfate and then with NaCN. After extraction and
crystallization the title compound was obtained as a yellow
crystalline material. Mp. 121-122.degree. C. (isopropanol), MS:
m/e=236 (M.sup.+)
c) 6-[2-(4-Methoxy-phenyl)-vinyl]-pyridine-2-carboxylic acid
[0095] Following the general method described in example 2c,
6-[2-(4-methoxy-phenyl)-vinyl]-pyridine-2-carbonitrile was
hydrolyzed with 37% HCl. After workup the title compound was
isolated as a yellow crystalline material. MS: m/e=255
(M.sup.+).
d) 6-[2-(4-Methoxy-phenyl)-vinyl]-pyridin-2-yl-amine 1:1
hydrochloride
[0096] Following the general method described in example 2d, the
title compound was obtained as a yellow crystalline material by
reaction of 6-[2-(4-methoxy-phenyl)-vinyl]-pyridine 2-carboxylic
acid with triethylamine, diphenyl phosphoryl azide and butanol
followed by hydrolysis with HCl. Mp. 224-226.degree. C.
(MeOH/Et.sub.2O), MS: m/e=226 (M.sup.+).
EXAMPLE 4
6-[2-(4-Chloro-phenyl)-vinyl]-pyridin-2-yl-amine hydrochloride
a) 2-[2-(4-Chloro-phenyl)-vinyl]-pyridine 1-oxide
[0097] Following the general method described in example 2a,
2-picoline-1-oxide was reacted with potassium tert.-butanolate and
4-chloro-benzaldehyde. After extraction and chromatography the
title compound was obtained as a yellow solid material. MS: m/e=231
(M.sup.+).
b) 6-[2-(4-Chloro-phenyl)-vinyl]-pyridine-2-carbonitrile
[0098] Following the general method described in example 2b,
2-[2-(4-chloro-phenyl)-vinyl]-pyridine 1-oxide was reacted first
with dimethylsulfate and then with NaCN. After extraction and
crystallization the title compound was obtained as a beige
crystalline material. Mp. 113-115.degree. C. (isopropanol), MS:
m/e=240 (M.sup.+).
c) 6-[2-(4-Chloro-phenyl)-vinyl]-pyridine-2-carboxylic acid
[0099] Following the general method described in example 2c,
6-[2-(4-chloro-phenyl)-vinyl]-pyridine-2-carbonitrile was
hydrolyzed with 37% HCl. After workup the title compound was
isolated as a yellow crystalline material. MS: m/e=259
(M.sup.+).
d) 6-[2-(4-Chloro-phenyl)-vinyl]-pyridin-2-yl-amine 1:1
hydrochloride
[0100] Following the general method described in example 2d, the
title compound was obtained as a yellow crystalline material by
reaction of 6-[2-(4-chloro-phenyl)-vinyl]-pyridine 2-carboxylic
acid with triethylamine, diphenyl phosphoryl azide and butanol
followed by hydrolysis with HCl. Mp.>250.degree. C.
(MeOH/Et.sub.2O), MS: m/e=231 (M.sup.+).
EXAMPLE 5
6-[2-(3,4-Dichloro-phenyl)-vinyl]-pyridin-2-yl-amine
hydrochloride
a) 2-[2-(3,4-Dichloro-phenyl)-vinyl]-pyridine 1-oxide
[0101] Following the general method described in example 2a,
2-picoline-1-oxide was reacted with potassium tert.-butanolate and
3,4-dichloro-benzaldehyde. After extraction and chromatography the
title compound was obtained as a yellow solid material. MS: m/e=265
(M.sup.+).
b) 6-[2-(3,4-Dichloro-phenyl)-vinyl]-pyridine-2-carbonitrile
[0102] Following the general method described in example 2b,
2-[2-(3,4-dichloro-phenyl)-vinyl]-pyridine 1-oxide was reacted
first with dimethylsulfate and then with NaCN. After extraction and
crystallization the title compound was obtained as a white
crystalline material. Mp. 124-125.degree. C. (hexane), MS: m/e=274
(M.sup.+).
c) 6-[2-(3,4-Dichloro-phenyl)-vinyl]-pyridine-2-carboxylic acid
[0103] Following the general method described in example 2c,
6-[2-(3,4-dichloro-phenyl)-vinyl]-pyridine-2-carbonitrile was
hydrolyzed with 37% HCl. After workup the title compound was
isolated as a yellow crystalline material. MS: m/e=293
(M.sup.+).
d) 6-[2-(3,4-Dichloro-phenyl)-vinyl]-pyridin-2-yl-amine 1:1
hydrochloride
[0104] Following the general method described in example 2d, the
title compound was obtained as a yellow crystalline material by
reaction of 6-[2-(3,4-dichloro-phenyl)-vinyl]-pyridine 2-carboxylic
acid with triethylamine, diphenyl phosphoryl azide and butanol
followed by hydrolysis with HCl. Mp.>250.degree. C. (EtOH), MS:
m/e=265 (M+H.sup.+).
EXAMPLE 6
6-[2-(4-Fluoro-phenyl)-vinyl]-pyridin-2-yl-amine hydrochloride
a) 2-[2-(4-Fluoro-phenyl)-vinyl]-pyridine 1-oxide
[0105] Following the general method described in example 2a,
2-picoline-1-oxide was reacted with potassium tert.-butanolate and
4-fluoro-benzaldehyde. After extraction and chromatography the
title compound was obtained as a yellow solid material. MS: m/e=215
(M.sup.+).
b) 6-[2-(4-Fluoro-phenyl)-vinyl]-pyridine-2-carbonitrile
[0106] Following the general method described in example 2b,
2-[2-(4-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first
with dimethylsulfate and then with NaCN. After extraction and
crystallization the title compound was obtained as a yellow
crystalline material. MS: m/e=224 (M.sup.+).
c) 6-[2-(4-Fluoro-phenyl)-vinyl]-pyridine-2-carboxylicacid
[0107] Following the general method described in example 2c,
6-[2-(4-fluoro-phenyl)-vinyl]-pyridine-2-carbonitrile was
hydrolyzed with 37% HCl. After workup the title compound was
isolated as a yellow crystalline material. MS: m/e=243
(M.sup.+).
d) 6-[2-(4-Fluoro-phenyl)-vinyl]-pyridin-2-yl-amine 1:1
hydrochloride
[0108] Following the general method described in example 2d, the
title compound was obtained as a yellow crystalline material by
reaction of 6-[2-(4-fluoro-phenyl)-vinyl]-pyridine 2-carboxylic
acid with triethylamine, diphenyl phosphoryl azide and butanol
followed by hydrolysis with HCl. Mp.>250.degree. C.
(MeOH/Et.sub.2O), MS: m/e=214 (M.sup.+).
EXAMPLE 7
6-[2-(3-Chloro-phenyl)-vinyl]-pyridin-2-yl-amine hydrochloride
a) 2-[2-(3-Chloro-phenyl)-vinyl]-pyridine 1-oxide
[0109] Following the general method described in example 2a,
2-picoline-1-oxide was reacted with potassium tert.-butanolate and
3-chloro-benzaldehyde. After extraction and chromatography the
title compound was obtained as a yellow solid material. MS: m/e=231
(M.sup.+).
b) 6-[2-(3-Chloro-phenyl)-vinyl]-pyridine-2-carbonitrile
[0110] Following the general method described in example 2b,
2-[2-(4-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first
with dimethylsulfate and then with NaCN. After extraction and
crystallization the title compound was obtained as a yellow
crystalline material which was directly used for the next step.
c) 6-[2-(3-Chloro-phenyl)-vinyl]-pyridine-2-carboxylic acid
[0111] Following the general method described in example 2c,
6-[2-(3-chloro-phenyl)-vinyl]-pyridine-2-carbonitrile was
hydrolyzed with 37% HCl. After workup the title compound was
isolated as a yellow crystalline material. MS: m/e=259
(M.sup.+).
d) 6-[2-(3-Chloro-phenyl)-vinyl]-pyridin-2-yl-amine 1:1
hydrochloride
[0112] Following the general method described in example 2d, the
title compound was obtained as a yellow crystalline material by
reaction of 6-[2-(3-chloro-phenyl)-vinyl]-pyridine 2-carboxylic
acid with triethylamine, diphenyl phosphoryl azide and butanol
followed by hydrolysis with HCl. Mp. 248-249.degree. C.
(MeOH/Et.sub.2O), MS: m/e=230 (M.sup.+).
EXAMPLE 8
6-[2-(2-Fluoro-phenyl)-vinyl]-pyridin-2-yl-amine hydrochloride
a) 2-[2-(2-Fluoro-phenyl)-vinyl]-pyridine 1-oxide
[0113] Following the general method described in example 2a,
2-picoline-1-oxide was reacted with potassium tert.-butanolate and
2-fluoro-benzaldehyde. After extraction and chromatography the
title compound was obtained as a yellow solid material. MS: m/e=215
(M.sup.+).
b) 6-[2-(2-Fluoro-phenyl)-vinyl]-pyridine-2-carbonitrile
[0114] Following the general method described in example 2b,
2-[2-(2-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first
with dimethylsulfate and then with NaCN. After extraction and
crystallisation the title compound was obtained as a brown
crystalline material. MS: m/e=224 (M.sup.+).
c) 6-[2-(2-Fluoro-phenyl)-vinyl]-pyridine-2-carboxylic acid
[0115] Following the general method described in example 2c,
6-[2-(2-fluoro-phenyl)-vinyl]-pyridine-2-carbonitrile was
hydrolyzed with 37% HCl. After workup the title compound was
isolated as a yellow crystalline material which was directly used
in the next step.
d) 6-[2-(2-Fluoro-phenyl)-vinyl]-pyridin-2-yl-amine 1:1
hydrochloride
[0116] Following the general method described in example 2d, the
title compound was obtained as a yellow crystalline material by
reaction of 6-[2-(2-fluoro-phenyl)-vinyl]-pyridine 2-carboxylic
acid with triethylamine, diphenyl phosphoryl azide and butanol
followed by hydrolysis with HCl. Mp.>250.degree. C.
(MeOH/Et.sub.2O), MS: m/e=214 (M.sup.+).
EXAMPLE 9
6-[2-(3-Trifluoromethyl-phenyl)-vinyl]-pyridin-2-yl-amine
hydrochloride
a) 2-[2-(3-Trifluoromethyl-phenyl)-vinyl]-pyridine 1-oxide
[0117] Following the general method described in example 2a,
2-picoline-1-oxide was reacted with potassium tert.-butanolate and
3-trifluoromethyl-benzaldehyde. After extraction and chromatography
the title compound was obtained as a yellow solid material. MS:
m/e=265 (M.sup.+).
b)
6-[2-(3-Trifluoromethyl-phenyl)-vinyl]-pyridine-2-carbonitrile
[0118] Following the general method described in example 2b,
2-[2-(3-trifluoromethyl-phenyl)-vinyl]-pyridine 1-oxide was reacted
first with dimethylsulfate and then with NaCN. After extraction and
chromatography (SiO.sub.2 with CH.sub.2Cl.sub.2/MeOH=97/3) the
title compound was obtained as a yellow oil and directly used in
the next step.
c) 6-[2-(3-Trifluoromethyl-phenyl)-vinyl]-pyridine-2-carboxylic
acid
[0119] Following the general method described in example 2c,
6-[2-(2-fluoro-phenyl)-vinyl]-pyridine-2-carbonitrile was
hydrolyzed with 25% HCl. After workup the title compound was
isolated as a yellow crystalline material. MS: m/e=293
(M.sup.+).
d) 6-[2-(3-Trifluoromethyl-phenyl)-vinyl]-pyridin-2-yl-amine 1:1
hydrochloride
[0120] Following the general method described in example 2d, the
title compound was obtained as a yellow crystalline material by
reaction of 6-[2-(3-trifluoromethyl-phenyl)-vinyl]-pyridine
2-carboxylic acid with triethylamine, diphenyl phosphoryl azide and
butanol followed by hydrolysis with HCl. Mp. 222-223.degree. C.
(iPrOH), MS: m/e=264 (M.sup.+).
EXAMPLE 10
6-[2-(3-Fluoro-phenyl)-vinyl]-pyridin-2-yl-amine hydrochloride
a) 2-[2-(3-Fluoro-phenyl)-vinyl]-pyridine 1-oxide
[0121] Following the general method described in example 2a,
2-picoline-1-oxide was reacted with potassium tert.-butanolate and
3-fluoro-benzaldehyde. After extraction and chromatography the
title compound was obtained as a yellow solid material. MS: m/e=215
(M.sup.+).
b) 6-[2-(3-Fluoro-phenyl)-vinyl]-pyridine-2-carbonitrile
[0122] Following the general method described in example 2b,
2-[2-(3-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first
with dimethylsulfate and then with NaCN. After extraction and
crystallization the title compound was obtained as a beige
crystalline material. Mp. 111-112.degree. C. (iPrOH), MS: m/e=224
(M.sup.+).
c) 6-[2-(3-Fluoro-phenyl)-vinyl]-pyridine-2-carboxylic acid
[0123] Following the general method described in example 2c,
6-[2-(3-fluoro-phenyl)-vinyl]-pyridine-2-carbonitrile was
hydrolyzed with 37% HCl. After workup the title compound was
isolated as a yellow crystalline material which was directly used
in the next step.
d) 6-[2-(3-Fluoro-phenyl)-vinyl]-pyridin-2-yl-amine 1:1
hydrochloride
[0124] Following the general method described in example 2d, the
title compound was obtained as a light yellow crystalline material
by reaction of 6-[2-(3-fluoro-phenyl)-vinyl]-pyridine 2-carboxylic
acid with triethylamine, diphenyl phosphoryl azide and butanol
followed by hydrolysis with HCl. Mp.>250.degree. C.
(MeOH/Et.sub.2O), MS: m/e=214 (M.sup.+).
EXAMPLE 11
4-[2-(6-Amino-pyridin-2-yl)-vinyl]-phenol
[0125] A suspension of
6-[2-(4-methoxy-phenyl)-vinyl]-pyridin-2-yl-amine (1.0 g, 3.8 mmol)
(example 3) in CH.sub.2Cl.sub.2 (60 ml) was treated with boron
tribromide (2.4 ml, 25 mmol) and stirred for 72 hr. The precipitate
was filtered, dissolved in AcOEt and washed with aqueous
NaHCO.sub.3 solution. The organic phase was dried
(Na.sub.2SO.sub.4), concentrated and the residue was
chromatographed (SiO.sub.2 with
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH=140/10/1) and crystallized to
provide 0.20 g (25%) of the light yellow title compound. Mp.
224-225.degree. C. (iPr.sub.2O), MS: m/e=213 (M+H.sup.+).
EXAMPLE 12
trans-4-Styryl-pyridin-2-yl-amine
[0126] Prepared according to the literature: R. Adams, A. W.
Schrecker, JACS, 1949, 71, 1186
EXAMPLE 13
trans-6-Methyl-4-styryl-pyridin-2-yl-amine
a) trans-2-Methyl-4-styryl-pyridine 1-oxide
[0127] Following the general method described in example 2a,
2,4-dimethylpyridine 1-oxide was reacted with potassium
tert.-butanolate and benzaldehyde. After extraction and
chromatography (SiO.sub.2 with CH.sub.2Cl.sub.2/MeOH=97/3) the
title compound was obtained as a yellow solid material (yield 7%).
NMR (250 MHz, DMSO): 2.37 (s, 3H, CH.sub.3), 7.20 (d, J=16.5 Hz,
1H, CH.dbd.CH), 7.25-7.75 (m, 8H, arom-H, CH.dbd.CH), 8.22 (d,
J=6.8 Hz, 1H, arom-H).
b) trans-6-Methyl-4-styryl-pyridine-2-carbonitrile
[0128] Following the general method described in example 2b,
2-methyl-4-styryl-pyridine 1-oxide was reacted first with
dimethylsulfate and then with NaCN. After extraction and
chromatography (SiO.sub.2 with CH.sub.2Cl.sub.2) the title compound
was obtained as a yellow crystalline material. MS: m/e=220
(M.sup.+).
c) trans-6-Methyl-4-styryl-pyridin-2-carboxylic acid
[0129] Following the general method described in example 2c,
6-methyl-4-styryl-pyridine-2-carbonitrile was hydrolyzed with 25%
HCl. After workup the title compound was isolated as a yellow
crystalline material which was directly used in the next step.
d) trans-6-Methyl-4-styryl-pyridin-2-yl-amine
[0130] Following the general method described in example 2d, the
title compound was obtained as a yellow crystalline material by
reaction of 6-methyl-4-styryl-pyridine-2-carboxylic acid with
triethylamine, diphenyl phosphoryl azide and butanol followed by
hydrolysis with HCl. Mp. 149-150.degree. C. (iPr.sub.2O), MS:
m/e=210 (M.sup.+).
EXAMPLE 14
trans-4-Methyl-6-styryl-pyridin-2-yl-amine hydrochloride
[0131] In analogy to example 2a-d, the title compound was obtained
as a yellow crystalline material by reaction of
4-methyl-2-styryl-pyridine 1-oxide (A. Silhankova et al., Collect.
Czech. Chem. Commun., 1989, 54, 1687) with dimethylsulfate followed
by NaCN, hydrolysis with HCl followed by treatment with
triethylamine, diphenyl phosphoryl azide and butanol followed by
hydrolysis with HCl. Mp.>250.degree. C. (EtOH), MS: m/e=210
(M.sup.+).
EXAMPLE 15
trans-6-Styryl-pyridin-3-yl-amine
[0132] Under inert atmosphere (Ar) a mixture of
palladium(II)-acetate (0.45 g, 2 mmol) and triphenylphosphine (0.95
g, 3.6 mmol) in DMF (50 ml) was stirred for 0.5 hr at rt. Then
2-chloro-5-nitropyridine (3.2 g, 20 mmol) and
tributyl-styryl-stannane (15.7 g, 40 mmol) was added and the
mixture was stirred at 130.degree. C. for 15 hr. The solvent was
evaporated and the residue partitioned between AcOEt and 1N HCl.
The aqueous phase was neutralized with 6N NaOH and extracted with
AcOEt. The organic phase was dried with Na.sub.2SO.sub.4,
concentrated and chromatographed (SiO2 with
CH.sub.2Cl.sub.2/CH.sub.3OH=97/3) to give the title compound (0.90
g, 23%) as a yellow solid. Mp. 159-160.degree. C. (AcOEt), MS: 196
(M.sup.+).
EXAMPLE 16
trans-2-Styryl-pyridin-4-yl-amine
[0133] Under inert atmosphere (Ar) a mixture of
palladium-(II)-acetate (0.117 mg, 0.5 mmol) and triphenylphosphine
(0.248 g, 0.9 mmol) in DMF (13 ml) was stirred for 30 min at rt.
2-Bromo-pyridin-4-ylamine (0.90 g, 5.2 mmol) (H. J. den Hertog, C.
R. Kolder and W. P. Combe, Rec. Trav. Chim., 1951, 70, 591) was
added followed by tributyl-styryl-stannane (3.93 g, 10 mmol). After
heating at 130.degree. C. for 15 min the solvent was evaporated and
the residue partitioned between AcOEt and 3N HCl. The aqueous phase
was neutralized with 6N NaOH and extracted with AcOEt. The organic
phase was dried with Na.sub.2SO.sub.4, concentrated and
chromatographed (SiO.sub.2 with
CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH=140/10/1) to give the title
compound (0.40 g, 39%) as a colorless solid. Mp. 164-165.degree. C.
(AcOEt), MS: 196 (M.sup.+).
EXAMPLE 17
trans-Methyl-(6-styryl-pyridin-2-yl)-amine hydrochloride
[0134] A solution of 6-styryl-pyridin-2-ylamine (1.0 g, 4.3 mmol)
(cf. example 1) in methanol (40 ml) was treated at rt with aqueous
formaldehyde (0.33 ml of an 40% solution, 4.3 mmol) and sodium
cyanoborohydride (0.27 g, 4.3 mmol). After 1 hr all volatiles were
evaporated and the residue was dissolved in AcOEt. The organic
phase was successively washed with saturated aqueous NaHCO.sub.3,
H.sub.2O, saturated aqueous citric acid and water, then dried
(Na.sub.2SO.sub.4), concentrated and chromatographed (SiO2 with
AcOEt/hexane/NEt.sub.3=10/10/1). The free base of the title
compound was obtained as a slightly yellow oil (0.18 g, 20%) and
crystallized as the yellow hydrochloride. Mp. 157-158.degree. C.
(MeOH/Et.sub.2O), MS: m/e=210 (M.sup.+).
EXAMPLE 18
trans-C-(6-Styryl-pyridin-2-yl)-methylamine hydrochloride
[0135] A solution of 6-styryl-pyridin-2-carbonitril (0.94 g, 4.5
mmol) (cf. example 1) in THF (20 ml) was cooled to 0.degree. C.
After dropwise addition of diisobutylaluminiumhydride (8.0 ml of a
1.2 M solution in toluene) the resulting mixture was stirred at
0.degree. C. for 1 hr and then quenched with saturated
Seignette-salt solution. After extraction with AcOEt the combined
organic phases were dried over Na.sub.2SO.sub.4, concentrated and
chromatographed (SiO.sub.2 with
CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH=140/10/1) to give the free
base of the title compound as a yellow oil (0.16 g, 17%) which was
crystallized as a beige hydrochloride salt. Mp. 170.degree. C.
(dec.) (MeOH/Et.sub.2O), MS: m/e=210 (M.sup.+).
EXAMPLE 19
2-(3,4-Dihydro-naphthalen-2-yl)-pyridin-4-yl-amine
hydrochloride
a) 4-Dihydro-naphthalene-2-boronic acid
[0136] A solution of 3-bromo-1,2-dihydro-naphthalene (7.7 g, 37
mmol) (M. Adamczyk and D. S. Watt, J. Org. Chem., 1984, 49, 4226)
in diethylether (370 ml) was cooled in a dry ice bath and
tert.-butyllithium solution (50 ml of a 1.5 M solution in pentane)
was added maintaining T<-65.degree. C. At this temperature
stirring was continued for 30 min, then triisopropylborate (17.3
ml, 75 mmol) was added. The reaction mixture was brought to rt and
treated with 3N HCl (100 ml). After 15 min the organic phase was
dried (Na.sub.2SO.sub.4), evaporated and precipitated with pentane
to provide the title compound (3.83 g, 60%) as a white solid
material. MS: m/e=173 (M-H.sup.-).
b) 2-(3,4-Dihydro-naphthalen-2-yl)-pyridin-4-yl-amine 1:1
hydrochloride
[0137] A solution of 2-bromo-pyridin-4-yl-amine (0.87 g, 5 mmol)
and palladium tetrakis(triphenylphosphine) (0.58 g, 0.5 mmol) in
toluene (25 ml) was stirred at rt for 15 min. Then,
3,4-dihydro-naphthalene-2-boronic acid (0.88 g, 5 mmol) and aqueous
2M K.sub.2CO.sub.3 solution (5 ml) was added and the resulting
mixture refluxed for 30 min. Toluene (50 ml) was added and the
organic phase was dried (Na.sub.2SO.sub.4), concentrated and
chromatographed (SiO.sub.2 with
CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH=300/10/1) to give the free
base of the title compound (0.72 g, 65%) as a colorless foam.
Treatment with hydrogen chloride gave white crystals, Mp.
231-232.degree. C. (EtOH/Et.sub.2O), MS: m/e=222 (M.sup.+).
EXAMPLE 20
6-(3,4-Dihydro-naphthalen-2-yl)-pyridin-2-yl-amine fumarate
[0138] Following the general method described in example 19b, the
title compound, was obtained as a light yellow crystalline material
by reaction of 6-bromo-pyridin-2-ylamine with palladium
tetrakis(triphenylphosphine), 3,4-dihydro-naphthalene-2-boronic
acid (example 19a) and 2M K.sub.2CO.sub.3 and crystallization of
the free base as the fumarate salt. Mp. 153-154.degree. C. (MeOH),
MS: m/e=223 (M+H.sup.+).
EXAMPLE 21
6-(3,4-Dihydro-naphthalen-2-yl)-4-methyl-pyridin-2-yl-amine
fumarate
[0139] Following the general method described in example 19b, the
title compound was obtained as a light yellow crystalline material
by reaction of 6-bromo-4-methyl-pyridin-2-ylamine (A. Kleeman, D.
Munro, B. Patel, Eur. Pat. 572093, Dec. 1, 1993) with palladium
tetrakis(triphenylphosphine), 3,4-dihydro-naphthalene-2-boronic
acid (example 19a) and aqueous 2M K.sub.2CO.sub.3 and
crystallization of the free base as the fumarate salt. Mp.
142-143.degree. C. (MeOH), MS: m/e=237 (M+H.sup.+).
EXAMPLE 22
2-(3,4-Dihydro-naphthalen-2-yl)-6-methyl-pyridin-4-yl-amine
fumarate
[0140] Following the general method described in example 19b, the
title compound was obtained as a white crystalline material by
reaction of 2-bromo-6-methyl-pyridin-4-ylamine (A. Puszko, Pr.
Nauk. Akad. Ekon. im. Oskara Langego Wroclawiu, 1984, 278, 169)
with palladium tetrakis(triphenylphosphine),
3,4-dihydro-naphthalene-2-boronic acid (example 19a) and aqueous 2M
K.sub.2CO.sub.3 and crystallization of the free base as the
fumarate salt. Mp. 202-203.degree. C. (MeOH/Et.sub.2O), MS: m/e=236
(M.sup.+).
EXAMPLE 23
[4-Amino-6-(3,4-dihydro-naphthalen-2-yl)-pyridin-2-yl]-methanol
fumarate
a) 6-Bromo-4-nitro-pyridine-2-carboxylic acid
[0141] To a solution of 2-bromo-6-methyl-4-nitro-pyridine (17.8 g,
82.0 mmol) (A. Puszko, Pr. Nauk. Akad. Ekon. im. Oskara Langego
Wroclawiu, 1984, 278, 169) in conc. H.sub.2SO.sub.4 (100 ml)
CrO.sub.3 (32.8 g, 328 mmol) was added maintaining T<55.degree.
C. After 4 hr the mixture was heated to 70.degree. C. for 30 min
and then cooled to rt. Ice-cold water (500 ml) was added
maintaining T<70.degree. C. The mixture was left overnight. The
title compound crystallized as a beige material (76%). Mp.
173-175.degree. C. (H.sub.2O), MS: m/e=246 (M.sup.+).
b) (4-Amino-6-bromo-pyridin-2-yl)-methanol
[0142] A solution of 6-bromo-4-nitro-pyridine-2-carboxylic acid
(6.60 g, 29.1 mmol) in THF (150 ml) was treated with borane/THF (87
ml of a 1M solution). The mixture was refluxed for 6 hr, then
powdered iron (16.3 g, 291 mmol) was added, followed by acetic acid
(150 ml). Reflux was maintained for 6 hr, the mixture was filtered,
evaporated and partitioned (AcOEt/aqueous NaHCO.sub.3-solution).
The organic phase was dried (Na.sub.2SO.sub.4), concentrated and
chromatographed (SiO.sub.2 with CH.sub.2Cl.sub.2/MeOH=93/7) to
provide 2.0 g (34%) of the title compound as a white solid
material. Mp. 144-145.degree. C. (AcOEt), MS: m/e=202
(M.sup.+).
c) [4-Amino-6-(3,4-dihydro-naphthalen-2-yl)-pyridin-2-yl]-methanol
1:1 fumarate
[0143] Following the general method described in example 19b, the
title compound was obtained as an off-white crystalline material by
reaction of (4-amino-6-bromo-pyridin-2-yl)-methanol with palladium
tetrakis(triphenylphosphine), 3,4-dihydro-naphthalene-2-boronic
acid (example 19a) and aqueous 2M K.sub.2CO.sub.3 and
crystallization of the free base as the fumarate salt. Mp.
113.degree. C. (dec) (MeOH/Et.sub.2O), MS: m/e=252 (M.sup.+).
EXAMPLE 24
2-(3,4-Dihydro-naphthalen-2-yl)-5-methyl-pyridin-4-yl-amine
fumarate
[0144] Following the general method described in example 19b, the
title compound was obtained as an off-white crystalline material by
reaction of 2-bromo-5-methyl-pyridin-4-ylamine (A. Puszko, Z.
Talik, Pol. Pr. Nauk. Akad. Ekon. Im. Oskara Langego Wroclawiu,
1980, 167, 177) with palladium tetrakis(triphenylphosphine),
3,4-dihydro-naphthalene-2-boronic acid (example 19a) and aqueous 2M
K.sub.2CO.sub.3 and crystallization of the free base as the
fumarate salt. Mp.>200.degree. C. dec. (MeOH), MS: m/e=236
(M.sup.+).
EXAMPLE 25
2-(3,4-Dihydro-naphthalen-2-yl)-3-methyl-pyridin-4-yl-amine
[0145] Following the general method described in example 19b, the
title compound was obtained as a dark grey crystalline material by
reaction of 2-bromo-3-methyl-pyridin-4-ylamine (A. Puszko, Z.
Talik, Pol. Pr. Nauk. Akad. Ekon. Im. Oskara Langego Wroclawiu,
1980, 167, 177) with palladium tetrakis(triphenylphosphine),
3,4-dihydro-naphthalene-2-boronic acid (example 19a) and aqueous 2M
K.sub.2CO.sub.3. Mp. 87-88.degree. C. (MeOH), MS: m/e=236
(M.sup.+).
EXAMPLE 26
2-(3,4-Dihydro-naphthalen-2-yl)-6-ethyl-pyridin-4-yl-amine
fumarate
a) 2-Bromo-6-ethyl-pyridine 1-oxide
[0146] To a solution of 2-bromo-6-ethyl-pyridine (15.4 g, 82.8
mmol) (S. G. Davies and M. R. Shipton, J. Chem. Soc., Perkin Trans.
1, 1991, 3, 501) in acetic acid (15 ml) peracetic acid (26 ml of a
39% solution) was added maintaining T<50.degree. C. After
completed addition the mixture was stirred at 50.degree. C. for 5
hr and then cooled to rt. Crushed ice (40 g) was added and the
mixture was made basic (pH 12) using 40% KOH solution. After
extraction with CHCl.sub.3 (6.times.60 ml) the combined organic
phases were dried (Na.sub.2CO.sub.3) and evaporated to give 20.0 g
(>100%) of the title compound, MS: m/e=201 (M.sup.+) as a yellow
oil.
b) 2-Bromo-6-ethyl-4-nitro-pyridine 1-oxide
[0147] With ice bath cooling HNO.sub.3 (100%, 25 ml) was added
dropwise to 2-bromo-6-ethyl-pyridine 1-oxide (20.0 g, 99 mmol),
followed by H.sub.2SO.sub.4 (98%, 17 ml). The mixture was stirred
at 90.degree. C. for 90 min and then cooled to rt. Crushed ice (500
g) was added and the mixture was made basic (pH 12) using 28% NaOH
solution. After extraction with AcOEt (4.times.250 ml) the combined
organic phases were dried (Na.sub.2CO.sub.3) and evaporated to give
15.9 g (65%) of a yellow solid mass which was directly used in the
next step
c) 2-Bromo-6-ethyl-pyridin-4-yl-amine
[0148] A solution of 2-bromo-6-ethyl-4-nitro-pyridine 1-oxide (15.9
g, 69 mmol) in acetic acid (310 ml) was treated with powdered iron
(25.8 g, 462 mmol). The mixture was slowly heated to 100.degree. C.
and kept for 1 hr. Then the reaction mixture was cooled to rt and
filtered. After evaporation of the solvent the residue was
crystallized to yield the title compound as a beige material (88%).
Mp. 75-77.degree. C. (pentane), MS: m/e=200 (M.sup.+).
d) 2-(3,4-Dihydro-naphthalen-2-yl)-6-ethyl-pyridin-4-yl-amine 1:1
fumarate
[0149] Following the general method described in example 19b, the
title compound was obtained as a beige crystalline material by
reaction of 2-bromo-6-ethyl-pyridin-4-yl-amine with palladium
tetrakis(triphenylphosphine), 3,4-dihydro-naphthalene-2-boronic
acid (example 19a) and aqueous 2M K.sub.2CO.sub.3 and
crystallization of the free base as the fumarate salt.
Mp.>230.degree. C. dec. (MeOH), MS: m/e=250 (M.sup.+).
EXAMPLE 27
[2-(3,4-Dihydro-naphthalen-2-yl)-pyridin-4-yl]-methyl-amine
fumarate
a) [2-(3,4-Dihydro-naphthalen-2-yl)-pyridin-4-yl]-carbamic acid
ethyl ester
[0150] A solution of
2-(3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine (0.80 g, 3.6
mmol) in pyridine (20 ml) was cooled to 0.degree. C. and
ethylchloroformate (0.47 g, 4.3 mmol) was slowly added. Stirring
was continued for 72 hr. Then the solvent was evaporated and the
residue was partitioned (AcOEt/H.sub.2O). The organic phase was
dried (MgSO.sub.4), concentrated and chromatographed (SiO.sub.2
with CH.sub.2Cl.sub.2/CH.sub.3OH=98/2) to give the title compound
(0.36 g, 36%) as a yellow oil. MS: m/e=294 (M.sup.+).
b) [2-(3,4-Dihydro-naphthalen-2-yl)-pyridin-4-yl]-methyl-amine 1:1
fumarate
[0151] A solution of
N-[2-(3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl]-oxalamic acid
ethyl ester (0.36 g, 1.2 mmol) in THF (20 ml) was slowly added to
an ice bath cooled mixture of lithium aluminum hydride (0.10 g, 2.6
mmol) in THF (20 ml). The resulting mixture was refluxed for 30
min, quenched with aqueous saturated Seignette-salt solution and
extracted with AcOEt. The organic phase was dried over
Na.sub.2SO.sub.4, concentrated and chromatographed (SiO.sub.2 with
CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH=140/10/1) to give
[2-(3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl]-methyl-amine as a
yellow oil (0.12 g, 42%) which was crystallized as the white
fumarate salt. Mp. 106-107.degree. C. (MeOH/Et.sub.2O), MS: m/e=236
(M.sup.+).
EXAMPLE 28
C-[6-(3,4-Dihydro-naphthalen-2-yl)-pyridin-2-yl]-methylamine
hydrochloride
a) 2-(6-Bromo-pyridin-2-yl-methyl)-isoindole-1,3-dione
[0152] A solution of (6-bromo-pyridin-2-yl)-methanol (3.37 g, 17.9
mmol) (H. Tsukube et al., J. Org. Chem., 1993, 58, 4389),
triphenylphosphine (5.17 g, 19.7 mmol) and phtalimide (2.90 g, 19.7
mmol) in THF was cooled in an ice bath. A solution of
diethylazodicarboxylate (3.43 g, 19.7 mmol) in THF (15 ml) was
added slowly and the mixture was left to reach rt. Stirring was
continued for 17 hr, then the solvent was distilled off and the
residue chromatographed (SiO.sub.2 with hexane/AcOEt=4/1) to
provide 3.42 g (66%) of the title compound as a colorless viscous
oil. MS: m/e=316 (M+H.sup.+).
b)
2-[6-(3,4-Dihydro-naphthalen-2-yl)-pyridin-2-yl-methyl]-isoindole-1,3-d-
ione
[0153] Following the general method described in example 19b, the
title compound was obtained as a white crystalline material by
reaction of 2-(6-bromo-pyridin-2-yl-methyl)-isoindole-1,3-dione
with palladium tetrakis(triphenylphosphine),
3,4-dihydro-naphthalene-2-boronic acid (example 19a) and aqueous 2M
K.sub.2CO.sub.3. MS: m/e=366 (M.sup.+).
c) C-[6-(3,4-Dihydro-naphthalen-2-yl)-pyridin-2-yl]-methylamine 1:1
hydrochloride
[0154] A solution of
2-[6-(3,4-dihydro-naphthalen-2-yl)-pyridin-2-yl-methyl]-isoindole-1,3-dio-
ne (0.88 g, 2.4 mmol) in ethanol (25 ml) was treated with hydrazine
hydrate (0.36 g, 7.2 mmol) and refluxed for 2 hr. The cooled
mixture was filtered, concentrated and chromatographed (SiO.sub.2
with CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH=140/10/1) to give the
free base of the title compound as a colorless oil (0.45 g, 79%)
which was crystallized as the white hydrochloride salt. Mp.
203-204.degree. C. (MeOH/Et.sub.2O), MS: m/e=236 (M.sup.+).
EXAMPLE 29
2-(6,7-Dihydro-benzo[b]thiophen-5-yl)-pyridin-4-yl-amine
fumarate
a) 5-Bromo-6,7-dihydro-benzo[b]thiophene
[0155] In analogy to the synthesis of
3-bromo-1,2-dihydro-naphthalene (referred to in example 19a) a
cooled (10.degree. C.) solution of
6,7-dihydro-5H-benzo[b]thiophen-4-one (10 g, 65.7 mmol) in ether
(100 ml) was treated dropwise with bromine (3.5 ml, 65.7 mmol).
After 1 hr the reaction mixture was successively extracted with ice
water (twice) and saturated aqueous NaHCO.sub.3. The organic phase
was dried (Na.sub.2SO.sub.4), concentrated and directly used in the
next step.
[0156] The bromoketone was dissolved in a mixture of THF (115 ml)
and EtOH (115 ml). Sodium borohydride (1.9 g, 50 mmol) was added
and the mixture was stirred for 90 min at rt. After addition of
aqueous HCl (1N, 90 ml) all volatiles were evaporated. The oily
residue was partitioned (toluene/H.sub.2O=125 ml: 50 ml) and the
organic phase directly used in the next step.
[0157] To the solution of the bromoalkohol in toluene was added
p-toluenesulfonic acid (0.65 g, 3.5 mmol) and the mixture was
refluxed for 15 hr. Then aqueous NaOH (1N, 65 ml) was added, and
the organic phase was dried (MgSO.sub.4), concentrated and
chromatographed (SiO.sub.2 with hexane) to provide 3.7 g (26%) of
the title compound as a yellow oil. .sup.1H-Nmr (250 MHz,
CDCl.sub.3): .delta.=2.87 and 2.98 (mc, CH.sub.2), 6.74 (s, 1H,
CH.dbd.CBr), 6.75-6.82 (m, 2H, arom-H).
b) 6,7-Dihydro-benzo[bl thiophene-5-boronic acid
[0158] Following the general method described in example 19a,
5-bromo-6,7-dihydro-benzo[b]thiophene was reacted with
tert.-butyllithium solution followed by triisopropylborate and 3N
HCl. The title compound was obtained as a white crystalline
material after chromatography (SiO.sub.2 with
CH.sub.2Cl.sub.2--MeOH=98:2). MS: m/e=179 (M-H.sup.-).
c) 2-(6,7-Dihydro-benzo[b]thiophen-5-yl)-pyridin-4-yl-amine 1:1
fumarate
[0159] Following the general method described in example 19b, the
title compound was obtained as a white crystalline material by
reaction of 2-bromo-pyridin-4-yl-amine with palladium
tetrakis(triphenylphosphine),
6,7-dihydro-benzo[b]thiophene-5-boronic acid and aqueous 2M
K.sub.2CO.sub.3 solution and crystallization of the free base as
the fumarate salt. Mp. 199-200.degree. C. (MeOH), MS: m/e=228
(M.sup.+).
EXAMPLE 30
2-(7-Chloro-3,4-dihydro-naphthalen-2-yl)-pyridin-4-ylamine
fumarate
a) 3-Bromo-6-chloro-1,2-dihydro-naphthalene
[0160] Following the general method described in example 29a, the
title compound was obtained as a colorless oil by reaction of
7-chloro-1-tetralone with bromine, sodium borohydride and
p-toluenesulfonic acid. .sup.1H-Nmr (250 MHz, CDCl.sub.3): =2.76
and 2.86 (mc, CH.sub.2), 6.73 (s, 1H, CH.dbd.CBr), 6.95 (d, J=2 Hz,
1H, arom-H), 7.01 (d, J=8 Hz, 1H, arom-H).), 7.10 (dd, J=8 Hz, J=2
Hz, 1H, arom-H).
b)-Chloro-3,4-dihydro-naphthalene-2-boronic acid
[0161] Following the general method described in example 19a, the
title compound was obtained as a white crystalline material by
reaction of 3-bromo-6-chloro-1,2-dihydro-naphthalene with
tert.-butyllithium solution followed by triisopropylborate and 3N
HCl. Mp. 151-152.degree. C. (pentane), MS: m/e=207 (M-H.sup.-).
c) 2-(7-Chloro-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine 1:1
fumarate
[0162] Following the general method described in example 19b, the
title compound was obtained as a white crystalline material by
reaction of 2-bromo-pyridin-4-ylamine with palladium
tetrakis(triphenylphosphine),
7-chloro-3,4-dihydro-naphthalene-2-boronic acid and aqueous 2M
K.sub.2CO.sub.3 solution and crystallization of the free base as
the fumarate salt. Mp. 205-207.degree. C. (MeOH), MS: m/e=250
(M.sup.+).
EXAMPLE 31
2-(5-Methoxy-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine
fumarate
a)-Bromo-8-methoxy-1,2-dihydro-naphthalene
[0163] Following the general method described in example 29a, the
title compound was obtained as a colorless oil by reaction of
5-methoxy-1-tetralone with bromine, sodium borohydride and
p-toluenesulfonic acid. .sup.1H-Nmr (250 MHz, CDCl.sub.3):
.delta.=2.74 and 2.94 (mc, CH.sub.2), 3.82 (s, 3H, OCH.sub.3), 6.62
(d, J=8 Hz, 1H, arom-H), 6.75 (s, 1H, CH.dbd.CBr), 6.76 (d, J=8 Hz,
1H, arom-H), 7.11 (t, J=8 Hz, 1H, arom-H).
b)-Methoxy-3,4-dihydro-naphthalene-2-boronic acid
[0164] Following the general method described in example 19a, the
title compound was obtained as a white crystalline material by
reaction of 3-bromo-8-methoxy-1,2-dihydro-naphthalene with
tert.-butyllithium solution followed by triisopropylborate and 3N
HCl. Mp. 174-175.degree. C. (pentane), MS: m/e=203 (M-H.sup.-).
c) 2-(5-Methoxy-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine 1:1
fumarate
[0165] Following the general method described in example 19b, the
title compound was obtained as a white crystalline material by
reaction of 2-bromo-pyridin-4-ylamine with palladium
tetrakis(triphenylphosphine),
5-methoxy-3,4-dihydro-naphthalene-2-boronic acid and aqueous 2M
K.sub.2CO.sub.3 solution and crystallization of the free base as
the fumarate salt. Mp. 207-208.degree. C. (MeOH), MS: m/e=252
(M.sup.+).
EXAMPLE 32
2-(5,8-Dimethyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine
fumarate a) 3-Bromo-5,8-dimethyl-1,2-dihydro-naphthalene
[0166] Following the method referred to in example 19a, the title
compound was obtained as a colorless oil by reaction of
5,8-dimethyl-1-tetralone with bromine, sodium borohydride and
p-toluenesulfonic acid. MS: m/e=236 (M.sup.+).
b) 8-Dimethyl-3,4-dihydro-naphthalene-2-boronic acid
[0167] Following the general method described in example 29a, the
title compound was obtained as a white crystalline material by
reaction of 3-bromo-5,8-dimethyl-1,2-dihydro-naphthalene with
tert.-butyllithium solution followed by triisopropylborate and 3N
HCl. Mp. 163-164.degree. C. (pentane), MS: m/e=261
(M+OAc.sup.-).
c) 2-(5,8-Dimethyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine
1:1 fumarate
[0168] Following the general method described in example 19b, the
title compound was obtained as a white crystalline material by
reaction of 2-bromo-pyridin-4-yl-amine with palladium
tetrakis(triphenylphosphine),
5,8-dimethyl-3,4-dihydro-naphthalene-2-boronic acid and aqueous 2M
K.sub.2CO.sub.3 solution and crystallization of the free base as
the fumarate salt. Mp. 232-233.degree. C. (MeOH), MS: m/e=250
(M.sup.+).
EXAMPLE 33
2-(7-Methoxy-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine
fumarate
a) 3-Bromo-6-methoxy-1,2-dihydro-naphthalene
[0169] Following the method referred to in example 29a, the title
compound was obtained as a colorless oil by reaction of
7-methoxy-1-tetralone with bromine, sodium borohydride and
p-toluenesulfonic acid. .sup.1H-Nmr (250 MHz, CDCl.sub.3):
.delta.=2.76 and 2.86 (mc, CH.sub.2), 3.76 (s, CH.sub.3), 6.54 (d,
J=3 Hz, 1H, arom-H), 6.68 (dd, J=8 Hz, J=3 Hz, 1H, arom-H), 6.75
(s, 1H, CH.dbd.CBr), 7.00 (d, J=8 Hz, 1H, arom-H).
b) 7-Methoxy-3,4-dihydro-naphthalene-2-boronic acid
[0170] Following the general method described in example 19a, the
title compound was obtained as a white solid material by reaction
of 3-bromo-6-methoxy-1,2-dihydro-naphthalene with
tert.-butyllithium solution followed by triisopropylborate and 3N
HCl. MS: m/e=263 (M+OAc.sup.-).
c) 2-(7-Methoxy-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine 1:1
fumarate
[0171] Following the general method described in example 19b, the
title compound was obtained as a beige crystalline material by
reaction of 2-bromo-pyridin-4-yl-amine with palladium
tetrakis(triphenylphosphine),
7-methoxy-3,4-dihydro-naphthalene-2-boronic acid and aqueous 2M
K.sub.2CO.sub.3 solution and crystallization of the free base as
the fumarate salt. Mp. 193-194.degree. C. (MeOH/Et.sub.2O), MS:
m/e=252 (M.sup.+).
EXAMPLE 34
2-(5,7-Dimethyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine
fumarate
a) 3-Bromo-6,8-dimethyl-1,2-dihydro-naphthalene
[0172] Following the method referred to in example 29a, the title
compound was obtained as a colorless oil by reaction of
5,7-dimethyl-1-tetralone with bromine, sodium borohydride and
p-toluenesulfonic acid. MS: m/e=236 (M.sup.+).
b) 5,7-Dimethyl-3,4-dihydro-naphthalene-2-boronic acid
[0173] Following the general method described in example 19a, the
title compound was obtained as a white solid material by reaction
of 3-bromo-6,8-dimethyl-1,2-dihydro-naphthalene with
tert.-butyllithium solution followed by triisopropylborate and 3N
HCl. MS: m/e=261 (M+OAc.sup.-).
c) 2-(5,7-Dimethyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine
1:1 fumarate
[0174] Following the general method described in example 19b, the
title compound was obtained as a white crystalline material by
reaction of 2-bromo-pyridin-4-yl-amine with palladium
tetrakis(triphenylphosphine),
5,7-dimethyl-3,4-dihydro-naphthalene-2-boronic acid and aqueous 2M
K.sub.2CO.sub.3 solution and crystallization of the free base as
the fumarate salt. Mp. 231-232.degree. C. (MeOH), MS: m/e=250
(M.sup.+).
EXAMPLE 35
rac.-2-(4-Methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine
funarate
a) rac.-3-Bromo-1-methyl-1,2-dihydro-naphthalene
[0175] Following the method referred to in example 29a, the title
compound was obtained as a colorless oil by reaction of
4-methyl-1-tetralone with bromine, sodium borohydride and
p-toluenesulfonic acid. MS: m/e=222 (M.sup.+).
b) rac.-4-Methyl-3,4-dihydro-naphthalene-2-boronic acid
[0176] Following the general method described in example 19a, the
title compound was obtained as a white crystalline material by
reaction of rac.-3-bromo-1-methyl-1,2-dihydro-naphthalene with
tert.-butyllithium solution followed by triisopropylborate and 3N
HCll. MS: m/e=187 (M-H.sup.-).
c) rac.-2-(4-Methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine
1:1 fumarate
[0177] Following the general method described in example 19b, the
title compound was obtained as a white crystalline material by
reaction of 2-bromo-pyridin-4-yl-amine with palladium
tetrakis(triphenylphosphine),
rac.-4-methyl-3,4-dihydro-naphthalene-2-boronic acid and aqueous 2M
K.sub.2CO.sub.3 solution and crystallization of the free base as
the fumarate salt. Mp. 176-177.degree. C. (MeOH/Et.sub.2O), MS:
m/e=237 (M+H.sup.+).
EXAMPLE 36
2-(7-Chloro-3,4-dihydro-naphthalen-2-yl)-6-ethyl-pyridin-4-yl-amine
fumarate
[0178] Following the general method described in example 19, the
title compound was obtained as a white crystalline material by
reaction of 2-bromo-6-ethyl-pyridin-4-ylamine (cf example 26c) with
palladium tetrakis(triphenylphosphine),
7-chloro-3,4-dihydro-naphthalene-2-boronic acid (cf example 30b)
and aqueous 2M K.sub.2CO.sub.3 and crystallization of the free base
as the fumarate salt. Mp. 232-233.degree. C. (MeOH), MS: m/e=285
(M+H.sup.+).
EXAMPLE 37
2-(7-Chloro-3,4-dihydro-naphthalen-2-yl)-6-methyl-pyridin-4-yl-amine
fumarate
[0179] Following the general method described in example 19b, the
title compound was obtained as a white crystalline material by
reaction of 2-bromo-6-methyl-pyridin-4-ylamine (cf example 22) with
palladium tetrakis(triphenylphosphine),
7-chloro-3,4-dihydro-naphthalene-2-boronic acid (cf example 30b)
and aqueous 2M K.sub.2CO.sub.3 and crystallization of the free base
as the fumarate salt. Mp. 232-233.degree. C. (MeOH), MS: m/e=271
(M+H.sup.+).
EXAMPLE 38
rac.-2-Methyl-6-(4-methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine
fumarate
[0180] Following the general method described in example 19b, the
title compound was obtained as an off-white crystalline material by
reaction of 2-bromo-6-methyl-pyridin-4-yl-amine (cf example 22)
with palladium tetrakis(triphenylphosphine),
rac.-4-methyl-3,4-dihydro-naphthalene-2-boronic acid (cf example
35b) and aqueous 2M K.sub.2CO.sub.3 and crystallization of the free
base as the fumarate salt. Mp. 183-185.degree. C. dec. (MeOH), MS:
m/e=250 (M.sup.+).
EXAMPLE 39
2-(7-Chloro-3,4-dihydro-naphthalen-2-yl)-5-methyl-pyridin-4-yl-amine
fumarate
[0181] Following the general method described in example 19b, the
title compound was obtained as a white crystalline material by
reaction of 2-bromo-5-methyl-pyridin-4-yl-amine (cf example 24)
with palladium tetrakis(triphenylphosphine),
7-chloro-3,4-dihydro-naphthalene-2-boronic acid (cf example 30b)
and aqueous 2M K.sub.2CO.sub.3 and crystallization of the free base
as the fumarate salt. Mp.>250.degree. C. (MeOH), MS: m/e=271
(M+H.sup.+).
EXAMPLE 40
rac.-5-Methyl-2-(4-methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine
fumarate
[0182] Following the general method described in example 19b, the
title compound, was obtained as a white crystalline material by
reaction of 2-bromo-5-methyl-pyridin-4-yl-amine (cf example 24)
with palladium tetrakis(triphenylphosphine),
rac.-4-methyl-3,4-dihydro-naphthalene-2-boronic acid (example 35b)
and aqueous 2M K.sub.2CO.sub.3 and crystallization of the free base
as the fumarate salt. Mp. 210-211.degree. C. (MeOH), MS: m/e=251
(M+H.sup.+).
EXAMPLE 41
2-(6,7-Dihydro-benzo[b]thiophen-5-yl)-5-methyl-pyridin-4-yl-amine
fumarate
[0183] Following the general method described in example 19b, the
title compound was obtained as a light yellow crystalline material
by reaction of 2-bromo-5-methyl-pyridin-4-ylamine (cf example 24)
with palladium tetrakis(triphenylphosphine),
6,7-dihydro-benzo[b]thiophene-5-boronic acid (cf example 29b) and
2M K.sub.2CO.sub.3 and crystallization of the free base as the
fumarate salt. Mp. 218-219.degree. C. (MeOH), MS: m/e=243
(M+H.sup.+).
EXAMPLE A
[0184] TABLE-US-00002 Tablet Formulation (Wet Granulation)
mg/tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Active
Ingredient* 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3.
Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5.
Magnesium Stearate 1 1 1 1 Total 167 167 167 831 *A compound of
formula 1A, 1B or a combination thereof or a pharmaceutically
acceptable salt thereof.
Manufacturing Procedure [0185] 1 Mix items 1, 2, 3 and 4 and
granulate with purified water. [0186] 2. Dry the granulation at
50.degree. C. [0187] 3. Pass the granulation through suitable
milling equipment. [0188] 4. Add item 5 and mix for three minutes;
compress on a suitable press.
EXAMPLE B
[0189] TABLE-US-00003 Capsule Formulation mg/capsule Item
Ingredients 5 mg 25 mg 100 mg 500 mg 1. Active Ingredient 5 25 100
500 2. Hydrous Lactose 159 123 148 -- 3. Corn Starch 25 35 40 70 4.
Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300
600
Manufacturing Procedure [0190] 1 Mix items 1, 2, and 3 in a
suitable mixer for 30 minutes. [0191] 2. Add items 4 and 5 and mix
for 3 minutes. [0192] 3. Fill into a suitable capsule. [0193] 4.
Add item 5 and mix for three minutes; compress on a suitable
press.
* * * * *