U.S. patent application number 11/570076 was filed with the patent office on 2007-10-25 for 1-aza-bicyclo3.3.1nonanes.
Invention is credited to Dominik Feuerbach, Mathias Frederiksen, Konstanze Hurth, Werner Muller, Bernard Lucien Roy, Thomas J. Troxler.
Application Number | 20070249657 11/570076 |
Document ID | / |
Family ID | 35045272 |
Filed Date | 2007-10-25 |
United States Patent
Application |
20070249657 |
Kind Code |
A1 |
Feuerbach; Dominik ; et
al. |
October 25, 2007 |
1-Aza-Bicyclo3.3.1Nonanes
Abstract
The present invention relates to 1-aza-bicycloalkyl derivatives
of Formula (I); wherein the substituents are as defined in the
specification, to processes for their production, their use as
pharmaceuticals and to pharmaceutical compositions comprising them.
Formula (I), wherein A represents O or N(R.sup.1); Y represents a
group of formula, or wherein the left bond is attached to the A
group and the right bond is attached to the R group; R represents a
substituted or unsubstituted C.sub.5-C.sub.10aryl, substituted or
unsubstituted hetero-C.sub.5-C.sub.10aryl, a group
N(R.sup.1)(R.sup.4), or a group N(R.sup.2)(CHP.sup.3R.sup.4); R
represent a hydrogen, C.sub.1-C.sub.4alkyl, or CF.sub.3; R.sup.2
represents hydrogen, C.sub.1-C.sub.4alkyl, or CF.sub.3; R.sup.3
represents hydrogen, C.sub.1-C.sub.4alkyl, or CF.sub.3; R.sup.4
represents a substituted or unsubstituted C.sub.5-C.sub.10 aryl or
a substituted or unsubstituted C.sub.5-C.sub.10heteroaryl; in free
base or acid addition salt form. ##STR1##
Inventors: |
Feuerbach; Dominik;
(Mullheim, DE) ; Muller; Werner; (Gumligen,
CH) ; Roy; Bernard Lucien; (Fribourg, CH) ;
Troxler; Thomas J.; (Wahlen b. Laufen, CH) ; Hurth;
Konstanze; (Saint Louis, FR) ; Frederiksen;
Mathias; (Basel, CH) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
35045272 |
Appl. No.: |
11/570076 |
Filed: |
June 17, 2005 |
PCT Filed: |
June 17, 2005 |
PCT NO: |
PCT/EP05/06566 |
371 Date: |
December 6, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60581020 |
Jun 18, 2004 |
|
|
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Current U.S.
Class: |
514/299 ;
540/477 |
Current CPC
Class: |
A61P 21/02 20180101;
A61P 1/04 20180101; A61P 25/28 20180101; A61P 25/36 20180101; A61P
25/06 20180101; A61P 25/04 20180101; A61P 43/00 20180101; A61P
25/08 20180101; A61P 15/08 20180101; C07D 471/08 20130101; A61P
1/14 20180101; A61P 25/34 20180101; A61P 17/02 20180101; A61P 15/00
20180101; A61P 9/06 20180101; A61P 25/30 20180101; A61P 25/32
20180101; A61P 1/12 20180101; A61P 29/00 20180101; A61P 25/00
20180101; A61P 25/14 20180101; A61P 25/10 20180101; A61P 9/12
20180101; A61P 25/02 20180101; A61P 27/10 20180101; A61P 25/18
20180101; A61P 25/16 20180101; A61P 25/24 20180101; A61P 15/10
20180101; A61P 9/10 20180101; A61P 5/14 20180101; A61P 35/00
20180101; A61P 25/12 20180101; A61P 25/22 20180101; A61P 27/02
20180101 |
Class at
Publication: |
514/299 ;
540/477 |
International
Class: |
A61K 31/439 20060101
A61K031/439; A61P 25/18 20060101 A61P025/18; C07D 487/08 20060101
C07D487/08 |
Claims
1. A compound of formula I ##STR14## wherein A represents O or
N(R.sup.1); Y represents a group of formula ##STR15## wherein the
left bond is attached to the A group and the right bond is attached
to the R group; R represents a substituted or unsubstituted
C.sub.5-C.sub.10aryl, substituted or unsubstituted
hetero-C.sub.5-C.sub.10aryl, a group N(R.sup.1)(R.sup.4), or a
group N(R.sup.2)(CHR.sup.3R.sup.4); R.sup.1 representa hydrogen,
C.sub.1-C.sub.4alkyl, or CF.sub.3; R.sup.2 represents hydrogen,
C.sub.1-C.sub.4alkyl, or CF.sub.3; R.sup.3 represents hydrogen,
C.sub.1-C.sub.4alkyl, or CF.sub.3; R.sup.4 represents a substituted
or unsubstituted C.sub.5-C.sub.10aryl or a substituted or
unsubstituted C.sub.5-C.sub.10heteroaryl; in free base or acid
addition salt form.
2. A compound of formula I according to claim 1 wherein A
represents oxygen
3. A compound of formula I according to claim 1 wherein Y
represents one of the following groups ##STR16##
4. A process for the preparation of a compound of formula I as
defined in claim 1, or a salt thereof, which comprises the step of
reacting a compound of formula II Z--Y--R (II) wherein Y and R are
as defined in claim 1 and Z is a leaving group with a compound of
formula III ##STR17## and recovering the so obtained compound of
formula I in free base or acid addition salt form.
5. A compound of claim 1 in free base or pharmaceutically
acceptable acid addition salt form, for use as a
pharmaceutical.
6. A compound of claim 1 in free base or pharmaceutically
acceptable acid addition salt form, for use in the prevention and
treatment of psychotic and neurodegenerative disorders.
7. A pharmaceutical composition comprising a compound of claim 1 in
free base or pharmaceutically acceptable acid addition salt form,
in association with a pharmaceutical carrier or diluent.
8. The use of a compound of claim 1 in free base or
pharmaceutically acceptable acid addition salt form, as a
pharmaceutical for the prevention and the treatment of psychotic
and neurodegenerative disorders.
9. The use of a compound of claim 1 in free base or
pharmaceutically acceptable acid addition salt form, for the
manufacture of a medicament for the prevention and treatment of
psychotic and neurodegenerative disorders.
10. A method for the prevention and treatment of psychotic and
neurodegenerative disorders, in a subject in need of such
treatment, which comprises administering to such subject a
therapeutically effective amount of a compound of claim 1 in free
base or pharmaceutically acceptable acid addition salt form.
11. A compound of claim 1 in free base or pharmaceutically
acceptable acid addition salt form, for use in the treatment or
prevention of a disease or condition in which .alpha.7 nAChR
activation plays a role or is implicated.
12. The use of a compound of claim 1 in free base or
pharmaceutically acceptable acid addition salt form, as a
pharmaceutical for the treatment or prevention of a disease or
condition in which .alpha.7 nAChR activation plays a role or is
implicated.
13. A method for treating or preventing a disease or condition in
which .alpha.7 nAChR activation plays a role or is implicated, in a
subject in need of such treatment, which comprises administering to
such subject a therapeutically effective amount of a compound of
claim 1 in free base or pharmaceutically acceptable acid addition
salt form.
14. A product obtained according to the process of claim 2
characterized in that (-)-1-Aza-bicyclo[3.3.1]nonan-4-ol is used as
starting material.
Description
[0001] The present invention relates to novel 1-aza-bicycloalkyl
derivatives, to processes for their production, their use as
pharmaceuticals and to pharmaceutical compositions comprising
them.
[0002] More particularly the present invention provides in a first
aspect, a compound of formula I ##STR2## wherein [0003] A
represents O or N(R.sup.1); [0004] Y represents a group of formula
##STR3## [0005] wherein the left bond is attached to the A group
and the right bond is attached to the R group; [0006] R represents
a substituted or unsubstituted C.sub.5-C.sub.10aryl, substituted or
unsubstituted hetero-C.sub.5-C.sub.10aryl, a group
N(R.sup.1)(R.sup.4), or a group N(R.sup.2)(CHR.sup.3R.sup.4);
[0007] R.sup.1 represents hydrogen, C.sub.1-C.sub.4alkyl, or
CF.sub.3; [0008] R.sup.2 represents hydrogen, C.sub.1-C.sub.4alkyl,
or CF.sub.3; [0009] R.sup.3 represents hydrogen,
C.sub.1-C.sub.4alkyl, or CF.sub.3; [0010] R.sup.4 represents a
substituted or unsubstituted C.sub.5-C.sub.10aryl or a substituted
or unsubstituted C.sub.5-C.sub.10heteroaryl; in free base or acid
addition salt form.
[0011] The general terms used hereinbefore and hereinafter
preferably have within the context of this disclosure the following
meanings, unless otherwise indicated:
[0012] The term "unsubstituted or substituted" as used herein means
that the respective radical can by substituted by one or more,
preferably up to three, especially one or two substituents. The
substituents are preferably selected from the group consisting of
amino, C.sub.1-C.sub.4alkyl amino, di(C.sub.1-C.sub.4alky)-amino,
C.sub.3-C.sub.5cycloalkyl amino, di(C.sub.3-C.sub.5)cycloalkyl
amino, N--C.sub.1-C.sub.4alkyl-N--C.sub.3-C.sub.5cycloalkyl amino,
halogen, C.sub.1-C.sub.4alkyl, C.sub.4-C.sub.6cycloalkyl, hydroxy,
C.sub.1-C.sub.4alkoxy, C.sub.3-C.sub.5cycloalkyloxy,
C.sub.1-C.sub.4alkoxy C.sub.1-C.sub.4alkoxy,
di(C.sub.1-C.sub.4alkyl)-amino C.sub.1-C.sub.4alkoxy, carbamoyl,
N--C.sub.1-C.sub.4alkyl-carbamoyl,
N,N-di(C.sub.1-C.sub.4alkyl)-carbamoyl, nitro, cyano, carboxy,
C.sub.1-C.sub.4alkoxy carbonyl, C.sub.1-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkanoyloxy, benzoyl, amidino, guanidino, ureido,
mercapto, C.sub.1-C.sub.4alkylthio, pyridyl, phenyl, phenoxy,
C.sub.1-C.sub.4alkoxy phenyl, phenylthio,
phenyl-C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.4alkylsulfonyl,
phenylsulfonyl, C.sub.1-C.sub.4alkylphenylsulfonyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylene dioxy bound at adjacent C-atoms of the
ring, and C.sub.1-C.sub.4alkyl, which is substituted by halogen,
hydroxy, C.sub.1-C.sub.4alkoxy, nitro, cyano, carboxy,
C.sub.1-C.sub.4alkoxy carbonyl, C.sub.1-C.sub.4alkanoyl or
C.sub.1-C.sub.4alkanoyloxy.
[0013] The terms "C.sub.5-C.sub.10aryl",
"C.sub.5-C.sub.10heteroaryl" are to be understood as aromatic
residues which are in each case unsubstituted or substituted by the
substituents provided above, preferably in each case unsubstituted
or substituted by one or more substituents selected from halogen,
CN or alkyl, which can be unsubstituted or substituted by halogen,
e.g. trifluoromethyl; or C.sub.1-C.sub.4alkoxy, or condensed, e.g.
to a benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]dioxine and/or to a
further heterocyclic ring. C.sub.5-C.sub.10heteroaryl is an
aromatic heterocyclic system wherein one or more carbon atoms are
replaced by hetero atoms. Preferred are 5 to 9 membered ring
systems containing one, two or three hetero atoms. Examples of
C.sub.5-C.sub.10aryl or C.sub.5-C.sub.10heteroaryl residues as
mentioned above include phenyl, naphthyl, isobenzofuranyl, thienyl,
indolyl.
[0014] The term "alkyl" represents a straight-chain or
branched-chain alkyl group, preferably represents a straight-chain
or branched-chain C.sub.1-7alkyl, particularly preferably
represents a straight-chain or branched-chain C.sub.1-4alkyl; for
example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or
tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl,
n-undecyl, n-dodecyl, with particular preference given to methyl,
ethyl, n-propyl and iso-propyl.
[0015] Each alkyl part of "alkoxy", "alkoxyalkyl",
"alkoxycarbonyl", "alkoxycarbonylalkyl" and "halogenalkyl" shall
have the same meaning as described in the above-mentioned
definition of "alkyl". Alkoxy is especially C.sub.1-C.sub.4alkoxy,
in particular methoxy, ethoxy or n-propoxy.
[0016] "Hetero atoms" are atoms other than Carbon and Hydrogen,
preferably Nitrogen (N), Oxygen (O) or Sulfur (S).
[0017] "Halogen" represents Fluoro, Chloro, Bromo or Iodo,
preferably represents Fluoro, Chloro or Bromo and particularly
preferably represents Chloro.
[0018] On account of the asymmetrical carbon atom(s) present in the
compounds of formula I and their salts, the compounds may exist in
optically active form or in form of mixtures of optical isomers,
e.g. in form of racemic mixtures. All optical isomers and their
mixtures including the racemic mixtures are part of the present
invention.
[0019] In view of the close relationship between the novel
compounds in free form and those in the form of their salts,
including those salts that can be used as intermediates, for
example in the purification or identification of the novel
compounds, any reference to the free compounds hereinbefore and
hereinafter is to be understood as referring also to the
corresponding salts, as appropriate and expedient.
[0020] Where the plural form is used for compounds, salts, and the
like, this is taken to mean also a single compound, salt, or the
like.
[0021] Preferred substituents, preferred ranges of numerical values
or preferred ranges of the radicals present in the formula (I) and
the corresponding intermediate compounds are defined below. These
substituents, preferred ranges of numerical values or preferred
ranges are preferred independently, collectively or in any
combination or sub-combination: [0022] X preferably represents
Oxygen. [0023] Y preferably represents one of the following groups:
##STR4## [0024] Y particularly preferably represents the following
group: ##STR5## [0025] R preferably represents
C.sub.5-C.sub.10aryl, which is unsubstituted or substituted by one
or more substituents, the substituents selected from the group
consiting of halogen; NO.sub.2; CN; C.sub.1-C.sub.4alkoxy which is
unsubstituted or substituted by halogen; C.sub.1-C.sub.4alkyl which
is unsubstituted or substituted by halogen,
C.sub.1-C.sub.4alkylC(O)NH, C.sub.1-C.sub.4alkylsulfonyl. [0026] R
preferably represents hetero-C.sub.5-C.sub.10aryl, which is
unsubstituted or substituted by one or more substituents, the
substituents selected from the group consisting of halogen;
C.sub.1-C.sub.2alkoxy; CN or C.sub.1-C.sub.2alkyl which is
unsubstituted or substituted by halogen. [0027] R preferably
represents N(R.sup.1)(R.sup.5) or N(R.sup.2)(CHR.sup.3R.sup.4).
[0028] R particularly preferably represents phenyl or substituted
phenyl, the substituents being selected from the group consiting of
chlorine, fluorine, methyl, ethyl, methoxy, trifluoromethyl,
trifluoromethoxy, cyano, nitro, acetamide, methylsulfonyl. [0029] R
particularly preferably represents unsubstituted or substituted
hetero-C.sub.5-C.sub.10aryl, the hetero-C.sub.5-C.sub.10aryl
selected from the group consisting of imidazolyl, triazolyl,
tetrazolyl, furanyl, thiophenyl, benzo[b]thiophenyl, oxazolyl,
isocazolyl, thiazolyl, isothiazolyl, 1-isobenzofuranyl,
benzo[1,3]-dioxolyl, 2,3-dihydrobenzo[1,4]-dioxinyl,
benzo[1,2,5]oxadiazolyl, benzo[1,2,5]thiadiazolyl, chinolinyl,
isochinolinyl; the substituents selected from the group consisting
of chlorine, fluorine, methyl, ethyl, methoxy, trifluoromethyl,
trifluoromethoxy, cyano, nitro, acetamide. [0030] R.sup.1, R.sup.2
and R.sup.3 preferably represent, independently H, methyl, or
CF.sub.3. [0031] R.sup.4 preferably represents C.sub.5-C.sub.10aryl
or hetero-C.sub.5-C.sub.10aryl, which is unsubstituted or
substituted by one or more substituents the substituents selected
from the group consiting of halogen, C.sub.1-C.sub.4alkoxy, CN or
C.sub.1-C.sub.2alkyl which is unsubstituted or substituted by
halogen.
[0032] In a further aspect, compounds of formula I are preferred,
wherein [0033] Y is a group of formula ##STR6## [0034] R is
C.sub.5-C.sub.10aryl, which is unsubstituted or substituted by one
or more substituents selected from halogen, C.sub.1-C.sub.4alkoxy,
CN or C.sub.1-C.sub.2alkyl which is unsubstituted or substituted by
halogen; hetero-C.sub.5-C.sub.10aryl, which which is unsubstituted
or substituted by one or more substituents selected from halogen,
C.sub.1-C.sub.4alkoxy, CN or C.sub.1-C.sub.2alkyl which is
unsubstituted or substituted by halogen; N(R.sup.1)(R.sup.4) or
N(R.sup.2)(CHR.sup.3R.sup.4); [0035] each of R.sup.1, R.sup.2 and
R.sup.3 is independently H, C.sub.1-C.sub.4alkyl, or CF.sub.3; and
[0036] R.sup.4 is C.sub.5-C.sub.10aryl, which is unsubstituted or
substituted by one or more substituents selected from halogen,
C.sub.1-C.sub.4alkoxy, CN or C.sub.1-C.sub.2alkyl which is
unsubstituted or substituted by halogen; or
hetero-C.sub.5-C.sub.10aryl, which which is unsubstituted or
substituted by one or more substituents selected from halogen,
C.sub.1-C.sub.4alkoxy, CN or C.sub.1-C.sub.2alkyl Which is
unsubstituted or substituted by halogen.
[0037] In still a further aspect, compounds of formula I are
preferred, wherein [0038] Y is a group of formula ##STR7## [0039] R
is phenyl, which is unsubstituted or substituted by one or more
substituents selected from halogen, C.sub.1-C.sub.4alkoxy, CN or
C.sub.1-C.sub.2alkyl which is unsubstituted or substituted by
halogen.
[0040] In still a further aspect, compounds of formula I are
preferred, wherein the starting material of formula (III) is the
(-) alcohol.
[0041] Particularly preferred compounds of the invention are the
compounds of the Examples.
[0042] In a further aspect, the present invention also provides a
process for the production of a compound of formula I, which
process comprises the step of reacting a compound of formula II
Z--Y--R (II); wherein Y and R are as defined above for a compound
of formula I and Z is a leaving group, e.g. F, Cl, Br, I or
OSO.sub.2CF.sub.3, with a compound of formula III ##STR8## wherein
A has the meaning as defined for a compound of formula I, and
recovering the so obtained compound of formula I in free base or
acid addition salt form.
[0043] The reaction may be carried out in accordance with standard
procedures, for example as illustrated in the Examples.
[0044] Compounds of formula II are known or may be prepared from
corresponding known compounds, e.g. as described in the Examples,
e.g. in analogy to Coates W J, McKillop A (1992) Synthesis 334-342.
The compounds of formula III are known (H. Stenbach, S. Kaiser
(1952) J. Amer. Chem. Soc. 74, 2219; F. D. King et al (1993) J.
Med. Chem. 36, 683). Furthermore, the compound of formula III
wherein A is O can also be transferred into a compound, wherein A
is NR.sup.1 by methods known in the art, e.g. a process wherein the
alcohol is first transferred into an alkyloxyphosphonium
perchlorate as described in Bull. Soc. Chim. Fr. 4368 (1971).
[0045] Alternatively, the compounds of formula I' ##STR9## wherein
[0046] R is defined as above for a compound of formula I and Y' is
##STR10## can be produced by a process comprising the step of
reacting a compound of formula IV ##STR11## wherein Y' is as
defined above for a compound of formula I' and Z' represents a
leaving group, with a compound of formula V ##STR12## wherein R is
as defined above for a compound of formula I, optionally in the
presence of a reaction auxiliary, e.g. a palladium catalyst, and
recovering the so obtained compound of formula I' in free base or
acid addition salt form.
[0047] Compounds of formula IV are known or may be prepared from
corresponding known compounds, e.g. by reacting compounds of
formula III with compounds of formula II'; Z--Y'--OH (II'); wherein
Y' represents one of the following groups ##STR13## and Z is as
described above.
[0048] Compounds of formula V (e.g. unsubstituted or substituted
phenylboronic acids) are known or may be prepared from
corresponding known compounds.
[0049] The following considerations apply to the individual
reaction steps described above:
[0050] a) One or more functional groups, for example carboxy,
hydroxy, amino, or mercapto, may need to be protected in the
starting materials by protecting groups. The protecting groups
employed may already be present in precursors and should protect
the functional groups concerned against unwanted secondary
reactions, such as acylations, etherifications, esterifications,
oxidations, solvolysis, and similar reactions. It is a
characteristic of protecting groups that they lend themselves
readily, i.e. without undesired secondary reactions, to removal,
typically by solvolysis, reduction, photolysis or also by enzyme
activity, for example under conditions analogous to physiological
conditions, and that they are not present in the end-products. The
specialist knows, or can easily establish, which protecting groups
are suitable with the reactions mentioned hereinabove and
hereinafter. The protection of such functional groups by such
protecting groups, the protecting groups themselves, and their
removal reactions are described for example in standard reference
works, such as J. F. W. McOmie, "Protective Groups in Organic
Chemistry", Plenum Press, London and New York 1973, in T. W.
Greene, "Protective Groups in Organic Synthesis", Wiley, New York
1981, in "The Peptides"; Volume 3 (editors: E. Gross and J.
Meienhofer), Academic Press, London and New York 1981, in "Methoden
der organischen Chemie" (Methods of organic chemistry), Houben
Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart
1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide,
Proteine" (Amino acids, peptides, proteins), Verlag Chemie,
Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann,
"Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry
of carbohydrates: monosaccharides and derivatives), Georg Thieme
Verlag, Stuttgart 1974.
[0051] b) Acid addition salts may be produced from the free bases
in known manner, and vice-versa. Alternatively, optically pure
starting materials can be used. Suitable acid addition salts for
use in accordance with the present invention include for example
the hydrochloride.
[0052] c) Stereoisomeric mixtures, e.g. mixtures of diastereomers,
can be separated into their corresponding isomers in a manner known
per se by means of suitable separation methods. Diastereomeric
mixtures for example may be separated into their individual
diastereomers by means of fractionated crystallization,
chromatography, solvent distribution, and similar procedures. This
separation may take place either at the level of a starting
compound or in a compound of formula I itself. Enantiomers may be
separated through the formation of diastereomeric salts, for
example by salt formation with an enantiomer-pure chiral acid, or
by means of chromatography, for example by HPLC, using
chromatographic substrates with chiral ligands. Alternatively,
optically pure starting materials can be used.
[0053] d) Suitable diluents for carrying out the above-described
are especially inert organic solvents. These include, in
particular, aliphatic, alicyclic or aromatic, optionally
halogenated hydrocarbons, such as, for example, benzine, benzene,
toluene, xylene, chlorobenzene, dichlorobenzene; petroleum ether,
hexane, cyclohexane, dichloromethane, chloroform, carbon
tetrachloride; ethers, such as diethyl ether, diisopropyl ether,
dioxane, tetrahydrofuran or ethylene glycol dimethyl ether or
ethylene glycol diethyl ether; ketones, such as acetone, butanone
or methyl isobutyl ketone; nitriles, such as acetonitrile
propionitrile or butyronitrile; amides, such as
N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide,
N-methyl-pyrrolidone or hexamethylphosphoric triamide; esters, such
as methyl acetate or ethyl acetate, sulphoxides, such as dimethyl
sulphoxide, alcohols, such as methanol, ethanol, n- or i-propanol,
ethylene glycol monomethyl ether, ethylene glycol monoethyl ether,
diethyelene glycol monomethyl ether, diethylene glycol monoethyl
ether. Further, mixtures of diluents may be employed. Depending on
the starting materials, reaction conditions and auxiliaries, water
or diluents containing water may be suitable. It is also possible
to use one a starting material as diluent simultaneously.
[0054] e) Reaction temperatures can be varied within a relatively
wide range. In general, the processes are carried out at
temperatures between 0.degree. C. and 150.degree. C., preferably
between 10.degree. C. and 120.degree. C. Deprotonation reactions
can be varied within a relatively wide range. In general, the
processes are carried out at temperatures between -150.degree. C.
and +50.degree. C., preferably between -75.degree. C. and 0.degree.
C.
[0055] f) The reactions are generally carried out under atmospheric
pressure. However, it is also possible to carry out the processes
according to the invention under elevated or reduced pressure--in
general between 0.1 bar and 10 bar.
[0056] g) Starting materials are generally employed in
approximately equimolar amounts. However, it is also possible to
use a relatively large excess of one of the components. The
reaction is generally carried out in a suitable diluent in the
presence of a reaction auxiliary, and the reaction mixture is
generally stirred at the required temperature for a number of
hours.
[0057] h) Working up the reaction mixtures according to the above
processes and purification of the compounds thus obtained may be
carried out in accordance to known procedures (cf. the Preparation
Examples).
[0058] The compounds of the invention and their pharmaceutically
acceptable acid addition salts, hereinafter referred to as
compounds of the invention, exhibit valuable pharmacological
properties when tested in vitro and in animals, and are therefore
useful as pharmaceuticals.
[0059] Thus, the compounds of the invention are found to be
cholinergic ligands of the nAChR. In addition preferred compounds
of the invention show selective .alpha.7-nAChR activity. The
compounds of the present invention may in particular be found to be
agonists, partial agonists, antagonists or allosteric modulators of
the receptor.
[0060] Due to their pharmacological profiles, compounds of the
invention are anticipated to be useful for the treatment of
diseases or conditions as diverse as CNS related diseases, PNS
related diseases, diseases related to inflammation, pain and
withdrawal symptoms caused by an abuse of chemical substances,
diseases or disorders related to the CNS include general anxiety
disorders, cognitive disorders, learning and memory deficits and
dysfunctions, Alzheimer's disease, ADHD, Parkinson's disease,
Huntington's disease, ALS, prionic neurodegenerative disorders such
as Creutzfeld-Jacob disease and kuru disease, Gilles de la
Tourette's syndrome, psychosis, depression and depressive
disorders, mania, manic depression, schizophrenia, the cognitive
deficits in schizophrenia, obsessive compulsive disorders, panic
disorders, eating disorders, narcolepsy, nociception,
AIDS-dementia, senile dementia, mild cognitive dysfunctions related
to age, autism, dyslexia, tardive dyskinesia, epilepsy, and
convulsive disorders, post-traumatic stress disorders, transient
anoxia, pseudodementia, pre-menstrual syndrome, late luteal phase
syndrome, chronic fatigue syndrome and jet lag. Furthermore,
compounds of the invention may be useful for the treatment of
endocrine disorders, such as thyrotoxicosis, pheochromocytoma,
hypertension and arrhythmias as well as angina pectoris,
hyperkinesia, premature ejaculation and erectile difficulty. Still
further, compounds of the invention may be useful in the treatment
of inflammatory disorders (Wang et al., Nature 2003, 421, 384),
disorders or conditions including inflammatory skin disorders,
Crohn's diesease, inflammatory bowel disease, ulcerative colitis
and diarrhoea. Compounds of the invention may further be useful for
the treatment of withdrawal symptoms caused by termination of the
use of addictive substances, like tobacco, nicotine, opioids,
benzodiazepines and alcohol. Finally, compounds of the invention
may be useful for the treatment of pain, e.g. caused by migraine,
postoperative pain, phantom limb pain or pain associated with
cancer. The pain may comprise inflammatory or neuropathic pain,
central pain, chronic headache, pain related to diabetic
neuropathy, to post therapeutic neuralgia or to peripheral nerve
injury.
[0061] Furthermore, degenerative ocular disorders which may be
treated include ocular diseases which may directly or indirectly
involve the degeneration of retinal cells, including ischemic
retinopathies in general, anterior ischemic optic neuropathy, all
forms of optic neuritis, age-related macular degeneration (AMD), in
its dry forms (dry AMD) and wet forms (wet AMD), diabetic
retinopathy, cystoid macular edema (CME), retinal detachment,
retinitis pigmentosa, Stargardt's disease, Best's vitelliform
retinal degeneration, Leber's congenital amaurosis and other
hereditary retinal degenerations, pathologic myopia, retinopathy of
prematurity, and Leber's hereditary optic neuropathy,
[0062] In another aspect, the compounds of the invention are used
as diagnostic agents and/or PET ligands, e.g. for the
identification and localization of nicotine receptors in various
tissues. Properly isotope-labeled agents of the invention exhibit
valuable properties as histopathological labeling agents, imaging
agents and/or biomarkers, hereinafter "markers", for the selective
labeling of the nAChR. More particularly the agents of the
invention are useful as markers for labeling the alpha7 nAChR
receptors in vitro or in vivo. In particular, compounds of the
invention which are properly isotopically labeled are useful as PET
markers. Such PET markers are labeled with one or more atoms
selected from the group consisting of .sup.11C, .sup.13N, .sup.15O,
.sup.18F.
[0063] The agents of the invention are therefore useful, for
instance, for determining the levels of receptor occupancy of a
drug acting at the nAChR, or diagnostic purposes for diseases
resulting from an imbalance or dysfunction of nAChR, and for
monitoring the effectiveness of pharmacotherapies of such
diseases.
[0064] In accordance with the above, the present invention provides
an agent of the invention for use as a marker for neuroimaging.
[0065] In a further aspect, the present invention provides a
composition for labeling brain and peripheral nervous system
structures involving nAChR in vivo and in vitro comprising an agent
of the invention.
[0066] In still a further aspect, the present invention provides a
method for labeling brain and peripheral nervous system structures
involving nAChR in vitro or in vivo, which comprises contacting
brain tissue with an agent of the invention.
[0067] The method of the invention may comprise a further step
aimed at determining whether the agent of the invention labeled the
target structure. Said further step may be effected by observing
the target structure using positron emission tomography (PET) or
single photon emission computed tomography (SPECT), or any device
allowing detection of radioactive radiations.
[0068] In particular, the agents of the invention are .alpha.7
nicotinic acetylcholine receptor (.alpha.7 nAChR) agonists.
[0069] In functional assays, the agents of the invention display
high affinity at the .alpha.7 nAChR as shown in the following
tests:
[0070] a) A functional assay for affinity at the .alpha.7 nAChR is
carried out with a rat pituitary cell line stably expressing the
.alpha.7 nAChR. Briefly, GH3 cells recombinantly expressing the
nAChR .alpha.7 were seeded 72 h prior to the experiment on black
96-well plates and incubated at 37.degree. C. in a humidified
atmosphere (5% CO.sub.2/95% air). On the day of the experiment
medium was removed by flicking the plates and replaced with 100
.mu.l growth medium containing af fluorescent calcium sensitive
dye, in the presence of 2.5 mM probenicid (Sigma). The cells were
incubated at 37.degree. C. in a humidified atmosphere (5%
CO.sub.2/95% air) for 1 h. Plates were flicked to remove excess of
Fluo-4, washed twice with Hepes-buffered salt solution (in mM: NaCl
130, KCl 5.4, CaCl.sub.2 2, MgSO.sub.4 0.8, NaH.sub.2PO.sub.4 0.9,
glucose 25, Hepes 20, pH 7.4; HBS) and refilled with 100 .mu.l of
HBS containing antagonists when appropriate. The incubation in the
presence of the antagonist lasted between 3 and 5 minutes. Plates
were then placed into an imaging plate reader and fluorescence
signal recordedd In this assay, compounds of the invention exhibit
pEC.sub.50 values of about 5 to about 9. Partial and potent
agonists in this test are preferred.
[0071] b) To assess the antagonist activity of the compounds of the
invention on the human neuronal nAChR .alpha.4.beta.2, a similar
functional assay is carried out using a human epithelial cell line
stably expressing the human .alpha.4.beta.2 subtype (Michelmore et
al., Naunyn-Schmiedeberg's Arch. Pharmacol. (2002) 366, 235) In
this assay, the preferred compounds of the invention show
selectivity for the .alpha.7 nAChR subtypes.
[0072] c) To assess the antagonist activity of the compounds of the
invention on the "ganglionic subtype" (.alpha.3.beta.4), the muscle
type of nicotinic receptor (.alpha.1.beta.1.gamma..delta.) and the
5-HT.sub.3 receptor, similar functional tests as just described
under a) are carried out with a human epithelial cell line stably
expressing the human ganglionic subtype, a cell line endogenously
expressing the human muscle type of nicotinic receptors or a cell
line endogenously expressing the murine 5-HT.sub.3 receptor
(Michelmore et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (2002)
366, 235. Compounds which display little or no activity on the
(.alpha.3.beta.4 nAChR, the muscle subtype of nicotinic receptor as
well as the 5-HT.sub.3 receptor are especially preferred.
[0073] In the model of mice showing sensory gating deficit
(DBA/2-mice) described by S. Leonard et al. in Schizophrenia
Bulletin 22, 431-445 (1996), the compounds of the invention induce
significant sensory gating at concentrations of about 10 to about
40 .mu.M.
[0074] The compounds of the invention may be shown to increase
attention in a test of attention for rodents (Robbins, J.
Neuropsychiatry Clin. Neurosci. (2001) 13, 326-35), namely the
5-choice serial reaction time test (5-CSRTT). In this test, the rat
must observe a wall containing 5 holes. When a light flash appears
in one of them, the rat must respond with a nose-poke into the
correct hole within 5 sec. in order to receive a food pellet
reward, delivered to a feeder in the opposite wall.
[0075] Compounds of the invention may also show learning/memory
enhancing effects in the social recognition test in mice and rats
(Ennaceur and Delacour, Behav. Brain Res. (1988) 31, 47-59).
[0076] The compounds of the invention are therefore useful for the
prevention and treatment (including mitigation and prevention) of
various disorders, especially those mentioned above. The usefulness
of .alpha.7 nAChR agonists in neurodegeneration is documented in
the literature, e.g. in Wang et al., J. Biol. Chem. 275, 5626-5632
(2000).
[0077] For the treatment of the above and other disorders, the
appropriate dosage of a compound (active ingredient) of the
invention will, of course, vary depending upon, for example, the
host, the mode of administration and the nature and severity of the
condition being treated as well as the relative potency of the
particular agent of the invention employed. For example, the amount
of active agent required may be determined on the basis of known in
vitro and in vivo techniques, determining how long a particular
active agent concentration in the blood plasma remains at an
acceptable level for a therapeutic effect. In general, satisfactory
results in animals are indicated to be obtained at daily dosages of
from about 0.01 to about 30.0 mg/kg p.o. In humans, an indicated
daily dosage is in the range of from about 0.7 to about 1400 mg/day
p.o., e.g. from about 50 to 200 mg (70 kg man), conveniently
administered once or in divided doses up to 4.times.per day or in
sustained release form. Oral dosage forms accordingly suitably
comprise from about 1.75 or 2.0 to about 700 or 1400 mg of a
compound of the invention admixed with an appropriate
pharmaceutically acceptable diluent or carrier therefor.
[0078] Pharmaceutical compositions contain, for example, from about
0.1% to about 99.9%, preferably from about 20% to about 60%, of the
active ingredient(s).
[0079] Examples for compositions comprising a compound of the
invention include, for example, a solid dispersion, an aqueous
solution, e.g. containing a solubilising agent, a microemulsion and
a suspension of, e.g. a salt of a compound of formula I or a free
compound of the formula I in the range of from 0.1 to 1%, e.g.
0.5%. The composition may be buffered to a pH in the range of, e.g.
from 3.5 to 9.5, e.g. to pH 4.5, by a suitable buffer.
[0080] The compounds of the invention are also commercially useful
as research chemicals.
[0081] For use according to the invention, a compound of the
formula I and/or a pharmaceutically acceptable salt thereof may be
administered as single active agent or in combination with one or
more other active agents of the formula I and/or a pharmaceutically
acceptable salt thereof or especially other active agents commonly
employed especially for the treatment of the disorders mentioned
herein or further other disorders, in any customary manner, e.g.
orally, for example in the form of tablets, capsules, or as nasal
spray, or parenterally, for example in the form of injection
solutions or suspensions. The other active agents employed in such
combinations are preferably selected from the group consisting of
benzodiazepines, selective serotonin reuptake inhibitors (SSRIs),
selective serotonin and norepinephrine reuptake inhibitors (SNRIs),
conventional antipsychotics, atypical antipsychotics, buspirone,
carbamazepine, oxcarbazepine, gabapentin and pregabalin.
[0082] An SSRI suitable for the present invention is especially
selected from fluoxetine, fuvoxamine, sertraline, paroxetine,
citalopram and escitalopram. An SNRI suitable for the present
invention is especially selected from venlafaxine and duloxetine.
The term "benzodiazepines" as used herein includes, but is not
limited to clonazepam, diazepam and lorazepam. The term
"conventional antipsychotics" as used herein includes, but is not
limited to haloperidol, fluphenazine, thiotixene and flupentixol.
The term "atypical antipsychotics" as used herein relates to
clozaril, risperidone, olanzapine, quetiapine, ziprasidone and
aripiprazol.
[0083] Buspirone can be administered in free form or as a salt,
e.g. as its hydrochloride, e.g., in the form as marketed, e.g.
under the trademark Buspar.TM. or Bespar.TM.. It can be prepared
and administered, e.g., as described in U.S. Pat. No. 3,717,634.
Fluoxetine can be administered, e.g., in the form of its
hydrochloride as marketed, e.g. under the trademark Prozac.TM.. It
can be prepared and administered, e.g., as described in CA 2002182.
Paroxetine
((3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine-
) can be administered, e.g., in the form as marketed, e.g. under
the trademark Paxil.TM.. It can be prepared and administered, e.g.,
as described in U.S. Pat. No. 3,912,743. Sertraline can be
administered, e.g., in the form as marketed, e.g. under the
trademark Zoloft.TM.. It can be prepared and administered, e.g., as
described in U.S. Pat. No. 4,536,518. Clonazepam can be
administered, e.g., in the form as marketed, e.g. under the
trademark Antelepsin.TM.. Diazepam can be administered, e.g., in
the form as marketed, e.g. under the trademark Diazepam
Desitin.TM.. Lorazepam can be administered, e.g., in the form as
marketed, e.g. under the trademark Tavor.TM.. Citalopram can be
administered in free form or as a salt, e.g. as its hydrobromide,
e.g., in the form as marketed, e.g. under the trademark
Cipramil.TM.. Escitalopram can be administered, e.g., in the form
as marketed, e.g. under the trademark Cipralex.TM.. It can be
prepared and administered, e.g., as described in AU623144.
Venlafaxine can be administered, e.g., in the form as marketed,
e.g. under the trademark Trevilor.TM.. Duloxetine can be
administered, e.g., in the form as marketed, e.g. under the
trademark Cymbalta.TM.. It may be prepared and administered, e.g.,
as described in CA 1302421. Carbamazepine can be administered,
e.g., in the form as marketed, e.g. under the trademark
Tegretal.TM. or Tegretol.TM.. Oxcarbazepine can be administered,
e.g., in the form as marketed, e.g. under the trademark
Trileptal.TM.. Oxcarbazepine is well known from the literature [see
for example Schuetz H. et al., Xenobiotica (GB), 16(8), 769-778
(1986)]. Gabapentin can be administered, e.g., in the form as
marketed, e.g. under the trademark Neurontin.TM.. Haloperidol can
be administered, e.g., in the form as marketed, e.g. under the
trademark Haloperidol STADA.TM.. Fluphenazine can be administered,
e.g., in the form of its dihydrochloride as marketed, e.g. under
the trademark Prolixin.TM.. Thiothixene can be administered, e.g.,
in the form as marketed, e.g. under the trademark Navane.TM.. It
can be prepared, e.g., as described in U.S. Pat. No. 3,310,553.
Flupentixol can be administered for instance in the form of its
dihydrochloride, e.g., in the form as marketed, e.g. under the
trademark Emergil.TM. or in the form of its decanoate, e.g., in the
form as marketed, e.g. under the trademark Depixol.TM.. It can be
prepared, e.g., as described in BP 925,538. Clozaril can be
administered, e.g., in the form as marketed, e.g. under the
trademark Leponex.TM.. It can be prepared, e.g., as described in
U.S. Pat. No. 3,539,573. Risperidone can be administered, e.g., in
the form as marketed, e.g. under the trademark Risperdal.TM..
Olanzapine can be administered, e.g., in the form as marketed, e.g.
under the trademark Zyprexa.TM.. Quetiapine can be administered,
e.g., in the form as marketed, e.g. under the trademark
Seroquel.TM.. Ziprasidone can be administered, e.g., in the form as
marketed, e.g. under the trademark Geodon.TM.. It can be prepared,
e.g., as described in GB 281,309. Aripiprazole can be administered,
e.g., in the form as marketed, e.g. under the trademark
Abilify.TM.. It can be prepared, e.g., as described in U.S. Pat.
No. 5,006,528.
[0084] The structure of the active ingredients identified by code
nos., generic or trade names may be taken from the actual edition
of the standard compendium "The Merck Index" or from databases,
e.g. Patents International (e.g. IMS World Publications). The
corresponding content thereof is hereby incorporated by reference.
Any person skilled in the art is fully enabled to identify the
active ingredients and, based on these references, likewise enabled
to manufacture and test the pharmaceutical indications and
properties in standard test models, both in vitro and in vivo.
[0085] In the case of a combination, the pharmaceutical
compositions for separate administration of the combination
partners and/or those for administration in a fixed combination,
i.e. a single galenical composition comprising at least two
combination partners, according to the invention can be prepared in
a manner known per se and are those suitable for enteral, such as
oral or rectal, and parenteral administration to mammals, including
man, comprising a therapeutically effective amount of at least one
pharmacologically active combination partner alone or in
combination with one or more pharmaceutically acceptable carriers,
especially suitable for enteral or parenteral application. When the
combination partners employed are applied in the form as marketed
as single drugs, their dosage and mode of administration can take
place in accordance with the information provided on the packet
leaflet of the respective marketed drug in order to result in the
beneficial effect described herein, if not mentioned herein
otherwise.
[0086] Pharmaceutical preparations for the combination therapy for
enteral or parenteral administration are, for example, those in
unit dosage forms, such as sugar-coated tablets, tablets, capsules
or suppositories, or furthermore ampoules. If not indicated
otherwise, these are prepared in a manner known per se, for example
by means of conventional mixing, granulating, sugar-coating,
dissolving or lyophilizing processes. It will be appreciated that
the unit content of a combination partner contained in an
individual dose of each dosage form need not in itself constitute
an effective amount since the necessary effective amount can
instead with a single dosage unit also be reached by administration
of a two or more dosage units.
[0087] In particular, a therapeutically effective amount of each of
the combination partners may be administered simultaneously or
sequentially and in any order, and the components may be
administered separately (e.g. sequentially after fixed or variable
periods of time), or as a fixed combination. For example, the
method of treatment (including mitigation) of a disorder according
to the invention may comprise (i) administration of the combination
partner (a) (a compound of the present invention) in free or
pharmaceutically acceptable salt form and (ii) administration of a
combination partner (b) (e.g. a different compound of the present
invention or an active ingredient of a different formula) in free
or pharmaceutically acceptable salt form, simultaneously or
sequentially in any order, in jointly therapeutically effective
amounts, preferably in synergistically effective amounts, e.g. in
daily dosages corresponding to the amounts described herein. The
individual combination partners can be administered separately at
different times during the course of therapy or concurrently in
divided or single combination forms. Furthermore, the term
"administering" also encompasses the use of a pro-drug of a
combination partner that convert in vivo to the combination partner
as such. The instant invention is therefore to be understood as
embracing all such regimes of simultaneous and/or alternating
treatment and the term "administering" is to be interpreted
accordingly.
[0088] The effective dosage of the combination partners employed
may vary, for example depending on the particular compound or
pharmaceutical composition employed, the mode of administration,
the disorder being treated, and/or the severity of the disorder
being treated. Thus, the dosage regimen is selected in accordance
with a variety of factors including the route of administration,
metabolism by and the renal and hepatic function of the patient. A
physician, clinician or veterinarian of ordinary skill can readily
determine and prescribe the effective amount of the single active
ingredients required to prevent, mitigate, counter or arrest the
disorder. Optimal precision in achieving concentration of the
active ingredients within the range that yields efficacy without
toxicity requires a regimen based on the kinetics of the active
ingredients' availability to target sites.
[0089] In accordance with the foregoing, the present invention also
provides:
[0090] (1) A compound of the formula I, and/or a salt thereof, for
use in the diagnostic or therapeutic treatment of a mammal,
especially a human; especially for use as an alpha-7 receptor
agonist, for example for use in the treatment (including
mitigation) of any one or more disorders, especially of any one or
more of the particular disorders set forth hereinbefore and
hereinafter.
[0091] (2) A pharmaceutical composition comprising a compound of
the formula I, and/or a pharmaceutically acceptable salt thereof,
as active ingredient together with a pharmaceutically acceptable
diluent or carrier.
[0092] (2') A pharmaceutical composition for the treatment or
prevention of a disorder in the treatment of which alpha-7 receptor
activation plays a role or is involved and/or in which alpha-7
receptor activity is involved, especially any one or more of the
disorders mentioned hereinbefore or hereinafter, comprising a
compound of the formula I, and/or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable diluent or
carrier.
[0093] (3) A method for the treatment of a disorder, especially any
one or more of the particular disorders set forth hereinbefore, in
a subject in need of such treatment, comprising administering a
pharmaceutically effective amount of a compound of the formula I,
or a pharmaceutically acceptable salt thereof.
[0094] (3') A method for treating or preventing a disorder in the
treatment of which alpha-7 receptor activation plays a role or is
involved and/or in which alpha-7 receptor activity is involved,
comprising administering to a mammal in need thereof a
therapeutically effective amount of a compound of the formula I,
and/or a pharmaceutically acceptable salt thereof.
[0095] (4) The use of a compound of the formula I, and/or a
pharmaceutically acceptable salt thereof, for the manufacture of a
medicament for the treatment or prevention of a disease or
condition in the treatment of which alpha-7 receptor activation
plays a role or is involved and/or in which alpha-7 receptor
activity is involved, especially one or more of the disorders
mentioned above.
[0096] (5) A method as defined above comprising co-administration,
e.g. concomitantly or in sequence, of a therapeutically effective
amount of an alpha-7 agonist of the formula I, and/or a
pharmaceutically acceptable salt thereof, and a second
pharmaceutically active compound and/or a pharmaceutically
acceptable salt thereof, said second pharmaceutically active
compound and/or salt thereof being especially for use in the
treatment of any one or more of the disorders set forth
hereinbefore or hereinafter.
[0097] (6) A combination comprising a therapeutically effective
amount of an alpha-7 agonist of the formula I, and/or a
pharmaceutically acceptable salt thereof, and a second
pharmaceutically active compound and/or a pharmaceutically
acceptable salt thereof, said second pharmaceutically active
compound being especially for use or of use in the treatment of any
one or more of the particular disorders set forth hereinbefore.
[0098] (7) A product obtained according to the above described
process, characterized in that (-)-1-Aza-bicyclo[3.3.1]nonan-4-ol
is used as starting material.
[0099] The Examples which follow serve to illustrate the invention
without limiting the scope thereof.
[0100] The following abbreviations are used:
AcOEt ethyl acetate
aq. aqueous
DEAD diethylazodicarboxylate
DMF dimethylformamide
EtOH ethanol
FC flash chromatography
HV high vacuum
MeOH MeOH
RP-HPLC reversed-phase high performance liquid chromatography
rt room temperature
rac. racemate
soln. solution
TFA trifluoroacetic acid
THF tetrahydrofuran
[0101] Temperatures are measured in degrees Celsius. Unless
indicated otherwise, reactions are carried out at room temperature.
The structure of final products, intermediates and starting
materials is confirmed by standard analytical methods, e.g.
microanalysis and spectroscopic characteristics (e.g. MS, IR,
NMR).
EXAMPLE 1 (Method A)
Preparation of
(rac.)-4-[6-(2-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[3-
.3.1]nonane
[0102] A solution of (rac.)-1-Aza-bicyclo[3.3.1]nonan-4-ol (1.3
mmol) in DMF (5 ml) is treated with sodium hydride (60% in mineral
oil; 1.3 mmol). After 1 hr at room temperature, a solution of
3-Chloro-6-(2-fluoro-4-methyl-phenyl)-pyridazine (1 mmol) in DMF
(30 ml) is added, and the reaction mixture heated to 50 deg. for 16
hrs. After cooling to room temperature, the DMF solution is
quenched with a 10% NaCl solution, extracted with ethyl acetate
(2.times.15 ml), followed by sodium chloride solution (20 ml). The
ethyl acetate is dried over anhydrous magnesium sulfate, filtered
and evaporated to dryness, and the residual oil purified by silica
gel column chromatography (eluent: ethyl
acetate-methanol-triethylamine (50:10:2) to afford
(rac.)-4-[6-(2-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[3-
.3.1]nonane as a colourless solid. MS (ES.sup.+): m/e=328
(MH.sup.+)
EXAMPLE 2 (Method B)
(rac.)-4-[6-(2,5-Difluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicycl-
o [3.3.1]nonane
[0103] Potassium trimethylsilylamine (5.25 mmol) is added to a
solution of (rac.)-1-Aza-bicyclo[3.3.1]nonan-4-ol (5.0 mmol) in THF
(20 ml) at room temperature and the solution is stirred for 30 min.
The resulting potassium alcoholate is slowly added to a precooled
solution of 3,6-dichloropyridazine (7.5 mmol) in THF (50 ml) and
the resulting mixture is stirred for another 20 minutes. The
solution is allowed to warm to 0.degree. C. is quenched with brine
and extracted with diethylether. The organic layer is dried over
magnesium sulfate and evaporated. The brown oil is purified by
silica gel column chromatography (CH.sub.2Cl.sub.2:MeOH:NH.sub.3,
9:1:0.1) to afford
(rac.)-4-(6-Chloro-pyridazin-3-yloxy)-1-aza-bicyclo[3.3.1]nonane
(320 mg).
[0104]
(Rac.)-4-(6-Chloro-pyridazin-3-yloxy)-1-aza-bicyclo[3.3.1]nonane
(1.4 mmol), 2,5-Difluoro-4-methyl-phenyl-boronic acid (1.8 mmol)
are dissolved in toluene (7.3 ml), ethanol 1 ml) and a
Na.sub.2CO.sub.3 solution (7.3 ml, 2M). The solution is degassed
with argon in a ultrasound bath after which Palladium (II) acetate
(0.003 mmol) and triphenylphosphine (0.14 mmol) were added. The
resulting mixture is heated at 100.degree. C. for 1.5 hours after
which the heating is stopped and the suspension is filtered over
Hyflo and the filtrate is extracted with ethylacetate. The organic
layer is dried over magnesium sulfate and evaporated. The oil is
purified by silica gel column chromatography
(CH.sub.2Cl.sub.2:MeOH:EtOH:NH.sub.3, 90:5:5:1) to afford
(rac.)-4-[6-(2,5-Difluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyc-
lo [3.3.1]nonane. MS (ES.sup.+): m/e=346 (MH.sup.+)
EXAMPLE 3
[0105] The following compounds are prepared using either method A
or B using appropriate starting materials:
[0106] 3a)
(4S,5S)-4-[6-(2-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[-
3.3.1]nonane, MS (ES.sup.+): m/e=328 (MH.sup.+)
[0107] 3b)
(4R,5R)-4-[6-(2-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[-
3.3.1]nonane, MS (ES.sup.+): m/e=328 (MH.sup.+)
[0108] 3c)
(4SR,5SR)-4-[6-(2,5-Difluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bi-
cyclo [3.3.1]nonane, MS (ES.sup.+): m/e=346 (MH.sup.+)
[0109] 3d)
N-(3-{6-[(4S,5S)-(1-Aza-bicyclo[3.3.1]non-4-yl)oxy]-pyridazin-3-yl}-pheny-
l)-acetamide, MS (ES.sup.+): m/e=353 (MH.sup.+)
[0110] 3e)
N-(3-{6-[(4R,5R)-(1-Aza-bicyclo[3.3.1]non-4-yl)oxy]-pyridazin-3-yl}-pheny-
l)-acetamide, MS (ES.sup.+): m/e =353 (MH.sup.+)
[0111] 3f)
N-(3-{6-[(4SR,5SR)-(1-Aza-bicyclo[3.3.1]non-4-yl)oxy]-pyridazin-3-yl}-phe-
nyl)-acetamide, MS (ES.sup.+): m/e=353 (MH.sup.+), Chiral
chromatography: [column: Chiralcel OD IMMOB (FA-2359/37) 12 .mu.m;
Eluent: hexane/CHCl.sub.3/MeOH 60:30:10 1 0.1% TFA; Flow: 1.5
ml/min.; Detector: UV 254 nm], peak 1: 15.470 min., peak 2: 20.826
min.
[0112] 3g)
(4SR,5SR)-4-[5-(1H-Indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[3.3.1]nonan-
e, MS (ES.sup.+): m/e=334.1 (MH.sup.+)
[0113] 3h)
(4S,5S)-4-[5-(1H-Indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane,
MS (ES.sup.+): m/e=334 (MH.sup.+), m.p. 234-238.degree. C.
[0114] 3i)
(4R,5R)-4-[5-(1H-Indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane
[0115] 3j)
(4SR,5SR)-4-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]non-
ane, MS (ES.sup.+): m/e=335 (MH.sup.+), m.p. 211.degree. C. dec
[0116] 3k)
(4S,5S)-4-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonan-
e, MS (ES.sup.+): m/e=335 (MH.sup.+)
[0117] 3l)
(4R,5R)-4-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonan-
e
[0118] 3m)
(4SR,5SR)-4-[6-(1H-Indol-5-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[3.3.1]non-
ane, MS (ES.sup.+): m/e=335 (MH.sup.+)
[0119] 3n)
(4SR,5SR)-4-[6-(3-Nitro-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[3.3.1]no-
nane, MS (ES.sup.+): m/e=341 (MH.sup.+)
[0120] 3o)
(4SR,5SR)-4-(6-p-Tolyl-pyridazin-3-yloxy)-1-aza-bicyclo[3.3.1]nonane,
MS (ES.sup.+): m/e=310 (MH.sup.+)
[0121] 3p)
(4SR,5SR)-4-(6-m-Tolyl-pyridazin-3-yloxy)-1-aza-bicyclo[3.3.1]nonane,
MS (ES.sup.+): m/e=310 (MH.sup.+)
[0122] 3q)
(4SR,5SR)-4-(6-Benzo[1,3]dioxol-5-yl)-pyridazin-3-yloxy)-1-aza-bicyclo[3.-
3.1]nonane, MS (ES.sup.+): m/e=340 (MH.sup.+)
[0123] 3r)
(4SR,5SR)-4-[6-(3,4-Dimethyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[3.3-
.1]nonane, MS (ES.sup.+): m/e=324.5 (MH.sup.+)
[0124] 3s)
(4SR,5SR)-4-(6-p-Tolyl-pyridin-3-yloxy)-1-aza-bicyclo[3.3.1]nonane,
MS (ES.sup.+): m/e=309 (MH.sup.+)
[0125] 3t)
(4SR,5SR)-4-[6-(3-Fluoro-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[3.3.1]n-
onane, MS: (ES.sup.+): m/e=314 (MH.sup.+)
[0126] 3u)
(4SR,5SR)-4-[6-(3,5-Difluoro-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[3.3-
.1]nonane, MS (ES.sup.+): m/e=332 (MH.sup.+)
[0127] 3v)
(4SR,5SR)-4-(5-Phenyl-[1,3,4]thiadiazol-2-yloxy)-1-aza-bicyclo[3.3.1]nona-
ne, MS (ES.sup.+): m/e=302 (MH.sup.+)
[0128] 3w)
(4SR,5SR)-5-[6-(1-Aza-bicyclo[3.3.1]non-4-yloxy)-pyridazin-3-yl]-quinolin-
e, MS (ES.sup.+): m/e=347 (MH.sup.+)
[0129] 3x)
(4SR,5SR)-4-[6-(3,5-Dimethyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[3.3-
.1]nonane, MS (ES.sup.+): m/e=324 (MH.sup.+)
[0130] 3z)
(4SR,5SR)-4-(6-Phenyl-pyridazin-3-yloxy)-1-aza-bicyclo[3.3.1]nonane,
MS (ES.sup.+): m/e=296 (MH.sup.+)
[0131] 3aa)
(4SR,5SR)-4-[6-(3,4-Difluoro-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[3.3-
.1]nonane, MS (ES.sup.+): m/e=332 (MH.sup.+)
[0132] 3ab)
(4SR,5SR)-4-[6-(3-Trifluoromethoxy-phenyl)-pyridazin-3-yloxy]-1-aza-bicyc-
lo[3.3.1]nonane, MS (ES.sup.+): m/e=380 (MH.sup.+)
[0133] 3ac)
(4SR,5SR)-3-[6-(1-Aza-bicyclo[3.3.1]non-4-yloxy)-pyridazin-3-yl]-benzonit-
rile, MS (ES.sup.+): m/e=321 (MH.sup.+)
[0134] 3ad)
(4SR,5SR)-4-[6-(4-Trifluoromethoxy-phenyl)-pyridazin-3-yloxy]-1-aza-bicyc-
lo[3.3.1]nonane, MS (ES.sup.+): m/e=380 (MH.sup.+)
[0135] 3ae)
(4SR,5SR)-4-[6-(3-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicycl-
o[3.3.1]nonane, MS (ES.sup.+): m/e=328 (MH.sup.+)
[0136] 3af)
(4SR,5SR)-4-[6-(2,4-Difluoro-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[3.3-
.1]nonane, MS (ES.sup.+): m/e=332 (MH.sup.+)
[0137] 3ag)
(4SR,5SR)-4-[6-(2-Methyl-benzothiazol-5-yl)-pyridazin-3-yloxy]-1-aza-bicy-
clo[3.3.1]nonane, MS (ES.sup.+): m/e=367.4 (MH.sup.+)
[0138] 3ah)
(4SR,5SR)-4-[6-(1-Aza-bicyclo[3.3.1]non-4-yloxy)-pyridazin-3-yl]-benzonit-
rile, MS (ES.sup.+): m/e=321 (MH.sup.+)
[0139] 3ai)
(4SR,5SR)-4-[6-(4-Fluoro-3-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicycl-
o[3.3.1]nonane, MS (ES.sup.+): m/e=328 (MH.sup.+)
[0140] 3aj)
(4SR,5SR)-4-[6-(4-Ethyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[3.3.1]no-
nane, MS (ES.sup.+): m/e=324 (MH.sup.+)
[0141] 3ak)
(4SR,5SR)-4-[6-(3-Trifluoromethyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicycl-
o[3.3.1]nonane, MS (ES.sup.+): m/e=364 (MH.sup.+)
[0142] 3al)
(4SR,5SR)-4-[6-(4-Trifluoromethyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicycl-
o[3.3.1]nonane, MS (ES.sup.+): m/e=364 (MH.sup.+)
[0143] 3am)
(4SR,5SR)-4-[6-(3,5-Bis-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-1-aza--
bicyclo[3.3.1]nonane, MS (ES.sup.+): m/e=432 (MH.sup.+)
[0144] 3an)
(4SR,5SR)-4-[6-(5-Methyl-thiophen-2-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[-
3.3.1]nonane, MS (ES.sup.+): m/e=316.4 (MH.sup.+)
[0145] 3ao)
(4SR,5SR)-4-[5-(1H-Indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[3.3.1]nonan-
e, MS (ES.sup.+): m/e=334.4 (MH.sup.+)
[0146] 3ap)
(4SR,5SR)-4-[6-(2,3-Dimethyl-1H-indol-5-yl)-pyridazin-3-yloxy]-1-aza-bicy-
clo[3.3.1]nonane, MS (ES.sup.+): m/e=363.4 (MH.sup.+)
[0147] 3aq)
(4SR,5SR)-4-(5-Benzo[1,3]dioxol-5-yl-pyrimidin-2-yloxy)-1-aza-bicyclo[3.3-
.1]nonane
[0148] 3ar)
(4SR,5SR)-4-(5-Benzo[1,3]dioxol-5-yl-pyridin-2-yloxy)-1-aza-bicyclo[3.3.1-
]nonane
[0149] 3as)
(4SR,5SR)-4-(6-Benzo[1,3]dioxol-5-yl-pyridin-3-yloxy)-1-aza-bicyclo[3.3.1-
]nonane
[0150] 3at)
(4SR,5SR)-4-[5-(2-Fluoro-4-methyl-phenyl)-pyrimidin-2-yloxy]-1-aza-bicycl-
o[3.3.1]nonane
[0151] 3au)
(4SR,5SR)-4-[5-(2-Fluoro-4-methyl-phenyl)-pyridin-2-yloxy]-1-aza-bicyclo[-
3.3.1]nonane
[0152] 3av)
(4SR,5SR)-4-[6-(2-Fluoro-4-methyl-phenyl)-pyridin-3-yloxy]-1-aza-bicyclo[-
3.3.1]nonane
[0153] 3aw)
(4SR,5SR)-4-(5-p-Tolyl-pyrimidin-2-yloxy)-1-aza-bicyclo[3.3.1]nonane
[0154] 3ay)
(4SR,5SR)-4-(5-p-Tolyl-pyridin-2-yloxy)-1-aza-bicyclo[3.3.1]nonane
[0155] 3az)
(4SR,5SR)-4-[5-(5-Methyl-thiophen-2-yl-pyrimidin-2-yloxy]-1-aza-bicyclo[3-
.3.1]nonane
[0156] 3ba)
(4SR,5SR)-4-[5-(5-Methyl-thiophen-2-yl)-pyridin-2-yloxy]-1-aza-bicyclo[3.-
3.1]nonane
[0157] 3bb)
(4SR,5SR)-4-[6-(5-Methyl-thiophen-2-yl)-pyridin-3-yloxy]-1-aza-bicyclo[3.-
3.1]nonane
[0158] 3bc)
(4SR,5SR)-(1-Aza-bicyclo[3.3.1]non-4-yl)-(6-p-tolyl-pyridin-3-yl)-amine,
MS (ES.sup.+l ): m/e=308 (MH.sup.+)
EXAMPLE 4
Soft Capsules
[0159] 5000 soft gelatin capsules, each comprising as active
ingredient 0.05 g of one of the compounds of formula I mentioned in
the preceding Examples, are prepared as follows: TABLE-US-00001
Composition Active ingredient 250 g Lauroglycol 2 litres
[0160] Preparation process: The pulverized active ingredient is
suspended in Lauroglykol.RTM. (propylene glycol laurate, Gattefosse
S. A., Saint Priest, France) and ground in a wet pulverizer to
produce a particle size of about 1 to 3 .mu.m. 0.419 g portions of
the mixture are then introduced into soft gelatin capsules using a
capsule-filling machine.
* * * * *