U.S. patent application number 10/925088 was filed with the patent office on 2005-02-03 for diaryl compounds.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Andrews, Mark David, Hepworth, David, Middleton, Donald Stuart.
Application Number | 20050026920 10/925088 |
Document ID | / |
Family ID | 32302994 |
Filed Date | 2005-02-03 |
United States Patent
Application |
20050026920 |
Kind Code |
A1 |
Andrews, Mark David ; et
al. |
February 3, 2005 |
Diaryl compounds
Abstract
The invention relates to compounds of formula I 1
Inventors: |
Andrews, Mark David; (County
of Kent, GB) ; Hepworth, David; (County of Kent,
GB) ; Middleton, Donald Stuart; (County of Kent,
GB) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
32302994 |
Appl. No.: |
10/925088 |
Filed: |
August 24, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10925088 |
Aug 24, 2004 |
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10632355 |
Jul 31, 2003 |
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6800652 |
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60410610 |
Sep 13, 2002 |
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Current U.S.
Class: |
514/247 ;
514/210.2; 514/252.1; 514/269; 514/345; 544/239; 544/316;
544/406 |
Current CPC
Class: |
C07D 213/38 20130101;
C07D 213/70 20130101 |
Class at
Publication: |
514/247 ;
514/252.1; 514/269; 514/345; 544/239; 544/316; 544/406;
514/210.2 |
International
Class: |
A61K 031/50; A61K
031/497; A61K 031/513 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 16, 2002 |
GB |
0219154.2 |
Claims
1-12. (canceled)
13. The method according to claim 16, wherein the disorder is
selected from hypertension, depression, generalized anxiety
disorder, phobias, post-traumatic stress syndrome, avoidant
personality disorder, sexual dysfunction (including premature
ejaculation and male impotence), eating disorders, obesity,
substance abuse disorders (including chemical dependencies),
cluster headache, migraine, pain, Alzheimer's disease,
obsessive-compulsive disorder, panic disorder, memory disorders,
Parkinson's diseases, endocrine disorders, vasospasm, cerebellar
ataxia, gastrointestinal tract disorders, negative symptoms of
schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress
incontinence, Tourette's syndrome, trichotillomania, kleptomania,
attention deficit hyperactivity disorder (ADHD), chronic paroxysmal
hemicrania, headache (associated with vascular disorders),
emotional lability, pathological crying, sleeping disorder
(cataplexy) and shock.
14. The method according to claim 13 wherein the disorder is
selected from depression, attention deficit hyperactivity disorder,
obsessive-compulsive disorder, post-traumatic stress syndrome,
substance abuse disorders and sexual dysfunction, including
premature ejaculation and male impotence.
15. The method according to claim 14 wherein the disorder is
premature ejaculation.
16. A method of treating a disorder in which the regulation of
monoamine transporter function is implicated by administering a
compound of Formula (I), 23wherein; X is S or CH.sub.2; L and U,
which may be the same or different, are --N--,
--N.sup.+(--O.sup.-)-- or --C(H)--; M and Q, which may be the same
or different, are --N--, --N.sup.+(--O.sup.-)-- or --C(R.sup.4)--;
wherein ring A contains 1 or 2 nitrogen atoms, and wherein when L,
U, M or Q is --N.sup.+(--O.sup.-)--, ring A contains no other
nitrogen atom; R.sup.1 and R.sup.2, which may be the same or
different, are hydrogen, C.sub.1-C.sub.6alkyl,
(CH.sub.2).sub.m(C.sub.3-C- .sub.6cycloalkyl) wherein m=0, 1, 2 or
3, or R.sup.1 and R.sup.2 together with the nitrogen to which they
are attached form an azetidine ring; W, Y and Z, which may be the
same or different, are hydrogen, halogen, C.sub.1-C.sub.6alkyl,
CF.sub.3, OCF.sub.3, C.sub.1-C.sub.4alkylthio or
C.sub.1-C.sub.4alkoxy; or Y and Z are linked so that, together with
the interconnecting atoms, Y and Z form a fused 5 to 7-membered
carbocyclic or heterocyclic ring which may be saturated,
unsaturated or aromatic, and wherein when Y and Z form a
heterocyclic ring, in addition to carbon atoms, the linkage
contains one or two heteroatoms independently selected from oxygen,
sulfur and nitrogen; and wherein W, Y and Z are not all hydrogen;
and each R.sup.4 is independently: --(CH.sub.2).sub.p--R.sup.5;
where p is 0, 1 or 2; R.sup.5 is hydrogen, CONR.sup.6R.sup.7,
SO.sub.2NR.sup.6R.sup.7, SO.sub.2NHC(.dbd.O)R.sup.6, hydroxy,
C.sub.1-C.sub.4alkoxy, NR.sup.8SO.sub.2R.sup.9, NO.sub.2,
NR.sup.6R.sup.11, CN, CO.sub.2R.sup.10, SR.sup.10, S(O)R.sup.9 or
SO.sub.2R.sup.10; R.sup.6, R.sup.7, R.sup.8 and R.sup.10 which may
be the same or different, are hydrogen or C.sub.1-C.sub.6alkyl
optionally substituted independently by one or more R.sup.12;
R.sup.9 is C.sub.1-C.sub.6 alkyl optionally substituted
independently by one or more R.sup.12; R.sup.11 is hydrogen,
C.sub.1-C.sub.6 alkyl optionally substituted independently by one
or more R.sup.12, C(O)R.sup.6, CO.sub.2R.sup.9, C(O)NHR.sup.6 or
SO.sub.2NR.sup.6R.sup.7; R.sup.12 is fluoro, hydroxy, CO.sub.2H,
C.sub.3-C.sub.6cycloalkyl, NH.sub.2, CONH.sub.2,
C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkoxycarbonyl or a 5- or
6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms
selected from N, S and O optionally substituted independently by
one or more R.sup.13; or R.sup.6 and R.sup.7, together with the
nitrogen to which they are attached, form a 4-, 5- or 6-membered
heterocyclic ring optionally substituted independently by one or
more R.sup.13; or a 5- or 6-membered heterocyclic ring containing
1, 2 or 3 heteroatoms selected from N, S and O, optionally
substituted independently by one or more R.sup.13; wherein R.sup.13
is hydroxy, C.sub.1-C.sub.4alkoxy, fluoro, C.sub.1-C.sub.6alkyl,
haloalkyl, haloalkoxy, --NH.sub.2, --NH(C.sub.1-C.sub.6alkyl) or
--N(C.sub.1-C.sub.6alkyl).sub.2; or when both M and Q are CR.sup.4,
the R.sup.4 groups are linked so that together with the
interconnecting atoms, the R.sup.4 groups form a fused 5- to
7-membered carbocyclic or heterocyclic ring which may be saturated,
unsaturated or aromatic.
Description
[0001] This invention relates to novel compounds which inhibit
monoamine re-uptake. In particular compounds of the present
invention exhibit activity as selective serotonin re-uptake
inhibitors (SSRIs) and have utility therefore in a variety of
therapeutic areas. Notably the compounds of the present invention
are useful in the treatment or prevention of a variety of
disorders, including those in which the regulation of monoamine
transporter function is implicated, such as depression, attention
deficit hyperactivity disorder, obsessive-compulsive disorder,
post-traumatic stress disorder, substance abuse disorders and
sexual dysfunction including premature ejaculation, and to
pharmaceutical formulations containing such compounds.
[0002] U.S. Pat. No. 5,190,965 and U.S. Pat. No. 5,430,063 disclose
a class of phenoxyphenyl compounds, which are a class of dopamine
antagonists. WO 93/12080, WO 97/17325 and EP 0,402,097 disclose
substituted diphenylsulfides, which are serotonin uptake
inhibitors. WO 01/72687, WO 00/50380 and WO 01/27068 describe
diphenyl ether derivatives, which are selective serotonin re-uptake
inhibitors. J. Med. Chem 2002, 45(6), 1253-1258, discloses diphenyl
sulfides as selective serotonin transporter ligands.
[0003] According to a first aspect the invention provides a
compound of general formula (I) or pharmaceutically acceptable
salts, solvates or polymorphs thereof; 2
[0004] wherein;
[0005] X is S or CH.sub.2;
[0006] L and U, which may be the same or different, are --N--,
--N.sup.+(--O.sup.-)-- or --C(H)--;
[0007] M and Q, which may be the same or different, are --N--,
--N.sup.+(--O.sup.-)-- or --C(R.sup.4)--;
[0008] wherein ring A contains 1 or 2 nitrogen atoms, and wherein
when L, U, M or Q is --N.sup.+(--O.sup.-)--, ring A contains no
other nitrogen atom;
[0009] R.sup.1 and R.sup.2, which may be the same or different, are
hydrogen, C.sub.1-C.sub.6alkyl,
(CH.sub.2).sub.m(C.sub.3-C.sub.6cycloalky- l) wherein m=0, 1, 2 or
3, or R.sup.1 and R.sup.2 together with the nitrogen to which they
are attached form an azetidine ring;
[0010] W, Y and Z, which may be the same or different, are
hydrogen, halogen, C.sub.1-C.sub.6alkyl, CF.sub.3, OCF.sub.3,
C.sub.1-C.sub.4alkylthio or C.sub.1-C.sub.4alkoxy; or Y and Z are
linked so that, together with the interconnecting atoms, Y and Z
form a fused 5 to 7-membered carbocyclic or heterocyclic ring which
may be saturated, unsaturated or aromatic, and wherein when Y and Z
form a heterocyclic ring, in addition to carbon atoms, the linkage
contains one or two heteroatoms independently selected from oxygen,
sulfur and nitrogen; and wherein W, Y and Z are not all
hydrogen;
[0011] and
[0012] each R.sup.4 is independently:
[0013] --(CH.sub.2).sub.p--R.sup.5;
[0014] where p is 0, 1 or 2;
[0015] R.sup.5 is hydrogen, CONR.sup.6R.sup.7,
SO.sub.2NR.sup.6R.sup.7, SO.sub.2NHC(.dbd.O)R.sup.6, hydroxy,
C.sub.1-C.sub.4alkoxy, NR.sup.8SO.sub.2R.sup.9, NO.sub.2,
NR.sup.6R.sup.11, CN, CO.sub.2R.sup.10, SR.sup.10, S(O)R.sup.9 or
SO.sub.2R.sup.10; R.sup.6, R.sup.7, R.sup.8 and R.sup.10 which may
be the same or different, are hydrogen or C.sub.1-C.sub.6alkyl
optionally substituted independently by one or more R.sup.12;
R.sup.9 is C.sub.1-C.sub.6 alkyl optionally substituted
independently by one or more R.sup.12; R.sup.11 is hydrogen,
C.sub.1-C.sub.6 alkyl optionally substituted independently by one
or more R.sup.12, C(O)R.sup.6, CO.sub.2R.sup.9, C(O)NHR.sup.6 or
SO.sub.2NR.sup.6R.sup.7; R.sup.12 is fluoro, hydroxy, CO.sub.2H,
C.sub.3-C.sub.6cycloalkyl, NH.sub.2, CONH.sub.2,
C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkoxycarbonyl or a 5- or
6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms
selected from N, S and O optionally substituted independently by
one or more R.sup.13; or R.sup.6 and R.sup.7, together with the
nitrogen to which they are attached, form a 4-, 5- or 6-membered
heterocyclic ring optionally substituted independently by one or
more R.sup.13; or
[0016] a 5- or 6-membered heterocyclic ring containing 1, 2 or 3
heteroatoms selected from N, S and O, optionally substituted
independently by one or more R.sup.13;
[0017] wherein R.sup.13 is hydroxy, C.sub.1-C.sub.4alkoxy, fluoro,
C.sub.1-C.sub.6alkyl, haloalkyl, haloalkoxy, --NH.sub.2,
--NH(C.sub.1-C.sub.6alkyl) or --N(C.sub.1-C.sub.6alkyl).sub.2;
or
[0018] when both M and Q are CR.sup.4, the R.sup.4 groups are
linked so that together with the interconnecting atoms, the R.sup.4
groups form a fused 5- to 7-membered carbocyclic or heterocyclic
ring which may be saturated, unsaturated or aromatic.
[0019] Unless otherwise indicated, any alkyl group may be straight
or branched and is of 1 to 6 carbon atoms, preferably 1 to 4 and
particularly 1 to 3 carbon atoms.
[0020] Unless otherwise indicated, any heterocyclyl group contains
5 to 7 ring-atoms up to 4 of which may be hetero-atoms such as
nitrogen, oxygen and sulfur, and may be saturated, unsaturated or
aromatic. Examples of heterocyclyl groups are furyl, thienyl,
pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl,
oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl,
pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,
oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl,
piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino,
pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl,
tetrazolyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl,
diazepinyl and thiazolinyl. In addition, the term heterocyclyl
includes fused heterocyclyl groups, for example benzimidazolyl,
benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl,
oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl,
quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido,
benzofuranyl, benzodiazepinyl, indolyl and isoindolyl. The term
heterocyclic should be similarly construed.
[0021] Unless otherwise indicated, any carbocyclyl group contains 3
to 8 ring-atoms, and may be saturated, unsaturated or aromatic.
Preferred saturated carbocyclyl groups are cyclopropyl, cyclopentyl
or cyclohexyl. Preferred unsaturated carbocyclyl groups contain up
to 3 double bonds. A preferred aromatic carbocyclyl group is
phenyl. The term carbocylic should be similarly construed. In
addition, the term carbocyclyl includes any fused combination of
carbocyclyl groups, for example naphthyl, phenanthryl, indanyl and
indenyl.
[0022] Preferably, L and U are --CH--.
[0023] Preferably, W, Y and Z are each independently selected from
hydrogen, methyl, ethyl, CF.sub.3, OCF.sub.3,
C.sub.1-C.sub.4alkylthio, methoxy, ethoxy, chloro, fluoro and
bromo.
[0024] Preferably, W and Z are hydrogen.
[0025] Preferably, Y is methylthio.
[0026] Preferably, M and Q are each independently selected from
--N-- and --CH--.
[0027] More preferably, one of M and Q is --N-- and the other is
--CH--.
[0028] More preferably, L and U are --CH--, one of M and Q is --N--
and the other is --CH--.
[0029] Preferably, R.sup.1 and R.sup.2 are each independently
selected from hydrogen and C.sub.1-C.sub.6alkyl.
[0030] More preferably, R.sup.1 is methyl and R.sup.2 is hydrogen
or methyl.
[0031] Preferred compounds are:
[0032]
N-methyl-N-[(4-{[4-(methylsulfanyl)phenyl]sulfanyl}-3-pyridinyl)met-
hyl]amine,
[0033]
N,N-dimethyl-N-[(4-{[4-(methylsulfanyl)phenyl]sulfanyl}-3-pyridinyl-
)methyl]amine,
[0034]
N-methyl-N-[(3-{[4-(methylsulfanyl)phenyl]sulfanyl}-4-pyridinyl)met-
hyl]amine,
[0035]
N,N-dimethyl-N-[(3-{[4-(methylsulfanyl)phenyl]sulfanyl}-4-pyridinyl-
)methyl]amine,
[0036]
N-methyl-N-({3-[4-(methylsulfanyl)benzyl]-4-pyridinyl}methyl)amine,
[0037]
N,N-dimethyl-N-({3-[4-(methylsulfanyl)benzyl]-4-pyridinyl}methyl)am-
ine,
[0038]
N-methyl-N-({4-[4-(methylsulfanyl)benzyl]-3-pyridinyl}methyl)amine,
and
[0039]
N,N-dimethyl-N-({4-[4-(methylsulfanyl)benzyl]-3-pyridinyl}methyl)am-
ine.
[0040] For the avoidance of doubt, unless otherwise indicated, the
term substituted means substituted by one or more defined groups.
In the case where groups may be selected from a number of
alternatives groups, the selected groups may be the same or
different.
[0041] For the avoidance of doubt, the term independently means
that where more than one substituent is selected from a number of
possible substituents, those substituents may be the same or
different.
[0042] The pharmaceutically or veterinarily acceptable salts of the
compounds of formula I which contain a basic centre are, for
example, non-toxic acid addition salts formed with inorganic acids
such as hydrochloric, hydrobromic, hydroiodic, sulfuric and
phosphoric acid, with carboxylic acids or with organo-sulfonic
acids. Examples include the HCl, HBr, HI, sulfate or bisulfate,
nitrate, phosphate or hydrogen phosphate, acetate, benzoate,
succinate, saccharate, fumarate, maleate, lactate, citrate,
tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and palmoate salts. Compounds
of formula I can also provide pharmaceutically or veterinarily
acceptable metal salts, in particular non-toxic alkali and alkaline
earth metal salts, with bases. Examples include the sodium,
potassium, aluminium, calcium, magnesium, zinc and diethanolamine
salts. For reviews on suitable pharmaceutical salts see Berge et
al, J. Pharm, Sci., 66, 1-19, 1977; Bighley et al, International
Journal of Pharmaceutics, 33 (1986), 201-217; and P L Gould,
Encyclopedia of Pharmaceutical Technology, Marcel Debker Inc, New
York 1996, Volume 13, page 453-497.
[0043] The pharmaceutically acceptable solvates of the compounds of
the invention include the hydrates thereof.
[0044] Also included within the scope of the compound and various
salts of the invention are polymorphs thereof.
[0045] Hereinafter, compounds their pharmaceutically acceptable
salts, their solvates or polymorphs, defined in any aspect of the
invention (except intermediate compounds in chemical processes) are
referred to as "compounds of the invention".
[0046] The compounds of the invention have the advantage that they
are selective inhibitors of the re-uptake of serotonin (SRIs) (and
so are likely to have reduced side effects), they have a rapid
onset of action (making them suitable for administration shortly
before an effect is required), they have desirable potency and
associated properties. Compounds that selectively inhibit the
re-uptake of serotonin, but not noradrenaline or dopamine, are
preferred.
[0047] The compounds of the invention may possess one or more
chiral centres and so exist in a number of stereoisomeric forms.
All stereoisomers and mixtures thereof are included in the scope of
the present invention. Racemic compounds may either be separated
using preparative HPLC and a column with a chiral stationary phase
or resolved to yield individual enantiomers utilising methods known
to those skilled in the art. In addition, chiral intermediate
compounds may be resolved and used to prepare chiral compounds of
the invention.
[0048] The compounds of the invention may exist in one or more
tautomeric forms. All tautomers and mixtures thereof are included
in the scope of the present invention. For example, a claim to
2-hydroxypyridinyl would also cover its tautomeric form,
.alpha.-pyridonyl.
[0049] The invention also includes radiolabelled compounds.
[0050] It will be appreciated by those skilled in the art that
certain protected derivatives of compounds of the invention, which
may be made prior to a final deprotection stage, may not possess
pharmacological activity as such, but may, in certain instances, be
administered orally or parenterally and thereafter metabolised in
the body to form compounds of the invention which are
pharmacologically active.
[0051] Such derivatives may therefore be described as "prodrugs".
Further, certain compounds of the invention may act as prodrugs of
other compounds of the invention.
[0052] All protected derivatives and prodrugs of compounds of the
invention are included within the scope of the invention. Examples
of suitable pro-drugs for the compounds of the present invention
are described in Drugs of Today, Volume 19, Number 9, 1983, pp
499-538 and in Topics in Chemistry, Chapter 31, pp 306-316 and in
"Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1
(the disclosures in which documents are incorporated herein by
reference).
[0053] It will further be appreciated by those skilled in the art,
that certain moieties, known to those skilled in the art as
"pro-moieties", for example as described by H. Bundgaard in "Design
of Prodrugs" (the disclosure in which document is incorporated
herein by reference) may be placed on appropriate functionalities
when such functionalities are present within compounds of the
invention.
[0054] Preferred prodrugs for compounds of the invention include:
esters, carbonate esters, hemi-esters, phosphate esters, nitro
esters, sulfate esters, sulfoxides, amides, carbamates,
azo-compounds, phosphamides, glycosides, ethers, acetals and
ketals.
[0055] Compounds of the invention may be prepared, in known manner
in a variety of ways. In the following reaction schemes and
hereafter, unless otherwise stated R.sup.1 to R.sup.13, L, U, M, Q,
W, Y and Z are as defined in the first aspect. These processes form
further aspects of the invention.
[0056] Throughout the specification, general formulae are
designated by Roman numerals I, II, III, IV etc. Subsets of these
general formulae are defined as Ia, Ib, Ic etc, . . . IVa, IVb, IVc
etc.
[0057] The present invention covers a process for the preparation
of a compound of formula (I) as hereinbefore defined, which
comprises reductively aminating a compound of formula (II) 3
[0058] wherein L, M, Q, U, X, W, Y and Z are as hereinbefore
defined and T is --CHO, with an amine of formula NHR.sup.1R.sup.2
wherein R.sup.1, R.sup.2 are as hereinbefore defined.
[0059] Preferably, the reducing agent is a borohydride reducing
agent.
[0060] A further aspect of the present invention is a process for
the preparation of a compound of formula (I) as hereinbefore
defined wherein R.sup.1 and R.sup.2 are hydrogen, which comprises
reducing a compound of formula (II) as hereinbefore defined wherein
T is --CN.
[0061] Preferably, the reducing agent is BH.sub.3.THF or lithium
aluminium hydride or hydrogen in the presence of a metal
catalyst.
[0062] A further aspect of the present invention is a process for
the preparation of a compound of formula (I) as hereinbefore
defined which comprises reducing a compound of formula (II) as
hereinbefore defined wherein T is --CONR.sup.1R.sup.2, and R.sup.1
and R.sup.2 are as hereinbefore defined.
[0063] Preferably, the reducing agent is BH.sub.3.THF or lithium
aluminium hydride.
[0064] A further aspect of the present invention is a compound of
formula (II) as hereinbefore defined wherein T is --CHO, CN or
CONR.sup.1R.sup.2, and R.sup.1 and R.sup.2 are as hereinbefore
defined.
[0065] A further aspect of the present invention is a process for
the preparation of a compound of formula (I) as hereinbefore
defined which comprises converting one compound of formula (I) into
another compound of formula (I) using conventional techniques
generally known in the art.
[0066] A further aspect of the present invention is a process for
the preparation of a compound of formula (I) as hereinbefore
defined which comprises deprotecting a protected compound of
formula (I) using conventional techniques generally known in the
art.
[0067] Compounds of general formula I may be prepared from
compounds of general formula II by a variety of methods (see Scheme
1) 4
[0068] i) Compounds of general formula I may be prepared from
compounds of general formula II where T is --CHO, by reaction with
an amine of formula HNR.sup.1R.sup.2 (or a salt thereof), followed
by reduction with a hydride reducing agent in a suitable solvent.
When either R.sup.1 or R.sup.2 is hydrogen, suitable solvents
include protic solvents such as ethanol, and sodium borohydride is
an appropriate reducing agent. When neither R.sup.1 or R.sup.2 are
hydrogen, tetrahydrofuran/dichloromethane is a suitable solvent
system and sodium triacetoxyborohydride is a suitable reducing
agent. In such reactions the use of a salt form of
HNR.sup.1R.sup.2, such as the hydrochloride or acetate is
preferable, and an auxiliary base, to aid solubility of the
HNR.sup.1R.sup.2 salt, such as triethylamine may optionally be
added along with acetic acid.
[0069] ii) Compounds of general formula I may be prepared from
compounds of general formula II where T is cyano, by reduction to
its corresponding amine of formula --CH.sub.2NH.sub.2, using
hydride reducing agents such as BH.sub.3.THF or lithium aluminium
hydride or by hydrogenation with a suitable metal catalyst for
example Raney Nickel.
[0070] iii) Compounds of general formula I may be prepared from
compounds of general formula II where T is --C(O)NR.sup.1R.sup.2,
by reduction to provide an amine, for example with a hydride
reducing agent such as BH.sub.3.THF or lithium aluminium hydride.
Compounds of formula II where T is --C(O)NR.sup.1R.sup.2 may be
prepared from the corresponding compounds of formula II where T is
--CO.sub.2H, by treatment with a coupling agent and an amine
HNR.sup.1R.sup.2 in a suitable inert solvent which does not
adversely affect the reaction. Compounds of formula II where T is
--CO.sub.2H may themselves be formed from compounds of formula II
where T is --CN or --CO.sub.2R.sup.10, and R.sup.10=methyl or
ethyl, by treatment with a suitable hydroxide salt in the presence
of water and a suitable co-solvent at an appropriate temperature.
Alternatively, Compounds of general formula II where T is
--C(O)NR.sup.1R.sup.2 may be prepared from compounds of general
formula II where T is --CO.sub.2R.sup.10 and R.sup.10=methyl or
ethyl, by reaction with an amine of general formula
NHR.sup.1R.sup.2.
[0071] Alternatively, compounds of general formula I having a
particular NR.sup.1R.sup.2 group may be converted into other
compounds of general formula I having a different NR.sup.1R.sup.2
group. For example:
[0072] i) Compounds of formula I wherein R.sup.1 or R.sup.2 is
hydrogen, can be converted into a compound of formula I wherein
neither R.sup.1 nor R.sup.2 is hydrogen, by reaction with an
aldehyde and a hydride reducing agent. Suitable aldehydes include
formaldehyde, suitable reducing agents include sodium
tri(acetoxy)borohydride and the reaction is preferably conducted in
a solvent which does not interfere with the reaction, such as
dichloromethane at or below room temperature.
[0073] ii) Compounds of formula I wherein R.sup.1 or R.sup.2 is
hydrogen, can be converted into a compound of formula I wherein
R.sup.1 or R.sup.2 is methyl, by reaction with a formylating agent,
for example pentafluorophenyl formate, in a suitable solvent,
followed by subsequent reduction of the intermediate N-formyl
compound with a hydride reducing agent such as BH.sub.3.THF or
lithium aluminium hydride in an inert solvent, preferably at
elevated temperature. Suitable formylating agents include
pentafluorophenyl formate (formed from formic acid,
pentafluorophenol and dicyclohexylcarbodiimide) and suitable
solvents for the formylation include dichloromethane. Suitable
reducing agents include borane-tetrahydrofuran complex and suitable
inert solvents for the reduction include tetrahydrofuran.
[0074] Compounds of formula I where M or Q is --C(R.sup.4)-- may be
prepared from the corresponding halo compound by a variety of
methods:
[0075] i) Compounds of formula I where M or Q is --C(CN)-- may be
prepared by reaction of the corresponding halo compound with a
cyanide salt in the presence of a Pd(0) or (II)catalyst in a high
boiling solvent at elevated temperatures. Suitable Pd catalysts
include palladium tetrakis(triphenylphosphine), suitable cyanide
salts include Zn(CN).sub.2 and suitable high boiling solvents which
do not adversely affect the reaction include dimethylformamide.
[0076] ii) Compounds of formula I where M or Q is --C(CO.sub.2R)--
may be prepared by reacting the corresponding halo compound with
carbon monoxide at high pressure with a Pd(0) or (II) catalyst, in
an alcohol solvent (ROH wherein R is C.sub.1-C.sub.4 alkyl), in the
presence of a base at elevated temperatures.
[0077] Alternatively compounds of formula I where M or Q is
--C(R.sup.4)-- may be prepared from the corresponding compound of
formula I where M or Q is --C(R.sup.4)-- by a variety of
methods.
[0078] i) Compounds of formula I where M or Q is --C(NH.sub.2)--
may be prepared from the corresponding compounds of formula I where
M or Q is --C(NO.sub.2)-- by treatment with a reducing agent in a
protic solvent at, or above, room temperature. Suitable reducing
agents include iron powder/calcium chloride, suitable protic
solvents include aqueous ethanol or acetic acid.
[0079] ii) Compounds of formula I where M or Q is
--C(NHSO.sub.2R.sup.9)-- may be prepared from the corresponding
compounds of formula I where M or Q is --C(NH.sub.2)-- by reaction
with a sulfonylating agent in the presence of a base in an inert
solvent which does not adversely affect the reaction at, or below,
room temperature. Suitable sulfonylating agents include
methanesulfonyl chloride, suitable bases include triethylamine and
suitable inert solvents include dichloromethane.
[0080] iii) Compounds of formula I where M or Q is
--C(NR.sup.8SO.sub.2R.s- up.9)-- may be prepared from the
corresponding compounds of formula I where M or Q is
--C(NHSO.sub.2R.sup.9)--, by treatment with an alkylating agent and
a base in a suitable inert solvent. Examples of suitable alkylating
agents include methyl iodide, suitable bases include potassium
carbonate and suitable inert solvents include acetonitrile.
[0081] iv) Compounds of formula I where M or Q is
--C(C(.dbd.O)NH.sub.2)-- may be prepared from the corresponding
compounds of formula I where M or Q is --C(CN)--, by hydrolysis
under basic, oxidative or acid conditions. Basic hydrolysis is
preferably conducted with a hydroxide salt such as potassium
hydroxide in a protic solvent such as t-butanol at elevated
temperatures.
[0082] v) Compounds of formula I where M or Q is --C(CH.sub.2OH)--
may be prepared from the corresponding compounds of formula I where
M or Q is --C(CO.sub.2R.sup.10)--, by treatment with a hydride
reducing agent, such as lithium aluminium hydride.
[0083] vi) Compounds of formula I where M or Q is --C(CO.sub.2H)--
may be prepared from the corresponding compounds of formula I where
M or Q is --C(CO.sub.2R.sup.9)--, by treatment with a suitable
hydroxide salt in the presence of water and a suitable
co-solvent.
[0084] vii) Compounds of formula I where M or Q is
--C(CONR.sup.6R.sup.7)-- - may be prepared from the corresponding
compounds of formula I where M or Q is --C(CO.sub.2H)--, by
treatment with a coupling agent, a base and an amine
HNR.sup.6R.sup.7 in a suitable inert solvent which does not
adversely affect the reaction.
[0085] viii) Compounds of formula I where M or Q is
--C(CO.sub.2H)-- may be prepared from the corresponding compounds
of formula I where M or Q is --C(Me)--, by treatment with a
suitable oxidising agent in a suitable solvent which does not
adversely affect the reaction.
[0086] Compounds of formula IIa, where X=S, may be prepared in turn
from the coupling of compounds of general formula IV with compounds
of general formula III, wherein LG is a suitable leaving group such
as halogen (F, Cl, Br or I) or a sulfonate ester such as
trifluoromethanesulfonate or methanesulfonate (preferably LG is F
or Cl) (See Scheme 2). Such coupling reactions may be accomplished
by techniques known in the art, such as via reaction with potassium
carbonate in a suitable solvent such as dimethylformamide under
appropriate reaction conditions such as elevated temperature and in
an inert atmosphere. 5
[0087] Compounds of formula IIb, where X=--CH.sub.2--, may be
prepared in turn from the coupling of compounds of general formula
V, wherein Hal is a halogen such as Br or Cl (preferably Hal is Br)
with compounds of general formula II, wherein LG is a suitable
leaving group such as halogen (F, Cl, Br or I) or a sulfonate ester
such as trifluoromethanesulfonate or methanesulfonate (preferably
LG is Cl) (See Scheme 3). Such coupling reactions may be
accomplished by techniques known in the art, such as via reaction
of V with a suitable form of Zinc metal, such as Riecke.RTM. Zinc,
in a suitable solvent, such as tetrahydrofuran, followed by
reaction of the resulting zincate with IIII in the presence of a
suitable catalyst, such as bis(triphenylphosphine)ni- ckel (II)
chloride, under appropriate reaction conditions such as under an
inert atmosphere. 6
[0088] Many compounds of formula IV and V are either known and
available from commercial sources or are available from
commercially available materials using known techniques
[0089] Compounds of formula III are either known and available from
commercial sources or are available from commercially available
materials using known techniques (see Examples hereinafter). In
particular compounds of formula III where M or Q are --C(R.sup.4)--
may be prepared from the corresponding halo compound, in analogous
fashion to the methods described above to prepare compounds of
formula I. Alternatively compounds of formula III where M or Q are
--C(R.sup.4)-- may be prepared from the corresponding compound of
formula II, in analogous fashion to the methods described above to
prepare compounds of formula 1.
[0090] The skilled person will appreciate that in appropriate cases
introduction/elaboration of R.sup.4 can be performed prior to
conversion of T to --CH.sub.2NR.sup.1R.sup.2.
[0091] Further, the skilled person will appreciate that the sulfide
or zincate coupling (see schemes 2 and 3) may be performed after
conversion of the group T to the group
--CH.sub.2NR.sup.1R.sup.2.
[0092] It will be apparent to those skilled in the art that
sensitive functional groups may need to be protected and
deprotected during synthesis of a compound of formula I. This may
be achieved by conventional techniques, for example as described in
`Protective Groups in Organic Synthesis`, 3rd edition, by T W
Greene and P G M Wuts, John Wiley and Sons Inc, 1999.
[0093] The compounds of the invention are useful because they have
pharmacological activity in mammals, including humans. More
particularly, they are useful in the treatment or prevention of a
disorder in which the regulation of monoamine transporter function
is implicated. Disease states that may be mentioned include
hypertension, depression (including depression in cancer patients,
depression in Parkinson's patients, postmyocardial infarction
depression, subsyndromal symptomatic depression, depression in
infertile women, paediatric depression, major depression, single
episode depression, recurrent depression, child abuse induced
depression, post partum depression and grumpy old man syndrome),
generalized anxiety disorder, phobias (including agoraphobia,
social phobia and simple phobias), posttraumatic stress syndrome,
avoidant personality disorder, sexual dysfunction (including
premature ejaculation and male impotence), eating disorders
(including anorexia nervosa and bulimia nervosa), obesity,
substance abuse disorders (including chemical dependencies such as
addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and
benzodiazepines), cluster headache, migraine, pain, Alzheimer's
disease, obsessive-compulsive disorder, panic disorder, memory
disorders (including dementia, amnestic disorders, and age-related
cognitive decline (ARCD)), Parkinson's diseases (including dementia
in Parkinson's disease, neuroleptic-induced parkinsonism and
tardive dyskinesias), endocrine disorders (including
hyperprolactinaemia), vasospasm (particularly in the cerebral
vasculature), cerebellar ataxia, gastrointestinal tract disorders
(involving changes in motility and secretion), negative symptoms of
schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress
incontinence, Tourette's syndrome, trichotillomania, kleptomania,
attention deficit hyperactivity disorder (ADHD), chronic paroxysmal
hemicrania, headache (associated with vascular disorders),
emotional lability, pathological crying, sleeping disorder
(cataplexy) and shock.
[0094] Disorders of particular interest include depression,
attention deficit hyperactivity disorder, obsessive-compulsive
disorder, post-traumatic stress syndrome, substance abuse disorders
and sexual dysfunction including male impotence and (in particular)
premature ejaculation. Premature ejaculation may be defined as
persistent or recurrent ejaculation before, upon or shortly after
penile penetration of a sexual partner. It may also be defined as
ejaculation occurring before the individual wishes [see `The Merck
Manual`, 16.sup.th edition, p 1576, published by Merck Research
Laboratories, 1992].
[0095] Thus, according to further aspects, the invention
provides:
[0096] i) A compound of formula (I), as defined in the first
aspect, pharmaceutically acceptable salts, solvates or polymorphs
thereof, for use as a medicament.
[0097] ii) The use of a compound of formula (I), as defined in the
first aspect, pharmaceutically acceptable salts, solvates or
polymorphs thereof, in the preparation of a medicament for the
treatment or prevention of a disorder in which the regulation of
monoamine transporter function is implicated, for example
hypertension, depression, generalized anxiety disorder, phobias,
posttraumatic stress syndrome, avoidant personality disorder,
sexual dysfunction (e.g. premature ejaculation and male impotence),
eating disorders, obesity, substance abuse disorders (e.g. chemical
dependencies such as addictions to alcohol, cocaine, heroin,
phenobarbital, nicotine and benzodiazepines), cluster headache,
migraine, pain, Alzheimer's disease, obsessive-compulsive disorder,
panic disorder, memory disorders, Parkinson's diseases, endocrine
disorders, vasospasm, cerebellar ataxia, gastrointestinal tract
disorders, negative symptoms of schizophrenia, premenstrual
syndrome, fibromyalgia syndrome, stress incontinence, Tourette's
syndrome, trichotillomania, kleptomania, attention deficit
hyperactivity disorder (ADHD), chronic paroxysmal hemicrania,
headache (associated with vascular disorders), emotional lability,
pathological crying, sleeping disorder (cataplexy) and shock.
[0098] iii) The use of a compound of formula (I), as defined in the
first aspect, pharmaceutically acceptable salts, solvates or
polymorphs thereof, in the preparation of a medicament for the
treatment or prevention of a disorder in which the regulation of
monoamine transporter function is implicated where that disorder is
depression, attention deficit hyperactivity disorder,
obsessive-compulsive disorder, post-traumatic stress syndrome,
substance abuse disorders or sexual dysfunction (e.g. premature
ejaculation and male impotence).
[0099] iv) The use of a compound of general formula (I) as defined
in the first aspect, pharmaceutically acceptable salts, solvates or
polymorphs thereof, in the manufacture of a medicament for the
treatment or prevention of premature ejaculation, and also provides
a method of treatment or prevention of premature ejaculation
comprising the administration of this compound to a patient in need
of such treatment or prevention.
[0100] v) A method of treatment or prevention of depression,
attention deficit hyperactivity disorder, obsessive-compulsive
disorder, post-traumatic stress syndrome, substance abuse disorders
and sexual dysfunction including male impotence and (in particular)
premature ejaculation, which comprises administering a
therapeutically effective amount of a compound of formula (I) as
defined in the first aspect, pharmaceutically acceptable salts,
solvates or polymorphs thereof, to a patient in need of such
treatment or prevention.
[0101] vi) A method of increasing ejaculatory latency which
comprises the administration of an effective amount of a compound
of formula (I) as defined in the first aspect, pharmaceutically
acceptable salts, solvates or polymorphs thereof, to a male
desiring increased ejaculatory latency.
[0102] vii) A compound of formula (I) as defined in the first
aspect, pharmaceutically acceptable salts, solvates or polymorphs
thereof, for the treatment or prevention of a disorder in which the
regulation of monoamine transporter function is implicated, for
example depression, attention deficit hyperactivity disorder,
obsessive-compulsive disorder, post-traumatic stress syndrome,
substance abuse disorders and sexual dysfunction including male
impotence and (in particular) premature ejaculation.
[0103] It is to be appreciated that all references herein to
treatment include curative, palliative and prophylactic
treatment.
[0104] The compounds of the invention may be administered alone or
as part of a combination therapy. If a combination of active agents
are administered, then they may be administered simultaneously,
separately or sequentially. In particular, the compounds of the
invention may be combined with the following for the treatment of
PE:
[0105] Alpha-blockers (e.g. phentolamine, doxazasim, tansulosin,
terazasin, prazasin and Example 19 of WO9830560;
[0106] Apomorphine--teachings on the use of apomorphine as a
pharmaceutical may be found in U.S. Pat. No. 5,945,117;
[0107] Dopamine D2 agonists (e.g. Premiprixal, Pharmacia Upjohn
compound number PNU95666);
[0108] Melanocortin receptor agonists (e.g. Melanotan II);
[0109] PGE1 receptor agonists (e.g. alprostadil);
[0110] Mono amine transport inhibitors, particularly Noradrenaline
Re-uptake Inhibitors (NRIs) (e.g. Reboxetine), other Serotonin
Re-uptake Inhibitors (SRIs) (e.g. paroxetine) or Dopamine Re-uptake
Inhibitors (DRIs);
[0111] 5-HT.sub.1A antagonists (e.g. robalzotan)
[0112] 5-HT3 antagonists (e.g. ondansetron and granisetron);
and
[0113] PDE inhibitors such as PDE2 (e.g.
erythro-9-(2-hydroxyl-3-nonyl)-ad- enine) and Example 100 of EP
0771799-incorporated herein by reference) and in particular a PDE5
inhibitor (e.g. sildenafil, 1-{[3-(3,4-dihydro-5-met-
hyl-4-oxo-7-propylimidazo[5,1-f]-as-trazin-2-yl)-4-ethoxyphenyl]sulfonyl}--
4-ethylpiperazine i.e. vardenafil/Bayer BA 38-9456 or IC351 (see
structure below, Icos Lilly)). 7
[0114] For human use the compounds of the invention can be
administered alone but in human therapy will generally be
administered in admixture with a suitable pharmaceutical excipient,
diluent or carrier selected with regard to the intended route of
administration and standard pharmaceutical practice. Accordingly
the present invention provides for a composition comprising a
compound of formula (I) as disclosed herein, or pharmaceutically
acceptable salts, solvates or polymorphs thereof, and a
pharmaceutically acceptable diluent or carrier.
[0115] For example, the compounds of the invention, can be
administered orally, buccally or sublingually in the form of
tablets, capsules (including soft gel capsules), ovules, elixirs,
solutions or suspensions, which may contain flavouring or colouring
agents, for immediate-, delayed-, modified-, sustained-, dual-,
controlled-release or pulsatile delivery applications. The
compounds of the invention may also be administered via
intracavernosal injection. The compounds of the invention may also
be administered via fast dispersing or fast dissolving dosage
forms.
[0116] Such tablets may contain excipients such as microcrystalline
cellulose, lactose, sodium citrate, calcium carbonate, dibasic
calcium phosphate, glycine, and starch (preferably corn, potato or
tapioca starch), disintegrants such as sodium starch glycollate,
croscarmellose sodium and certain complex silicates, and
granulation binders such as polyvinylpyrrolidone,
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
sucrose, gelatin and acacia. Additionally, lubricating agents such
as magnesium stearate, stearic acid, glyceryl behenate and talc may
be included.
[0117] Solid compositions of a similar type may also be employed as
fillers in gelatin capsules. Preferred excipients in this regard
include lactose, starch, a cellulose, milk sugar or high molecular
weight polyethylene glycols. For aqueous suspensions and/or
elixirs, the compounds of the invention, and their pharmaceutically
acceptable salts, may be combined with various sweetening or
flavouring agents, colouring matter or dyes, with emulsifying
and/or suspending agents and with diluents such as water, ethanol,
propylene glycol and glycerin, and combinations thereof.
[0118] Modified release and pulsatile release dosage forms may
contain excipients such as those detailed for immediate release
dosage forms together with additional excipients that act as
release rate modifiers, these being coated on and/or included in
the body of the device. Release rate modifiers include, but are not
exclusively limited to, hydroxypropylmethyl cellulose, methyl
cellulose, sodium carboxymethylcellulose, ethyl cellulose,
cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer,
ammonio methacrylate copolymer, hydrogenated castor oil, carnauba
wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl
cellulose phthalate, methacrylic acid copolymer and mixtures
thereof. Modified release and pulsatile release dosage forms may
contain one or a combination of release rate modifying excipients.
Release rate modifying excipients may be present both within the
dosage form i.e. within the matrix, and/or on the dosage form, i.e.
upon the surface or coating.
[0119] Fast dispersing or dissolving dosage formulations (FDDFs)
may contain the following ingredients: aspartame, acesulfame
potassium, citric acid, croscarmellose sodium, crospovidone,
diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin,
hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl
methacrylate, mint flavouring, polyethylene glycol, fumed silica,
silicon dioxide, sodium starch glycolate, sodium stearyl fumarate,
sorbitol, xylitol. The terms dispersing or dissolving as used
herein to describe FDDFs are dependent upon the solubility of the
drug substance used i.e. where the drug substance is insoluble a
fast dispersing dosage form can be prepared and where the drug
substance is soluble a fast dissolving dosage form can be
prepared.
[0120] The compounds of the invention can also be administered
parenterally, for example, intravenously, intra-arterially,
intraperitoneally, intrathecally, intraventricularly,
intraurethrally, intrasternally, intracranially, intramuscularly or
subcutaneously, or they may be administered by infusion techniques.
For such parenteral administration they are best used in the form
of a sterile aqueous solution which may contain other substances,
for example, enough salts or glucose to make the solution isotonic
with blood. The aqueous solutions should be suitably buffered
(preferably to a pH of from 3 to 9), if necessary. The preparation
of suitable parenteral formulations under sterile conditions is
readily accomplished by standard pharmaceutical techniques well
known to those skilled in the art.
[0121] The following dosage levels and other dosage levels herein
are for the average human subject having a weight range of about 65
to 70 kg. The skilled person will readily be able to determine the
dosage levels required for a subject whose weight falls outside
this range, such as children and the elderly.
[0122] For oral and parenteral administration to human patients,
the daily dosage level of the compounds of the invention or salts
or solvates thereof will usually be from 10 to 500 mg (in single or
divided doses).
[0123] Thus, for example, tablets or capsules of the compounds of
the invention or salts or solvates thereof may contain from 5 mg to
250 mg of active compound for administration singly or two or more
at a time, as appropriate. The physician in any event will
determine the actual dosage which will be most suitable for any
individual patient and it will vary with the age, weight and
response of the particular patient. The above dosages are exemplary
of the average case. There can, of course, be individual instances
where higher or lower dosage ranges are merited and such are within
the scope of this invention. The skilled person will also
appreciate that, in the treatment of certain conditions (including
PE), compounds of the invention may be taken as a single dose on an
"as required" basis (i.e. as needed or desired).
[0124] Example Tablet Formulation
[0125] In general a tablet formulation could typically contain
between about 0.01 mg and 500 mg of a compound according to the
present invention (or a salt thereof) whilst tablet fill weights
may range from 50 mg to 1000 mg. An example formulation for a 10 mg
tablet is illustrated:
1 Ingredient % w/w Free acid, Free base or Salt of Compound 10.000*
Lactose 64.125 Starch 21.375 Croscarmellose Sodium 3.000 Magnesium
Stearate 1.500 *This quantity is typically adjusted in accordance
with drug activity.
[0126] The compounds of the invention can also be administered
intranasally or by inhalation and are conveniently delivered in the
form of a dry powder inhaler or an aerosol spray presentation from
a pressurised container, pump, spray or nebulizer with the use of a
suitable propellant, e.g. dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetra-fluoro-ethane, a
hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A
[trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade
mark]), carbon dioxide or other suitable gas. In the case of a
pressurised aerosol, the dosage unit may be determined by providing
a valve to deliver a metered amount. The pressurised container,
pump, spray or nebulizer may contain a solution or suspension of
the active compound, e.g. using a mixture of ethanol and the
propellant as the solvent, which may additionally contain a
lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made,
for example, from gelatin) for use in an inhaler or insufflator may
be formulated to contain a powder mix of a compound of the
invention and a suitable powder base such as lactose or starch.
[0127] Aerosol or dry powder formulations are preferably arranged
so that each metered dose or "puff" contains from 1 to 50 mg of a
compound of the invention for delivery to the patient. The overall
daily dose with an aerosol will be in the range of from 1 to 50 mg
which may be administered in a single dose or, more usually, in
divided doses throughout the day.
[0128] The compounds of the invention may also be formulated for
delivery via an atomiser. Formulations for atomiser devices may
contain the following ingredients as solubilisers, emulsifiers or
suspending agents: water, ethanol, glycerol, propylene glycol, low
molecular weight polyethylene glycols, sodium chloride,
fluorocarbons, polyethylene glycol ethers, sorbitan trioleate,
oleic acid.
[0129] Alternatively, the compounds of the invention can be
administered in the form of a suppository or pessary, or they may
be applied topically in the form of a gel, hydrogel, lotion,
solution, cream, ointment or dusting powder. The compounds of the
invention may also be dermally or transdermally administered, for
example, by the use of a skin patch. They may also be administered
by the ocular, pulmonary or rectal routes.
[0130] For ophthalmic use, the compounds can be formulated as
micronized suspensions in isotonic, pH adjusted, sterile saline,
or, preferably, as solutions in isotonic, pH adjusted, sterile
saline, optionally in combination with a preservative such as a
benzylalkonium chloride. Alternatively, they may be formulated in
an ointment such as petrolatum.
[0131] For application topically to the skin, the compounds of the
invention can be formulated as a suitable ointment containing the
active compound suspended or dissolved in, for example, a mixture
with one or more of the following: mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene
polyoxypropylene compound, emulsifying wax and water.
Alternatively, they can be formulated as a suitable lotion or
cream, suspended or dissolved in, for example, a mixture of one or
more of the following: mineral oil, sorbitan monostearate, a
polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters,
wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
[0132] The compounds of the invention may also be used in
combination with a cyclodextrin. Cyclodextrins are known to form
inclusion and non-inclusion complexes with drug molecules.
Formation of a drug-cyclodextrin complex may modify the solubility,
dissolution rate, bioavailability and/or stability property of a
drug molecule. Drug-cyclodextrin complexes are generally useful for
most dosage forms and administration routes. As an alternative to
direct complexation with the drug the cyclodextrin may be used as
an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
Alpha-, beta- and gamma-cyclodextrins are most commonly used and
suitable examples are described in WO-A-91/11172, WO-A-94/02518 and
WO-A-98/55148.
[0133] For oral or parenteral administration to human patients the
daily dosage levels of the compounds of the invention will be from
0.01 to 30 mg/kg (in single or divided doses) and preferably will
be in the range 0.01 to 5 mg/kg. Thus tablets will contain 1 mg to
0.4 g of compound for administration singly or two or more at a
time, as appropriate. The physician will in any event determine the
actual dosage which will be most suitable for any particular
patient and it will vary with the age, weight and response of the
particular patient. The above dosages are, of course only exemplary
of the average case and there may be instances where higher or
lower doses are merited, and such are within the scope of the
invention.
[0134] Oral administration is preferred. Preferably, administration
takes place shortly before an effect is required.
[0135] For veterinary use, a compound of the invention, or a
veterinarily acceptable salt thereof, or a veterinarily acceptable
solvate or pro-drug thereof, is administered as a suitably
acceptable formulation in accordance with normal veterinary
practice and the veterinary surgeon will determine the dosing
regimen and route of administration which will be most appropriate
for a particular animal.
[0136] Thus according to a further aspect, the invention provides a
pharmaceutical formulation containing a compound of formula (I), as
defined in the first aspect, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable adjuvant, diluent or
carrier.
[0137] The invention is illustrated by the following non-limiting
examples in which the following abbreviations and definitions are
used:
[0138] DMF N,N-dimethylformamide
[0139] DMSO dimethylsulfoxide
[0140] Ex Example
[0141] ES.sup.+ electrospray ionisation positive scan
[0142] ES.sup.- electrospray ionisation negative scan
[0143] h hours
[0144] m/z mass spectrum peak
[0145] min minutes
[0146] MS mass spectrum
[0147] Prec Precursor
[0148] Prep Preparation
[0149] THF tetrahydrofuran
[0150] TS.sup.+ thermospray ionisation positive scan
[0151] .sup.1H Nuclear magnetic resonance (NMR) spectra were in all
cases consistent with the proposed structures. Characteristic
chemical shifts (.delta.) are given in parts-per-million downfield
from tetramethylsilane using conventional abbreviations for
designation of major peaks: e.g. s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad. Where thin layer
chromatography (TLC) has been used it refers to silica gel TLC
using silica gel 60 F.sub.254 plates.
EXAMPLE 1
N-Methyl-N-[(4-{[4-(methylsulfanyl)phenyl]sulfanyl}-3-pyridinyl)methyl]ami-
ne
[0152] 8
[0153] The aldehyde of Preparation 1 (from 3.5 mmol of
4-chloronicotinaldehyde) was dissolved in an 8M solution of
methylamine in EtOH (9 mL, 72 mmol) and the mixture was stirred at
room temperature for 1 h. NaBH.sub.4 (190 mg, 5.0 mmol) was added
in one portion and stirring was continued overnight. The reaction
was quenched by the cautious addition of 2M HCl (20 mL) and stirred
for 1 h before being basified to pH 10 with 10% aqueous
K.sub.2CO.sub.3. The mixture was extracted with EtOAc (200 mL) and
the organic layer was dried (MgSO.sub.4) and evaporated.
Purification of the residue by column chromatography [SiO.sub.2;
CH.sub.2Cl.sub.2 increasing polarity to 10% (9:1, MeOH:NH.sub.4OH)
in CH.sub.2Cl.sub.2) gave (4-{[4-(methylsulfanyl)--
phenyl]sulfanyl}-3-pyridinyl)methanol (608 mg, 66%) and the title
amine (133 mg, 14%) as a colourless oil. A sample of the title
amine was taken up in CH.sub.2Cl.sub.2 and treated with 1M ethereal
HCl. Removal of the solvent then gave the bis HCl salt as a white
solid; .delta..sub.H (CD.sub.3OD, 400 MHz) 2.56 (3H, s), 2.93 (3H,
s), 4.58 (2H, s), 7.22 (1H, d), 7.50 (2H, d), 7.61 (2H, d), 8.47
(1H, d), 8.84 (1H, s); MS m/z (ES.sup.-) 347 (M+2HCl-H.sup.+).
EXAMPLE 2
N,N-Dimethyl-N-[(4-{[4-(methylsulfanyl)phenyl]sulfanyl}-3-pyridinyl)methyl-
]amine
[0154] 9
[0155] Formaldehyde (100 .mu.L, 1.23 mmol) was added to a solution
of the amine of Example 1 (112 mg, 0.41 mmol) in CH.sub.2Cl.sub.2
(4 mL) and the mixture was stirred at room temperature for 15 min
before the addition of sodium triacetoxyborohydride (348 mg, 1.64
mmol). The reaction was stirred a further 16 h at room temperature
and then partitioned between 10% aqueous K.sub.2CO.sub.3 (30 mL)
and EtOAc (50 mL). The organic layer was dried (MgSO.sub.4) and
evaporated and the residue was taken up in CH.sub.2Cl.sub.2 and
treated with 1M ethereal HCl to give the bis HCl salt of the title
amine (142 mg, 96%) as a white solid; .delta..sub.H (CD.sub.3OD,
400 MHz) 2.56 (3H, s), 3.07 (6H, s), 4.72 (2H, s), 7.22 (1H, d),
7.51 (2H, d), 7.62 (2H, d), 8.49 (1H, d), 8.96 (1H, s); MS m/z
(ES.sup.+) 291 (MH.sup.+).
EXAMPLE 3
N-Methyl-N-[(3-{[4-(methylsulfanyl)phenyl]sulfanyl}-4-pyridinyl)methyl]ami-
ne
[0156] 10
[0157] Ti(O.sup.iPr).sub.4 (2 mL, 6.77 mmol) was added to a
solution of the aldehyde of Preparation 2 (from 3.9 mmol of
3-chloroisonicotinaldehyd- e) in an 8M solution of methylamine in
EtOH (5 mL, 40 mmol) and the mixture was stirred at room
temperature for 3 h. NaBH.sub.4 (200 mg, 5.3 mmol) was added in one
portion and stirring was continued overnight. The reaction was
quenched by the cautious addition of 2M HCl (20 mL) and stirred for
1 h before being basified to pH 10 with 10% aqueous
K.sub.2CO.sub.3. The mixture was extracted with EtOAc (2.times.50
mL) and the combined organic layers were washed with brine, dried
(MgSO.sub.4) and evaporated. The residue was taken up in EtOAc (10
mL) and 1M ethereal HCl (.about.10 mL) was added to precipitate the
bis HCl salt. The resulting suspension was stirred for 1 h and then
filtered and dried in vacuo, to give the bis HCl salt of the title
compound (1.08 g, 79%) as a pale yellow powder; .delta..sub.H
(CD.sub.3OD, 300 MHz) 2.53 (3H, s), 2.93 (3H, s), 4.56 (2H, s),
7.19 (2H, d), 7.49 (2H, d), 7.88 (1H, d), 8.36 (1H, s), 8.70 (1H,
d); MS m/z (ES.sup.+) 277 (MH.sup.+).
EXAMPLE 4
N,N-Dimethyl-N-[(3-{[4-(methylsulfanyl)phenyl]sulfanyl}-4-pyridinyl)methyl-
]amine
[0158] 11
[0159] The title compound was prepared by the method of Example 2,
starting from the secondary amine of Example 3. Bis HCl salt:
.delta..sub.H (CD.sub.3OD, 300 MHz) 2.52 (3H, s), 3.04 (6H, s),
4.70 (2H, s), 7.39 (2H, d), 7.46 (2H, d), 7.99 (1H, d), 8.39 (1H,
s), 8.70 (1H, d); MS m/z (ES.sup.+) 291 (MH.sup.+).
EXAMPLE 5
N-methyl-N-({3-[4-(methylsulfanyl)benzyl]-4-pyridinyl}methyl)amine
[0160] 12
[0161] BH.sub.3.THF (1M soln in THF, 10.7 mL, 10.7 mmol) was added
to a solution of the amide of Preparation 5 (970 mg, 3.57 mmol) in
THF (5 mL) under nitrogen and the mixture was heated at reflux for
2 h. After cooling to room temperature the reaction was cautiously
quenched by the addition of 6M HCl (10 mL) and the resulting
mixture was heated at reflux for 2 h. After cooling to room
temperature the mixture was concentrated in vacuo to remove THF and
the yellow solution was washed with ether (10 mL). The aqueous
layer was basified with conc. NH.sub.3 (aq) and extracted with
CH.sub.2Cl.sub.2 (5.times.10 mL). The combined CH.sub.2Cl.sub.2
extracts were dried (MgSO.sub.4) and evaporated to an oil. The
residue was purified by column chromatography [SiO.sub.2;
CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH, 95:5:0.5] to give the title
compound (768 mg, 83%) as a colourless oil. A sample was taken up
in CH.sub.2Cl.sub.2 and treated with 1M ethereal HCl to give the
bis HCl salt of the title amine as a white powder; .delta..sub.H
(CD.sub.3OD, 400 MHz) 2.47 (3H, s), 2.87 (3H, s), 4.32 (2H, s),
4.55 (2H, s), 7.19 (2H, d), 7.28 (2H, d), 8.13 (1H, d), 8.61 (1H,
s), 8.88 (1H, d); MS m/z (TS.sup.+) 259 (MH.sup.+).
EXAMPLE 6
N,N-dimethyl-N-({3-[4-(methylsulfanyl)benzyl]-4-pyridinyl}methyl)amine
[0162] 13
[0163] The title compound was prepared by the method of Example 2,
starting from the secondary amine of Example 5. Bis HCl salt:
.delta..sub.H (CD.sub.3OD, 400 MHz) 2.47 (3H, s), 2.96 (6H, s),
4.38 (2H, s), 4.71 (2H, s), 7.20 (2H, d), 7.29 (2H, d), 8.37 (1H,
d), 8.65 (1H, s), 8.89 (1H, d); MS m/z (TS.sup.+) 273
(MH.sup.+).
EXAMPLE 7
N-methyl-N-({4-[4-(methylsulfanyl)benzyl]-3-pyridinyl}methyl)amine
[0164] 14
[0165] The title compound was prepared by the method of Example 5,
starting from the amide of Preparation 7. Bis HCl salt:
.delta..sub.H (CD.sub.3OD, 400 MHz) 2.48 (3H, s), 2.89 (3H, s),
4.44 (2H, s), 4.57 (2H, s), 7.21 (2H, d), 7.30 (2H, d), 7.72 (1H,
d), 8.78 (1H, d), 9.02 (1H, s); MS m/z (TS.sup.+) 259
(MH.sup.+).
EXAMPLE 8
N,N-dimethyl-N-({4-[4-(methylsulfanyl)benzyl]-3-pyridinyl}methyl)amine
[0166] 15
[0167] The title compound was prepared by the method of Example 2,
starting from the secondary amine of Example 7. Bis HCl salt:
.delta..sub.H (CD.sub.3OD, 400 MHz) 2.46 (3H, s), 2.99 (6H, s),
4.47 (2H, s), 4.74 (2H, s), 7.21 (2H, d), 7.30 (2H, d), 7.74 (1H,
d), 8.78 (1H, d), 9.15 (1H, s); MS m/z (TS.sup.+) 273
(MH.sup.+).
PREPARATIONS
Preparation 1
4-{[4-(Methylsulfanyl)phenyl]sulfanyl}nicotinaldehyde
[0168] 16
[0169] 4-Chloronicotinaldehyde [prepared according to D. Albanese,
M. Penso, M. Zenoni, Synthesis 1999, 1294-1296] (500 mg, 3.5 mmol),
4-methylsulfanyl-benzenethiol (606 mg, 3.88 mmol) potassium
carbonate (586 mg, 4.24 mmol) and DMF (7 mL) were combined, the
mixture was heated together at 50.degree. C. for 1.5 h and then
stirred at room temperature overnight. The solvent was removed in
vacuo and the residue was partitioned between EtOAc (100 mL) and
10% aqueous K.sub.2CO.sub.3 (100 mL). The organic layer was dried
(MgSO.sub.4) and evaporated to give the title compound (1.05 g) as
a yellow oil. The .sup.1H NMR spectrum showed the material to be of
sufficient purity (90-95%) to be used without further purification;
.delta..sub.H (CDCl.sub.3, 400 MHz) 2.54 (3H, s), 6.69 (1H, d),
7.35 (2H, d), 7.47 (2H, d), 8.35 (1H, d), 8.87 (1H, s), 10.24 (1H,
s); MS m/z (TS.sup.+) 262 (MH.sup.+).
Preparation 2
3-{[4-(Methylsulfanyl)phenyl]sulfanyl}isonicotinaldehyde
[0170] 17
[0171] 3-Chloroisonicotinaldehyde [prepared according to R. B.
Moffett et al., J. Heterocycl. Chem. 1979, 16, 1459] (550 mg, 3.9
mmol), 4-methylsulfanyl-benzenethiol (732 mg, 4.7 mmol) potassium
carbonate (700 mg, 5.1 mmol) and DMF (10 mL) were combined and the
mixture was heated together at 65.degree. C. for 2 h. The solvent
was removed in vacuo and the residue was partitioned between EtOAc
(50 mL) and water (50 mL). The organic layer was washed with brine,
dried (MgSO.sub.4) and evaporated to give the title compound (1.124
g) as a yellow oil. The .sup.1H NMR spectrum showed the material to
be of sufficient purity (90-95%) to be used without further
purification; .delta..sub.H (CDCl.sub.3, 300 MHz) 2.52 (3H, s),
7.28 (2H, d), 7.40 (2H, d), 7.64 (1H, d), 8.39 (1H, s), 8.61 (1H,
d), 10.42 (1H, s); MS m/z (ES.sup.-) 260 (M-H.sup.+).
Preparation 3
Methyl 3-[4-(methylsulfanyl)benzyl]isonicotinate
[0172] 18
[0173] A solution of 1-(bromomethyl)4-(methylsulfanyl)benzene
(prepared according to D. D. M. Wayner, D. R. Arnold, Can J. Chem.,
1984, 62, 1164) (2.54 g, 11.7 mmol) in THF (10 mL) was added
dropwise to a slurry of Riecke.RTM. Zinc in THF (22.8 mL of a
commercial suspension [5 g Zn/100 mL], 17.5 mmol) under nitrogen.
During this time the temperature rose steadily to 35.degree. C.
After allowing the black slurry to cool to room temperature over 30
min bis(triphenylphosphine)nickel (II) chloride (762 mg, 1.17 mmol)
was added followed by a solution of methyl 3-chloroisonicotinate
(prepared according to J. Epsztajn, M. W. Plotka, A. Grabowska,
Synth. Commun., 1997, 27, 1075) (1.0 g, 5.83 mmol) in THF (10 mL),
dropwise, taking care to keep the temperature below 30.degree. C.
After the addition was complete the reaction was allowed to cool to
room temperature over 1 h before being quenched by the addition of
sat. NH.sub.4Cl (aq) (20 mL) while cooling with an ice bath. The
mixture was filtered through Celite.RTM., washing well with EtOAc
(3.times.20 mL), the organic layer was separated, dried
(MgSO.sub.4) and evaporated to give a brown oil. The residue was
purified by column chromatography [SiO.sub.2; EtOAc:pentane, 1:3
increasing polarity to EtOAc:pentane, 1:1 and then to
(EtOAc:MeOH:NH.sub.4OH, 95:5:0.5):pentane, 1:1] to give the title
compound as an orange oil; .delta..sub.H (CDCl.sub.3, 400 MHz) 2.43
(3H, s), 3.82 (3H, s), 4.30 (2H, s), 7.05 (2H, d), 7.18 (2H, d),
7.67 (1H, br), 8.59 (2H, br); MS m/z (TS.sup.+) 274 (MH.sup.+).
Preparation 4
3-[4-(methylsulfanyl)benzyl]isonicotinic acid
[0174] 19
[0175] The ester of Preparation 3 (1.50 g, 5.5 mmol) was combined
with NaOH (1.10 g, 27.5 mmol), water (6.5 mL) and MeOH (13 mL) and
the mixture was heated at reflux for 2 h. After cooling in an ice
bath the mixture was acidified with conc. HCl and the resulting
yellow suspension was concentrated in vacuo to remove MeOH before
being filtered and washed with ice water (3.times.5 mL). After
drying in vacuo this gave the title acid (1.31 g, 81%) as a pale
green solid; .delta..sub.H (DMSO, 300 MHz) 2.42 (3H, s), 4.27 (2H,
s), 7.10 (2H, d), 7.15 (2H, d), 7.62 (1H, d), 8.58 (1H, d), 8.61
(1H, s), 13.6 (1H, br); MS m/z (TS.sup.+) 260 (MH.sup.+).
Preparation 5
N-methyl-3-[4-(methylsulfanyl)benzyl]isonicotinamide
[0176] 20
[0177] Oxalyl chloride (575 .mu.L, 6.6 mmol) was added to a
suspension of the acid of Preparation 4 (1.3 g, 4.4 mmol) in
CH.sub.2Cl.sub.2 (10 mL) containing 2 drops of DMF. The mixture was
stirred at room temperature for 1.5 h then evaporated to dryness,
suspended in CH.sub.2Cl.sub.2 (10 mL) and re-evaporated. The
residue was re-suspended in CH.sub.2Cl.sub.2 (10 mL) and treated
with triethylamine (1.84 mL, 13.2 mmol) followed by a 2M solution
of methylamine in THF (3.3 mL, 6.6 mmol). The resulting brown
mixture was stirred at room temperature for 1 h before the addition
of sat. NaHCO.sub.3 (aq) (20 mL). The layers were separated, the
aqueous layer was extracted with CH.sub.2Cl.sub.2 (4.times.20 mL)
and the combined organic layers were dried (MgSO.sub.4) and
evaporated. The residue was purified by column chromatography
[SiO.sub.2; CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH, 96:4:0.4] to give the
title compound (971 mg, 81%) as an off-white solid; .delta..sub.H
(CDCl.sub.3, 400 MHz) 2.40 (3H, s), 2.81 (3H, d), 4.07 (2H, s),
5.50 (1H, br), 7.04 (2H, br), 7.07-7.19 (3H, m), 8.50 (2H, m); MS
m/z (TS.sup.+) 273 (MH.sup.+).
Preparation 6
4-chloro-N-methylnicotinamide
[0178] 21
[0179] Oxalyl chloride (1.01 mL, 11.6 mmol) was added to a
suspension of 4-chloronicotinic acid (prepared according to F.
Guillier et al. J. Org. Chem. 1995, 60, 292) (1.5 g, 7.7 mmol) in
CH.sub.2Cl.sub.2 (15 mL) containing 2 drops of DMF. The mixture was
stirred at room temperature for 1 h then evaporated to dryness,
suspended in CH.sub.2Cl.sub.2 (10 mL) and re-evaporated. The
residue was re-suspended in CH.sub.2Cl.sub.2 (10 mL), cooled to
0.degree. C. and treated with triethylamine (3.23 mL, 23.2 mmol)
dropwise followed by a 2M solution of methylamine in THF (7.7 mL,
15.4 mmol) dropwise. The resulting orange mixture was stirred at
0.degree. C. for 20 min before being concentrated in vacuo. The
residue was treated with sat. NaHCO.sub.3 (aq) (30 mL), extracted
with CH.sub.2Cl.sub.2 10.times.25 mL) and the combined organic
layers were dried (MgSO.sub.4) and evaporated to give an orange oil
which crystallised. The solid was triturated with ether (10 mL),
stirred for 30 min, then filtered and washed with 1:1 ether/pentane
(20 mL) to give the title amide (986 mg, 75%) as an off-white
solid; .delta..sub.H (CDCl.sub.3, 400 MHz) 3.07 (3H, d), 6.20 (1H,
br), 7.37 (1H, d), 8.53 (1H, d), 8.86 (1H, s).
Preparation 7
N-methyl-4-[4-(methylsulfanyl)benzyl]nicotinamide
[0180] 22
[0181] The title compound was prepared by the method of Preparation
3, using 4-chloro-N-methylnicotinamide instead of methyl
3-chloroisonicotinate. This gave the title amide as a pale brown
solid; .delta..sub.H (CDCl.sub.3, 400 MHz) 2.47 (3H, s), 2.93 (3H,
d), 4.13 (2H, s), 5.75 (1H, br), 7.08-7.16 (3H, m), 7.19 (2H, d),
8.45-8.60 (2H, br); MS m/z (TS.sup.+) 273 (MH.sup.+).
[0182] Biological Activity
[0183] A number of compounds were tested for biological activity by
their ability to inhibit the uptake of serotonin by human serotonin
transporters as follows.
[0184] (i) Cell Culture
[0185] Human embryonic kidney cells (HEK-293) stably transfected
with either the human serotonin transporter (hSERT), noradrenaline
transporter (hNET) or dopamine transporter (hDAT) were cultured
under standard cell culture techniques (cells were grown at
37.degree. C. and 5% CO.sub.2 in DMEM-culture media (supplemented
with 10% dialysed foetal calf serum (FCS), 2mM I-glutamine and 250
.mu.g/ml geneticin)). Cells were harvested for the assay to yield a
cell suspension of 750,000 cells/ml.
[0186] (ii) Determination of inhibitor potency
[0187] All test compounds were dissolved in 100% DMSO and diluted
down in assay buffer to give appropriate test concentrations.
Assays were carried out in 96-well filter bottom plates. Cells
(7500 cells/assay well) were pre-incubated in standard assay buffer
containing either test compound, standard inhibitor or compound
vehicle (1% DMSO) for 5 minutes. Reactions were started by addition
of either .sup.3H-Serotonin, .sup.3H-Noradrenaline or
.sup.3H-Dopamine substrates. All reactions were carried out at room
temperature in a shaking incubator. Incubation times were 5 minutes
for the hSERT and hDAT assays and 15 minutes for the hNET assay.
Reactions were terminated by removal of the reaction mixture using
a vacuum manifold followed by rapid washing with ice cold assay
buffer. The quantity of .sup.3H-substrate incorporated into the
cells was then quantified.
[0188] Assay plates were dried in a microwave oven, scintillation
fluid added, and radioactivity measured. Potency of test compounds
was quantified as IC.sub.50 values (concentration of test compound
required to inhibit the specific uptake of radiolabelled substrate
into the cells by 50%).
[0189] (iii) Standard Assay Buffer Composition:
[0190] Trizma hydrochloride (26 mM)
[0191] NaCl (124 mM)
[0192] KCl (4.5 mM)
[0193] KH.sub.2PO.sub.4 (1.2 mM)
[0194] MgCl.sub.2.6H.sub.2O (1.3 mM)
[0195] Ascorbic acid (1.136 mM)
[0196] Glucose (5.55 mM)
[0197] pH 7.40
[0198] CaCl.sub.2 (2.8 mM)
[0199] Pargyline (100 .mu.M)
[0200] Note: The pH of the buffer was adjusted to 7.40 with 1M NaOH
before addition of CaCl.sub.2 and pargyline.
[0201] (iv) Summary of Assay Parameters
2 hSERT hDAT hNET Assay Assay Assay Cell concentration per 75,000
75,000 75,000 assay well. Substrate .sup.3H-5HT .sup.3H- .sup.3H-
Concentration. (50 nM) Dopamine Noradrenaline (200 nM) (200 nM)
Incubation time 5 5 15 (minutes)
[0202] The compounds of the invention are potent and selective
inhibitors of serotonin re-uptake and the compounds of Examples 1-8
have a serotonin re-uptake inhibition (SRI) IC.sub.50 value of less
than or equal to 25 nM and are more than 100-fold as potent in the
inhibition of serotonin re-uptake than in the inhibition of
dopamine re-uptake and noradrenaline re-uptake.
[0203] The following results were obtained for Example 2:
3 Example No. SRI (nM) DRI (nM) NRI (nM) 2 2.2 11698 564
* * * * *